ABIM181 • Internal Medicine #1 - Reportable to ABIM

Table of Contents

ABIM181 • Internal Medicine #1 - Reportable to ABIM

How to Receive Credit

NetCE 5 Hour Course #41472 • Risk Management

41472 • Risk Management

1. INTRODUCTION

2. DEFINITION OF RISK MANAGEMENT

3. ANATOMY OF MALPRACTICE

4. AN EFFECTIVE RISK MANAGEMENT PROGRAM

5. CONCLUSION

6. RESOURCES

Works Cited

NetCE 10 Hour Course #94423 • Influenza: A Comprehensive Review

94423 • Influenza: A Comprehensive Review

1. INTRODUCTION

2. HISTORY

3. INFLUENZA VIRUS

4. INFLUENZA DISEASE

5. INFLUENZA-LIKE ILLNESSES

6. COMPLICATIONS OF INFLUENZA

7. INFLUENZA VACCINE

8. PROMOTING THE USE OF INFLUENZA VACCINE

9. OTHER METHODS TO PREVENT INFLUENZA

10. ANTIVIRAL MEDICATIONS

11. CARE OF THE PATIENT WITH INFLUENZA

12. AVIAN INFLUENZA

13. SWINE INFLUENZA

14. INFLUENZA PANDEMIC

15. CONCLUSION

16. GLOSSARY OF TERMS

17. RESOURCES

18. APPENDIX 1

19. APPENDIX 2

20. APPENDIX 3

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #98783 • Healthcare-Associated Infections

98783 • Healthcare-Associated Infections

1. OVERVIEW

2. EPIDEMIOLOGY AND BACKGROUND

3. MICROBIAL PATHOGENESIS AND DEVELOPMENT OF DRUG RESISTANCE

4. SOURCES OF HAIs

5. TYPES OF INFECTIONS

6. INFECTION CONTROL

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

ABIM181 • Internal Medicine #1 - Reportable to ABIM

Lori L. Alexander, MTPW, ELS, MWC

Elizabeth T. Murane, PHN, BSN, MA

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

ABIM181 • Internal Medicine #1 - Reportable to ABIM

Expiration Date: 02/28/2022

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

41472 • Risk Management

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

The course begins with an overview of risk management and related issues, emphasizing the need for primary care clinicians to establish risk management strategies in their practice. A definition of tort (personal-injury) law and several legal issues related to malpractice lay the foundation for a better understanding of such key concepts as medical negligence and the standard of care, adequate informed consent, statutes of limitations, and measure of damages. In addition, the course discusses malpractice-related laws such as apology statutes, good Samaritan laws, and charitable immunity laws; knowledge of these laws can help healthcare professionals better protect themselves from malpractice. Descriptions of the common characteristics of malpractice claims and the consequences of malpractice are included to enhance healthcare professionals' understanding of the underlying causes and motivations of malpractice claims and to improve their ability to handle a malpractice lawsuit. Tort reform is addressed to enable clinicians to become familiar with the proposed solutions to malpractice problems and participate in this national debate. The course closes with a brief discussion of the initial steps involved in responding to a malpractice claim and minimizing loss.

Table of Contents

41472 • Risk Management

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINITION OF RISK MANAGEMENT

3. ANATOMY OF MALPRACTICE

KEY CONCEPTS IN MALPRACTICE

MALPRACTICE-RELATED LAWS

CHARACTERISTICS OF MALPRACTICE CLAIMS

CONSEQUENCES OF MALPRACTICE

4. AN EFFECTIVE RISK MANAGEMENT PROGRAM

OPTIMUM PATIENT-PHYSICIAN COMMUNICATION

MANDATE FOR INFORMED CONSENT

APPROPRIATE AND COMPLETE DOCUMENTATION

ESTABLISH AND USE EFFICIENT OFFICE PROCESSES

QUALITY ASSURANCE PROGRAM

OTHER ISSUES

5. CONCLUSION

6. RESOURCES

Works Cited

41472 • Risk Management

Education Category. Management

Release Date. 03/01/2019

Expiration Date. 02/28/2022

Course Overview

The course begins with an overview of risk management and related issues, emphasizing the need for primary care clinicians to establish risk management strategies in their practice. A definition of tort (personal-injury) law and several legal issues related to malpractice lay the foundation for a better understanding of such key concepts as medical negligence and the standard of care, adequate informed consent, statutes of limitations, and measure of damages. In addition, the course discusses malpractice-related laws such as apology statutes, good Samaritan laws, and charitable immunity laws; knowledge of these laws can help healthcare professionals better protect themselves from malpractice. Descriptions of the common characteristics of malpractice claims and the consequences of malpractice are included to enhance healthcare professionals' understanding of the underlying causes and motivations of malpractice claims and to improve their ability to handle a malpractice lawsuit. Tort reform is addressed to enable clinicians to become familiar with the proposed solutions to malpractice problems and participate in this national debate. The course closes with a brief discussion of the initial steps involved in responding to a malpractice claim and minimizing loss.

Audience

This course is designed for physicians, physician assistants, and nurse practitioners seeking to enhance their knowledge of risk management strategies, especially in the outpatient setting.

Course Objective

With patient safety as the priority, risk management should focus on the avoidance of medical errors, as they are, along with inadequate informed consent, the most common assertions in malpractice claims in the United States. The purpose of this course is to provide healthcare professionals with the information necessary to engage in risk management practices, including a variety of proven strategies to avoid malpractice.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define the most important issues and trends related to risk management and malpractice.

2. Define the key concepts in malpractice.

3. Outline malpractice-related laws, such as Good Samaritan laws, charitable immunity laws, and apology statutes.

4. Identify the most common underlying causes and characteristics of malpractice claims.

5. Describe the consequences of malpractice with respect to healthcare delivery and personal and professional effects on physicians.

6. Describe measures to enhance patient-physician communication, ensure appropriate disclosure of errors to patients, and guarantee adequate informed consent.

7. Develop efficient office processes to enhance documentation, diagnosis, test tracking, medication management, and other issues.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

John V. Jurica, MD, MPH

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Risk management in the healthcare professions refers to strategies designed to enhance patient safety, decrease the risk of malpractice claims, and minimize loss. Effective risk management is essential not only because of the inherent value of patient safety but also because of the high prevalence of malpractice claims, which exact great costs in terms of money, time, and personal and professional losses [1,2].

Healthcare institutions implement interdisciplinary risk management programs to ensure that high-quality medical care is provided to patients and to reduce the risk of malpractice claims brought against the institution and/or its attending physicians and other healthcare professionals. While physicians in surgery and obstetrics/gynecology are most likely to be named in a malpractice suit, primary care physicians in private practice are very vulnerable to malpractice claims and often face greater professional and personal consequences of a malpractice suit [3,20,21]. Thus, this course primarily addresses risk management programs for healthcare providers in private practice.

The course begins with a definition of risk management, emphasizing the need for primary care physicians to establish risk management strategies in their practice. A definition of tort (personal-injury) law and several legal issues related to malpractice lay the foundation for a better understanding of such key concepts as medical negligence and the standard of care, adequate informed consent, and malpractice-related laws such as apology statutes, Good Samaritan laws, and charitable immunity laws. The focus is on the issues that cause the most common allegations in malpractice claims in the United States [4].

Descriptions of the common characteristics of malpractice claims and the consequences of malpractice are included to enhance healthcare professionals' understanding of the underlying causes and motivations of malpractice claims. Such an understanding can help physicians develop targeted risk management strategies and enhance patient safety, and a variety of proven strategies to avoid malpractice are discussed.

2. DEFINITION OF RISK MANAGEMENT

Risk management is a program of strategies to minimize the risk of harm to patients and to decrease the healthcare provider's exposure to liability. An effective risk management program includes both proactive and reactive components [5]. The proactive component consists of strategies to prevent adverse occurrences, and the reactive component includes strategies for responding to such occurrences (i.e., minimizing loss). Minimizing loss involves developing a process to handle a malpractice claim as efficiently as possible. Quality assurance is also an important factor in risk management, as improving the quality of medical care is the theoretical underpinning of avoiding malpractice [6].

The following are among the most important issues related to risk management [7]:

- Communication (with patients and among staff and other healthcare professionals)

- Follow-up on test results

- Documentation

- Management of medications

- Patient satisfaction

- Scope of practice

- Patient termination

- Medical record retention

In addition, in 2014, the American Society for Healthcare Risk Management developed a holistic approach to risk management called enterprise risk management that includes traditional reactive strategies combined with proactive strategies. The following eight risk domains make up enterprise risk management [24]:

- Operational

- Clinical and patient safety

- Strategic

- Financial

- Human capital

- Legal and regulatory

- Technological

- Environmental- and infrastructure-based hazards

Surveys of medical office practices have shown that problems related to risk management are common across all physician specialties [21]. These problems warrant attention and improvement efforts not only because they are associated with a risk of malpractice but also because they have the potential for causing medical errors, which have been reported to be highly prevalent and highly preventable [9]. An overall understanding of malpractice and its key components is needed to provide a framework for defining and discussing effective risk management strategies.

3. ANATOMY OF MALPRACTICE

Physicians are the primary target of malpractice. According to records of malpractice payments in 2017, 89% of payments were made in claims against physicians and dentists; professional nurses accounted for 5%, and all other healthcare practitioners constituted 6% [10]. In total, 34% of physicians have been sued, with 16.8% having been sued more than twice [15]. Lower quality of care does not appear to be the cause of most malpractice claims, as no significant differences have been found in quality between physicians who have and have not been sued [11].

For physicians in low-risk specialties (e.g., pediatrics, psychiatry), there is a substantial gap between physicians' perceived risk of malpractice and their actual risk, with physicians perceiving a much greater risk of malpractice than has been documented for their specialty [12,13]. For example, in a survey regarding malpractice concerns, 62.5% of pediatric physicians agreed or strongly agreed that they were at risk, compared with American Medical Association (AMA) data that indicated 17.8% of pediatric physicians had ever been sued [14,15]. Similarly, radiologists have estimated their risk of litigation within five years as 35%, which compares with an actual rate of approximately 10% [12]. By contrast, using the same datasets, physicians in high-risk specialties (i.e., obstetrics/gynecology and surgery) had a much closer concern/reality gap, with concern data showing 81% for obstetricians/gynecologists and 75.3% for surgical specialists, compared with a lifetime malpractice claim rate of 63.6% and 63.2%, respectively [14,15].

The risk of malpractice varies among medical specialties and typically increases with the frequency with which procedures are performed and with a greater potential for catastrophic injury [17,21]. The rates of malpractice claims against family medicine and internal medicine physicians have historically been low, but the rates have increased since the late 1990s [18]. According to paid claims between 1992 and 2014, family medicine and internal medicine were the specialties with the second and third leading number of claims (behind obstetrics//gynecology), with 18,349 and 17,174 paid claims, respectively (Table 1) [21]. It has been estimated that the typical family physician can expect to be sued about once every 7 to 10 years [44]. One study noted that by 65 years of age, 75% of physicians in low-risk specialties faced a malpractice claim, compared with 99% of physicians in high-risk specialties. It should be noted, however, that more than 75% of these malpractice claims do not result in indemnity payment [26]. In an analysis of overall paid malpractice claims between 1992 and 2014, it was found that the rate of paid claims decreased by 55.7%; however, the mean payment amount increased by 23.3% (Table 1) [21].

Table 1: ANNUAL PAID MALPRACTICE CLAIMS ACCORDING TO SPECIALTY, 1992–2014

Specialty

Total Paid Claimsa

Mean Payment

Obstetrics and gynecology (includes surgery)

20,060

$432,959

Family medicine

18,349

$290,698

Internal medicine

17,174

$318,071

General surgery

12,981

$298,625

Orthopedics (includes surgery)

10,641

$258,763

Radiology

9,079

$333,422

Emergency medicine

8,007

$309,411

Anesthesiology

7,892

$377,499

Pediatrics

5,799

$413,974

Cardiology (includes surgery)

5,378

$365,029

General practice

4,435

$231,622

Ophthalmology

4,044

$244,039

Urology (includes surgery)

3,631

$23,290

Otolaryngology

3,226

$282,822

Plastic surgery

3,156

$189,219

Psychiatry

3,115

$238,909

Gastroenterology

2,881

$349,013

Neurosurgery

2,797

$469,222

Pathology

2,372

$411,529

Thoracic surgery

2,179

$380,402

Neurology (nonsurgical)

2,156

$431,049

Otorhinolaryngology

1,081

$282,822

Dermatology

1,717

$189,065

Colon and rectal surgery

549

$337,976

aIncludes physicians with more than one paid claim.

Source: [21]

Overall rates of medical malpractice claims declined between 2007 and 2017. The same trend occurred in the number of paid malpractice claims and the average compensation (Figure 1 andFigure 2) [10]. In 2017, 11,260 malpractice claims were paid in the United States, with the compensation totaling more than $3.7 billion [10]. It has been argued that malpractice claims represent a substantial factor in rising healthcare costs. However, estimates for 2010 demonstrate that the total costs related to malpractice claims (compensation plus administrative costs) represented only 0.23% (range: 0.13% to 0.33%) of the $2.8 trillion (range: $2.6 trillion to $3 trillion) spent on health care in the United States that year [22,141].

Figure 1: NUMBER OF PAID MEDICAL MALPRACTICE CLAIMS, 2007-2017

Source : [10]

Figure 2: TOTAL DOLLARS IN PAID MEDICAL MALPRACTICE CLAIMS, 2007-2017

Source : [10]

The average compensation varies widely according to geography, type of injury, and physician specialty. In 2017, the average compensation ranged from $145,625 (South Dakota) to $727,486 (Illinois) [10]. Total compensation also varies considerably. In 2017, compensations in New York State accounted for 16% of all payments that year in the United States, and the top six states (New York, Pennsylvania, New Jersey, Illinois, Florida, and California) accounted for more than half of all 2017 compensation payments [10]. Claims payments are typically lowest for "insignificant injury" (average of $34,333 in 2017) and highest for quadriplegia, brain damage, or lifelong care (average of $1,029,105 in 2017) [23]. Of 24 specialties, general and family medicine ranks 18th in mean compensation (approximately $290,698) and internal medicine ranks 14th (approximately $318,071) [21].

Malpractice draws a great deal of attention by the public at large, but the actual number of malpractice claims that are filed is lower than the number of individuals who seek legal advice about a medical issue, and the number of claims that are won is still lower. One study found that in closed claims in 2015, 68% were dropped, dismissed, or withdrawn. In addition, only 7% of claims were decided by a trial verdict, and of these, 88% were won by the defendant [57]. Additionally, a 2017 survey of physicians with a malpractice claim indicated that the result of the lawsuit was settled before trial (30%); dismissed within first few months (14%); verdict in physician's favor (12%); ongoing or in process (9%); dismissed prior to settling (9%); dismissed by court (7%); dismissed prior to trial (6%); voluntarily dismissed by plaintiff prior to trial (5%); verdict in plaintiff's favor (2%); and settled at trial (2%) [20].

The primary goals of the U.S. medical malpractice system are to compensate individuals who have been harmed through medical negligence, to hold a responsible individual accountable, and to provide deterrence to unsafe medical practices or medical errors [6,140]. (The AMA defines a medical error as an "unintended act or omission, or a flawed system or plan, that harms or has the potential to harm a patient" [27].) According to the 2000 landmark Institute of Medicine report, To Err is Human: Building a Safer Health System, 44,000 to 98,000 deaths are caused by medical errors in U.S. hospitals each year, with more than 7,000 of those deaths attributable to medication errors [9]. In addition, a national survey conducted in 2017 indicated that 21% of patients personally experienced a medical error, and 31% have personally been involved in the care of someone who has experienced an error. Combined, 41% of individuals surveyed experienced or were involved in a medical error [28]. However, the true number of adverse outcomes attributable to medical errors or negligence is difficult to determine. In a large study of hospital discharge records and malpractice claims, researchers determined that only 17% of claims involved an injury caused by medical negligence and that there were 7.6 times as many negligent injuries as there were claims, with only 2% of negligent injures resulting in claims [29]. A later study of 1,452 closed malpractice claims demonstrated that 37% did not involve a medical error, and the findings of another study indicated that more than three-quarters of 26,126 malpractice claims against primary care physicians were not considered to involve negligence [2,3]. A separate analysis of four major studies on lethal medical errors indicated that in 2013 there were 251,454 preventable deaths due to medical error [147]. However, this was quickly debated and an estimate of 174,901 preventable deaths was given after adjusting for perceived biases [148]. In either case, medical error was still found to be the third leading cause of death in the United States [147,148]. These results show the difficulty in determining the true number of medical errors and indicate that most patients who sustain a medical injury as a result of medical negligence do not sue and that a substantial number of claims do not involve negligence, which leaves the primary goals of the malpractice system unmet [2,29,30,31]. Calls for reform of the malpractice system have been made in light of these findings, and several organizations, including the AMA, have taken steps toward medical liability reform, with the goal of creating an accurate and fair liability process, while ensuring patient access to physicians and a full range of healthcare services [57].

KEY CONCEPTS IN MALPRACTICE

Medical malpractice is processed in the civil court system or according to tort law. Overall, the civil court system provides a mechanism for an individual or group to recover damages when a tort (derived from the French word for "wrong") is committed against a person or property. Torts are classified as either intentional or negligent. Several intentional torts may be committed by physicians, including assault and battery (e.g., operating on a patient without informed consent), false imprisonment (e.g., forcing a patient to stay in the office until a bill is paid), and fraud (e.g., claiming cure when the physician knows cure is not possible) [32]. A negligent tort involves the omission or commission of an act that a reasonably prudent person would or would not do under given circumstances [33].

The statutes of limitations for medical malpractice vary according to the state, with many states having statutes that vary by cause of action and special rules for minors. In general, a medical claim must be filed within 1 to 5 years after the malpractice occurred or after the alleged injury was discovered if it was not immediately evident.

Standard of Care and Medical Negligence

In a medical malpractice case, the plaintiff has the burden of establishing the appropriate standard of care and demonstrating that the standard of care has been breached. The standard of care is primarily defined by other practitioners with similar qualifications, who provide expert testimony about how they would have managed an individual's care under the same or similar circumstances [149]. In general, expert testimony is based on the physician expert's knowledge, skill, experience, and training and may be supplemented by published literature, practice guidelines, and surveys of practitioners [149]. The focus is whether the physician's actions met or breached the standard of care and, if the latter, whether the plaintiff was harmed as a result of the breach [149].

According to tort law, four elements must be established for a ruling of malpractice [34]:

- Duty: The physician owed a duty to meet a particular standard of care.

- Breach of duty: The physician failed to perform the owed duty.

- Causation: There is a causal connection between the physician's failure and the patient's injury.

- Damages: An injury occurred for which monetary compensation is adequate relief.

These elements must be shown by a "preponderance of the evidence," defined as more than 50% probability, a lower standard than the "beyond a reasonable doubt" used in criminal law [35,149]. Malpractice cases are decided on the basis of what a "jury is likely to think is fact" rather than actual fact [36,150].

A duty is owed if there is an active patient-physician relationship at the time of alleged injury [33]. This relationship is defined as any service given by a provider to an individual, whether in the provider's office, in an emergency department, or within a telephone discussion [33]. Breach of duty can be claimed if the healthcare provider does not meet a relevant standard of care or there is an obvious error (e.g., retained surgical instruments). Causation requires that the plaintiff establishes that the physician's negligence led to the stated injury; an association can be interpreted as causation by a jury who may be sympathetic to the plaintiff [33]. Damages sustained by the patient are compensatory and/or punitive. Compensatory damages consist of compensation for directs costs, such as for lost earnings and medical expenses (current and future), as well as compensation for indirect costs, such as pain, emotional distress, and loss of consortium. Punitive damages are awarded to a plaintiff when the physician's actions are found to be intentionally harmful or grossly negligent [33].

Informed Consent

The informed consent law in medicine was originally developed from battery, an intentional tort [34]. The definition of battery as unwanted physical touching of the body by others was extended to include a treatment provided by a physician without a patient's consent [34]. Battery was also applied to cases in which the procedure performed was substantially different from the one for which consent was given, in which the procedure exceeded the scope of the consent, or in which the procedure was performed by a physician other than the one to whom consent was given [34]. Cases of medical informed consent are now classified as negligence, carrying with it the burden to prove the four elements for liability [34,114].

The primary goal of informed consent is to protect patients by requiring that physicians provide a balanced discussion of a proposed procedure/treatment as well as of the alternative options, so patients can make informed medical decisions [34]. Informed consent was once required only for invasive procedures but the scope of procedures has expanded to include complex treatments (e.g., radiation therapy, chemotherapy), and a separate written consent is required for the use of anesthesia (general, spinal/epidural, or regional) in some states [4,37,114].

The informed consent discussion should focus on the expected benefits, the risks involved with the procedure/treatment, and the feasible alternatives [4,114]. The adequacy of the disclosure of risks is defined differently among states. In most states, a "professional standard" is applied, which means that adequate disclosure is defined as what a reasonable medical practitioner would disclose in a similar situation; in other states, a "lay standard" is applied, with adequate disclosure defined as what a reasonably prudent individual would want to know before consenting to the particular procedure/treatment [4]. In general, physicians must disclose all severe risks, such as death, paralysis, or loss of an extremity, regardless of the likelihood of the event. Less severe events should be disclosed if they are frequent, whereas nominal risks do not need to be disclosed if they are not frequent [34,114].

The Centers for Medicare and Medicaid Services (CMS) mandates that all medical records (inpatient and outpatient) contain completed written informed consent forms for all procedures and treatments [37]. In 2007, CMS also issued new interpretive guidelines for informed-consent documentation in patients' medical records. According to these guidelines, informed consent is defined as, "the patient or patient representative is given (in a language or means of communication he/she understands) the information, explanations, consequences, and options needed in order to consent to a procedure or treatment" [37].

MALPRACTICE-RELATED LAWS

Several laws have been established to provide healthcare professionals specific types of protection against legal liability. These laws, which include Good Samaritan laws, charitable immunity laws, and apology statutes, vary by state.

Good Samaritan Laws

Good Samaritan laws, also known as volunteer protection laws, were enacted to protect individuals from being sued as a result of voluntarily rendering emergency aid to an injured person [38,39]. A "volunteer" can help an injured person on the grounds of implied consent, but if the person is conscious and can respond, first asking permission to help him or her is recommended [38]. In most states, a person is not legally obligated to provide first aid (unless it is part of a job description), but when such aid is provided, the person giving aid has a duty to be reasonably careful [38]. Good Samaritan laws protect a volunteer against legal liability in the event he or she makes an error during the provision of emergency care [38]. Some Good Samaritan laws may hold the volunteer liable if he or she does not act to assist during an emergency. Whether the volunteer chooses to act or not, the important consideration is to act in a manner that will not render the volunteer liable [38].

Charitable Immunity Laws

Charitable immunity laws are designed to protect physicians and other healthcare professionals who volunteer their services in free health clinics and other community initiatives to provide health care to uninsured individuals. These laws also differ from state to state, but they act to either raise the negligence standard of care (from simple negligence to gross negligence) or indemnify volunteer healthcare professionals with liability protection as if they were government employees [40]. Some state laws have elements of both approaches.

Requiring evidence of gross negligence (defined as "willful," "wanton," or "reckless" negligence) makes it more difficult to prove medical negligence [41]. States that indemnify volunteer healthcare professionals as government employees have a legal defense fund to cover defense costs and monetary damages; in some cases, there is an established limit on the total amount of compensation that can be paid [41]. Thus, such indemnification, also known as the State Tort Claims Act, can help to limit loss. In addition to state statutes, federal legislation also protects healthcare professionals who provide free health care.

The Volunteer Protection Act of 1997 provides protection against liability for a volunteer clinician "acting within his or her scope of duties in a nonprofit organization" [40]. This law also limits punitive damages to cases in which there is clear and convincing evidence of willful or criminal misconduct or conscious, flagrant indifference to the rights or safety of the individual harmed [40]. All states had laws limiting liability of certain volunteers at the time the Volunteer Protection Act was adopted, and these laws are not preempted if they provide additional protections [142].

Although state and federal charitable immunity laws do not guarantee that a malpractice claim will not be filed, the laws appear to have limited the number of malpractice claims, as physicians in volunteer settings are rarely targets of malpractice claims [41].

Apology Statutes

Apology statutes are designed to promote disclosure of medical errors by protecting physicians who apologized for an error. According to these laws, expressions of apology made after a medical error are excluded from evidence in a malpractice suit. There are two types of apology statutes [42]:

- Sympathy only: protects a physician's expression of sympathy, regret, and condolence

- Admission of fault: protects a physician's admission of fault and error (in addition to expressions of sympathy, regret, and condolence)

Massachusetts was the first state to enact an apology law, in 1986. Since then, apology laws have been enacted in 39 states and the District of Columbia. These states have enacted one of the two types of apology statutes, but the majority of states have adopted the sympathy only law [42,43,143,151]. As of 2019, six states have provisions that specifically relate to accidents [151]. However, physicians are often skeptical of apologizing for potential error or adverse outcomes. In a 2017 survey of physicians with malpractice suits, 83% indicated that apologizing would not have made a difference, while only 2% indicated that it would have [20].

CHARACTERISTICS OF MALPRACTICE CLAIMS

Closed malpractice claims have been used in a host of studies to gain a better understanding of the specific factors associated with claims. Data on medical malpractice claims are found in three primary sources, and each source provides slightly different types of data. The most comprehensive source of claims information is the National Practitioner's Data Bank (NPDB), maintained by the U.S. Department of Health and Human Services [10]. The Health Care Quality Improvement Act of 1986 requires that all payments in settlement of malpractice claims must be reported to this system. The drawbacks to this source are that only claims that have been paid are included and queries cannot be made on the basis of physician specialty. Another source is the Medical Professional Liability (MPL) Association (formerly Physician Insurers Association of America) data sharing project. The MPL Association is a trade association of more than 50 medical malpractice insurance companies that represent more than two-third of private practice physicians and 2,000 hospitals, and the data represent approximately 25% of the medical malpractice claims in the United States at a given time [45]. The MPL Association includes both paid and unpaid claims, and queries on physician specialty can be carried out. The third source is Jury Verdicts on Westlaw; this source has limited value, as the number of malpractice claims that are decided by jury verdict is small [46].

Studies of malpractice claims have provided valuable information on the most common underlying causes of alleged injuries/events (also known as "medical misadventures") and the diagnoses at highest risk for malpractice. Additional studies have identified a wide variety of factors that motivate individuals to file a malpractice claim. Understanding the risk factors and patient motivators for malpractice can help physicians develop risk management strategies that address the most common issues related to patient safety.

Underlying Causes

Diagnostic error (misdiagnosis or missed or delayed diagnosis) is the most common allegation in malpractice claims, noted in 22% to 78% of all claims [2,3,13,144,21,152]. In a study of 307 claims alleging diagnostic error in the ambulatory setting, researchers found that 59% of the claims involved a diagnostic error that harmed the patient [48]. Among the errors that caused harm, 59% caused serious harm and 30% caused death [48]. Another study analyzing paid claims noted that there was a substantial difference in paid claims for diagnostic errors among specialties. The percentage of paid claims for which diagnostic error was alleged was highest among pathology (87%) and radiology (83.9%), and lowest among anesthesiology (3.5%) and plastic surgery (4.3%) [21].

Although "failure in judgment" is usually a contributing factor for diagnostic errors, most errors involve several contributing factors [47,49,50]. The origins of diagnostic errors are multifaceted and may involve communication problems, system-related problems (e.g., lack of supervision, workload, technology issues), physician-related factors (e.g., stress, fatigue, hurriedness), patient-related factors, or a combination of any of these [47,48,51,153]. Researchers have narrowed the diagnostic process down to seven stages, with diagnostic errors occurring in one or more of these stages [153]:

- Access and presentation

- History taking/collection

- Physical exam

- Testing

- Assessment

- Referral

- Follow-up

One study in the primary care setting noted that diagnostic process breakdown most frequently occurred during the patient-practitioner clinical encounter (78.9%), which includes errors in history-taking (56.3%), examination (47.4%), and/or ordering diagnostic tests for further work-up (57.4%). Other areas of process breakdown included referrals (19.5%), patient-related factors (16.3%), follow-up and tracking of diagnostic information (14.7%), and performance and interpretation of diagnostic tests (13.6%). A total of 43.7% of cases involved more than one of these processes [154].

Medication errors and adverse drug events represent 6.3% of malpractice claims, and the adverse event has been considered to be preventable in approximately 28% to 73% of claims [52,53,155]. Most medication errors do not cause adverse events, but when they do, serious harm may be the result; 38% to 46% of adverse drug events were reported to be life-threatening or fatal [52,53].

A variety of other underlying causes have been identified, including delayed or inappropriate treatment, failure to supervise or monitor the case, improper performance of procedure, failure/delay in referral, and failure to recognize complications of treatment [2,3,16,47,54]. In one analysis of 369 closed claims, 659 risk management/patient safety events were identified; most events were issues related to diagnosis (58%) [54]. Other allegations were related to medical treatment (23%); improper medication management (9.5%); ordering errors (2.2%); insufficient patient monitoring (1.6%); and miscellaneous (5.7%) [54].

Diagnoses

The leading diagnoses-related allegations have varied somewhat across studies. One analysis of internal medicine malpractice found that 79% of allegations were failure to diagnose, with the remainder due to delay in diagnosis [54]. Of the failures to diagnose, 29% were cardiovascular disorders, 26% were infections, 18% were neoplasms, 10% were neurologic disorders, and 9% were gastrointestinal disorders [54]. Of the diagnostic delays, 40% were neoplasms, 18% were infections, 16% were gastrointestinal disorders, 16% were neurologic disorders, and 2% were cardiovascular disorders. In another study of claims settled between 1985 and 2000, acute myocardial infarction was the leading diagnosis (5%), followed by lung, breast, and colon cancer (each accounted for 3% of claims) and appendicitis (2%) [3]. Another study of missed diagnoses in the primary care setting found that more than 35% of missed diagnoses were conditions common in primary care, including pneumonia (6.7%), decompensated congestive heart failure (5.7%), acute renal failure (5.3%), cancer (primary) (5.3%), and urinary tract infection or pyelonephritis (4.8%) [154]. Diagnostic errors are also a predominant source of emergency department allegations (37%) [145]. A 2010 study identified the most common conditions associated with emergency department claims, with fractures (6%), acute myocardial infarction (5%), and appendicitis (2%) topping the list [145].

In a review of 307 claims of diagnosis error in an ambulatory setting, cancer accounted for 59% of the missed or delayed diagnoses; breast cancer was the leading type of cancer (24%), followed by colorectal cancer (7%), and skin, gynecologic, and hematologic cancers (4% each) [48]. Other diagnoses frequently missed or delayed according to that review were infection (5%), myocardial infarction (4%), and fractures (4%) [48].

Patient Motivations

Given that a high number of malpractice claims do not involve a medical injury, other factors must motivate patients and families to sue [17,56]. Patient motivations for malpractice have been extensively studied, and a wide variety of motivations have been identified (Table 2) [17,47,56,58]. In general, these motivations are not related to financial need but rather to problems with patient-physician communication or the patient-physician relationship and unmet expectations of the patient [56]. The overwhelming majority of patients and families say they just want information about what happened, and many wish to prevent the situation from happening again [17,56,59].

Table 2: SPECIFIC REASONS INDIVIDUALS GIVE FOR FILING A MALPRACTICE CLAIM

Problems with patient-physician communication

Poor relationship with the healthcare provider

Desire for information about what happened

Feeling of not being informed

Desire to prevent situation from happening to another person

Unmet expectations or unwanted outcomes

Desire for accountability/revenge

Suspicion of cover-up

Feeling of not being appropriately referred

Financial need

Pain and suffering

Advice from another (knowledgeable friend or acquaintance or healthcare provider)

Television ad for law firm

Source: [17,47,56,58,59]

CONSEQUENCES OF MALPRACTICE

Malpractice exacts a substantial cost on healthcare delivery, physicians, and patients. The fear of litigation alone (real or perceived) has led many physicians to reconsider their profession. For example, the risk of litigation has prompted one-third of radiologists to consider leaving the field of breast imaging [12]. Fear of malpractice also influences physicians' practice behaviors, primarily through the use of defensive medicine. The legal process involved with a malpractice claim takes physicians away from patient care and their families, a burden that is heightened by the amount of time required for resolution of a case.

Defensive Medicine

The threat of malpractice—real or perceived—has been shown to affect clinical decision making, prompting many physicians to practice so-called defensive medicine, or care based primarily on avoidance of litigation rather than on defined clinical need [13,60,61,20]. Defensive medicine has been defined in two categories: "assurance behavior" or "avoidance behavior" [6,13]. Assurance behavior, referred to as "positive defensive medicine," involves excessive ordering of tests and hospitalization of patients and referrals for consultations; avoidance behavior, referred to as "negative defensive medicine," involves decreasing the delivery of high-risk services or declining to treat high-risk patients [6,13,14,60,62,63].

The use of defensive medicine has been evaluated among general practitioners as well as several physician specialties and has been found to be widely prevalent [57]. Surveys of urologists have shown that 77% have practiced defensive medicine, with 58% to 60% saying they had considered referring difficult cases and/or limiting the scope of their practice because of the threat of malpractice [6]. Neurologists with higher malpractice concerns were found to order more tests in clinical scenarios related to seizures and Alzheimer disease [14]. A survey of defensive practices among 1028 neurosurgeons found that 72% ordered additional imaging studies, 67% ordered additional laboratory tests, 66% referred patients to consultants, and 40% prescribed medication. Forty-five percent of respondents reported eliminating high-risk procedures from their practices [64]. Among emergency physicians, the fear of malpractice accounted for significant variability in decision making, especially with regard to individuals with chest pain, and was associated with the increased use of diagnostic tests and the increased hospitalization of low-risk patients [62]. These findings are consistent with those from broad samples of physicians. In a survey of 824 physicians in six high-risk specialties (i.e., emergency medicine, general surgery, orthopedic surgery, neurosurgery, obstetrics/gynecology, radiology), 93% of respondents reported practicing defensive medicine, and in the largest study, a 2009 online survey of more than 3,000 physicians (in all specialties), 92% of respondents said they practiced defensive medicine [63,65]. A national survey of 1,214 orthopedic surgeons showed that 96% reported having practiced defensive medicine by ordering imaging, laboratory tests, specialist referrals, or hospital admissions to avoid potential malpractice liability [66].

All of these studies and surveys have shown that assurance behaviors are more common than avoidance behaviors, with the most frequent practice being the excessive ordering of tests, especially imaging studies [14,62,63,65]. For example, in the survey of physicians in high-risk specialties, 92% of respondents reported ordering more tests, performing more diagnostic procedures, and referring more patients for consultation [63]. Approximately 42% of the respondents said they had recently limited their practice to eliminate procedures with a high risk of complications or had avoided patients with complex medical problems or who were perceived as litigious [63]. In the 2009 survey of more than 3,000 physicians, respondents estimated that 35% of diagnostic tests were ordered defensively, as were 29% of laboratory studies, 19% of hospitalizations, 14% of prescriptions, and 8% of surgeries [65].

Both types of defensive medicine have several important implications for health care and healthcare costs. Unneeded testing may be associated with false-positive results and treatment complications, and limitations in physician services can lead to unmet care needs [14,61]. The financial cost of defensive medicine is difficult to quantify, primarily because of the challenges in identifying and measuring assurance and avoidance behaviors. A 1994 study estimated the cost to be between $5 and $15 billion in 1991 U.S. dollars [60]. A later economic study estimated that malpractice reforms that reduced liability pressure for providers could lead to 5% to 9% reductions in medical costs, with no substantial effects on complications or mortality [67]. According to the findings of the 2009 online survey, physicians estimated that defensive medicine costs $650 to $850 billion annually; however, a study conducted for Blue Cross Blue Shield found that, at most, $46 billion was spent on defensive medicine in 2010 by hospitals and physicians [65].

Personal and Professional Effects

A malpractice claim has a profound impact on a physician in terms of time, psychologic effects, and reputation. The average length of time between the date of an incident and closure of the claim is approximately four to five years [1,2,20,58]. During this time, the physician is distracted with the malpractice defense and the legal process robs time from personal and professional activities.

Malpractice litigation has a negative psychologic effect on a physician because of its threat to personal integrity and honor. In general, physicians share personality traits that render them particularly vulnerable to malpractice litigation in which fault must be established [68]. These traits include self-criticism, exaggerated sense of responsibility, and vulnerability to guilt [69]. Physicians may experience loss of self-esteem and engage in self-questioning (e.g., "What did I do wrong?" or "What could I have done better?") [19,58]. In addition, the adversarial nature of litigation contradicts the normal work environment of a physician. As a result, approximately 80% to 95% of physicians have reported emotional distress during the process of malpractice litigation [70,71]. This distress affects not only the physician but also his or her family and office staff [58]. A physician's reaction to a malpractice claim has been described as beginning with a sense of shock, outrage, or dread, followed by feelings of intense anger, frustration, isolation, and inner tension [68]. In a study of physicians with a malpractice claim, 58% indicated that they were very surprised by the claim, 29% were somewhat surprised, and 13% were not surprised [20]. In cases in which there is clearly a negative outcome, the physician may also feel a substantial amount of guilt. Among the most common reactions to malpractice are [71,72]:

- Adjustment disorder symptoms (20% to 50%)

- Major depressive disorder symptoms (27% to 39%)

- Onset or exacerbation of physical illness (2% to 15%)

A malpractice suit may also cause negative professional effects. In addition to the time spent away from the practice to defend a claim, a physician's and/or practice's reputation can be damaged by a claim, regardless of the outcome of the litigation [19]. In a 2017 survey of physicians who have had a malpractice lawsuit, more than 50% indicated changes to their practice. Among these changes were lack of trust in patients or treating them differently (26%); leaving the practice setting (6%); changing insurer (3%); and/or purchasing more insurance (2%) [20]. In addition, 33% of physicians surveyed felt that the lawsuit negatively affected their medical career [20]. A malpractice suit may also have implications on licensing and credentialing [58]. In general, patterns in the type of adverse events and the severity (amount) of payment to resolve the claim are the focal points for licensing boards and credentialing bodies [4]. Availability and cost of liability insurance may also be concerns; the frequency and severity of claims influence insurance underwriting, but a favorable settlement will weigh positively in the risk evaluation of the insurer [4].

The risk of negative physical and psychologic outcomes during and after a medical malpractice claim has been termed medical malpractice stress syndrome; it presents similarity to post-traumatic stress disorder. Strategies to ensure emotional and physical health due to the consequences of medical malpractice stress syndrome include increasing social support systems, replacing the mystery surrounding litigation with knowledge, and seeking the appropriate medical and psychiatric help [156].

4. AN EFFECTIVE RISK MANAGEMENT PROGRAM

When developing an office-based risk management program, a physician should address the underlying causes, diagnoses, and patient motivators that have been identified most often in malpractice claims, especially as they pertain to his or her medical specialty. Surveys of medical office practices have shown that, across all physician specialties, the most common problems related to risk management include [21]:

- Ineffective process to track diagnostic test results/consults

- Incomplete or poor documentation

- Failure to review patients' medications and provide education on taking prescribed medications

The following elements are essential for an effective risk management program:

- Optimum patient-physician communication

- Mandate for informed consent

- Appropriate and complete documentation

- Establishment and maintenance of efficient office processes

- Quality assurance program

- System for evaluating practice behaviors

- Continued development of diagnostic and technical skills

OPTIMUM PATIENT-PHYSICIAN COMMUNICATION

The lack of effective patient-physician communication has been noted to be perhaps the second leading cause of malpractice [17,58]. In one study, communication problems were noted by patients in 70% of malpractice depositions [73]. In addition, problems with patient-physician communication have been reported to contribute significantly to patient dissatisfaction, which is commonly a precursor to a malpractice claim [74]. The quality of the patient-physician relationship affects many areas within a risk management program, including diagnosis, patient satisfaction, disclosure of errors, informed consent, and medication management.

Effective communication also serves to build rapport, to strengthen mutual trust, and to demonstrate the physician's respect of the patient's preferences and culture, which can help avoid malpractice claims [75]. In contrast, ineffective patient-physician communication can lead to anger, misunderstandings, and unrealistic expectations, all of which have been associated with malpractice claims [31,76]. Improved patient-physician communication may mitigate the harm from medical errors in some cases and may also help reduce the frequency of future errors [42]. Thus, optimizing patient-physician communication and strengthening the patient-physician relationship is a priority in managing risk.

Optimum patient-physician communication involves ensuring that patients are adequately informed, which includes addressing the patient's literacy level and cultural context, ensuring that patients are satisfied with their care, and alerting patients about errors in a timely manner.

Adequately Inform Patients

Physicians with a history of malpractice claims have been described by their patients as not providing enough information about their condition, prognosis, medication side effects, and alternative treatment options [77]. This information is necessary to enable individuals to be active participants in their healthcare decisions. Physicians should also educate patients about realistic outcomes, as surveys have demonstrated a gap between individuals' perceived outcomes and realistic outcomes [5]. As examples, patients have reported that the pain or complications related to a procedure or surgery were not expected, and women have overestimated by 100-fold the value of screening mammography in reducing breast cancer-related mortality [77,78].

To help ensure that individuals are adequately informed about their health and care, the Partnership for Clear Health Communication launched the Ask Me 3 campaign. This patient education initiative is designed to encourage patients to understand the answers to three basic questions [79]:

- What is my main problem?

- What do I need to do?

- Why is it important for me to do this?

If a patient does not ask these questions, the physician should emphasize the importance of understanding the answers. Educational resources for patients are available at the Institute for Healthcare Improvement/National Patient Safety Foundation website, https://www.npsf.org.

Several other strategies have been recommended as ways to strengthen communication and enhance the patient-physician relationship (Table 3) [25,34,75,80].

Table 3: ENHANCING THE PATIENT-PHYSICIAN RELATIONSHIP

Introduce yourself to new patients.

Listen attentively, without interrupting.

Avoid acting rushed, and provide adequate time to talk to each patient.

Explain plans for treatment and follow-up.

Use language the patient can understand—avoid jargon and provide interpreter services, if necessary.

Apologize for any delays in the office schedule.

Remain within your scope of care and competence, providing timely referrals if necessary.

Encourage patients to write down their questions before they come to the office.

Do not guarantee the outcome of a treatment.

Provide educational resources for patients, asking them their preference for media format.

Ask the patient about his or her preferred level of involvement in decision making (and document this in the patient's record).

Source: [25,34,75,80]

Consider Literacy and Cultural Context

Communicating effectively and establishing rapport are more challenging when the patient's literacy level is low or his or her primary language differs from that of the practitioner. Misunderstandings can lead patients to think that a poor health outcome or adverse event is the result of physician error rather than related to the lack of a clear understanding.

Health literacy, the ability to understand health information and make informed health decisions, is integral to good health outcomes [81]. Yet, the National Assessment of Adult Literacy estimated that only 12% of adults have "proficient" health literacy and 14% have "below basic" health literacy [82]. Rates of health literacy are especially low among ethnic minority populations and individuals older than 60 years of age [81]. Compounding the issue of health literacy is the high rate of individuals with limited English proficiency. According to U.S. Census Bureau data from 2017, more than 64 million Americans speak a language other than English at home, with approximately 25.6 million of them (8.5% of the population) speaking English less than "very well" [83].

Physicians should assess their patients' literacy level and understanding and implement interventions as appropriate. It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" (if the healthcare professional is English-speaking) [84]. In addition, physicians should ask what language patients prefer for their medical care information, as some prefer their native language even though they have said they can understand and discuss symptoms in English [84].

Physicians should use plain language in their discussions with patients who have low literacy or limited English proficiency. They should ask them to repeat pertinent information in their own words to confirm understanding [85]. Reinforcement with the use of low-literacy or translated written educational materials is helpful.

"Ad hoc" interpreters, such as family members, friends, and bilingual staff members, are often used instead of professional interpreters for a variety of reasons, including convenience and cost. Physicians should check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [86]. Even when allowed by law, the use of a patient's family member or friend as an interpreter should be avoided, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [86]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [86]. Individuals with limited English language skills have actually indicated a preference for professional interpreters rather than family members [87].

Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [88]. A systematic review of the literature showed that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters, and many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication, utilization, clinical outcomes, and patient satisfaction with care [89,90]. The importance of professional interpreters to effective communication and patient safety has been recognized by the development of The National Board of Certification for Medical Interpreters, founded in 2010 by the International Medical Interpreters Association [91].

When professional interpreters are not feasible or available, bilingual staff members may be used, and their adherence to several principles can enhance their effectiveness [86]:

- Use the universal form of the language when possible

- Avoid assuming the role of interviewer or decision-maker

- Allow the patient to lead the discussion

- Translate everything (without additions, deletions, or changes to meaning)

- Translate in a way to convey the patient's cultural context

- Meet the patient before the interaction to be translated

- Meet with the physician before the visit, to develop a structure to the interaction

- Seek continuing education to improve interpretation skills

Physicians should encourage their bilingual staff members to enhance their interpretation skills. Resources for such training include the Cross Cultural Health Care Program and the National Council on Interpreting in Health Care.

When no professional or ad hoc interpreters are available, physicians may be able to obtain an interpreter from a community organization. In addition, several translation businesses offer fee-based interpretation over the phone or Internet. Many of these businesses also provide translation of documents. Partnering with healthcare plans and hospitals can help identify the best services for your practice [85].

If a patient refuses to use an interpreter, the physician should emphasize to the patient and family the importance of accurate interpretation and understanding on both sides of the patient-physician discussion. A referral to a physician who speaks the patient's primary language may be appropriate [85].

The AMA offers several health literacy resources for healthcare professionals on its website, and the U.S. Department of Health and Human Resources offers valuable information on cultural competency from the Health Resources and Services Administration (HRSA) and the Office of Minority Health. The HRSA also offers a free online course, "Unified Health Communication 101: Addressing Health Literacy, Cultural Competency, and Limited English Proficiency." Another resource is Diversity Rx, a joint initiative of the Resources for Cross Cultural Health Care and the Center for Health Equality at Drexel University School of Public Health.

Issues related to literacy and interpretation should be noted in the patient's record to provide documentation of the physician's assessment of understanding.

Strive to Achieve and Maintain Patient Satisfaction

Patients who have experienced harm from a medical error are less likely to file a malpractice claim if they consider their physician to be caring or compassionate; in contrast, patients who are dissatisfied with their physician are more apt to file a claim [31,92]. Thus, making efforts to ensure that patients are satisfied with their care is another integral aspect of a risk management program.

Patients are satisfied when they feel as if they receive sufficient attention from healthcare professionals. Patients of physicians with prior malpractice claims have reported feeling rushed and ignored, being given explanations and advice that were inadequate, and having shorter office visit times than patients of physicians with no malpractice history [93]. A study of primary care physicians and their patients showed that physicians with no history of malpractice differed significantly from those with previous claims in terms of the use of facilitation statements, the amount of information given to orient the patient to the office visit, and the use of humor [92]. In addition, the length of a routine office visit was a significant predictor of a malpractice claim [92].

Patient satisfaction can be enhanced by improving service throughout the office. Physicians should assess every aspect of the office, including the waiting room, front desk staff and procedures, billing and scheduling, and staff interactions, to ensure that patients receive a positive experience throughout the office [58]. After these aspects have been assessed, ways to improve service should be discussed with all staff members and service should be assessed in an ongoing manner [58].

Assigning a staff member to receive and review complaints and address them in a timely manner can help mitigate patient dissatisfaction [58]. In addition to helping to address a patient's concern, handling a complaint also provides evidence of efforts to address the situation should a claim be presented [58]. Documenting complaints and their resolution can also serve as an important aspect of a quality assurance program [58].

Disclose Errors

Numerous studies have shown that patients prefer full disclosure of a medical error and want details about how the error occurred, what the consequences are (including financial costs), and what measures are being taken to prevent the same error from occurring again [59,94,95,96,97,98,99]. Disclosure of errors has been linked to many benefits, including increased patient satisfaction, greater trust with the physician, and higher likelihood of a patient's positive experience, all of which are related to a lower likelihood that a patient will sue [42]. Physicians have indicated that they want to apologize for errors, but in practice, a substantial number of physicians have admitted that they did not disclose an error [95,100,101]. In addition, in a national survey of individuals who had experienced a medical error, only 32% said that the involved healthcare professional had disclosed the error [28].

Physicians and ethicists have long acknowledged that physicians have an ethical and moral obligation to disclose errors [59,102]. However, for many years, defense lawyers have advised physicians to avoid apologizing to a patient for an adverse event for fear that the apology would be used as an admission of wrongdoing [94,98,100,103]. This approach is changing. Several professional associations and patient safety organizations have established statements endorsing disclosure (Table 4) [27,104,105,106,107]. Legislation has also addressed disclosure, with some states requiring that hospitals notify a patient (or patient's family) about a "serious event" in writing within a specific amount of time after the event [99]. The Sorry Works! Coalition was established in 2005 and has become the leading advocacy group for disclosure, apology (when appropriate), and compensation (if necessary) after adverse medical events [108]. Sorry Works! notes four basic facts every physician should know about disclosure [108]:

- Disclosure benefits doctors as well as nurses, hospitals, and insurers.

- Successful disclosure depends on overall good communication, informed consent, and excellent customer service.

- An empathetic apology should be provided immediately after an adverse event.

- After apologizing, the healthcare professional should immediately call a risk manager, insurance company, or defense counsel.

Table 4: STATEMENTS ENDORSING DISCLOSURE

Organization

Statement

American Medical Association

Code of Medical Ethics (8.6 Promoting Patient Safety)

Patients have a right to know their past and present medical status, including conditions that may have resulted from medical error. Open communication is fundamental to the trust that underlies the patient-physician relationship, and physicians have an obligation to deal honestly with patients at all times, in addition to their obligation to promote patient welfare and safety. Concern regarding legal liability should not affect the physician’s honesty with the patient. Individual physicians who have been involved in a (possible) medical error should:

- Disclose the occurrence of the error, explain the nature of the (potential) harm, and provide the information needed to enable the patient to make informed decisions about future medical care.

- Acknowledge the error and express professional and compassionate concern toward patients who have been harmed in the context of health care.

- Explain efforts that are being taken to prevent similar occurrences in the future.

- Provide for continuity of care to patients who have been harmed during the course of care, including facilitating transfer of care when a patient has lost trust in the physician.

National Quality Forum

Safe Practice 7

Following serious unanticipated outcomes, including those that are clearly caused by systems failures, the patient and, as appropriate, the family should receive timely, transparent, and clear communication concerning what is known about the event.

Source: [27,106]

As discussed, apology statutes now protect physicians and other healthcare professionals who apologize, but not all states have enacted apology statutes, and the statutes vary across states. In addition, the majority of physicians are unfamiliar with their state statutes. Physicians are encouraged to talk to their state medical associations and legal counsel to determine how best to comply with their state's apology statute.

Most physicians are uncomfortable with disclosing errors and, because they have not received formal training in how to conduct such a discussion, they are unclear about how much information to provide and what words and phrases to use [103,109]. As a result, physicians who disclose errors often provide minimal information and express incomplete apologies [96,98]. Guidelines have been developed to help physicians disclose errors in a way that provides patients (and family) with the information they desire [107,110,157]. These guidelines recommend:

- Disclose the error as soon as possible; do not wait for the patient (or family) to ask.

- Be prepared for strong emotions.

- Tell what you know; focus on what happened and the possible consequences.

- Accept responsibility for the outcome, but avoid attributions of blame.

- Express apology and regret.

- Outline a plan of care to address the harm and to prevent recurrence.

- Offer to get second opinions, when appropriate.

- Suggest a family meeting (with the option of having lawyers present).

- Document the disclosure discussion.

- Offer to have follow-up meetings if the patient desires.

The impact of full disclosure on malpractice liability is unclear [98,103]. Early reports of full-disclosure policies at two institutions (the University of Michigan and the Lexington Veterans Affairs Medical Center, Kentucky) indicated that such policies can reduce the number of malpractice claims, increase the number of settled claims, and decrease legal expenses [74,111]. Studies in which individuals are presented with clinical scenarios or vignettes involving adverse events have also suggested that patients would be less likely to sue if physicians provided disclosure and an apology [59,96,97,102,112]. However, there is no conclusive evidence demonstrating that disclosing errors decreases the likelihood of litigation [94,103]. Some have argued that uniform disclosure of errors may actually lead to an increase in malpractice claims [74].

MANDATE FOR INFORMED CONSENT

Informed consent requires patients to sign a document stating that they understand the risks and benefits of a procedure or treatment plan and alternative treatment options. However, the principle of informed consent extends beyond the signed form. The process of informed consent helps patients assume an active role in healthcare decision making and aids in the management of patients' expectations, both of which can reduce the likelihood of a malpractice claim [113].

Essential elements of the informed consent conversation include the diagnosis, the proposed procedure or treatment plan and its potential risks and expected benefits, the risks and benefits of any alternative treatment options, the typical recovery process, and the expected long-term and short-term effects (Table 5) [113,114]. In addition, physicians should tailor the informed consent discussion to a patient's unique situation, noting risks that may be applicable to a patient because of his or her medical history or current comorbidities [37].

Table 5: DISCUSSION POINTS FOR INFORMED CONSENT

Diagnosis (if known)

Nature and purpose of treatment or procedure

Potential risks of proposed treatment

Expected benefits of proposed treatment

Probability of a good outcome with the proposed treatment

Potential problems during recovery

Estimated time to return to normal activities

Availability of alternative treatment options

Risks and benefits of alternative treatment options (including no treatment or procedure)

Likely results if no treatment is given

Source: [113,114]

In a study to assess the levels of knowledge of patients, more than 80% of patients were satisfied with an informed consent discussion about pending surgery and considered themselves to be fully informed, but more than half could not list a single potential complication related to the surgery [115]. A patient's dissatisfaction with an informed consent discussion is most likely to surface only if an adverse event occurs after the treatment was given. Because of the gap between what is told and what is remembered, a patient may think that an adverse event is the result of inadequate informed consent or negligent care [116].

Given the challenge of knowing whether a patient has understood the informed consent discussion, physicians should take several efforts to enhance understanding. Asking the patient to read a section of the informed consent form aloud enables the physician to assess the patient's literacy level [37]. Physicians should plan sufficient time to speak with the patient and should present information in easy-to-understand language. Patients should be encouraged to ask questions and to take an active role in decision making [116]. Lastly, the patient should be asked to describe a section or sections of the form in his or her own words to demonstrate the level of understanding. Physicians should have consent forms translated into languages spoken by any large percentage of their patient population [37].

Informational resources in a variety of media may be helpful as a supplement to the discussion. These resources help emphasize realistic expectations and address different learning preferences; as such, they have been shown to enhance understanding, especially for patients with low educational levels [58,117,118]. A systematic review of 55 trials on decision aids indicated that they increase patients' involvement and are more likely to lead to informed values-based decisions, but the size of this effect has varied across studies [119].

If time allows, it is reasonable to let patients consider a decision made after signing an informed consent form [34]. Giving a patient 24 to 48 hours to think about the risks and benefits can reinforce the validity of the informed consent [34]. If a patient withdraws consent, it should be documented in the medical record, with the date and time of withdrawal.

Documenting the informed consent discussion in the patient's record and including the signed informed consent form in the record decreases the probability of a successful malpractice case against the physician [34]. A signed informed consent form is not automatic protection; patients can argue that the risks were discussed by a healthcare professional other than the physician who performed the treatment or that they did not understand the risks.

APPROPRIATE AND COMPLETE DOCUMENTATION

The patient's medical record is a legal document that reflects the care provided to a patient, and it serves as the basis of defense against malpractice claims and other types of lawsuits [7]. As such, it is crucial for physicians to document all encounters and patient information carefully and accurately [7]. Experts indicate that no amount of documentation is too much, especially in situations at high risk for malpractice claims because of the patient's diagnosis or the physician's specialty [19]. Careful, complete documentation provides proof that the physician did the right thing and demonstrates that the physician gave logical thought and consideration to the case [19,25].

Despite the importance of complete medical records, surveys of office practices have shown that documentation is frequently incomplete or poor, with the most often lacking elements being [8]:

- Updated problem list

- Discussion of medications

- Allergies

- Informed consent process

- Physician signature (to indicate review)

Physicians should ensure that all essential information is documented in every patient's record (Table 6) [7,19,120,121]. In addition, the record should include written instructions that were provided to the patient. Documentation should be clear, objective, specific, and dated. The use of abbreviations should be limited to those that are approved.

Table 6: ESSENTIAL INFORMATION TO DOCUMENT

Full date (month, date, year) and time of the encounter

Updated patient problem list

Medication list (including over-the-counter drugs and supplements)

Informed consents

Thorough patient history (including experience with drugs or alcohol, and psychologic or social issues)

Drug allergies and sensitivities

Physician's advice

Diagnosis (including thought process and list of possible diagnoses if uncertain)

Physical examination findings (especially changes or absence of abnormality)

Changes in the clinical course of a condition

All tests ordered or recommended

All discussions with the patient

All telephone conversations with the patient

All test results

Follow-up plan

Patient's refusal of care or noncompliance with medications, treatment, or scheduled follow-up or appointments (and the physician's efforts to educate the patient about the risks of noncompliance)

Reports of consultations, with dates and times

Results of all testing, including the dates they were ordered, interpreted, and reviewed

Notes regarding patient dissatisfaction and the response of the physician or other staff

Source: [7,19,120,121]

Problems exist with both paper and electronic medical records. Paper records are often found to be illegible, and electronic medical records are frequently used inconsistently by the physicians within a practice [8]. Practices with electronic medical records should have a reliable backup system as well as a disaster recovery program [7]. A physician should never alter a medical record after a claim has been filed [7,19].

ESTABLISH AND USE EFFICIENT OFFICE PROCESSES

Most medical errors have been found to be related to faulty systems rather than incompetence, which means that improving office and practice routines can help physicians avoid adverse outcomes [51]. Efficient office processes and procedures enhance the quality of patient care while decreasing the risk for medical error.

Electronic health records are increasingly being used in hospitals and office-based practices, with 80% of physician offices and 90% of hospitals using electronic health records [158]. Preliminary data suggest that physicians who use electronic health records are less likely to have paid malpractice claims [122]. However, the effect of electronic health records on the quality of care and the potential for mitigating malpractice is unclear. One study of electronic health record-related malpractice claims found that 50% of claims were caused by system factors such as failure of drug or clinical decision support alerts, and 58% of claims were caused by user factors, such as copying and pasting progress notes [158]. In addition, a 2018 survey of physician attitudes toward electronic health records showed that 69% felt that the clerical aspect of updating records takes valuable time away from their patients, and 49% felt that using an electronic health records detracts from their clinical effectiveness [123]. Regardless of whether an office is paper-based or technology-based, the most important systems that should be established are standardized procedures and tools for improving diagnosis, ordering and tracking tests, and managing patient's medications.

Standardized Procedures

Each task in a physician practice should be standardized to ensure that the task is carried out accurately and efficiently each time, regardless of who is performing the task [123,124,125]. The use of standardized procedures helps to avoid errors related to lapses in staff members' memory or to the use of new staff. Following a standardized approach to each patient ensures consistent, high-quality care for all patients. This approach is also helpful in the event the physician does not provide comprehensive documentation for a visit. For example, if a physician forgets to document a breast examination during a female patient's annual physical examination but uses a standardized approach that includes this examination for all women during an annual physical examination, the physician can confidently describe the care given despite the lack of documentation [25].

Establishment of standardized procedures should begin with evidence-based protocols or standing order sets for chronic diseases and vital sign checks for all patients, regardless of the nature of the visit. Flowcharts, checklists, templates, and/or automatic alerts or reminders can help ensure that standardized procedures are carried out [124,125].

Diagnosis

Given that missed or delayed diagnosis is the leading basis of malpractice suits, enhancing diagnostic accuracy is imperative. As stated earlier, diagnostic errors are usually the result of several breakdowns in the diagnostic process [48]. Physicians should develop risk management strategies that focus on the most common breakdowns in the diagnostic process. Thus, physicians should ensure that they:

- Obtain a thorough history

- Perform a comprehensive physical examination

- Order and track diagnostic tests appropriate for a patient's signs and symptoms

- Create a proper follow-up plan

- Seek additional interpretation of diagnostic tests if results are uncertain or inconclusive or seem incongruous with the patient's condition

Reviews of malpractice claims, as well as a systematic review of the literature, have shown that diagnostic errors are most often involved with atypical or nonspecific presentations, rarity of the disease, or masking comorbidities [19,50]. For example, claims related to myocardial infarction are often associated with no history of cardiac problems, a normal electrocardiogram, and atypical signs and symptoms [19]. Similarly, malpractice claims related to breast cancer often involve younger women (average age: 45 years). Physicians should take care not to exclude diagnoses because of nontraditional presentations or low prevalence of a condition.

An inappropriate or inadequate follow-up plan has been alleged in nearly one-half of claims of misdiagnosis [48,153]. Failure to follow-up has often involved a lack of follow-up after abnormal testing, an uncertain diagnosis, or referrals [25,48]. In addition to providing guideline-based follow-up, physicians should seek ways to improve scheduling procedures, to check patient compliance with testing and referrals, and to track test results.

Most physicians are not aware that they need help in making accurate diagnoses, which means that automatic strategies, such as clinical decision support integrated into electronic health records, may be most helpful [48,126]. Other effective interventions include electronic prompts in response to input of certain data and automated systems for tracking test results and scheduling follow-up [48].

Documentation of the differential diagnosis in the patient's record will reflect the physician's thought process in determining a diagnosis, which can be helpful if a malpractice claim is made [19]. This is especially important for diagnoses at high risk for malpractice, such as cancer (especially breast cancer) and myocardial infarction. The patient's report of symptoms should be carefully documented, as well as all tests ordered, the patient's compliance with screening and testing, and scheduled follow-up visits.

Test Ordering and Tracking

Laboratory and/or imaging studies are often an integral aspect of determining a definitive diagnosis, and inadequacies in managing test results can be an important factor in enhancing the timeliness and accuracy of diagnoses. Inadequate test tracking is an important factor in medical errors, with studies of primary care patients indicating that 15% to 54% of medical errors are related to test processes [127].

Ordering and tracking test results is a complex process, and the volume and variety of tests ordered within a practice add to the challenge. Four principle steps are involved in managing patients' test results [125,128]:

- Tracking tests until the results have been received

- Notifying patients of test results

- Documenting that patients were notified

- Ensuring that patients with abnormal results receive the recommended follow-up care

A literature review indicated that there is no clearly defined method for tracking results that is effective and efficient at each of these steps, but a task flow can be created from some "good processes" that have been defined (Figure 3) [129,130]. Studies have shown that most physician practices do not have an established protocol for managing test results, and the processes used to track test results vary widely, even within a single multiphysician practice [127,129,130]. In fact, the most common finding in a survey of office practices (across a broad range of specialties) was the lack of an effective tracking system for test results [8]. In one study, 92% of physicians said that each physician in their group practice used a different method for reporting lab results, with 61% using different processes for different types of tests [129].

Figure 3: TASK FLOW FOR EFFECTIVE TEST TRACKING

Source : [7,19,130]

The lack of a clearly defined system for tracking or managing test results has led to high rates of failure to inform patients of test results and delays in notifying patients. The most common problems are a lack of a consistent system to verify that the physician has reviewed the results and communicated them to the patient and the practice of notifying patients only when the results are abnormal [8]. According to one study, 7% to 26% of patients with test results were not informed of the results (or did not have documentation of notification) [130]. In another study, patient notification was documented in 58% to 85% of charts, but rates were lower for documentation of the physician's response to the result (47% to 84%) and for follow-up after abnormal results (28% to 55%) [8,123,127]. As noted, prompting through electronic health record systems may help alleviate this issue [123].

Physicians recognize the inadequacy of test results tracking. When surveyed, most physicians have expressed dissatisfaction with their practice's process for tracking test results. These surveys have indicated that only 15% to 41% of physicians said they were satisfied with how test results were managed in their offices [123,131,132]. Physicians were most likely to be satisfied when they actively tracked test orders to completion and/or used tools to help set priorities for workflow and generate letters to patients [132].

The optimum process for managing test results will vary according to a practice's specific needs and resources, especially technology. A focus on patient safety and a willingness to embrace technology throughout a practice are important factors in establishing and maintaining an effective test tracking system [127,158]. In the past, several practices have established systems in which staff log ordered tests in a notebook or date-defined card boxes, check them off when test results come in and again when the physician signs off on the results, and note when the patient has been notified [19,125]. Although this system is effective, automated systems that perform the same tasks are more reliable and are less labor-intensive, a factor especially important in large practices [125]. Electronic clinical reminders are more efficient, and systems can be programmed to provide alerts when a test result is due or a patient should return for follow-up care [131]. Creating templates of patient notification letters for the most common tests is also helpful [125]. Also available are telephone and web-based programs that allow patients to obtain their test results; privacy is ensured with the need for a password, and some programs enable the physician to include specific comments to the patient [125].

Given the high risk of malpractice claims in association with various types of cancer, physicians should also be thorough in their approach to recommending screening tests. Follow-up should be done to ensure that the patient has had the screening and has been notified of the results. If the patient refuses to have screening despite the physician's recommendation and explanation of the risks, the refusal should be clearly documented in the patient's medical record [19].

Because appropriate follow-up after abnormal test results is often lacking, a test tracking system must involve a consistent process for scheduling follow-up visits. Failure to follow-up on abnormal mammography and ultrasound are common assertions in malpractice claims [19]. In addition, studies have shown that at least 20% to 36% of women do not receive guideline-directed follow-up after abnormal findings on mammography or Pap tests [55,133,134]. Failure to follow-up on suspicious findings on lung radiographs or computed tomography scans has also been noted [16].

Medication Management

Management of patients' medications is a frequent problem in medical office practice and a common basis for malpractice claims [8,52,53]. As noted earlier, a substantial proportion of medication errors and adverse drug events are considered to be preventable [52,53].

In the office and outpatient setting, preventable medication errors occur primarily in the prescribing and monitoring stages [53,135]. Prescribing errors were identified in up to 11% of prescriptions written in the primary care setting and were typically related to dosage errors [47,146]. Prescribing errors have also frequently involved the use of inappropriate drugs [53]. Inadequate monitoring has caused a wide variety of adverse effects, such as electrolyte/renal imbalance, bleeding, gastrointestinal toxicity, and neuropsychiatric events, and often requires hospitalization of the patient [53,135]. Other common medication-related errors are a failure to prescribe prophylactic agents when appropriate (as for patients taking nonsteroidal anti-inflammatory agents or anticoagulants) and drug-drug interactions [47,135].

Studies and reviews of malpractice claims have identified several drug classes that are most often associated with preventable medication errors: antibiotics, antidepressants or antipsychotic agents, cardiovascular drugs, anticoagulants, analgesics, hypoglycemic agents, and diuretics [52,53,135]. As with most medical errors, preventable medication errors are most frequently caused by system deficiencies [52]. Electronic prescribing systems have not been found to reduce the number of prescribing errors; for example, handwriting legibility issues have now been replaced by e-prescribing issues, such as selecting the wrong box in a dropdown menu [146]. General medication errors are still common. A 2014 observational study found that the most frequent prescribing errors were wrong drug quantity (40%), wrong duration of therapy (21%), wrong dosing directions (19%), and wrong dosage formulation (11%) [146]. Several strategies can help physicians avoid medication errors (Table 7) [7,80,136,137].

Table 7: STRATEGIES FOR AVOIDING MEDICATION ERRORS

Perform a thorough examination before prescribing medication or renewing a prescription (especially opioids).

Review medication list with the patient (including all over-the-counter medications, dietary supplements, herbal remedies, vitamins, etc.) at each visit and during transitions of care (e.g., hospital to outpatient).

Give a written medication list to the patient; the list should include the name of the drug, its purpose, the dosage, the directions for use, and side effects.

Discuss how and when the patient should take the medication.

Review the side effects of a new medication, as well as potential drug-drug or drug-food interactions, and tell the patient what to do if side effects or interactions occur.

Review the role of the medication in the overall context of the patient's health.

Establish guidelines to manage prescription calls and refills and record the calls with the date and time in the patient's chart.

Inform the pharmacist about the patient's comorbidities, allergies, and weight when calling in a prescription.

If providing medication samples, record the lot number in the patient's record (in case of a recall of the medication).

When administering a medication:

- Double check the vial or bottle label against the order.

- Ask the patient if he or she has an allergy to the medication, even if no drug allergies are noted in the medical record.

Source: [7,80,136,137]

QUALITY ASSURANCE PROGRAM

Risk management should also involve a quality assurance program in which the efficiency and outcomes related to policies and procedures are evaluated on an ongoing basis. All staff should be encouraged to provide feedback on ways to improve care; patient complaints can also provide opportunities for improvements [7]. In addition, physicians should evaluate their practice behaviors to identify evidence of defensive medicine to help eliminate variations in care and promote better patient outcomes.

It is also important to create an environment in which patient safety is emphasized. Physicians should provide leadership within the practice, encouraging teamwork, offering feedback on performance, and providing access to necessary training and continuing education for all staff [7].

OTHER ISSUES

Other issues that should be addressed in a risk management program are the scope of practice, termination of the patient-physician relationship, and retention of medical records.

Scope of Practice

All staff should perform only those tasks that are within the scope of their job descriptions, licensure, or certification [7]. In addition, staff should operate or maintain medical equipment or devices only if they have received appropriate training and have been certified (if required).

Termination of Relationship

Physicians should have a standardized procedure for dismissing patients (i.e., terminating the patient-physician relationship when the patient presents insurmountable problems, such as unresolved issues with missed appointments, abusive treatment of staff, or threatening behavior) [138]. It is recommended that a physician dismiss a patient who has filed a malpractice suit [56,138].

When terminating a patient-physician relationship, the physician should send a letter to the patient, notifying him or her that the relationship will be terminated by a specific date, typically 30 days from the date of the letter [138]. The letter should be sent by certified mail with a return receipt requested to ensure appropriate delivery. A copy of the letter and the return receipt should be kept in the patient's medical record. Physicians should not refill a patient's prescription beyond the date of termination [7,138]. Physicians are not obligated to help patients find another physician, but assisting with the transfer of medical records demonstrates an interest in facilitating continuity of care, which may be helpful in the event of litigation [138].

Retention of Medical Records

Most state and federal laws regarding mandatory retention times for medical records apply to hospitals rather than office-based practices. In the absence of state or federal laws, state medical boards and medical associations have recommended retention times [139]. It is recommended to retain medical records indefinitely, but if not, they should be kept for at least 10 years, and some associations recommend 25 years [139]. Medical records should be destroyed appropriately, and an inventory of all destroyed records should be kept.

5. CONCLUSION

Although overall paid medical malpractice claims have decreased since the early 2000s, the number of claims against primary care physicians increased during that time. The association of malpractice and medical errors is complex. Large studies have shown that malpractice claims often do not involve a negligent injury and that most patients who do sustain an injury due to negligence do not file a claim. These findings indicate that factors other than true medical error are motivators for a malpractice claim. A wide variety of motivators have been identified, the most common being inadequate patient-physician communication. Thus, physicians should protect their liability not only through patient safety efforts but also through enhancement of patient-physician communication and the patient-physician relationship.

The threat of malpractice—whether real or perceived—has a negative effect on physicians personally and professionally and ultimately adversely affects healthcare delivery, primarily through the use of defensive medicine. An effective risk management program helps physicians ensure patient safety and avoid the time and stress associated with litigation. The most effective risk management strategies are those that address specific issues identified in studies of closed malpractice claims and surveys of office practices.

Studies of malpractice claims have shown that diagnostic error (missed or delayed diagnosis) is the leading underlying cause of claims and is most often related to cancer (especially breast cancer) and myocardial infarction. Diagnostic errors are usually the result of several contributing factors rather than faulty judgment alone, and the most common breakdowns in the diagnostic process have been failure to order an appropriate diagnostic test or to create a proper follow-up plan. Surveys of medical office practices have shown that the most common risk management-related problem is an ineffective process for tracking diagnostic test results. As such, an effective system for ordering and tracking tests, including follow-up plans for abnormal results, is an essential component of a risk management program. Other essential components include a mandate for informed consent, appropriate and complete documentation, establishment and maintenance of efficient office processes, a quality assurance program, a system for evaluating practice behaviors, and continued development of diagnostic and technical skills of the physician and other healthcare professionals in the practice.

As noted, perhaps the most important element of a risk management program is optimum patient-physician communication. The quality of patient-physician communication and the patient-physician relationship affects many areas within a risk management program, including diagnosis, patient satisfaction, disclosure of errors, informed consent, and medication management. Effective communication also serves to build rapport, foster trust, avoid misunderstandings, and ensure realistic patient expectations, all of which have been shown to be associated with a lower risk of malpractice claims. Improved patient-physician communication may mitigate the harm from medical errors as well as help reduce the frequency of future errors.

6. RESOURCES

American Medical Association Code of Medical Ethics

https://www.ama-assn.org/delivering-care/ethics

American Medical Association State Medical Liability Reform

https://www.ama-assn.org/practice-management/sustainability/state-medical-liability-reform

Diversity Rx

http://www.diversityrx.org

Institute for Healthcare Improvement and National Patient Safety Foundation

https://www.npsf.org

National Council on Interpreting in Health Care

https://www.ncihc.org

Works Cited

1. Cohen D, Chan SB, Dorfman M. Malpractice claims on emergency physicians: time and money. J Emerg Med. 2012;42(1):22-27.

2. Studdert DM, Mello MM, Gawande AA, et al. Claims, errors, and compensation payments in medical malpractice litigation.N Engl J Med. 2006;354(19):2024-2033.

3. Phillips RJ, Bartholomew LA, Dovey SM, Fryer GE Jr, Miyoshi TJ, Green LA. Learning from malpractice claims about negligent, adverse events in primary care in the United States. Qual Saf Health Care. 2004;13(2):121-126.

4. Nepps ME. The basics of medical malpractice. Chest. 2008;134(5):1051-1055.

5. Fowler PR. Risk Management and Medical Liability: A Manual for Indian Health Service and Tribal Health Care Professionals. 3rd ed. Rockville, MD: Indian Health Service; 2018.

6. Loughlin KR. Medical malpractice: the good, the bad, and the ugly. Urol Clin North Am. 2009;36(1):101-110.

7. Medical Mutual Liability Insurance Society of Maryland. The Top Ten Risk Management Issues for Medical Office Practices. Available at http://www.medicalmutualofmd.com/pdf/os_top-issues.pdf. Last accessed February 11, 2019.

8. Diamond R. Top findings in our office practice surveys. Doctor's Advocate. 2008;3:4-5.

9. Institute of Medicine Committee on Quality of Health Care in America. To Err is Human: Building a Safer Health System. Washington, DC: The National Academies Press; 2000.

10. U.S. Department of Health and Human Services. National Practitioner Data Bank. Available at https://www.npdb.hrsa.gov/analysistool/. Last accessed February 12, 2019.

11. Bilimoria KY, Chung JW, Minami CA, et al. Relationship between state malpractice environment and quality of health care in the United States. Jt Comm J Qual Patient Saf. 2017;43:241-250.

12. Dick JF 3rd, Gallagher TH, Brenner RJ, et al. Predictors of radiologists' perceived risk of malpractice lawsuits in breast imaging. AJR. 2009;192(2):327-333.

13. Carrier ER, Reschovsky JD, Katz DA, Mello MM. High physician concern about malpractice risk predicts more aggressive diagnostic testing in office-based practice. Health Affairs. 2013;32(8):1383-1391.

14. Carrier ER, Reschovsky JD, Mello MM, Mayrell RC, Katz D. Physicians' fears of malpractice lawsuits are not assuaged by tort reforms. Health Affairs. 2010;29(9):1585-1592.

15. Guardado JR. Policy Research Perspectives: Medical Liability Claim Frequency Among U.S. Physicians. Chicago, IL: American Medical Association; 2017.

16. Luce JM. Medical malpractice and the chest physician. Chest. 2008;134(5):1044-1050.

17. Pritchard DJ. A plaintiff attorney's candid view of medical malpractice. Clin Perinatol. 2005;32(1):191-202.

18. Blackston JW, Bouldin MJ, Brown CA, Duddleston DN, Hicks GS, Holman HE. Malpractice risk prevention for primary care physicians. Am J Med Sci. 2002;324(4):212-219.

19. Davenport J. Documenting high-risk cases to avoid malpractice liability. Fam Pract Manage. 2000;7(9):33-36.

20. Levy S, Kane L. Medscape Malpractice Report, 2017. Available at https://www.medscape.com/slideshow/2017-malpractice-report-6009206#1. Last accessed February 11, 2019.

21. Schaffer AC, Jena AB, Seabury SA, et al. Rates and characteristics of paid malpractice claims among us physicians by specialty, 1992–2014. JAMA Intern Med. 2017;177(5):710-718.

22. Blek D. Medical Malpractice: Myths and Realities. Available at http://truecostofhealthcare.org/malpractice. Last accessed February 12, 2019.

23. Diederich Healthcare. 2018 Medical Malpractice Payout Analysis. Available at https://www.diederichhealthcare.com/the-standard/2018-medical-malpractice-payout-analysis. Last accessed February 12, 2019.

24. American Society for Healthcare Risk Management. Enterprise Risk Management: A Framework for Success. Available at http://www.ashrm.org/pubs/files/white_papers/ERM-White-Paper-8-29-14-FINAL.pdf. Last accessed February 12, 2019.

25. Zurad EG. Don't be a target for a malpractice suit. Fam Pract Manage. 2006;13(6):57-64.

26. Jena AB, Seabury S, Lakdawalla D, Chandra A. Malpractice risk according to physician specialty. N Engl J Med. 2011;365:629-636.

27. American Medical Association. Code of Medical Ethics. Available at https://www.ama-assn.org/delivering-care/ethics/code-medical-ethics-overview. Last accessed February 12, 2019.

28. NORC at the University of Chicago, IHI/NPSF Lucian Leape Institute. Americans' Experiences with Medical Errors and Views on Patient Safety. Cambridge, MA: Institute for Healthcare Improvement and NORC at the University of Chicago; 2017.

29. Localio AR, Lawthers AG, Brennan TA, et al. Relation between malpractice claims and adverse events due to negligence: results of the Harvard Medical Practice Study III. N Engl J Med. 1991;325(4):245-251.

30. Studdert DM, Thomas EJ, Burstin HR, Zbar BI, Orav EJ, Brennan TA. Negligent care and malpractice claiming behavior in Utah and Colorado. Med Care. 2000;38(3):250-260.

31. Virshup BB, Oppenberg AA, Coleman MM. Strategic risk management: reducing malpractice claims through more effective patient-doctor communication. Am J Med Qual. 1999;14(4):153-159.

32. Taber's Online Medical Dictionary. Available at https://www.tabers.com/tabersonline/ub. Last accessed February 13, 2019.

33. Cornell University Law School Legal Information Institute. Negligence. Available at https://www.law.cornell.edu/wex/negligence. Last accessed February 13, 2019.

34. Paterick TJ, Carson GV, Allen MC, Paterick TE. Medical informed consent: general considerations for physicians. Mayo Clin Proc. 2008;83(3):313-319.

35. Sage WM, Kersh R (eds). Medical Malpractice and the U.S. Health Care System. Cambridge: Cambridge University Press; 2006.

36. Werth B. Damages. New York, NY: Simon and Schuster; 1998.

37. Dixon LA. Informed consent: new requirements from Centers for Medicare and Medicaid Services. Doctor's Advocate. 2007;2.

38. LawInfo. What are Good Samaritan Laws? Available at https://resources.lawinfo.com/personal-injury/what-are-good-samaritan-laws.html. Last accessed February 13, 2019.

39. U.S. Department of Homeland Security. The Federal Good Samaritan Act (and Related Statutes). Available at https://www.fletc.gov/sites/default/files/imported_files/training/programs/legal-division/downloads-articles-and-faqs/downloads/other/gtoodsamar.pdf. Last accessed February 13, 2019.

40. Hattis P, Staton S. Charitable Immunity Manual: A Review of U.S. Charitable Immunity Legislation for Volunteer Health Care Providers. Providence, RI: Volunteers in Health Care; 2002.

41. Shapiro HB. Providing charity care: a primer on liability risk. Fam Pract Manage. 2003;10(1):52-54.

42. McDonnell WM, Guenther E. Narrative review: do state laws make it easier to say "I'm sorry?" Ann Intern Med. 2008;149(11): 811-816.

43. Ho B, Liu E. Does Sorry Work? The Impact of Apology Laws on Medical Malpractice. Available at http://irving.vassar.edu/ faculty/bh/Ho-Liu-Apologies-and-Malpractice-nov15.pdf. Last accessed February 13, 2019.

44. Iacobucci G. GPs can expect to be sued once every 10 years, MDU warns. BMJ. 2018;362:k4016.

45. Medical Professional Liability Association. Available at https://www.mplassociation.org. Last accessed February 13, 2019.

46. Thomson Reuters Expert Witness Services. Verdict Finder Report. Available at https://legal.thomsonreuters.com/en/products/westlaw/jury-verdicts. Last accessed February 13, 2019.

47. Sandars J, Esmail A. The frequency and nature of medical error in primary care: understanding the diversity across studies.Fam Practice. 2003;20(3):231-236.

48. Gandhi TK, Kachalia A, Thomas EJ, et al. Missed and delayed diagnoses in the ambulatory setting: a study of closed malpractice claims. Ann Intern Med. 2006;145(7):488-496.

49. Kachalla A, Gandhi TK, Puopolo AL, et al. Missed and delayed diagnoses in the emergency department: a study of closed malpractice claims from 4 liability insurers. Ann Emerg Med. 2007;49(2):196-205.

50. Kostopoulou O, Delaney BC, Munro CW. Diagnostic difficulty and error in primary care—a systematic review. Fam Pract. 2008;25(6):400-413.

51. Troxel DB. Do health system errors cause medical malpractice claims? Bull Am Coll Surg. 2009;94(5):30-31.

52. Rothschild JM, Federico FA, Gandhi TK, Kaushal R, Williams DH, Bates DW. Analysis of medication-related malpractice claims: causes, preventability, and costs. Arch Intern Med. 2002;162(21):2414-2420.

53. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289(9):1107-1116.

54. Troxel DB. An Analysis of Internal Medicine Malpractice Claims. Available at https://www.thedoctors.com/internalmedicinestudy. Last accessed February 12, 2019.

55. Zapka J, Taplin SH, Price RA, Cranos C, Yabroff R. Factors in quality care: the case of follow-up to abnormal cancer screening tests—problems in the steps and interfaces of care. J Natl Cancer Inst Monogr. 2010;2010(40):58-71.

56. Roberts RG. Seven reasons family doctors get sued and how to reduce your risk. Fam Pract Manage. 2003;10(3):29-34.

57. American Medical Association. Medical Liability Reform NOW! The Facts You Need to Know to Address the Broken Medical Liability System, 2018 Edition. Available at https://www.ama-assn.org/sites/ama-assn.org/files/corp/media-browser/premium/ arc/mlr-now.pdf. Last accessed February 12, 2019.

58. Saxton JW, Finkelstein MM. Reducing your risk of malpractice claims. Available at https://physiciansnews.com/2005/04/13/reducing-your-risk-of-malpractice-claims. Last accessed February 13, 2019.

59. Mazor KM, Simon SR, Yood RA, et al. Health plan members' views about disclosure of medical errors. Ann Intern Med. 2004;140(6):409-418.

60. Rubin RJ, Mendelson DN. How much does defensive medicine cost? J Am Health Policy. 1994;4(4):7-15.

61. Bernstein J, MacCourt D, Abramson BD. Topics in medical economics: medical malpractice. J Bone Joint Surg. 2008;90(8):1777-1782.

62. Katz DA, Williams GC, Brown RL, et al. Emergency physicians' fear of malpractice in evaluating patients with possible acute cardiac ischemia. Ann Emerg Med. 2005;46(6):525-533.

63. Studdert DM, Mello MM, Sage WM, et al. Defensive medicine among high-risk specialist physicians in a volatile malpractice environment. JAMA. 2005;293(21):2609-2617.

64. Nahed BV, Babu MA, Smith TR, Heary RF. Malpractice liability and defensive medicine: a national survey of neurosurgeons.PLoSOne. 2012;7(6):e39237.

65. Jackson Healthcare, LLC. Quantifying the Cost of Defensive Medicine: Lawsuit Driven Medicine Creates $650–$850 Billion Annual Healthcare Costs. Available at https://jacksonhealthcare.com/media-room/surveys/defensive-medicine-study-2010. Last accessed February 13, 2019.

66. Sethi MK, Obremskey WT, Natividad H, Mir HR, Jahanqir AA. Incidence and costs of defensive medicine among orthopedic surgeons in the United States: a national survey study. Am J Orthop (Belle Mead NJ). 2012; 41(2):69-73.

67. Kessler DP, McClellan M. Do doctors practice defensive medicine? Quart J Econ. 1996;111(2):353-390.

68. Charles SC. Coping with a medical malpractice suit. West J Med. 2001;174(1):55-58.

69. Gabbard GO. The role of compulsiveness in the normal physician. JAMA. 1985;254(20):2926-2929.

70. Elmore JG, Taplin SH, Barlow WE, et al. Does litigation influence medical practice? The influence of community radiologists' medical malpractice perceptions and experience on screening mammography. Radiology. 2005;236(1):37-46.

71. Charles SC, Pyskoty CE, Nelson A. Physicians on trial: self-reported reactions to malpractice trials. West J Med. 1988;148(3): 358-360.

72. Charles SC, Wilbert JR, Kennedy EC. Physicians' self-reports of reactions to malpractice litigation. Am J Psychiatry. 1984;141: 563-565.

73. Beckman HB, Markakis KM, Suchman AL, Frankel RM. The doctor-patient relationship and malpractice: lessons from plaintiff depositions. Arch Intern Med. 1994;154(12):1365-1370.

74. Studdert DM, Mello MM, Gawande AA, Brennan TA, Wang YC. Disclosure of medical injury to patients: an improbable risk management strategy. Health Aff. 2007;26(1):215-226.

75. American Congress of Obstetricians and Gynecologists Committee on Health Care for Underserved Women, Committee on Patient Safety and Quality Improvement. Effective Patient-Physician Communication. Available at https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Effective-Patient-Physician-Communication. Last accessed February 15, 2019.

76. Stelfox HT, Gandhi TK, Orav EJ, Gustafson ML. The relation of patient satisfaction with complaints against physicians and malpractice lawsuits. Am J Med. 2005;118(10):1126-1133.

77. Adamson TE, Tschann JM, Gullion DS, Oppenberg AA. Physician communication skills: a complex relationship. West J Med. 1989;150(3):356-360.

78. Black WC, Nease RF Jr, Tosteson AN. Perceptions of breast cancer risk and screening effectiveness in women younger than 50 years of age. J Natl Cancer Inst. 1995;87(10):720-731.

79. The National Patient Safety Foundation. Ask Me 3. Available at http://www.ihi.org/resources/Pages/Tools/Ask-Me-3-Good-Questions-for-Your-Good-Health.aspx. Last accessed February 15, 2019.

80. Shepard S, Murray C. Shared Responsibility for Preventing Malpractice Suits–Patient Interactions. Available at https://www.thedoctors.com/articles/shared-responsibility-for-preventing-malpractice-suitspatient-interactions/. Last accessed February 16, 2019.

81. Committee on Health Literacy Board on Neuroscience and Behavioral Health. Health Literacy: A Prescription to End Confusion. Washington, DC: The National Academies Press; 2004.

82. Kirsch IS, Jungeblut A, Jenkins L, Kolstad A. Adult Literacy in America: A First Look at the Findings of the National Adult Literacy Survey (NALS). Washington, DC: National Center for Education Statistics, U.S. Department of Education; 1993.

83. U.S. Census Bureau. Selected Social Characteristics in the United States: 2013–2017 American Community Survey 5-Year Estimates. Available at https://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid=ACS_14_5YR_DP02&src=pt. Last accessed February 16, 2019.

84. Karliner LS, Napoles-Springer AM, Schillinger D, Bibbins-Domingo K, Pérez-Stable EJ. Identification of limited English proficient patients in clinical care. J Gen Intern Med. 2008;23(10):1555-1560.

85. Shepard S. Challenges in cultural diversity: protect your patients and yourself. Doctor's Advocate. 2007;4.

86. Sevilla Mátir JF, Willis DR. Using bilingual staff members as interpreters. Fam Pract Manage. 2004;11(7):34-36.

87. Ngo-Metzger Q, Massagli MP, Clarridge BR, et al. Linguistic and cultural barriers to care: perspectives of Chinese and Vietnamese immigrants. J Gen Intern Med. 2003;18(1):44-52.

88. Flores G. Language barriers to health care in the United States. N Engl J Med. 2006;355(3):229-231.

89. Flores G. The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev. 2005;62(3):255-299.

90. Karliner LS, Jacobs EA, Chen AH, Mutha S. Do professional interpreters improve clinical care for patients with limited English proficiency? A systematic review of the literature. Health Serv Res. 2007;42(2):727-754.

91. The National Board of Certification for Medical Interpreters. Available at https://www.certifiedmedicalinterpreters.org. Last accessed February 16, 2019.

92. Levinson W, Roter DL, Mullooly JP, Dull VT, Frankel RM. Physician-patient communication: the relationship with malpractice claims among primary care physicians and surgeons. JAMA. 1997;277(7):553-559.

93. Hickson GB, Clayton EW, Entman SS, et al. Obstetricians' prior malpractice experience and patients' satisfaction with care. JAMA. 1994;272(20):1583-1587.

94. Calvert JF Jr, Hollander-Rodriguez J, Atlas M, Johnson KE. Clinical inquiries: what are the repercussions of disclosing a medical error? J Fam Pract. 2008;57(2):124-125.

95. Gallagher TH, Waterman AD, Ebers AG, Fraser VJ, Levinson W. Patients' and physicians' attitudes regarding the disclosure of medical errors. JAMA. 2003;289(8):1001-1007.

96. Mazor KM, Reed GW, Yood RA, Fischer MA, Baril J, Gurwitz JH. Disclosure of medical errors: what factors influence how patients respond? J Gen Intern Med. 2006;21(7):704-710.

97. Schwappach DLB, Koeck CM. What makes an error unacceptable? A factorial survey on the disclosure of medical errors.Int J Qual Health Care. 2004;16(4):317-326.

98. Robbennolt JK. Apologies and medical error. Clin Orthop Relat Res. 2009;467(2):376-382.

99. Liebman CB, Hyman CS. A mediation skills model to manage disclosure of errors and adverse events to patients. Health Aff. 2004;23(4):22-32.

100. O'Rourke PT, Hershey KM. The power of "sorry." The Hospitalist. 2007;(10).

101. Kaldjian LC, Jones EW, Wu BJ, Forman-Hoffman VL, Levi BH, Rosenthal GE. Disclosing medical errors to patients: attitudes and practices of physicians and trainees. J Gen Intern Med. 2007;22(7):988-996.

102. Mazor KM, Simon SR, Gurwitz JH. Communicating with patients about medical errors: a review of the literature. Arch Intern Med. 2004;164(15):1690-1697.

103. Kachalia A, Shojania KG, Hofer TP, Piotrowski M, Saint S. Does full disclosure of medical errors affect malpractice liability? The jury is still out. Jt Comm J Qual Saf. 2003;29(10):503-511.

104. Finkelstein D, Wu AW, Holtzman NA, Smith MK. When a physician harms a patient by a medical error: ethical, legal, and risk-management considerations. J Clin Ethics. 1997;8(4):330-335.

105. American College of Physicians. Ethics manual, fourth edition. Ann Intern Med. 1998;128(7):576-594.

106. National Quality Forum. Safe Practices for Better Healthcare—2010 Update. A Consensus Report. Washington, DC: National Quality Forum; 2010.

107. Solomon RC. Ethical issues in medical malpractice. Emerg Med Clin N Am. 2006;24(3):733-747.

108. Sorry Works! Available at https://www.sorryworks.net. Last accessed February 16, 2019.

109. Gallagher TH, Garbutt JM, Waterman AD, et al. Choosing your words carefully: how physicians would disclose harmful medical errors to patients. Arch Intern Med. 2006;166(15):1585-1593.

110. Massachusetts Coalition for the Prevention of Medical Errors. When Things Go Wrong: Responding to Adverse Events. A Consensus Statement of the Harvard Hospitals. Available at http://www.macoalition.org/documents/respondingToAdverseEvents.pdf. Last accessed February 17, 2019.

111. Kraman SS, Hamm G. Risk management: extreme honesty may be the best policy. Ann Intern Med. 1999;131(12):963-967.

112. Wu AW, Huang IC, Stokes S, Pronovost PJ. Disclosing medical errors to patients: it's not what you say, it's what they hear.J Gen Intern Med. 2009;24(9):1012-1017.

113. Morton R. Informed Consent: Substance and Signature. Available at https://www.thedoctors.com/articles/informed-consent-substance-and-signature/. Last accessed February 17, 2019.

114. American Medical Association. Informed Consent. Available at https://www.ama-assn.org/delivering-care/ethics/informed- consent. Last accessed February 13, 2019.

115. Burns P, Keogh I, Timon C. Informed consent: a patients' perspective. J Laryngol Otol. 2005;119(1):19-22.

116. Murphy JB. Benefits and challenges of informed consent [editorial]. Mayo Clin Proc. 2008;83(3):272-273.

117. Langdon IJ, Hardin R, Learmonth ID. Informed consent for total hip arthroplasty: does a written information sheet improve recall by patients? Ann Roy Coll Surg Engl. 2002;84(6):404-408.

118. Rossi M, McClellan R, Chou L, Davis K. Informed consent for ankle fracture surgery: patient comprehension of verbal and videotaped information. Foot Ankle Int. 2004;25(10):756-762.

119. Barry MJ, Bennett CL, Stacey D, et al. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev. 2011;10:CD001431.

120. Gorney M, Jenkins PA, Dixon LA, Shepard S. Accurate Medical Records: Your Primary Line of Defense. Available at https://www.thedoctors.com/articles/accurate-medical-records-your-primary-line-of-defense/. Last accessed February 17, 2019.

121. Mingea GD. Documenting away a malpractice suit [letter]. Fam Pract Manage. 2006;13(9):16.

122. Virapongse A, Bates DW, Shi P, et al. Electronic health records and malpractice claims in office practice. Arch Intern Med. 2008;168(21):2362-2367.

123. Stanford Medicine. How Doctors Feel About Electronic Health Records: National Physician Poll by The Harris Poll. Available at https://med.stanford.edu/content/dam/sm/ehr/documents/EHR-Poll-Presentation.pdf. Last accessed February 17, 2019.

124. Elgert S. Reliability science: reducing the error rate in your practice. Fam Pract Manag. 2005;12(9):59-63.

125. White B. Four principles for better test-result tracking. Fam Pract Manag. 2002;9(7):41-44.

126. Friedman CP, Gatti GG, Franz TM, et al. Do physicians know when their diagnoses are correct? Implications for decision support and error reduction. J Gen Intern Med. 2005;20(4):334-339.

127. Elder NC, McEwen TR, Flach JM, Gallimore JJ. Management of test results in family medicine offices. Ann Fam Med. 2009;7(4):343-351.

128. Bookhaker EA, Ward RE, Uman JE, McCarthy BD. Patient notification and follow-up of abnormal test results. Arch Intern Med. 1996;156(3):327-331.

129. Mold JW, Cacy DS, Dalbir DK. Management of laboratory test results in family practice. J Fam Pract. 2000;49(8):709-715.

130. Casalino LP, Dunham D, Chin MH, et al. Frequency of failure to inform patients of clinically significant outpatient test results. Arch Intern Med. 2009;169(12):1123-1129.

131. Murff HJ, Gandhi TK, Karson AK, et al. Primary care physician attitudes concerning follow-up of abnormal test results and ambulatory decision support systems. Int J Med Inform. 2003;71(2-3):137-149.

132. Poon EG, Gandhi TK, Sequist TD, Murff HJ, Karson AS, Bates DW. "I wish I had seen this test result earlier!": dissatisfaction with test result management systems in primary care. Arch Intern Med. 2004;164(20):2223-2228.

133. Haas JS, Cook EF, Puopolo AL, Burstin HR, Brennan TA. Differences in the quality of care for women with an abnormal mammogram or breast complaint. J Gen Intern Med. 2000;15(5):321-328.

134. Marcus AC, Crane LA, Kaplan CP, et al. Improving adherence to screening follow-up among women with abnormal Pap smears: results from a large clinic-based trial of three intervention strategies. Med Care. 1992;30(3):216-230.

135. Thomsen LA, Winterstein AG, Sondergaard B, Haugbolle LS, Melander A. Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care. Ann Pharmacother. 2007;41(9):1411-1426.

136. Committee on Identifying and Preventing Medication Errors Institute of Medicine. Preventing Medication Errors: Quality Chasm Series. Washington, DC: The National Academies Press; 2007.

137. Shepard S. Medication Safety. Available at https://www.thedoctors.com/articles/medication-safety/. Last accessed February 17, 2019.

138. Willis DR, Zerr A. Terminating a patient: is it time to part ways? Fam Pract Manag. 2005;12(8):34-38.

139. Cahill R. Medical Record Retention. Available at https://www.thedoctors.com/articles/medical-record-retention. Last accessed February 18, 2019.

140. Kessler DP. Evaluating the medical malpractice system and options for reform. J Econ Perspect. 2011;25(2):93-110.

141. Public Citizen's Congress Watch. Medical Malpractice Payments Sunk to Record Low in 2011. Available at https://www.citizen.org/documents/npdb-report-2012.pdf. Last accessed February 12, 2019.

142. Nonprofit Rick Management Center. State Liability Laws for Charitable Organizations and Volunteers. Available at https://www.nonprofitrisk.org/app/uploads/2017/01/state-liability-laws.pdf. Last accessed February 13, 2019.

143. Beaulieu-Volk D. Apology Laws: Talking to Patients about Adverse Events. Available at https://www.medicaleconomics.com/medical-economics/content/tags/apology-laws/apology-laws-talking-patients-about-adverse-events?page=full. Last accessed February 13, 2019.

144. Wallace E, Lowry J, Smith SM, Fahey T. The epidemiology of malpractice claims in primary care: a systematic review. BMJ Open. 2013;3(7).

145. Brown TW, McCarthy ML, Kelen GD, Levy F. An epidemiologic study of closed emergency department malpractice claims in a national database of physician malpractice insurers. Acad Emerg Med. 2010;17(5):553-560.

146. Odukoya OK, Stone JA, Chui MA. E-prescribing errors in community pharmacies: exploring consequences and contributing factors. Int J Med Inform. 2014;83(6):427-437.

147. Makary MA, Daniel M. Medical error—the third leading cause of death in the U.S. BMJ. 2016;353:i2139.

148. Baldor DJ, Kravietz A. Rapid Response Re: Medical Error—The Third Leading Cause of Death in the U.S. Available at https://www.bmj.com/content/353/bmj.i2139/rapid-responses. Last accessed February 12, 2019.

149. Stimson C.J. Hospital risk management and the U.S. legal system: an introduction to U.S. medical malpractice tort law. In: Merkle W (ed). Risk Management in Medicine. Berlin: Springer; 2016.

150. Bal BS. An introduction to medical malpractice in the United States. Clin Orthop Relat Res. 2008;467(2):339-347.

151. National Conference of State Legislatures. Medical Professional Apologies Statutes. Available at http://www.ncsl.org/research/financial-services-and-commerce/medical-professional-apologies-statutes.aspx. Last accessed February 13, 2019.

152. Gupta A, Snyder A, Kachalia A, et al. Malpractice claims related to diagnostic errors in the hospital. BMJ Qual Saf. 2018;27:53-60

153. Committee on Diagnostic Error in Health Care, Board on Health Care Services, Institute of Medicine, The National Academies of Sciences, Engineering, and Medicine, Balogh EP, Miller BT, Ball JR (eds). Improving Diagnosis in Health Care. Washington, DC: National Academies Press; 2015.

154. Singh H, Giardina TD, Meyer AN, et al. Types and origins of diagnostic errors in primary care settings. JAMA Intern Med. 2013;173(6):418-425.

155. Neumiller JJ, Setter SM, White AM, et al. Advances in Patient Safety and Medical Liability: Medication Discrepancies and Potential Adverse Drug Events During Transfer of Care from Hospital to Home. Available at https://www.ahrq.gov/professionals/quality-patient-safety/patient-safety-resources/resources/liability/advances-in-patient-safety-medical-liability/neumiller.html. Last accessed February 13, 2019.

156. Reyes R, Reyes C. At your defense: medical malpractice stress syndrome takes its toll. EMN. 2017;39(2):19.

157. Agency for Healthcare Research and Quality. Patient Safety Primer: Disclosure of Errors. Available at https://psnet.ahrq.gov/primers/primer/2/Disclosure-of-Errors. Last accessed February 17, 2019.

158. The Doctors Company. Electronic Health Record Closed Claims Study: Navigating the Rising Risks of EHRs. Available at https://www.thedoctors.com/articles/navigating-the-rising-risks-of-ehrs. Last accessed February 17, 2019.

94423 • Influenza: A Comprehensive Review

Elizabeth T. Murane, PHN, BSN, MA

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Because medications to treat acute illness due to influenza are just recently appearing, there is a tendency to accept the existence of influenza and to forget the fact that 49,000 Americans die annually from the flu and its complications. In addition, the resulting hospitalizations and medical care cost the healthcare system up to $12 billion each year. Sadly, there are underused vaccines that can prevent many of the hospitalizations and deaths, thus lessening the suffering and financial burden of this disease. This course will explore the history of influenza, symptoms, communicability, care of the patient, the makeup of the virus, avian and swine types of flu, vaccine issues, and pandemic planning. Reproducible patient education materials will be included. The vital roles of the healthcare professional and community involvement will be stressed.

Table of Contents

94423 • Influenza: A Comprehensive Review

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. HISTORY

3. INFLUENZA VIRUS

INFLUENZA VIRUS TYPES

INFLUENZA A SUBTYPES AND ANTIGENIC SHIFT

VIRUS NAMING

4. INFLUENZA DISEASE

SYMPTOMS AND SIGNS

TRANSMISSION

DIAGNOSTIC TESTS FOR INFLUENZA

5. INFLUENZA-LIKE ILLNESSES

INFLUENZA COMPARED TO THE COMMON COLD

OTHER FLU-LIKE ILLNESSES

6. COMPLICATIONS OF INFLUENZA

PNEUMONIA

REYE SYNDROME

MYOSITIS AND RHABDOMYOLYSIS

STAPHYLOCOCCUS AUREUS SUPERINFECTION

CARDIAC COMPLICATIONS

PULMONARY COMPLICATIONS

CENTRAL NERVOUS SYSTEM COMPLICATIONS

7. INFLUENZA VACCINE

HIGH-DOSE INFLUENZA VACCINE

HIGH-RISK GROUPS WHO SHOULD RECEIVE THE INFLUENZA VACCINE

OTHER GROUPS ADVISED TO RECEIVE THE INFLUENZA VACCINE

GROUPS WHO SHOULD NOT RECEIVE THE INFLUENZA VACCINE

MANUFACTURE OF THE VACCINE

HANDLING AND STORAGE OF THE VACCINE

VACCINE PREVENTION OF SEASONAL INFLUENZA, 2021–2022

ADMINISTERING THE VACCINE

SIDE EFFECTS OF THE INFLUENZA VACCINE

ADVERSE EVENTS

EFFECTIVENESS OF THE INFLUENZA VACCINE

COST-EFFECTIVENESS OF THE INFLUENZA VACCINE

INTRADERMAL INFLUENZA VACCINE

NASAL SPRAY INFLUENZA VACCINE

8. PROMOTING THE USE OF INFLUENZA VACCINE

FACTORS INFLUENCING INFLUENZA IMMUNIZATION

IMPROVING INFLUENZA VACCINE USAGE

9. OTHER METHODS TO PREVENT INFLUENZA

HANDWASHING

AVOID TOUCHING EYES, NOSE, OR MOUTH

PROPER COVER FOR A COUGH OR SNEEZE

AVOID PEOPLE WITH RESPIRATORY SYMPTOMS

ANTIVIRAL MEDICATIONS AS PREVENTION

10. ANTIVIRAL MEDICATIONS

ZANAMIVIR

OSELTAMIVIR

PERAMIVIR

BALOXAVIR

AMANTADINE AND RIMANTADINE

TREATMENT OF ACUTE ILLNESS RESULTING FROM INFLUENZA

11. CARE OF THE PATIENT WITH INFLUENZA

AT HOME

PREVENTIVE MEASURES FOR THE CAREGIVER

SELF-CARE

OBSERVATIONS INDICATING URGENT MEDICAL HELP IS NEEDED

THE PATIENT WITH INFLUENZA IN THE HOSPITAL, MEDICAL OFFICE, OR CLINIC

12. AVIAN INFLUENZA

AVIAN INFLUENZA VIRUSES

AVIAN INFLUENZA AND HUMANS

PREVENTING OR LESSENING THE EFFECTS OF A PANDEMIC

13. SWINE INFLUENZA

TRANSMISSION

PREVENTION

SYMPTOMS

DIAGNOSIS

TREATMENT

INVESTIGATIONAL DRUGS

14. INFLUENZA PANDEMIC

PLANNING FOR A PANDEMIC

CHALLENGES OF A PANDEMIC

15. CONCLUSION

16. GLOSSARY OF TERMS

17. RESOURCES

18. APPENDIX 1

HOME CARE OF A PATIENT WITH INFLUENZA

19. APPENDIX 2

CARING FOR YOURSELF TO PREVENT THE FLU

20. APPENDIX 3

WHEN TO CALL THE DOCTOR

Works Cited

Evidence-Based Practice Recommendations Citations

94423 • Influenza: A Comprehensive Review

Education Category. Infection Control / Internal Medicine

Release Date. 11/01/2019

Expiration Date. 10/31/2022

Course Overview

Because medications to treat acute illness due to influenza are just recently appearing, there is a tendency to accept the existence of influenza and to forget the fact that 49,000 Americans die annually from the flu and its complications. In addition, the resulting hospitalizations and medical care cost the healthcare system up to $12 billion each year. Sadly, there are underused vaccines that can prevent many of the hospitalizations and deaths, thus lessening the suffering and financial burden of this disease. This course will explore the history of influenza, symptoms, communicability, care of the patient, the makeup of the virus, avian and swine types of flu, vaccine issues, and pandemic planning. Reproducible patient education materials will be included. The vital roles of the healthcare professional and community involvement will be stressed.

Audience

This course is designed to help healthcare professionals and allied personnel understand influenza and their role in its prevention.

Course Objective

The purpose of this course is to provide healthcare professionals with an updated review of influenza, including clinical aspects, public health issues, and strategies for prevention. The goals are to minimize the burden of influenza on patients and communities, prevent complications and hospitalizations, and save healthcare dollars.

Learning Objectives

Upon completion of this course, you should be able to:

1. Articulate the history and burden of influenza on the community.

2. Explain the types of influenza viruses, including the H and N designations.

3. Describe the symptoms, transmission, and diagnosis of influenza.

4. Distinguish between influenza and influenza-like illnesses.

5. Identify complications of influenza.

6. Articulate the effectiveness and importance of the influenza vaccines.

7. Implement a strategy to increase vaccine administration to vulnerable patients.

8. Describe the best method of hand hygiene and other ways of protecting against influenza.

9. List the current antiviral medications available and their use.

10. Teach family members how to care for people with the flu, including interventions for non-English-proficient patients and caregivers.

11. Identify the significance of avian and swine influenza, particularly issues related to pandemic disease.

Faculty

Elizabeth T. Murane, PHN, BSN, MA, received her Bachelor’s degree in nursing from the Frances Payne Bolton School of Nursing, Case Western Reserve University in Cleveland, Ohio and a Master of Arts in Nursing Education from Teachers College, Columbia University, New York, New York.

Her nursing experience includes hospital nursing on pediatric, medical, and surgical units. She lived for 15 years in a village in Eastern Papua New Guinea providing medical and linguistic/literacy services for the villagers. She was a public health nurse for a year with the Brooklyn, New York Health Department and 20 years with the Shasta County Public Health Department in Redding, California. As a public health nursing director, she developed response plans for environmental and health issue disasters for both Shasta County and adjacent Tehama County Public Health Departments.

Faculty Disclosure

Contributing faculty, Elizabeth T. Murane, PHN, BSN, MA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

In this course, the term "influenza" is defined strictly as an acute viral respiratory illness caused by influenza A or B, occurring in seasonal outbreaks and periodic epidemics and characterized by the abrupt onset of systemic symptoms (e.g., malaise, fever, myalgia, headache) and cough. (Note: This is not to be confused with the gastroenteritis syndrome of nausea, vomiting, and diarrhea often erroneously referred to as "flu.") Influenza occurs mainly in winter months (October to March) in temperate climates north of the equator. In the United States, "flu season" usually begins in November, peaks in late December or January, and is generally over by March. However, earlier outbreaks in October can also occur and peak activity may continue as late as mid-March and April. Each summer some localized outbreaks and sporadic cases occur. Often, there is no history of recent travel or epidemiologic links between such outbreaks.

Based on a statistical analysis for the period 2010 to 2016, the incidence of symptomatic influenza among United States residents, including both medically attended and nonattended infections, is approximately 8% and varies from 3% to 11% among seasons [9]. All age groups are susceptible to influenza, but the median incidence among children younger than 18 years of age (9.3%) is somewhat higher than for adults 18 to 64 years of age (8.9%) [9].

Influenza is a disease that is often accepted as "a part of life." While considered bothersome, it is not perceived to be a "serious" clinical or public health issue, in contrast to newly emerging infections that make headlines because of hospitalizations and fatalities. Much effort and money is expended to contain or find a way to prevent new diseases like sudden acute respiratory syndrome (SARS), Ebola virus disease, and Zika virus infection, but little notice is given to the fact that in the United States influenza and pneumonia are leading causes of hospitalization and death each year [1,2]. In 2017, pneumonia/influenza was listed as one of the top 10 causes of death in all age groups, except for children younger than 1 year of age [7]. As the cause of death, pneumonia/influenza ranked sixth in children 1 to 9 years of age, eighth in those 10 to 24 years of age, and sixth in those 85 years of age and older. When all age groupings were combined, pneumonia/influenza ranked eighth as a leading cause of death, ahead of nephritis and intentional self-harm (9th and 10th, respectively) [7]. Influenza is the only communicable disease still listed as a leading cause of death in the United States.

Rates of serious illness and death from seasonal influenza are higher among those who are 65 years of age and older with medical conditions that place them at increased risk for complications from influenza. Approximately 90% of the annual fatalities resulting from influenza occur in this age group [2,3]. However, much media attention is directed to fatalities among children. Pediatric deaths increased markedly during the 2009–2010 H1N1 (swine flu) pandemic, with 276 deaths reported [12]. During pandemics, the burden of disease is skewed toward younger individuals; in the 2009 H1N1 pandemic, which caused illness in 60 million Americans, 90% of hospitalizations and deaths were in persons younger than 65 years of age [3].

The cost of a flu epidemic is estimated to be $12 billion [3]. The pain and suffering caused by influenza is often not considered when discussing costs [3,4]. Between 1957 and 1986, 19 different annual influenza epidemics in the United States caused up to 40,000 deaths per year. Direct annual costs for medical care alone were between $1 billion and $3 billion [4]. A study based on 2010 Census data found that the annual economic costs of influenza varied from $13,900 to $957.5 million across U.S. counties, with a median of $2.47 million [5]. It has been estimated that the economic costs of the next influenza pandemic in the United States will be $713 million to $166.5 billion in direct healthcare costs (e.g., outpatient visits, hospitalization) alone [6]. Large amounts of time, energy, and money have been spent to find a vaccine against SARS while the flu vaccine, though not perfect, is markedly underused.

Surveillance conducted by the Centers for Disease Control and Prevention (CDC) of laboratories and outpatient facilities in 2017–2018 showed that influenza activity began to increase in November and remained at high levels for several weeks during January and February [2]. Influenza A (H3N2) viruses predominated through February, and influenza B viruses were more commonly reported starting in March. The burden of illness during the 2017–2018 season was unusually high, with an estimated 48.8 million influenza illnesses, 22.7 million healthcare provider visits, 959,000 hospitalizations, and 79,400 deaths attributed to influenza [2]. More than 48,000 hospitalizations occurred in children; however, 70% of hospitalizations and 90% of deaths occurred in older adults 65 years of age or older.

The economic burden of influenza on the community, the potential excess mortality among vulnerable members of the population, and the benefit to be derived from simple preventive measures and regular immunization are often under-recognized by the public and medical professionals alike. Vaccination provides protection from influenza illness, its complications, and the spread of infection to others. During the six influenza seasons from 2010–2011 through 2015–2016, influenza vaccination prevented an estimated average 1.6 to 6.7 million illnesses, 790,000 to 3.1 million outpatient medical visits, 39,000 to 87,000 hospitalizations, and 3,000 to 10,000 respiratory and circulatory deaths each season in the United States [8].

Because it takes two weeks to develop the immunity provided by the flu vaccine, most campaigns to immunize the population occur from the middle of October through November. However, immunization through December and early January is encouraged for those who have not been vaccinated earlier. Persons of any age with chronic conditions that increase their risk of complications from influenza should be immunized as early as September.

2. HISTORY

The term "influenza" originated in Italy sometime in the 15th century from an epidemic that was attributed to the "influence of the stars." In 1580, there was a worldwide epidemic that, from written description, was most likely caused by the influenza virus. Several other pandemics have occurred throughout the centuries. The most famous of these pandemics, the "Spanish flu," lasted for 10 months in 1918–1919 and resulted in an estimated 21 million deaths worldwide, with approximately 500,000 of these deaths in the United States [3]. Other more recent pandemics include the "Asian flu" (1957), "Hong Kong flu" (1968), "Swine flu" (1976), and "Swine flu" (2009).

Influenza A and B are the two virus types that cause disease in humans. Influenza A virus was first isolated in 1933 by Smith, Andrews, and Laidlaw in ferrets. In 1936, influenza B virus was isolated by Francis. Swine influenza viruses (closely related to human influenza viruses) were isolated in 1930 [14]. In that same decade, researchers discovered that influenza virus could be grown in embryonated chicken eggs. These discoveries led to the development of inactivated (killed) vaccines [3].

For many years, the proposed influenza epicenter has been thought to be Southeast Asia. Farming practices there bring pigs, fowl, and people into close contact, allowing swine, avian, and human flu viruses to mix. The cycle is thought to be birds to pigs to humans. Now it is clear that this cycle can occur at any place in the world where there is the domestication of animals [14].

3. INFLUENZA VIRUS

INFLUENZA VIRUS TYPES

Influenza belongs to the orthomyxovirus family and consists of a single-stranded, helically shaped ribonucleic acid (RNA) virus. There are three types of influenza viruses designated A, B, and C. The differentiation is made by the type of proteins within the nucleus, specifically antigenic properties in their internal nucleocapsid and matrix proteins. The individual types have different effects on the humans who become infected.

Influenza type A is the virus that causes moderate-to-severe illness in all age groups and is highly infectious, with an attack rate of 10% to 20%. It also causes influenza in pigs, birds, and other animals. There are several subtypes of influenza A.

Influenza type B generally causes milder disease. It primarily affects children but has also caused outbreaks in military camps and occasionally in long-term care facilities. It does not cause illness in animals and birds and, as a result, tends to be more stable with less antigenic change. Subtypes have not been defined for influenza B.

Influenza type C is rarely ever reported, probably because any disease it causes is usually subclinical or mild. It does not affect animals and birds.

Because type A influenza virus causes more severe illness and also occurs in animal and birds, this course will focus on influenza A.

INFLUENZA A SUBTYPES AND ANTIGENIC SHIFT

Influenza A subtypes are defined by the occurrence of the glycoproteins hemagglutinin (H) and neuraminidase (N), which are surface antigens on the virus. The hemagglutinins H1, H2, and H3 are involved in attaching the virus to cells. The neuraminidases N1 and N2 facilitate virus penetration into cells. There are 15 different subtypes of hemagglutinins and 9 different subtypes of neuraminidases leading to several possible combinations, which are indicated in the name of the virus (e.g., H1N2, H2N3). Many combinations of the various hemagglutinin and neuraminidase antigen subtypes are possible. However, H1N1, H1N2, H2N2, and H3N2 have historically occurred in humans.

Pigs are susceptible to three of the same subtypes of influenza. Historically, they have not been infected by the H2N2 subtype. Wild waterfowl, in contrast, appear to acquire all influenza A subtypes. An additional difference is that the virus causes respiratory illness in humans, pigs, and other mammals but infects the gastrointestinal tract in wild birds without causing disease. However, the virus is shed in the bird droppings, leading to the contamination of water supplies, barnyards, farms, fields, and animal food supplies.

The genes of influenza viruses are carried on eight separate segments of RNA rather than on one long single molecule. This means that if two or more subtypes of influenza virus infect the same cell in a host, these viruses can exchange RNA segments during replication and create viruses with new gene combinations. This reassortment is termed "antigenic shift." It often occurs in pigs and is the source of influenza epidemics because the human population has little immunity to the new subtype that results.

In comparison, "antigenic drift" refers to changes in the surface glycoproteins. This does not result in a new subtype but does influence the choice of the particular influenza viral subtypes for the annual influenza vaccine. Depending on the degree of antigenic drift, immunity developed to one virus may be adequate to protect against the related virus. In other situations, the drift has resulted in enough change that there is little protection.

In the past, the influenza subtypes present in birds did not directly infect humans. A different host was usually required to complete the shift from an avian subtype to a subtype capable of infecting humans. This host has been the pig, which can be infected with avian, human, and swine influenza viruses. A possible scenario is that the food or water supply of the pig is contaminated by bird feces containing a subtype or subtypes of influenza A. The pig also acquires different influenza subtypes from other pigs and/or humans. Reassortment of the viral RNA occurs in the pig host, thus infecting other pigs. Farm workers catch the new subtype from the pigs and develop highly contagious influenza because they do not have immunity against this new subtype. Thus, a new influenza strain is launched [14]. It is possible that antigenic shift could occur in a person who acquires a strain from a bird and also has a human strain. Realignment of H and N in the person's cells would result in a new strain. This new strain could become a pandemic if there is very little or no immunity in the human population and there is efficient, effective transmission from person to person [3].

Major pandemics of 1889–1891, 1918–1920, 1957–1958, and 1968–1969 have resulted from antigenic shifts. Characteristics of a pandemic are high attack rates in all age groups and a high mortality rate. Historically, pandemics have moved along trade routes, with rapidity of spread matching available transportation methods [3]. Rapid movement of people around the world by aircraft and fewer border restrictions by partners such as the European Union allow new influenza subtypes to spread more quickly. However, cooperation among the World Health Organization (WHO), the CDC in the United States, and the European Centre for Disease Prevention and Control, which was established in 2005, has contributed to slowing the spread of the virus. Also, minimizing the transmission of influenza virus from any of the hosts to any of the other hosts (e.g., birds, pigs, humans) will decrease the antigenic shift and lessen the development of new subtypes to which the population has not developed immunity [14].

Research has shown that work-related travel rates affect the spread of influenza more than geographical distance or air travel [15]. Based on 30 years of weekly data, influenza imported into a state with many inflows and outflows of workers, such as California, spreads much faster than if it enters a less-connected state, such as Wyoming. Epidemics also tend to start and spread from more populated states. This information is especially important in the event of the appearance of a new virus to which most of the population is susceptible. It usually takes five to seven weeks for annual influenza disease to spread across the continent. However, if a new strain originates in a highly connected state, it could spread to all states within two to four weeks. The study also revealed that adults, not children, are responsible for the transmission of influenza across regions because they travel farther and more frequently. One proposed intervention is to limit interregional travel to slow the spread [15].

VIRUS NAMING

The name of each influenza virus is developed following this formula [3]:

- Virus type (A or B): A/

- Geographic origin (place where virus was first isolated): Wuhan/

- Strain number: 395/

- Year of isolation: 95/

- Virus subtype (based on combination of hemagglutinin [H] and neuraminidase [N] antigens): (H3N2)

This was the principal virus isolated in the United States during most of the 1997–1998 influenza season.

Thus A/New Caledonia/20/99/(H1N1) would be read influenza A, which was first isolated in New Caledonia, strain number 20, isolated in 1999, with hemagglutinin subtype 1 antigen and neuraminidase subtype 1antigen.

4. INFLUENZA DISEASE

As discussed, a brief definition for influenza is "respiratory illness with fever." This is a quick way for healthcare providers who are participating in the annual surveillance of influenza activity to categorize each of their patients. Approximately 1,000 sentinel medical practitioners in the United States participate in the U.S. Influenza Sentinel Provider Surveillance System by providing statistics about the number of "respiratory illness with fever" cases that have been seen each week. These figures are collected weekly by designated local health departments and reported to the CDC by the corresponding state health department. The CDC compiles and publishes these figures, which give a current view and contribute to a historical picture of influenza activity for that week. Monitoring and analyzing these figures also alerts medical professionals to changes in patterns. Any change in the historical pattern is especially important in early detection of a biologic change, whether introduced naturally or by terrorist activity. Several biologic agents that could be used by a terrorist first manifest their presence with flu-like symptoms.

SYMPTOMS AND SIGNS

Uncomplicated influenza is characterized by an abrupt onset of:

- Constitutional symptoms: Fever, chills, myalgia, headache, severe and persistent malaise, eye pain, light sensitivity, and substernal burning in the chest

- Respiratory symptoms: Nonproductive cough, sore throat, and rhinitis

Initially, there are more constitutional than respiratory symptoms. If there are no complications, the chest is usually clear to auscultation.

Children may also experience any of the accompanying effects of fever, such as listlessness, irritability, anorexia, and convulsions. In addition, otitis media, nausea, vomiting, and diarrhea are frequently reported in children with influenza [8]. Pneumonia and encephalopathy are serious complications in children with influenza [17]. Elderly patients may exhibit confusion in addition to other symptoms.

The patient with influenza usually appears febrile and fatigued with hot, moist skin, a flushed face, and red watery eyes. More than half of patients infected with the influenza virus will have nasal discharge with obstruction and pharyngeal redness. Younger patients may have nontender cervical lymphadenopathy [18].

Influenza onset is so abrupt that many patients can pinpoint the hour in which they became ill. This is an important feature that helps distinguish influenza from other diseases with flu-like symptoms. The fever is generally 101 to 102 degrees F (38.3 to 39 degrees C). Children may run higher fevers. Patients may complain of body aches. Myalgia often localizes in the back muscles. These systemic symptoms usually last from two to three days and may persist as long as five days. Most systemic symptoms respond to antipyretics and analgesics. It is important to remember that any medications containing aspirin should never be used in children or teenagers because of the risk of Reye syndrome [3]. This will be discussed in more detail later in this course.

Uncomplicated influenza is generally a self-limiting illness. Fever, myalgia, and respiratory symptoms usually resolve in five to seven days, but most patients experience some degree of malaise and fatigue for a week or more after resolution of acute symptoms (Figure 1).

Figure 1: COURSE OF INFLUENZA IN ADULTS

Source: Author

TRANSMISSION

Influenza is highly contagious, with an attack rate of 10% to 20% from the day before symptoms begin through approximately five days after onset in adults. It is spread from person to person through coughing and sneezing by the infected individual. Influenza is spread by the airborne route, which means that a person coughing in the room can transmit the virus to others in the room without close personal contact. This is in contrast to droplet transmission in which heavier particles (droplets) are transmitted to those with close contact (less than 3–6 feet, depending on the organism). Droplet transmission also probably occurs in influenza. Airborne transmission is especially significant in congregate situations like institutions, daycare facilities, airplanes, and cruise ships [19].

As noted, the influenza virus may be transmitted between humans and pigs. More than 25 examples of transmission from pigs to humans have been documented in the medical literature [14]. It is assumed that many more undocumented cases occur in individuals who work with swine. Usually, this swine-human connection is missed because the flu seasons in both pigs and people overlap. However, this connection should not be minimized. Its influence in antigenic drift or shift and the introduction of new subtypes is important to traditional transmission patterns.

Contaminated hands are a frequent source of transmission and infection. Contagious individuals cough or sneeze into their hands and deposit virus on whatever they touch. Or, they cough or sneeze the virus into the air, which settles on objects in the area. Others handle these objects and then touch their eyes, nose, or mouth and are infected. Following an incubation period of one to four days (average: two days), the individual develops symptoms. Another major factor in the spread of influenza is that it is transmitted to others before infected individuals even realize that they are sick [20].

Children are another source of infection, as they can be contagious for 10 or more days. In addition, young children can shed virus for up to six days before illness onset [16]. This is one reason to discourage the practice of kissing infants and children on the mouth.

DIAGNOSTIC TESTS FOR INFLUENZA

Evidence Based Practice Recommendation

The Advisory Committee on Immunization Practices recommends clinicians should use rapid molecular assays (i.e., nucleic acid amplification tests) over rapid influenza diagnostic tests in outpatients to improve detection of influenza virus infection.

https://academic.oup.com/cid/article/68/6/e1/5251935#127789601

Last Accessed: September 21, 2020

Level of Evidence: A-II (Good evidence to support a recommendation based on one or more well-designed clinical trials, without randomization; from cohort or case-controlled analytic studies (preferably from more than one center); from multiple time-series; or from dramatic results from uncontrolled experiments)

Obviously, an accurate diagnosis of influenza on the basis of symptoms alone is difficult. The quickest way to decide if the patient has influenza, or some other disease, is to use a rapid diagnostic test for influenza. However, medical practitioners should be aware that false-negative and false-positive results do occur. Within three to four days after onset of influenza, the virus can be found from throat and/or nasopharyngeal swabs. Highest viral shedding occurs during the first four days of illness. Nasopharyngeal specimens generally are more accurate. There are several rapid diagnostic tests available, and these tests usually require only about 15 minutes of laboratory time [22,23]. The specimen to collect and the information provided by the results vary according to the test being used. These various rapid diagnostic tests for influenza A are 65% to 95% accurate [21]. The accuracy rate depends on the particular rapid diagnostic test used and collection of the specimen at the optimum time [22]. Other factors that may improve the accuracy of these tests include knowledge that influenza is circulating in the community and obtaining the specimen from a patient within the first four days of illness [23]. The package insert should always be consulted as to the percentage of inaccurate results for the specific test. The rapid diagnostic test, therefore, can leave the medical practitioner with the need to base decisions about diagnosis and treatment on his or her clinical judgment [22]. Recent immunization with intramuscular (IM) influenza vaccine will not affect a rapid diagnostic test. Intranasal vaccine will affect any serology test; however, the intranasal vaccine is no longer recommended [8,24]. Not all patients with influenza symptoms require a rapid diagnostic test. They should be done only if the results will help with the diagnosis and/or influence treatment decisions [23]. In an institutional setting, such as a nursing home, use of a rapid test combined with a viral culture will help provide more effective treatment and allow for rapid prevention and control measures [21].

Culture of the virus takes a minimum of 48 hours. Another one to two days are needed to identify the virus type. Viral culture can take as long as 10 days to complete. Obviously, these tests provide information as to the virus responsible for the illness but are not practical for individual case management. Knowing the virus or viruses responsible, however, allows more accurate planning for vaccine preparations. This information also helps evaluate the effectiveness of the formulation used in the current vaccine [3].

There are several ways that the influenza diagnosis can be confirmed [23,25]:

- Rapid test

- Viral culture

- Direct or indirect immunofluorescent antibody staining

- Reverse transcriptase polymerase chain reaction

- Immunohistochemical analysis of tissues collected during autopsy

- Paired serology (comparison of antibody levels during acute and convalescent—two to three weeks later—phases). Antibodies in the convalescent specimen should be at least four times greater than in the acute specimen to confirm influenza.

For more information on available tests, please refer to the CDC's website at https://www.cdc.gov/flu/professionals/diagnosis. Monitoring the status of influenza circulating in the community through the information provided by the CDC can also assist the practitioner in the diagnosis [23].

5. INFLUENZA-LIKE ILLNESSES

Making the correct diagnosis when a patient presents with flu-like symptoms is becoming more critical. The purpose of the discussion below is to highlight the importance of making a careful observation of the patient and obtaining an accurate history of the illness.

INFLUENZA COMPARED TO THE COMMON COLD

Because both influenza and the common cold are caused by viruses that affect the respiratory tract, distinguishing between them is important. Adults rarely develop fever with a cold (coryza) but usually have a fever of 101 to 102 degrees F (38.3 to 39 degrees C) with the flu. Headaches, muscle aches, and extreme exhaustion are mild or nonexistent with a cold but are usual and severe with the flu. The prodromal signs of sneezing, runny nose, and sore throat signal that a cold is developing and may be present for one or more days before onset. These symptoms may occur with influenza but usually occur concurrently with the sudden onset rather than signaling an approaching illness. The flu develops suddenly, without warning. Like influenza, a cold may have a dry (nonproductive) cough. Some use a "rule of thumb" to distinguish between a cold, in which symptoms are from the neck up, and influenza, which is systemic (Table 1).

Table 1: INFLUENZA COMPARED TO COMMON COLD

Clinical Presentation

Influenza

Common Cold

Prodrome

None

One or more days

Onset

Sudden

Gradual

Fever

101 to 102 degrees F

Rare in adults

Headache

May be severe

Rare

Myalgia

Usual, often severe

Mild

Extreme exhaustion

Usual

Never

Tiredness/weakness

May last longer than two weeks

Mild

Sore throat

Common

Often

Sneezing

Occasionally

Usual

Rhinitis

Occasionally

Usual

Cough

Usual, nonproductive

Mild hacking

Source: Author

OTHER FLU-LIKE ILLNESSES

There are many other illnesses that initially look like influenza. For discussion and consideration in making a diagnosis, these diseases are sometimes grouped into influenza-like illnesses (ILI). Adults will average one to three ILI a year. Children can average three to six ILI in a year. The common cold is one of these, and the differences between influenza and colds have been discussed above. Other bacteria that cause ILI are Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, and Legionella pneumophila. In addition, respiratory syncytial virus (RSV) has similar symptoms. None of these ILIs are as significant as biologic agents that may be used by a terrorist, such as anthrax, ricin, plague, and smallpox, all of which may present with influenza-like symptoms. However, they are a significant source of disease and should be considered when deciding if a patient has influenza or something else. Because bacterial diseases are treatable with antibiotics, but influenza is not, an accurate diagnosis is important. Much of the overuse of antibiotics occurs when patients request them for any illness or when careful diagnosis is not made between viral and bacterial diseases.

It may be helpful to consider the time of year in which the diagnosis is being made. Generally, pneumococcal disease peaks in the winter, as does influenza and RSV. Mycoplasma and legionellosis are more common during the summer and fall. Rhinoviruses and parainfluenza virus peak during the fall and spring. Adenoviruses circulate throughout the year [21]. Information on the presence of influenza and predominant strains in the community can usually be found from the surveillance system maintained by the local health department [16].

Other information to consider is that, in healthy individuals, influenza is a self-limiting disease that strikes suddenly with most of its fury, maintains that level of illness for three to five days, and then shows improvement, even though the aftereffects of weakness and tiredness may persist for a week or more. In most other ILI diseases the patient's condition continues to worsen.

These last two considerations are not meant to figure in the diagnosis but to guide thinking about the patient's illness. For instance, if a greater than usual number of cases of ILI are being seen and it is the wrong time of year for influenza, another disease or a terrorist attack should be considered.

Some studies have been conducted on the use of clinical definitions for influenza-like illness. The results were [22]:

- Fever, cough, and acute onset accurately predict influenza 30% of the time in nonhospitalized older patients.

- Fever, cough, and illness of less than seven days in hospitalized older patients with chronic cardiopulmonary disease accurately predict influenza 73% of the time.

- Fever, but not cough, in vaccinated older persons with chronic lung disease was 54% specific for influenza.

6. COMPLICATIONS OF INFLUENZA

Complications of influenza leading to hospitalizations and death are greater in persons 50 years of age and older, in young children, in pregnant women in the second and third trimester, and in persons of any age with underlying medical conditions. Data for the 2017–2018 influenza season show that laboratory-confirmed influenza virus infection was responsible for 183 deaths in children younger than 18 years of age [2]. Since becoming a nationally notifiable condition in 2004–2005, the number of annual pediatric deaths has ranged from 37 to 171, excluding the 2009–2010 H1N1 epidemic, which will be discussed later in this course.

PNEUMONIA

The major complication of influenza is pneumonia, and three types have been well-described in association with influenza epidemics: primary influenza (viral) pneumonia, secondary bacterial pneumonia, and mixed influenza/bacterial pneumonia. The incidence and mortality are highest in the elderly and in persons with underlying chronic illness, especially those with heart, lung, and renal diseases. However, in pandemic periods, half the deaths from pneumonia are seen in persons younger than 65 years of age [18].

Primary influenza pneumonia is the least common but most devastating form. It arises when the virus directly invades lung parenchyma and tends to present early as a rapidly deteriorating illness with high fever, profound dyspnea, and progressive respiratory failure. Patients with conditions that cause elevated left atrial pressures, such as heart failure and third-trimester pregnancy, are particularly at risk. Chest radiographs show bilateral diffuse reticulonodular opacities and basal (lower lobe) consolidation. Mortality is high.

Secondary bacterial pneumonia is the most common type and constitutes the major cause of excess morbidity and mortality in the elderly. The typical clinical presentation is a patient who appears to be convalescing from influenza only to experience an exacerbation of symptoms with renewed fever, worsening cough, purulent sputum, pleuritic chest pain, and radiographic evidence of a localized pulmonary infiltrate. The pathogens most often responsible are Streptococcus pneumoniae (50%), Staphylococcus aureus (20%), and Haemophilus influenzae. A number of factors affecting lung defense mechanisms are at play in the pathogenesis of bacterial superinfection, including [18]:

- The prime target cell for influenza virus in humans is the ciliated epithelial cell of the tracheobronchial tree.

- Damage to this epithelium leads to impaired mucociliary clearance of any potential pathogens that happen to be colonizing the upper respiratory tract.

- Alveolar macrophage phagocytosis is transiently impaired.

As might be expected, mixed influenza/bacterial pneumonia is a third type encountered during influenza outbreaks. This type of patient is vulnerable to severe, direct infection of the lung and happens, at the same time, to be colonized by a virulent respiratory bacterial pathogen (e.g., pneumococcus or staphylococcus).

Signs that a patient has developed pneumonia are [18]:

- Symptoms continue after the expected five to seven days

- Symptoms worsen after the patient has started to improve

- Fever returns and is higher than with the initial illness

- Dyspnea

- Productive cough

- Abnormal x-ray (pulmonary infiltrates)

- Rales on auscultation

REYE SYNDROME

An unfortunate complication of influenza in patients younger than 18 years of age is Reye syndrome. Much education for parents has focused on the danger of giving aspirin to anyone younger than 18 years of age with a fever. This education has led to a decrease in Reye syndrome. Unfortunately, acetylsalicylic acid or salicylic acid is a component in some over-the-counter preparations and may be unintentionally given to a child with a fever. Influenza virus, especially influenza A virus, and varicella (chicken pox) interact with acetylsalicylic acid to produce Reye syndrome. Symptoms are nausea and vomiting, decreased consciousness and/or convulsions caused by cerebral edema, hypoglycemia, and liver failure. Parents must be reminded to read the labels of all medications and that aspirin is listed as acetylsalicylic acid [18].

MYOSITIS AND RHABDOMYOLYSIS

Myositis (inflammation of muscle tissue) and rhabdomyolysis (involving striated muscle tissue) can be complications of influenza. These complications occur most often in children and are manifested by extreme muscle tenderness, especially in the legs. Myoglobulinuria may lead to renal failure in these patients. Serum creatinine phosphokinase (CPK) is markedly increased [18].

STAPHYLOCOCCUS AUREUS SUPERINFECTION

Influenza can be complicated by Staphylococcus aureus, leading to pneumonia as discussed above. Superinfection with S. aureus, leading to bacteremia, endocarditis, or epidural abscess, can also occur following influenza. Influenza B and S. aureus have led to toxic shock.

CARDIAC COMPLICATIONS

Other less common complications from influenza are myocarditis (inflammation of the cardiac tissues), and pericarditis (inflammation of the pericardial lining). A study conducted in Australia from 2008 to 2010 showed that recent influenza vaccination was significantly protective against acute myocardial infarction [26].

PULMONARY COMPLICATIONS

Besides the more common complication of bacterial or viral pneumonia, influenza can lead to the worsening of chronic bronchitis and other chronic pulmonary diseases.

CENTRAL NERVOUS SYSTEM COMPLICATIONS

Encephalitis, postencephalitic Parkinson disease, transverse myelitis, Guillain-Barré syndrome (GBS), and possibly amyotrophic lateral sclerosis have followed cases of influenza. There has been research suggesting that cases of Parkinson disease resulted from the "Spanish flu" pandemic of 1918–1919 [55,56,57,58,59,60].

Any person with a serious medical condition can be placed in jeopardy by influenza, not only from the complications listed above, but also from exacerbation of the underlying condition [18].

7. INFLUENZA VACCINE

Evidence Based Practice Recommendation

The Centers for Disease Control and Prevention asserts that routine annual influenza vaccination is recommended for all persons 6 months of age and older.

https://www.cdc.gov/mmwr/volumes/70/rr/rr7005a1.htm

Last Accessed: October 12, 2021

Level of Evidence: Consensus Statement and/or Expert Opinion

Influenza vaccine is the primary preventive measure against the virus. It is efficacious in preventing influenza. Among those at higher risk, it lessens the severity of the illness, decreases complications, reduces hospitalizations, and lowers the fatality rate. It is disappointing that a vaccine with such benefits and few side effects is not used more widely. With a highly communicable disease like influenza, children are the most likely to contract and spread the infection. Nearly all children must be immune to achieve community (herd) immunity [4]. The Advisory Committee on Immunization Practices (ACIP) recommends routine annual influenza vaccination for all persons 6 months of age and older who do not have contraindications [8]. A licensed, recommended, and age-appropriate vaccine should be used.

The timing of vaccination is predicated on timing of onset of the influenza season balanced against concerns that vaccine-induced immunity might wane over the course of a season. The 2021–2022 recommendation is that vaccination be offered by the end of October [8]. Children 6 months through 8 years of age who require two doses should receive their first dose as soon as possible after the vaccine becomes available. This approach is based on clinical trials that suggest protection from the influenza viruses covered by the vaccine lasts six to eight months and may last up to one year in college students. Because those 50 years of age and older have a diminished response to the vaccine, the immunity probably does not last as long [8].

HIGH-DOSE INFLUENZA VACCINE

A vaccine containing an increased amount of the hemagglutinin antigen of the influenza virus was licensed by the U.S. Food and Drug Administration (FDA) in 2009 [4]. In 2021, the trivalent version was replaced with a quadrivalent formulation [8]. It is a single-dose, inactivated, quadrivalent, injectable vaccine sold under the brand name Fluzone High-Dose, manufactured by Sanofi-Pasteur. This high-dose vaccine was developed for individuals 65 years of age and older who are at a greater risk of hospitalization and death from seasonal flu and are known to develop lower antibody titers to the influenza virus. The vaccine is available for the 2021–2022 flu season [8].

Prelicensure clinical trials showed no preference for the new vaccine over other inactivated trivalent influenza vaccines. All were equally safe and equally effective at producing immunity [4]. However, the high-dose formulation resulted in significantly higher hemagglutination inhibition titers against each strain than the standard formulation [8]. A 2014 trial showed that recipients had 25% greater protection against influenza illness. A comparison between the standard and high-dose flu vaccines showed that in each 0.5-mL dose the standard vaccine contained 45 mcg while the high-dose vaccine had 180 mcg [8].

As with the standard vaccine, the high-dose should not be given to anyone with a known severe reaction to egg proteins or other components of the vaccine. Vaccination with the high-dose formulation produced more frequent injection site reactions and systemic adverse events than the standard formulation, but typically they were mild and transient [4,8].

HIGH-RISK GROUPS WHO SHOULD RECEIVE THE INFLUENZA VACCINE

In the event of a vaccine shortage, the following high-risk groups should receive the vaccination first.

Persons 50 years of age and older have the highest fatality and hospitalization rate from influenza and its complications. Of the annual deaths from influenza, 90% occur in those 65 years of age and older. In addition, 58% of the hospitalizations are in this age bracket [2]. Those who are between 50 and 64 years of age are high risk because of the high prevalence of chronic diseases in this population. These patients often do not receive the vaccine because the publicity about the need to receive the vaccine has tended to focus on those 65 years of age and older. Only 48.1% of persons 50 to 64 years of age receive the vaccination; the vaccination rate among persons 65 years of age and older is 69.1% [183]. In addition, Medicare pays for the vaccine after the person reaches 65 years of age. Therefore, individuals who fall into the 50 to 64 age group may be disinclined to receive the vaccine.

Persons with chronic health problems who are 6 months of age or older are at high risk for complications from influenza or exacerbation of their condition. Such chronic conditions include:

- Cardiac disease, such as congestive heart failure

- Pulmonary disease, such as chronic obstructive pulmonary disease, cystic fibrosis, or asthma

- Renal disease

- Diabetes and other metabolic diseases

- Hepatic disorders

- Neurologic disorders

- Anemia and blood disorders, such as sickle cell disease

Persons with compromised immune systems from any cause—human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), autoimmune conditions, cancer, long-term steroid treatment, and medications—should receive the inactivated vaccine [8]. Because the vaccine is inactivated (killed), it can and should be given to immunosuppressed people. However, because of the depressed immune system of this group of people, the expected antibody response may not be obtained. HIV-infected patients with minimal AIDS-related symptoms and high CD4 T-lymphocyte cell counts have been shown to develop substantial antibody titers against influenza. For those with more advanced HIV disease and low CD4 T-cell counts, the vaccine might not induce protective antibody titers, and a second dose has not been shown to increase the titer. Some studies have shown that there is a temporary (two- to four-week) increase in replication of HIV after receiving the influenza vaccine [62]. However, other studies have not demonstrated this increase nor has progression of HIV disease been shown to occur following the administration of the influenza vaccine. Each immunocompromised individual should be evaluated before the vaccine is administered because an increase in plasma HIV levels and/or a decrease in CD4 count has been transient in most, but not all, cases of those receiving the influenza vaccine [62].

Persons with conditions or diseases that may compromise respiratory function or increase the risk of aspiration should also be vaccinated against influenza to prevent any possible complications or damage.

All healthcare providers should receive the influenza vaccine annually. Additionally, healthcare facilities are encouraged to make available the vaccine to their workers. In its 2012 recommendations, the ACIP encouraged healthcare facilities to obtain a signed declination form from healthcare workers who refuse influenza vaccination [63]. Those who refuse vaccination may be required to wear a mask during influenza season. This issue is not specifically discussed in the 2021–2022 recommendations [8].

Persons who reside in skilled nursing facilities (nursing homes) or other chronic care facilities are at high risk for influenza-related problems because of their weakened physical state and close living arrangements.

Persons 6 months to 18 years of age on long-term aspirin therapy should be immunized against influenza because of the interaction of the influenza virus and aspirin that can lead to Reye syndrome.

Women who are pregnant during influenza season have the same complication and hospitalization rate from influenza as persons with chronic diseases and, therefore, should receive the vaccine. This would include women who will deliver from the beginning of October through the end of May. Increased severity of influenza among pregnant women was reported during the pandemics of 1918–1919, 1957–1958, and 2009–2010 [8]. Severe infections among postpartum women also were observed in the 2009–2010 pandemic, and 56 deaths (36 during the third trimester) were reported among 280 pregnant women admitted to intensive care units. Although there are some recommendations that a woman should not receive the influenza vaccine before the 14th week of gestation, the ACIP and the American Congress of Obstetricians and Gynecologists (ACOG) recommend influenza vaccination for all women who are or will be pregnant during the influenza season, regardless of trimester [8,64]. There is a coincidental association of spontaneous abortion, which is common in the first trimester. Also, many practitioners avoid any exposure to vaccines during the first trimester. However, no adverse fetal effects have been associated with influenza immunization [8,65]. Infants born to women who contracted the 1918 flu during their second and third trimesters had higher rates of cardiovascular disease at 60 to 82 years of age [66]. For men this rate of increase was 23.1%; for women, it was 17%. In addition, individuals exposed prenatally were less successful economically and educationally. Studies of other influenza pandemics have shown schizophrenia risk is three times higher in those exposed to influenza in utero [66]. This information should help healthcare workers to recognize the importance of immunizing pregnant women.

All children 6 to 59 months of age, especially children 6 to 23 months of age, even without any chronic conditions, should receive the annual influenza immunization because they are at a substantially increased risk for influenza-related hospitalizations [8]. Many of the hospitalizations are due to dehydration that can occur rapidly in a child who has a fever and will not drink fluids. The hospitalization rate in this age group matches the hospitalization rate for other groups at high risk for complications and death from influenza. At this point, these higher hospitalization rates cannot be totally assigned to influenza because RSV circulates at the same time. Since 2003, the Vaccines for Children (VFC) program has covered the cost of the influenza vaccine for all eligible children 6 to 23 months of age and all eligible children 2 to 18 years of age who are household contacts of a child 0 to 23 months of age [16]. The ACIP, the American Academy of Pediatrics, the ACOG, and the American Academy of Family Physicians (AAFP) published the Recommended Immunization Schedule for Persons Age 0 Through 18 Years, which includes a recommended yearly influenza immunization for all children 6 months of age and older [8,67]. Data from two studies showed that a side benefit from the influenza vaccine has been a reduction in otitis media [8].

Other groups who should receive vaccine during a shortage include American Indians/Alaskan Natives; the morbidly obese (body mass index ≥40); household contacts/caregivers of children younger than 6 months of age for whom there is no vaccine; and persons with medial conditions that put them at higher risk for severe complications from influenza [8].

Before 2004, influenza-related deaths in children were not on the list of deaths that should be reported. When it became apparent that a significant number of children were dying, the CDC requested that all influenza-related deaths of children younger than 18 years of age be reported to the appropriate state health department. Any postmortem tissue specimens that were collected or autopsy reports that were completed were also asked to be sent to the CDC [25]. However, in the subsequent years there have been even more deaths of children. As noted, in the 2017–2018 flu season, there were 183 deaths among persons younger than 18 years of age [2]. During the 2009 H1N1 pandemic, 32% of hospitalizations and 10% of deaths (approximately 1,250 deaths) were children younger than 18 years of age [68].

Data from the Internet Panel Survey of healthcare personnel indicated that only 49% of healthcare workers were immunized against influenza, in spite of the fact that vaccination reduced work absenteeism and resulted in fewer deaths among nursing home residents [69]. In the 2011–2012 season, only 67% were immunized. That percentage rose to 72% during the 2012–2013 season and then to 79% in the 2015–2016 season [70,87]. Studies have also shown that ill workers account for as much as 60% of corporate healthcare costs. To respond to these situations, many companies now offer free influenza vaccinations and expanded telecommuting options [71]. The Healthy People 2030 objective is a 70% vaccination rate, but obviously 100% coverage is preferable [82].

The public continues to follow the example of their healthcare providers. Although approximately 218 million Americans could have benefited from the influenza vaccine in the 2007–2008 flu season, millions of unused doses were destroyed [72]. To emphasize the importance of flu vaccinations, the CDC has established the National Influenza Vaccination Week. In 2020, the week is scheduled for December 6 through 12 [73]. While meaningful improvements in vaccination coverage have been observed in children over the past seven flu seasons (from 44% to 60%), a significant increase has not occurred in the adult population (from 40.4% to 41.7%) [184].

OTHER GROUPS ADVISED TO RECEIVE THE INFLUENZA VACCINE

Persons who provide essential services, such as law enforcement personnel and firefighters, should be immunized. This is especially important in a pandemic situation. Students living in dormitories should receive the vaccine in order to avoid disruption of their studies.

Travelers should be evaluated for influenza immunization when "travel shots" are being recommended. Influenza in temperate climates occurs in the winter months (October through March in the Northern hemisphere; April through September in the Southern hemisphere); it occurs year-round in tropical climates. People taking a cruise could be infected with influenza at any time of the year because many of the service crew members are from tropical areas and a cruise ship is a closed community, which helps to assist in the spread of the virus [65].

The need for healthcare workers to be immunized against influenza cannot be overemphasized. All healthcare workers should receive the influenza vaccine. Not only does it protect the patient, but it also protects the healthcare worker. Healthcare workers who have been immunized tend to remember to advise their patients to get the immunization. This can strengthen the advice by example and can also provide anecdotal reassurance about the pain or side effects experienced. Studies have shown that residents in long-term care facilities have fewer deaths from influenza when their caregivers have been immunized against influenza [16].

GROUPS WHO SHOULD NOT RECEIVE THE INFLUENZA VACCINE

Persons with a severe allergic reaction to eggs should not be given most types of influenza vaccine [8]. A person with a severe hypersensitivity to eggs may develop an anaphylactic reaction (e.g., sudden sense of great uneasiness or anxiety, pounding headache, hypotension, urticaria, dyspnea). Most influenza vaccines are grown in eggs, and although they go through a purification process, a small amount of egg protein remains. This minute amount could trigger a reaction in those who are severely allergic to eggs. A dislike for eggs, mild gastrointestinal symptoms, or hives (alone, without other, more severe symptoms) following ingestion of eggs is not a contraindication for the inactivated influenza vaccine. Usually, asking a person receiving the influenza vaccine for the first time if they can eat soft-cooked eggs without a problem is a quick screening tool and an adequate precaution. In 2013, the FDA approved the first vaccine that is not grown in eggs, eliminating any risk for those with severe allergic reactions to eggs [185]. Persons who have experienced only hives after exposure to egg may receive any appropriate influenza vaccine. In the case of cell-culture and recombinant vaccines, previous history of severe allergic reaction (e.g., anaphylaxis) to any influenza vaccine is considered a precaution rather than a contraindication [8]. In these instances, administration of the cell-culture or recombinant vaccines should occur in a medical setting under the supervision. However, a severe or anaphylactic reaction to the cell-culture or recombinant vaccine is considered a contraindication to the use of that vaccine [8].

Persons with acute respiratory or other active infections or illnesses should be advised to wait until they have recovered to receive the vaccine [8].

Persons with a history of GBS are more prone to another episode of this syndrome [8]. Because GBS is such a rare condition, it is impossible to know if the influenza vaccine is involved in its occurrence. During the 1976 swine flu epidemic, there was an increase of GBS (1 additional case per 100,000 vaccinated) in those who had received the vaccine [8]. However, an increased incidence of GBS following administration of other influenza vaccine formulations since 1976 is extremely low (1 additional case per 1 million vaccinated). According to the package insert for Fluzone, for patients who have recovered from GBS, it is better to err on the side of caution and avoid giving them the influenza vaccine until more information is available [65]. The Epidemiology and Prevention of Vaccine-Preventable Diseases, known as the "Pink Book," states that persons who have developed GBS within six weeks of receiving the influenza vaccine would be wise to avoid a subsequent flu shot [3,8]. However, the recommendation of the ACIP is that recovered GBS persons with risk factors that increase their vulnerability to the complications of influenza should receive the vaccine because the risk of complications is greater than the risk of a recurrence of GBS [8].

Persons with an allergic reaction to dry natural latex rubber should be evaluated before being given the vaccine because the stopper in some of the vials contains dry natural latex rubber [8]. According to data provided to CDC, Fluvirin and Fluad (manufactured by Seqirus) are the only vials that are expected to possibly contain latex.

Note: Influenza immunization is NOT contraindicated in breastfeeding persons. In fact, it should be encouraged because the patient could transmit influenza to a vulnerable infant if she gets the disease [8]. The patient could also be liable to a decreased milk supply because of decreased fluid intake and fever and would have the added burden of infant care and breastfeeding while experiencing exhaustion and other flu symptoms.

MANUFACTURE OF THE VACCINE

Because of antigenic drift, each year the ACIP and the FDA must decide which influenza strains to include in the formulation of the season's vaccine. Because the formulation changes each year to provide protection against the expected circulating strains, an annual influenza immunization is needed. Obviously, the point is to include the strains that will be expected to spread globally. There are two type A strains included in the trivalent formulations, because type A influenza strains are usually those that lead to more complications, hospitalizations, and deaths. The third strain included is always a type B; the quadrivalent formulation includes a second type B strain. In the 2003–2004 influenza season, the expected dominant strain killed the embryonated egg where the virus was grown due to the virulence of the strain [17]. A virus that was close to the expected circulating strain was chosen instead. However, the match was not close enough to the circulating strain for the vaccine to be as effective as it usually is. To the credit of the ACIP, this was only the second mismatch in 15 years [74,75]. In some cases, antibodies produced against one strain can overcome another strain, but the strains must be closely related. Antibodies produced by the strains in the 2003–2004 formulation were not close enough to the dominant circulating strain to destroy it, so people who had received the vaccine still developed influenza. In fact, the choice of which strains to include is based on the current knowledge as to which will be the most virulent strains in circulation. Due to the fact that there are only three strains in the vaccine and there are multiple influenza strains, people who are vaccinated can still develop illness from a strain of influenza virus that was not included in the vaccine.

Another extremely significant factor in the choice of a strain is the ability to grow the strain so that the vaccine can be produced in millions of doses. When vaccine distribution is delayed, it is often due to the fact that one particular strain would not reproduce well or quickly enough. As noted, some strains kill the culture medium.

Production of influenza vaccine involves the following steps [65]:

1. The chosen strains of influenza virus are incubated in fertilized chicken eggs.

2. Fluids containing the virus are harvested.

3. The virus is inactivated (killed) by formaldehyde.

4. The virus is concentrated.

5. The virus is chemically disrupted to produce a "split virus." (All influenza vaccine used in the United States is split virus.)

6. Further purification of the virus by chemical means is done.

7. The virus is suspended in sodium phosphate-buffered isotonic sodium chloride solution.

8. No antibiotics are used in the preparation of influenza vaccine.

Thimerosal is a preservative used in multi-dose vials to inhibit bacterial growth that might occur because of multiple introductions of needles to withdraw individual doses. It is a compound containing 49.6% mercury. Because of the allegation that thimerosal is connected to conditions such as autism and the fact that there have been warnings to avoid fish that has a high mercury content, thimerosal has been removed from most childhood vaccines. Vaccines without thimerosal are packaged in single-dose vials. However, thimerosal is still used in multi-dose vials (5-mL dose vials) and in one brand (Fluvirin) of single-dose prefilled syringes of influenza vaccine [8]. There are 25 mcg of mercury in each 0.5-mL dose of vaccine. One should note that there have been no studies proving any link between mercury poisoning and autism. Thimerosal is made from ethyl mercury, which is different from methyl mercury, the compound named in the government warning about consumption of or exposure to mercury [74]. More influenza vaccine without thimerosal has been made each year and should be used for those who have a severe allergic reaction to thimerosal. More than 188 million doses of thimerosal-free vaccine will be available for the 2021–2022 flu season [76].

These production methods have been used for decades and do not apply some of the modern technology available in the production of vaccines against other organisms, such as hepatitis A or hepatitis B. As noted, most influenza vaccine is incubated in fertilized chicken eggs. It takes one egg to produce one dose. More than 80 million doses are made for annual distribution in the United States alone. The number of chickens and eggs needed for this production is almost beyond comprehension. Also sobering is the thought of what would happen if one or more of the major flocks used for producing the eggs for the vaccine became infected with an avian influenza, which would require destruction of the flock(s).

Another issue involved is the amount of time required to produce the annual influenza vaccine—about six to eight months. Any new strain of influenza could circulate around the world much faster than the vaccine could be produced, resulting in a pandemic. Experimentation is being conducted on faster ways to produce the vaccine. Some companies are experimenting with caterpillar cells to incubate the virus. Experiments have indicated that the vaccine can be produced more quickly and that it would be available to protect people against emerging strains. Phase I trials indicated that the vaccine incubated in caterpillar cells is safe. In a clinical trial of 400 elderly people, the vaccine stimulated the production of nearly twice the number of antibodies as the vaccine produced using eggs. In addition, there were no adverse effects. Phase II trials in 400 elderly participants showed that 97% of them developed antibodies if the highest dose of the vaccine was used [77,78].

Another approach being explored in influenza vaccine production is to genetically engineer cells to replicate continuously. Such a process would lead to faster production and a more consistent vaccine [79]. One example of this is the Flublok vaccine, which uses protein-producing machines to make hundreds of copies of hemagglutinin, the small piece of the influenza virus needed for immunity [80]. Flublok is available for the 2021–2022 influenza season.

Other experimentation is being done using DNA-based approaches to develop a broadly protective vaccine that utilizes influenza virus proteins from multiple strains. Several companies are working to develop new ways to grow the antigens that cause the immune system to fight infection [79,81].

Using the reverse genetics method, in which genomes of the influenza viruses are manipulated in order to transfer genes between viral strains, seed viruses for vaccine manufacture can be rapidly generated. In addition, highly pathogenic influenza viruses can be altered so that they are safer for vaccine manufacturers to handle [81].

Another method of vaccine development, cell culture, has been well tolerated and has successfully led to antibody development in trials. Some research has shown that vaccines developed based on cell culture have been efficacious against all strains of influenza A, including H5N1 [81]. Using cell-based vaccines creates a more consistent manufacturing process and could reduce production time to 9 to 12 weeks. Although there are some side effects from cell-based vaccines, including headaches and injection site reactions, they appear to have a similar tolerability profile to egg-based vaccines [27].

In another area, one small study has been conducted that indicates that mild exercise before having a flu shot may make the vaccine more effective. Lifting weights before a flu shot increased antibody response in women but reduced the response in men. However, the cell-mediated response in men was increased by weight lifting. The researchers suggest that exercise increases the number of immune cells in muscle tissues, which in turn increases activity in the lymph nodes and creates a more efficient immune response [29,30].

HANDLING AND STORAGE OF THE VACCINE

The following information pertains to the egg-based vaccine in use. As is the case for all vaccines, the package insert should be consulted for proper handling and storage in order to preserve its effectiveness. Influenza vaccine should be stored at a temperature of 36 to 46 degrees F (2 to 8 degrees C) [8]. It should be transported in insulated containers with cold packs; however, it should not be directly in contact with the cold packs nor should it be placed anywhere in a refrigerator where it can be frozen. Freezing destroys the effectiveness of influenza vaccine. The vaccine can tolerate being out of the refrigerator while an influenza clinic is being prepared or conducted. However, only enough vaccine for the first half hour should be taken from the refrigerator at a time. When immunizing individual patients in an office setting, the vaccine vial should be returned to the refrigerator as soon as the dose has been withdrawn.

It is important that the temperature of the vaccine storage refrigerator be checked and recorded each morning before starting to dispense immunizations and each evening before leaving for the day. Older refrigerators can develop cold spots where items can freeze, or they may not maintain a constant temperature. All inactivated vaccines, like influenza vaccine, are destroyed by freezing. Large bottles of water should be kept in the refrigerator at all times to help maintain an even temperature and to preserve cold longer in case of a power outage. Some live vaccines, such as chickenpox and oral polio (no longer used in the United States), must be kept frozen. Vaccine should never be stored on the shelves in the door as the temperature there is erratic.

VACCINE PREVENTION OF SEASONAL INFLUENZA, 2021–2022

Each year the CDC and the ACIP provide updated recommendations for the prevention and control of seasonal influenza [8]. A variety of vaccines are available for the 2021–2022 flu season. These include standard-dose inactivated vaccines, high-dose inactivated vaccines, and recombinant and live attenuated vaccine, all of which are quadrivalent formulations. U.S.-licensed influenza vaccines for the 2021-2022 season contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture–based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus [8].

In addition, the age indication for Flucelvax Quadrivalent has been expanded from 4 years of age or older to 2 years of age or older [8]. The approved dose volume is 0.5 mL per dose for all patients.

Various influenza vaccines have been licensed and approved for the 2021–2022 season. More than one type or brand might be appropriate within approved indications and ACIP recommendations. Current prescribing information should be consulted for authoritative, up-to-date information. Children younger than 18 years of age should not receive Flublok (IM) or Afluria administered with a jet injector [8]. The following inactivated or recombinant influenza vaccines (all quadrivalent) are expected to be available for the 2021–2022 influenza season: Fluad, Fluarix, Flublok, Fluzone High-Dose, Fluzone, Flucelvax, and Afluria; the live, attenuated vaccine FluMist will be available (Table 2).

Table 2: INFLUENZA VACCINES—UNITED STATES, 2021–2022 INFLUENZA SEASON

Trade Name

Supplied As

Age Indication

Route

Mercury (from Thimerosal)

IIV4 (Standard dose, egg-based)

Afluria Quadrivalent

0.25-mL prefilled syringe

6 through 35 months

IM

—

0.5-mL prefilled syringe

≥3 years

—

5.0-mL multidose vial

≥6 months (needle/syringe)

18 through 64 years (jet injector)

24.5 mcg/0.5mL

Fluarix Quadrivalent

0.5-mL prefilled syringe

≥6 months

IM

—

FluLaval Quadrivalent

0.5-mL prefilled syringe

≥6 months

IM

—

Fluzone Quadrivalent

0.5-mL prefilled syringe

≥6 months

IM

—

0.5-mL single-dose vial

≥6 months

—

5.0-mL multidose vial

≥6 months

25 mcg/0.5mL

ccIIV4 (Standard dose, cell culture-based)

Flucelvax Quadrivalent

0.5-mL prefilled syringe

≥2 years

IM

—

5.0-mL multidose vial

≥2 years

25 mcg/0.5mL

HD-IIV4 (High dose, egg-based)

Fluzone High-Dose Quadrivalent

0.7-mL prefilled syringe

≥65 years

IM

—

aIIV4 (Standard dose, egg-based with MF59 adjuvant)

Fluad Quadrivalent

0.5-mL prefilled syringe

≥65 years

IM

—

RIV4 (Recombinant HA)

Flublok Quadrivalent

0.5-mL prefilled syringe

≥18 years

IM

—

LAIV4 (Egg-based)

FluMist Quadrivalent

0.2-mL prefilled single-use intranasal sprayer

2 through 49 years

Nasal

—

Source: [8,76]

Monitoring the 2010 influenza season in Australia produced data indicating that Afluria (marketed as Fluvax in the Southern Hemisphere) was associated with increased frequency of fever and febrile seizures in children 6 months through 4 years of age when compared to previous years [33]. Generally, the fever occurs 4 to 24 hours after the vaccine is given [33]. It would be prudent to instruct the parents or caregivers of these children to monitor the child's temperature and give nonaspirin fever-reducing medication as needed. In some public health immunization clinics, parents are instructed to give a dose of a fever-reducing medication to the child as soon as they get home, as a preventive measure. In a 2009 clinical trial in the United States, increased fever was noted among recipients of Afluria 6 months through 8 years of age. For the 2010–2011 influenza season, the U.S. Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink reviewed adverse event reports carefully for febrile seizures in children younger than 9 years of age [33].

ADMINISTERING THE VACCINE

The influenza vaccine discussed in this section is for IM use only; the intranasal and intradermal preparations are discussed later in the course. The IM vaccine is for all people 6 months of age or older. In order to assure that the vaccine is given IM, it is necessary to use needles of the proper length. Vaccine that is administered subcutaneously because of improper technique or a needle that is too short is ineffective.

The recommended site for adults and for children 3 years of age and older is the deltoid muscle [8]. A 1-inch needle will reach the deltoid in most children and adults. Some patients with large arms will need a 1.5-inch needle. One should be careful to make sure that the patient's sleeve can go high enough so that the needle can be inserted in the middle of the arm, about 1.5 inches below the top of the shoulder. Usually the firmness of the deltoid can be felt in that area. In patients who are very thin, it is wise to squeeze the deltoid between the thumb and finger to avoid hitting the bone. Administration of the vaccine distal in the deltoid is more painful. The posterior portion of the arm should not be used.

In children younger than 3 years of age, the deltoid is usually not big enough to receive the vaccine. The vastus lateralis muscle should be used [8]. This is the muscle on the outer aspect of the child's thigh and can usually be palpated. At times, when the infant kicks, the outline of the muscle can be seen. Two key elements to administering an injection to a child are to have the child properly and quickly restrained. An assistant, either the parent or a helper, should position the child so that the leg or arm where the injection will be given will not move. The upper body, the leg not being used for the shot, and the foot of the leg being used should be held tightly by the parent. Young children 3 years of age and older should sit sideways on the parent's lap so that the child's legs can be clamped between the parent's knees. The arm that will not be used for the injection should go around the parent's waist and be clamped under the parent's arm. The hand of the arm being used for the injection should be held by the parent. The person giving the vaccination should have all injections prepared so that they can be administered quickly. It is also good to distract the older child by having them blow, count, or see how loudly they can say "ouch."

Children should receive split-virus vaccine. This is not an issue in the United States as all vaccines are split-virus. Because some influenza vaccine comes in multidose vials, a small amount of thimerosal is in the vaccine [8]. For parents who are unwilling to accept the studies showing no connection between thimerosal and autism or other negative health effects, several thimerosal-free preparations are available [8,65].

FluMist, Fluarix, Flulaval (single-dose), Fluzone (single-dose), and Flublok do not contain thimerosal. There are additional vaccines in use with reduced or no thimerosal. Information on the amount of thimerosal present in each vaccine dose is available on the CDC website [8].

Children younger than 9 years of age receiving influenza vaccine for the first time should receive two doses, one month apart. The dose for a child is age-related [35]. Children from 6 to 35 months of age should be given 0.25 mL administered IM with a 1-inch needle in the outer aspect of the thigh. If it is the first time the child has received a flu shot, a second 0.25 mL dose IM should be given one month later [35]. In subsequent years, the child will receive only one influenza vaccine each year. Children 3 years of age and older should be given 0.5 mL IM using a 1-inch needle in the deltoid. Children who are 3 to 8 years of age receiving influenza vaccine for the first time will need a second vaccine in one month. These second doses in those not previously immunized against influenza are given to maximize a satisfactory antibody response to all antigens in the vaccine. Preferably, the series should be started as soon as possible after the vaccine becomes available [8,36,74]. Late-season immunization is acceptable and should be encouraged for those who have not received the vaccine [63].

As an inactivated vaccine, influenza can be administered with other vaccines if required. Separate needles and separate sites should always be used. In fact, for patients 65 years of age or older who have never received the immunization against pneumococcal disease, that vaccine should be given at the same visit. This is also an excellent time to check on the status of the patient's tetanus immunization. Tetanus vaccine should be given every 10 years, a fact that is often forgotten in adults, especially older individuals.

All patients or their parent/guardian must receive the Vaccine Information Statement (VIS) appropriate to the vaccine being administered. The patient signs that he or she has read the VIS. The record the patient signs must contain the date that the VIS was provided to the patient. Many people think that they are signing permission for the vaccine to be given. Actually, they are signing that they have read the VIS [37].

Children younger than 18 years of age should not be given any vaccines without a parent/guardian present. Grandparents who are not legal guardians frequently bring children to immunization clinics. A written permission from the child's parent/guardian should be presented to the staff before the vaccine is administered.

INFLUENZA VACCINES AND COVID-19

During the 2021–2022 influenza season, it is expected that SARS-CoV-2 will continue to circulate in the United States, and COVID-19 vaccinations are expected to continue. Current guidance for the use of COVID-19 vaccines indicates that these vaccines can be coadministered with other vaccines, including influenza vaccines [8]. Influenza vaccination during the COVID-19 pandemic is particularly important, as preventing influenza will avoid burdening and already stressed healthcare system. There is also evidence that respiratory virus activity has increased in 2021, leading some to predict a worse-than-usual influenza season [189]. If influenza and COVID-19 vaccines are administered at the same visit, they should be given at different sites (separated by at least 1 inch [190]. If used, high-dose or adjuvant influenza vaccines should be administered on a separate limb from the COVID-19 vaccine, if possible. There is no requirements regarding which vaccine is administered first.

There is little experience to guide recommendations for providing influenza vaccines to persons with COVID-19. In general, those who are in quarantine or isolation should not be brought to a vaccination setting if doing so could expose others to COVID-19. For those who have moderate or severe COVID-19, vaccination should generally be deferred until they have recovered [8]. For persons who have mild or asymptomatic COVID-19, further deferral might be considered to avoid confusing COVID-19 illness symptoms with postvaccination reactions.

SIDE EFFECTS OF THE INFLUENZA VACCINE

The most common side effect following influenza immunization is a local reaction—soreness, redness, or induration at the injection site—that occurs in 15% to 20% of the recipients. Generally, these effects last only one or two days. Some people (<1%) experience fever, chills, malaise, and myalgias, usually within 6 to 12 hours. This effect occurs most often in those receiving the vaccine for the first time. As with the local reaction, these systemic reactions last only one to two days. In a comparative study with a placebo, the systemic reactions occurred as often with the placebo as with the influenza injection. Neurologic reactions to influenza do occur, but they are rare [8].

A certain percentage of people will be incubating an influenza virus when they receive the influenza injection. When they have symptoms of influenza within a few days of vaccination, they are certain it is the result of the flu shot. Healthcare workers should try to reassure their patients that the vaccine cannot be responsible because the virus in it is split and dead.

Immediate severe allergic reactions can occur after administration of influenza vaccine. These reactions are probably due to hypersensitivity to a component of the vaccine, usually a severe egg allergy. As noted, this concern may be eliminated with new technologies that have become available. The CDC recommends that all patients receiving the influenza vaccine, especially for the first time, should be carefully screened for severe egg allergy. However, the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology updated their practice parameter in 2017 and now assent that any appropriate, licensed influenza vaccine may be safely used for persons with egg allergy of any severity, eliminating the need for careful prescreening [186]. If a person has a severe allergic reaction to thimerosal, a thimerosal-free vaccine should be used. For those allergic to eggs but who have factors that increase their risk of complications from influenza infection, protocols to vaccinate them are available. Flublok or Flucelvax may be used in these patients as they are egg-free [8]. A sheet with the symptoms of anaphylaxis and the dosage of therapeutic epinephrine should be posted near the preloaded epinephrine syringe and should be readily available and known to all staff. In addition, crushable packets of ammonia should be available in any area in which immunizations will be administered. It should be noted that anaphylactic reactions are extremely rare. Patients, especially teenagers, may faint and the crushed ammonia passed quickly under the nose is enough to revive them. Never ignore a patient who verbalizes fear of shots or mentions that they have fainted in the past. Make sure such a patient is seated or lying down if in an exam room. Reassure the patient and administer the vaccine as quickly as possible. Position your body in such a way as to be able to support the patient if he or she begins to faint.

ADVERSE EVENTS

Adverse events are any unusual conditions, such as fever, dizziness, behavior change, or serious allergic reactions (e.g., difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, tachycardia), following influenza vaccine. The National Childhood Vaccine Injury Act of 1986 mandates that healthcare providers report adverse events following vaccination to VAERS. Providers are additionally encouraged to report any clinically significant adverse event following vaccination to VAERS [8]. Any person can report an adverse event following the administration of any vaccine by calling VAERS or by obtaining a form online. Adverse events usually occur within 48 hours of vaccine administration. However, GBS may occur as long as six weeks after administration. The VAERS form will ask for detailed information on the vaccine, such as lot number, administration site, administrator, and date. Patients to whom influenza vaccine is administered should be instructed to call a physician if there is an adverse event. Careful investigation follows the receipt of a VAERS report. The provider is notified of the results of the investigation usually several months after the report was made. Therefore, it is important to keep a copy of the report in the patient's file and a copy in a special file for VAERS reports. As the report is investigated, the provider may be contacted for clarification or additional information.

EFFECTIVENESS OF THE INFLUENZA VACCINE

The effectiveness of any vaccine depends upon the age and immunocompetence of the person receiving the vaccine. Most children and young adults receiving the vaccine have a good antibody response to the strains included in the vaccine and develop titers sufficient to protect them against those strains. For healthy adults younger than 65 years of age, if the vaccine strains match the circulating strains, illness will be prevented in 70% to 90% of those adults. In children, various studies have shown that children as young as 6 months of age develop antibodies. Children at high risk to develop complications with influenza may have a lower antibody response than healthy children. Also, children receiving the vaccine in the second year exhibit lower attack rates. Otitis media rates are lowered in some studies but not in others. Overall, because the vaccine is beneficial to children in preventing disease and lowering hospitalization rates, the ACIP recommends a yearly influenza immunization for all children 6 months of age and older [4,8].

In adults 60 years of age and older who are not institutionalized, a randomized trial showed that the vaccine was 58% effective against influenza respiratory illness. Efficacy might be lower in those older than 70 years of age. However, the vaccine appears to be effective in preventing secondary complications, hospitalization, and death among older adults, both those who are healthy and those with chronic medical conditions. Among noninstitutionalized older adults, the vaccine prevented hospitalization for pneumonia and influenza 30% to 70% of the time. Among institutionalized older adults, the vaccine can be 50% to 60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death even though it is only 20% to 40% effective in preventing respiratory illness among this population [8]. Overall, in those 65 years of age and older, influenza immunizations have reduced hospitalization by 70% and death by 85% [36].

COST-EFFECTIVENESS OF THE INFLUENZA VACCINE

In preventing illness among younger workers, the vaccine may help reduce economic losses caused by absenteeism. Decreasing hospitalization rates of healthy infants and toddlers, of older noninstitutionalized and institutionalized adults, and of persons with chronic conditions is cost-effective. Studies have demonstrated that flu-related hospitalizations are decreased 40% to 42% overall with vaccination, that there is a 25% decrease in antibiotic usage for secondary illness associated with influenza, and that there is possibly a decrease in lost workdays. A 2014 study found that a vaccinated child's risk of being hospitalized due to influenza was reduced 74%; for individuals 50 years of age or older, flu-related hospitalization risk was reduced 57% [84]. These statistics indicate a significant annual savings of healthcare dollars for each person who received influenza vaccine. In an era of escalating healthcare costs and increasing antibiotic resistance, these are important figures [8].

INTRADERMAL INFLUENZA VACCINE

In 2011, the FDA approved a new version of Fluzone to be administered intradermally via microinjection system [34]. The vaccine is packaged in 0.1 mL single-dose, prefilled syringes, and it contains no preservative [8,39]. The microinjection consists of an ultra-thin needle 0.06 inches (1.5 mm) in length, or less than one-tenth the length of the standard needles used for the traditional IM route [34]. The system deposits the vaccine into the dermal layer of the skin, where dendritic cells generate an immune response. Research indicates that use of the intradermal route results in an immune response as good as or better than IM administration using a lower dose of hemagglutinin (9 mcg of hemagglutinin for each influenza strain compared to 15 mcg) [40,41]. As such, this route may be preferred when sparing vaccine is advised.

Fluzone intradermal is recommended for use in adults 18 to 64 years of age [8,39]. Initial research indicates that it may also be effective in older adults (60 to 95 years of age), but more research is necessary before Fluzone intradermal can be recommended for this group [42]. Potential adverse effects associated with intradermal administration are similar to those seen with IM administration, although local injection site reactions may be more common and more visible [34,40]. The most common injection-site reactions are erythema (>75%), swelling (>50%), induration (>50%), pain (>50%), and pruritus (>40%); all of these reactions occur more often with intradermal than with IM administration, with the exception of pain, which occurs at similar rates in both [34]. Due to the small size of the needle, it may also be useful for patients with fear or anxiety related to injections or needles.

NASAL SPRAY INFLUENZA VACCINE

Live attenuated influenza vaccines (LAIVs) have been in development in the United States since the 1960s [43,44]. FluMist (a LAIV trivalent formulation), manufactured by MedImmune, LLC, was originally approved in June 2003. FluMist quadrivalent LAIV contains two subtype A strains and two subtype B strains. It was approved by the FDA in February 2012 and was first available for the 2013–2014 flu season [45,46]. FluMist, which is delivered intranasally, is licensed only for healthy, nonpregnant persons 2 to 49 years of age. Live vaccines are unsuitable for healthcare workers who care for immunocompromised patients [8].

For two flu seasons, FluMist was not recommended based on data indicating inefficacy of the formulation. However, FluMist was reintroduced in the 2018–2019 season [8,187]. People with chronic health conditions should not be given the intranasal vaccine. The ACIP does not recommend the use of LAIV in immunosuppressed patients, and family members of close contacts of severely immunocompromised individuals are advised to avoid contact with them for at least seven days following vaccination [45]. LAIV can be administered at the same time with other vaccines, live and inactivated, but if not given at the same time, should be given four weeks after any other vaccine. Family members or close contacts of severely immunocompromised patients should not be given LAIV [45,61].

LAIV appears to induce both mucosal and serum antibodies. It is easier to administer than an IM injection, and it is preferred in some cases. In addition, no serious illnesses have been reported among unvaccinated contacts who were infected by those who had received the live vaccine [8].

Who Should Not Receive LAIV

The following groups of people should not be given LAIV [8,31,43,45,46,61]:

- Anyone younger than 2 years of age or older than 49 years of age

- Children 2 through 4 years of age who have received the diagnosis of asthma or have had a wheezing episode within the past 12 months

- Anyone with chronic underlying medical conditions, such as cardiac or pulmonary disease, diabetes, renal dysfunction, or a compromised immune system

- Children on long-term aspirin therapy

- Persons with a history of GBS

- Pregnant women

- Persons with hypersensitivity to any of the components of LAIV, including eggs

- Persons who have been on antiviral medications in the previous 48 hours

- Persons with a history of asthma or other reactive airway disease

Administration and Dosage

Intranasal influenza vaccine is supplied in prefilled single-use sprayers containing 0.2 mL of vaccine and must be refrigerated at 2 to 8 degrees C (35 to 46 degrees F) [46]. Half of the dose in the sprayer, approximately 0.1 mL, is sprayed into one nostril while the patient is sitting upright. The attached dose-divider clip is removed so the rest of the dose can be sprayed into the other nostril. The dose is not repeated if the person sneezes [45].

8. PROMOTING THE USE OF INFLUENZA VACCINE

The Healthy People 2030 objective is to increase the proportion of persons who are vaccinated annually against seasonal influenza to at least 70% of the target population [82]. Among high-risk people 65 years of age and older, the overall influenza vaccination rate is 67%. However, people of color have much lower rates [36].

There are several other high-risk groups, discussed previously in this course, that fall far short of the 90% influenza immunization rate goal. According to data from the National Health Interview Survey, only 49.2% of high-risk people 6 months to 64 years of age were immunized against influenza in 2017 [82]. Since 1999, in years without vaccine shortages, immunization levels have ranged between 63% to 66% for high-risk individuals [70,87].

FACTORS INFLUENCING INFLUENZA IMMUNIZATION

One of the major factors influencing people with conditions that put them at high-risk for complications, hospitalization, and death from influenza is the misconception that the flu shot will give them the flu. This misconception is fueled by the fact that, in such a large cohort receiving the influenza immunization, a certain percentage will already be incubating the flu. When the symptoms of influenza appear one day or so after getting the shot, the natural assumption is that the illness came from the shot. Some take the opposite view that the flu shot will protect them against colds, so they are disappointed the "the flu shot didn't work" when they get a cold [84].

Another factor is that patients rely on their physician's advice. Unfortunately, physicians may not specifically suggest that their patients get the influenza vaccine. This leads the patient to think that it is not important or it would have been mentioned.

Cost may be a prohibitive factor for those too young for Medicare, which covers influenza and pneumococcal immunizations. Some people may assume that the influenza immunization is effective for several years. Others feel that a healthy person should not take anything, like a flu shot, that might make them sick [84]. Some patients do not realize how effective the influenza vaccine is in preventing complications, hospitalizations, deaths, and actual influenza disease when the vaccine antigens correspond to the circulating antigens.

Probably one of the biggest factors affecting influenza immunization rates is the fact that influenza is so common—a true illustration of "familiarity breeds contempt." Few are aware of the number of hospitalizations and deaths and the economic burden associated with influenza. Media attention focuses on deaths from SARS or other diseases while influenza kills far more each year.

IMPROVING INFLUENZA VACCINE USAGE

Start Administration As Soon As Vaccine is Available

Now that studies have shown that the immunity produced by the vaccine lasts several months, the ACIP recommends that influenza immunizations start as soon as the vaccine is available. Thus patients who are seen infrequently by their healthcare providers can receive the vaccine when they have an appointment and avoid a special visit just for the immunization. Providers should offer the vaccine to all patients, especially children 6 months to 8 years of age, as soon as they have a supply. The CDC also recommends that the offer of the vaccine and its refusal be documented in the patient's medical record [8].

The Role of the Healthcare Provider

One of the major factors in increasing the number of administrations of influenza vaccine is the involvement of the medical practitioner providing care in a variety of settings, such as physicians' offices, clinics, outpatient rehabilitation programs, or any place where there is contact between medical providers and their patients. To encourage practitioner involvement, providers should be informed of the reimbursement for the vaccine and its administration by Medicare and Medicaid and should be instructed as to billing methods, especially roster billing.

The majority of flu shots given are administrated by the person's personal healthcare provider, and studies have shown that a healthcare provider's recommendation plays a critical role in a patient's decision to get a seasonal flu vaccine [85]. As many as 75% of patients at high risk for influenza or for death from a complication of influenza have seen a healthcare provider in the last year. One of the most effective methods of encouraging a high-risk patient to receive the flu shot is a verbal recommendation from the patient's physician [85].

To ensure that high-risk patients receive the recommendation, a variety of reminder techniques might be employed, such as placing stickers on the charts of high-risk patients, creating computer-generated lists of patients not scheduled to be seen, sending reminders via email or regular mail, and telephoning patients. Educational efforts by public health departments through media and personnel could encourage high-risk people to ask their healthcare provider for the flu shot [86]. Beginning in September, emergency rooms and walk-in clinics should display posters and educational materials about the need for the flu shot and either provide the vaccine or provide information about where it may be obtained [16].

Influenza immunization is also recommended for all people who have contact with high-risk populations. Obviously, this includes all healthcare professionals, a group for which the ACIP recommends annual influenza vaccination [8]. According to results of a survey conducted by the CDC among 2,258 self-selected healthcare personnel, 79% of survey participants reported having had an influenza vaccination for the 2015–2016 season, a significant increase from 67% during the 2011–2012 season [70,87]. Vaccination coverage was highest among hospital-based healthcare personnel (91.2%) and lowest among healthcare personnel at long-term care facilities (69.2%). Coverage was also higher in occupational settings that offered no-cost, onsite vaccination for one or more days compared with settings that did not offer no-cost coverage. Vaccination coverage was 85.8% overall among healthcare personnel in all occupational settings who reported an employer mandate to receive vaccination [70,87].

Immunization lowers worker absenteeism and transmission to vulnerable patients. Those who supervise or manage other healthcare personnel should set an example for their staff and patients by making sure to get a flu shot each year. It seems that those who have received the vaccine are more aware of the need to inform patients of the value of the flu shot, and their example is an encouragement.

As noted, LAIV should not be used to immunize contacts of severely immunocompromised patients unless no contact for seven days following receipt of LAIV can be assured [8]. There have been no reported instances in which a healthcare professional immunized with LAIV has transmitted influenza to a patient. Unvaccinated healthcare workers are more likely to transmit the virus [88]. To encourage more healthcare professionals and allied personnel to get the flu shot, it should be provided at the work site free of charge [16].

Standing Orders

Implementation of standing orders in acute care hospitals is another way to help increase influenza vaccine coverage. Patients who are hospitalized as flu season approaches, or during flu season, should have their records checked for chronic illness that is impacted by influenza and for influenza vaccine status. Those who have risk factors for complications and have not received the influenza immunization should receive the flu shot before discharge, as covered by the standing order. Such standing orders would have to be developed and implemented by the medical board of the hospital. All medical personnel connected with the hospital should be made aware of the standing order and reminded by posters or other means during influenza season. A study of Medicare patients hospitalized during flu season showed that only 31.6% had received the flu vaccine before admission, 1.9% during admission, and 10.6% after admission [43].

In long-term care facilities, there should be a standing order for each patient to receive a flu shot in October. When a patient is admitted to the facility, the attending medical professional and family member(s) should be informed of the standing order. If there is a reason that the patient should not receive the influenza vaccine, the physician can so order or the family member can so request. All residents should be immunized on the same day, if possible, before flu season. Those admitted after this day should receive the vaccine upon admission [43]. One study showed that only 62% of residents in nursing homes received influenza immunization in spite of its demonstrated effectiveness in preventing complications, hospitalization, and death in long-term care patients. Another study showed that if 80% or more of the residents in the facility were immunized against influenza, hospitalization from all causes was reduced regardless of the vaccination status of the individual resident [89]. As noted, another protective measure for residents of institutions is for the care providers to receive an influenza immunization.

Home healthcare agencies should also have protocols in place to immunize patients under their care during the flu season and to inform the in-home caregivers of their need to be immunized. Staff members with patient contact should also be immunized [43].

All healthcare providers of patients in hospitals, long-term care facilities, and home health agencies should be aware that the Centers for Medicare and Medicaid Services has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to patients covered by Medicare and Medicaid [43].

The Role of Community Agencies

Religious meeting places are a point of contact for many groups. Patient education materials can be included in the organization's bulletin. In some areas, the local public health department will provide an influenza immunization clinic in conjunction with a religious service.

Reminder posters and educational materials can also be displayed at banks, grocery stores, and community centers. These materials are available from the local public health department or on the CDC website. Organizations such as Lions, Kiwanis, Rotary, and the AARP, that are interested in controlling the cost of health care, should be enlisted to help encourage their friends and neighbors to be immunized against influenza.

Many public health departments provide influenza immunizations in community settings, such as churches, community centers, meetings of minority groups, airports, and malls—any place where a clinic can be temporarily set up. Some even provide "drive-up clinics" where the person does not need to get out of the car to receive the flu shot. These clinics are especially helpful for a person who cannot wait in line or walk easily.

9. OTHER METHODS TO PREVENT INFLUENZA

The primary and most effective way to prevent influenza is vaccination. However, in cases when antigens of the vaccine are not close enough to the circulating antigen, when there is a shortage of vaccine, or when a new strain has emerged and is circulating before the vaccine can be made and distributed, people will have to resort to other ways to protect themselves from infection.

HANDWASHING

Good handwashing is difficult to practice, is rarely known or taught, and is one of the single most effective ways to prevent transmission of many diseases, including influenza. Everyone knows to wash their hands before eating and after using the restroom. However, few do little more than remove obvious dirt. Good handwashing involves removing the skin oils where organisms can remain even when the hands look clean. A quick pass under the water faucet and fast dry with a towel removes visible dirt, but the oils and organisms remain.

To effectively remove the oils and organisms, the process should take at least 20 seconds (e.g., the amount of time that it takes to sing "Twinkle, Twinkle Little Star"). The hands should be soaped and rubbed vigorously for 15 seconds to create a good lather and to assure that all parts of each hand are soaped and rubbed well. Then the hands should be rinsed thoroughly and dried, preferably with a paper towel. The towel should be used to turn off the water and then properly thrown away. Such handwashing removes the oils that harbor the organisms, but 20 seconds can seem like a long time in the busy life of a healthcare provider. If there is no visible dirt or contamination, a waterless hand sanitizer with at least 60% alcohol can be used between patients. However, nothing is as good as washing well with soap and water. Some mistakenly think that hot water must be used to kill the organisms. Water hot enough to kill organisms would be too hot to touch. Warm water mainly adds to comfort and hopefully encourages better washing technique. Careful attention to handwashing and cleansing may result in chapped skin, so the medical professional should find the proper lotions to care for his/her hands [90,91].

AVOID TOUCHING EYES, NOSE, OR MOUTH

The eyes, nose, and mouth are entryways for bacteria and viruses. Everyone tends to unconsciously touch their eyes, nose, and mouth when going about their activities. Because organisms are not visible and handwashing is often less than adequate, infection occurs. Though difficult, the person trying to prevent illness should make a conscious effort to avoid touching his/her face [92].

PROPER COVER FOR A COUGH OR SNEEZE

Covering a cough or sneeze is of primary importance however it is done [93]. Ideally, disposable paper tissues will be readily available during cold and flu season and used to cover the nose and mouth when coughing or sneezing. Patients and children should be instructed that, when this is not possible, they should cough or sneeze into their upper sleeve or elbow instead of into their hands. This will avoid contaminating the hands with an offending virus or bacteria [93]. In those instances when coughs and sneezes are covered with only the bare hands, the hands should be cleaned with soap and water or with an alcohol-based hand sanitizer as soon as possible to prevent transfer of the organisms to another person. Coughing, sneezing, or blowing nasal secretions into a cloth handkerchief is not recommended as this results in creating a moist, viable culture that is then carried in the pocket or purse, potentially resulting in prolonged episodes of re-infection or transfer from cross-contamination.

AVOID PEOPLE WITH RESPIRATORY SYMPTOMS

During cold and flu season, trips to the store, school, church, and workplace bring contact with those who are coughing and sneezing. If at all possible, avoid close contact. This is an excellent time to consciously work on keeping your hands away from your face. Good handwashing should be done as soon as possible after contact with someone exhibiting symptoms of respiratory illness. Help the immune system to overcome the organisms by getting enough rest, drinking six to eight glasses of water per day, and eating fresh fruits and vegetables [94]. Healthcare providers can lessen the spread of influenza by utilizing proper cough etiquette, providing tissues and safe disposal, using rapid diagnostic tests and antiviral chemoprophylaxis for suspected flu in healthcare workers, and recommending that influenza sufferers stay home [95].

ANTIVIRAL MEDICATIONS AS PREVENTION

Antiviral medications can also be used to prevent influenza. Three of the four antiviral drugs used to treat illness due to influenza can also be used to prevent it, although this is complicated by growing resistance to available agents. Amantadine (Symmetrel) and rimantadine (Flumadine) have been approved for treatment and prevention, but both of these agents have also been associated with decreasing effectiveness due to viral resistance and are no longer recommended for these uses [45,96,97]. Oseltamivir (Tamiflu) is an effective treatment of uncomplicated acute illness due to influenza A and B viruses in adults and children older than 2 weeks of age, and it is approved as a preventive treatment in persons 1 year of age and older. In 2007, the Japanese Ministry of Health, Labor, and Welfare issued a warning that oseltamivir may cause psychiatric problems and suicide in patients 10 to 19 years of age [98]. This warning has been the subject of much controversy, and no such warning has been issued in the United States. Zanamivir (Relenza) is approved for prophylaxis in persons 5 years of age and older; ACIP recommends that prophylaxis with zanamivir be considered for individuals at high risk of influenza complications, for unvaccinated healthcare workers exposed to influenza, and for eligible residents of institutions that house high-risk patients when outbreak control is needed [45].

A physician's order is required to obtain any of the antivirals. In the past, amantadine and rimantadine prevented influenza A illness 70% to 90% of the time [16]. However, the increasing incidence of amantadine- and rimantadine-resistant strains of influenza in the United States has made these medications less effective [96]. Therefore, they are no longer recommended for treatment or prophylaxis of circulating influenza A strains [45,97].

Antiviral medications can make a person less contagious to others, so they are prescribed for contacts of people who are at high risk for complications from the flu. A subclinical infection may develop in a patient taking an antiviral. This allows the body to make antibodies against the virus. If any antiviral medication is to be totally effective, it must be taken as long as influenza is active in the community. Some studies indicate that taking an antiviral during peak influenza activity in a community is also effective. Of course, the less expensive single application vaccine is the best choice in preventing influenza in contacts of high-risk persons. However, in situations in which the individual has a hypersensitivity to one of components of the vaccine, or the needed two weeks to develop immunity are not available before contact, an antiviral medication can be used. Another reason to use an antiviral prophylaxis would be if the available vaccine does not match the circulating virus.

Antivirals are also used in closed environments, such as institutions or cruise ships, to control flu outbreaks. In such cases, it is best to combine the vaccine with an antiviral to provide protection for those exposed but who have not developed illness until the vaccine can stimulate the immune system to make protective antibodies. This also avoids the protracted use of the antiviral medication. The antiviral will not interfere with the antibody response elicited by the vaccine [3,16,99].

10. ANTIVIRAL MEDICATIONS

Evidence Based Practice Recommendation

According to the Advisory Committee on Immunization Practices, clinicians should start antiviral treatment as soon as possible for adults and children with documented or suspected influenza, irrespective of influenza vaccination history, who meet the following criteria:

- Persons of any age who are hospitalized with influenza, regardless of illness duration prior to hospitalization

- Outpatients of any age with severe or progressive illness, regardless of illness duration

- Outpatients who are at high risk of complications from influenza, including those with chronic medical conditions and immunocompromised patients

- Children younger than 2 years and adults 65 years of age or older

- Pregnant women and those within two weeks postpartum

https://academic.oup.com/cid/article/68/6/e1/5251935#127789601

Last Accessed: October 27, 2019

Level of Evidence: A-II (Good evidence to support a recommendation based on one or more well-designed clinical trials, without randomization; from cohort or case-controlled analytic studies; from multiple time-series; or from dramatic results from uncontrolled experiments) and A-III (Good evidence to support a recommendation based on opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees)

The antiviral medications zanamivir and oseltamivir are also used to treat acute illness due to influenza (Table 3). To be effective, any of these medications must be started within 48 hours of symptom onset. Generally, a course of one of these antivirals will reduce the illness by one to two days, prevent serious complications, and make the patient less contagious to others. These medications are effective only against influenza viruses and will not affect the common cold or other ILI of viral origin [16,99,100]. All require a prescription from a physician.

Table 3: COMPARISON OF ANTIVIRALS USED IN INFLUENZA

Characteristics

Zanamivir

Oseltamivir

Peramivir

Baloxavir

Type of antiviral

Neuraminidase inhibitor

Neuraminidase inhibitor

Neuraminidase inhibitor

Endonuclease inhibitor

Effective for type

Influenza types A and B

Influenza types A and B

Influenza types A and Ba

Influenza type A and B, including avian strains and strains resistant to oseltamivir

Route of administration

Inhaled

Oral

IV

Oral

Age that can receive

Treatment: 7 years of age and older

Prevention: 5 years of age and older

Treatment: 1 year of age and older

Prevention: 13 years of age and older

Treatment: 18 years of age and older

Prevention: NA

Treatment: 12 years of age and older

Prevention: 12 years of age and older

Action

Decrease symptoms

Decrease symptoms

Decrease antibiotic use

Decrease symptoms

Decrease symptoms

Side effects

Throat/tonsil pain, nasal symptoms, diarrhea, nausea, headache, cough

Nausea and vomiting

Diarrhea

Diarrhea, nasopharyngitis

Sold as

Relenza

Tamiflu

Rapivab

Xofluza

aPeramivir efficacy is based on clinical trials in which the predominant influenza virus type was influenza A; a limited number of subjects infected with influenza B virus were enrolled.

Source: [45,96,97,121]

ZANAMIVIR

Zanamivir belongs to the antiviral group of neuraminidase inhibitors. It is effective against both influenza A and B and was approved in 1999 to treat uncomplicated illness due to influenza virus in adults and children 7 years of age and older. The dosage is 10 mg twice daily by inhalation for five days. Doses should be 12 hours apart. It may also be used to prevent influenza virus in adults and children 5 years of age and older. The dosage is two 10-mg inhalations once daily for seven days after last known exposure [45,101]. Zanamivir can lead to a decrease in respiratory function and bronchospasm. It is not recommended for patients with asthma, obstructive pulmonary disease, or other chronic lung diseases. More common (>10%) side effects include headache, throat/tonsil discomfort or pain, nasal signs and symptoms, and cough. Other effects that occur in less than 10% of patients include diarrhea, nausea, headache, dizziness, nasal infections, sinusitis, and bronchitis [45]. Some allergic responses of oropharyngeal or facial edema have also occurred [16,22,100,102].

OSELTAMIVIR

Oseltamivir also is a neuraminidase inhibitor and effective against both influenza A and B viruses. It is marketed as Tamiflu, which should not be confused with Theraflu. Like zanamivir, it was approved in 1999. It can be used as treatment in adults and children who have been symptomatic for no more than two days. The treatment dosing for adults and children 13 years of age and older is 75 mg twice daily. The treatment dosing for children younger than 13 year of age is weight dependent [101]:

- 3 mg twice daily for children aged 2 weeks to younger than one year

- 30 mg twice daily for children aged 1 year and older who weigh ≤15 kg

- 45 mg twice daily for children who weigh >15 kg and up to 23 kg

- 60 mg twice daily for children who weigh >23 and up to 40 kg

- 75 mg twice daily for children who weigh >40 kg

Oseltamivir can also be used as a preventive in anyone 1 year of age or older, but such usage should be rare [97]. The dose is 75 mg twice daily by mouth for adults and once daily for children and adolescents who weigh more than 40 kg (88 lbs.) [45]. Studies have shown that oseltamivir reduces the incidence of complications that may require antibiotics. Although the neuraminidase inhibitors promote a drug-resistant mutant of the virus, less resistance appears to occur with oseltamivir than with zanamivir. The reported side effects with oseltamivir are nausea and vomiting, which are lessened if the medication is taken with food [8,16,22,100,102].

Since 2005, some resistance to all of the antivirals has been documented. However, the 2009 H1N1 outbreak remained sensitive to oseltamivir except in a few cases [8]. Serious reactions to the four antiviral medications should be reported to the FDA MedWatch program.

PERAMIVIR

Approved in 2014, peramivir is a neuraminidase inhibitor for use in patients 18 years of age or older with acute uncomplicated influenza who have shown symptoms for no longer that two days [45,97]. Peramivir injection preparation is a 200 mg/20 mL single-use vial, stored at 59 to 86 degrees F (15 to 30 degrees C). After being diluted, it should either be administered immediately or refrigerated and administered within 24 hours [159]. Peramivir is typically given in a single 600-mg dose; the dose should be adjusted based on renal function. The most common side effect is diarrhea (8%) [45]. An efficacy study showed that overall symptoms were relieved 21 hours sooner in participants given peramivir compared to those given placebo [32]. Efficacy studies have primarily been conducted in patients with A type influenza viruses, and it is effective for 2009 H1N1 [45,159].

BALOXAVIR

In 2018, the FDA approved the first antiviral influenza treatment with a novel mechanism of action in nearly 20 years—baloxavir. Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease. It is approved for use in persons 12 years of age and older if administered within 48 hours of onset of symptoms [121]. It is also approved for avian influenza strains and strains with proven resistance to oseltamivir. In 2020, approval of baloxavir was extended to include post-exposure prevention in persons 12 years of age or older who have been exposed to influenza [188]. Studies indicate that baloxavir, which has the advantage of once-a-day dosage, is as effective as oseltamivir in alleviating symptoms and shortening the duration of illness [10]. Baloxavir is administered as a single oral dose of 40 mg for persons 40 to <80 kg or 80 mg for persons ≥80 kg. The most common side effects are diarrhea and nasopharyngitis [121].

AMANTADINE AND RIMANTADINE

Amantadine was approved in 1966 as a treatment for uncomplicated respiratory tract illness caused by influenza. It belongs to a group of chemically related drugs called adamantanes (tricyclic amines) and is effective only against influenza A viruses. Rimantadine, approved in 1993, is also in the adamantanes group. Therefore, it is also only effective against influenza A. However, circulating influenza A (H3N2) and 2009 H1N1 viruses are resistant to adamantanes. As a result, these medications are no longer recommended for the treatment or prophylaxis of influenza A [45,103].

TREATMENT OF ACUTE ILLNESS RESULTING FROM INFLUENZA

All antiviral treatment for influenza should begin within 48 hours of symptom onset to be effective [104]. In most individuals without underlying medical conditions, influenza is a self-limiting disease. Recovery usually occurs after one week, although fatigue and malaise may persist two or more weeks. The decision to use an antiviral is influenced by the type of work the patient does. In an epidemic or pandemic, persons providing critical services should be treated because shortening their absence by one or two days is important. For other personnel, the decision should be based on the comparison between the wages that would be lost and the cost of the medication [100]. If an outbreak of influenza occurs in an institution, antiviral medications should be used for both treatment and prophylaxis [104].

Some people may desire treatment because of upcoming plans or because they do not like to be sick. These individuals should be encouraged to obtain the annual influenza vaccine in the future, as disease that develops in spite of the vaccine is usually milder unless the vaccine strains do not match the circulating strains.

Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization. It is also recommended for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions [96,104]. Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness if treatment can be initiated within 48 hours of illness onset.

Pregnancy should not be considered a contraindication to the use of oseltamivir or zanamivir; however, peramivir and baloxavir are not recommended for these patients. Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses, and if influenza is confirmed or suspected in these patients, it should be treated with oseltamivir or zanamivir; fever should be treated with acetaminophen. [101]. Because antivirals have a potential but unknown risk during pregnancy, it is important to continue to vaccinate pregnant women. The seasonal flu shot has been given to pregnant women for many years without any harm to the women or their fetuses. Vaccines that contain thimerosal result in exposure to only trace amounts of mercury and are not associated with toxicity [45].

11. CARE OF THE PATIENT WITH INFLUENZA

AT HOME

Family members or friends should be located to care for the high-risk patient who lives alone. With enough community support (e.g., home health, neighbors, "Meals on Wheels"), a patient might be able to remain alone, but it would require careful planning and coordination among all involved. During an epidemic or a pandemic, it may be necessary to set up temporary facilities, such as a shelter for medically fragile patients, to provide care. A normally healthy adult living alone may only need help in the form of shopping.

Points in the care of the patient include: careful observation, providing symptomatic relief, help with activities of daily living, helping the patient remain hydrated, and emotional support (Appendix 1).

PREVENTIVE MEASURES FOR THE CAREGIVER

Attention should also be given to the person(s) caring for the patient with influenza in the home to protect him/her from the disease. This would include influenza immunization, with or without an antiviral medication for two weeks, instruction on effective handwashing, wearing a mask when providing care or when the patient is coughing, getting adequate rest, consuming five to nine or more fruits, fruit juices, and vegetables each day, and drinking eight glasses of water every day (Appendix 2).

SELF-CARE

Of course, the most important aspect of self-care is obtaining the immunization. However, should one develop influenza and not be at high risk for complications, there are a few general steps to speed recovery and protect others [105]:

- Consider obtaining an antiviral if flu is in the first or second day of illness.

- Stay home to protect others from infection.

- Get plenty of rest.

- Drink plenty of liquids.

- Do not drink alcohol or use tobacco products.

- Consider over-the-counter medications to relieve the symptoms.

- Cover coughs and sneezes.

- Wash hands well and frequently, especially after coughing or sneezing.

OBSERVATIONS INDICATING URGENT MEDICAL HELP IS NEEDED

By keeping a written record of observations, a patient's subtle changes become more apparent, and the information will also help a physician. As discussed, there are many diseases that initially present like influenza or conditions that can be complicated by influenza; therefore, each person with influenza should be watched. The patient with influenza usually starts to improve after a few days. Patients and/or caregivers should be given a list of symptoms that indicate when a physician should be notified (Appendix 3). Any difficulty in breathing, a fever that is not responding to antipyretics, change in mental state, inability to maintain hydration, or worsening of symptoms should be reported to a physician, or the patient should be taken to the emergency room if a physician is unavailable.

The healthcare professional should review the following items with patients with influenza or their family member(s), so a physician can be notified appropriately and promptly [105]:

- High or prolonged fever

- Breathing (fast or difficult with retractions in children, or cyanosis, labored breathing, shortness of breath, or pain or pressure in the chest in adults)

- Inadequate fluid intake (e.g., fewer wet diapers, darker urine)

- Changes in mental status (e.g., hard to arouse, confusion, too irritable to be comforted)

- Fainting or near-fainting, seizures

- Severe or persistent vomiting

- Worsening of a chronic disease

- Worsening of influenza symptoms, increasing weakness

- Any rash or jaundice

- Dry cough that becomes productive

THE PATIENT WITH INFLUENZA IN THE HOSPITAL, MEDICAL OFFICE, OR CLINIC

Infection control procedures should be followed carefully as soon as any contact with a patient with influenza occurs so that transmission can be prevented. In order to protect staff, posters prominently displayed or warning signs at the sign-in desk should request that the staff be informed if the patient has any respiratory symptoms.

Patient education posters about flu, the vaccine, and cough etiquette should be displayed in emergency rooms, waiting rooms, exam rooms, elevators, and other appropriate traffic areas used by patients and visitors. Messages should be brief but clear. Pictures could also be included for children who cannot read or for non-English speakers. All education materials should be provided in the major languages of the community.

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such a vital aspect of the prevention and treatment of influenza, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.

Educational materials might include:

Cough Etiquette

- Cover your cough.

- Use a tissue.

- Throw the tissue away in the wastebasket.

- Wash your hands.

- Tissues and wastebaskets should be easily accessed.

Handwashing

- Use soap.

- Rub your hands well to make a good lather.

- Rub your hands for 15 seconds.

- Rinse well.

- Dry with a paper towel.

- Turn off water with a paper towel.

- Throw the paper towel in the wastebasket.

If no facilities to wash hands are available, alcohol-based hand cleaner should be available.

When influenza is present in the community, patients who are coughing should be given a mask and asked to sit in a separate area. If a separate area is not available, they should be at least 3 feet away from other people. Masks can be the surgical masks with ties or procedural masks with ear loops. They do not need to be respirator N95 masks.

Staff involved with patients who have respiratory symptoms with fever should follow droplet precautions as developed at their work place. For all patient contact, a mask (surgical or procedural) should be worn. Hands should be washed thoroughly following contact. During an epidemic, staff circulating between floors in the hospital should be limited [106].

12. AVIAN INFLUENZA

The influenza viruses that are carried by birds, both domesticated and wild, rarely have infected humans. This is partly due to the fact that avian influenza (AI) viruses attach to receptors found on bird cells but not found on human cells. Human viruses prefer the receptors found in the human respiratory tract. Pigs have receptors used by avian, swine, and human influenza viruses and have traditionally been the link between avian and human influenza viruses. Because pigs acquire all three types of viruses, reassortment/antigenic shift of the hemagglutinin and neuraminidase proteins occurs in the pig host, which then transmits the new strain to humans or other pigs [14,107].

However, there now exists evidence that avian influenza can spread directly to humans [107]. In 2004, areas of Asia experienced large-scale outbreaks of avian influenza, specifically the H5N1 virus, in poultry. The virus went on to infect humans, with a high mortality rate. The number of countries, people, and animals affected by the virus reached unprecedented levels. In 2006, the CDC summarized the H5N1 outbreak. Wild birds and poultry had been infected in Asia, parts of Europe, the Middle East, and Africa. Human infections continued to be reported in China, Egypt, Indonesia, Azerbaijan, Cambodia, and Djibouti. There were some probable human-to-human transmissions of H5N1, but these were rare. As of October 2016, there had been more than 850 human cases of H5N1 since 2003, with a continued fatality rate of approximately 53% [108,109]. In 2013, an outbreak of H7N9 virus in China spread to humans, with 14 reported infections and 6 deaths in the first two months [110]. Both the CDC and the WHO have reported that there is a strong threat of a future pandemic of avian influenza and that preparedness is vital [111,112].

Although influenza A viruses can infect all birds, domestic poultry flocks are more vulnerable to infections that can reach epidemic proportions. Generally, domesticated fowl transmit the virus in saliva, nasal secretions, and feces. However, it is thought that the fecal-oral route is the common way the virus is spread among flocks. Wild birds rarely become sick but are a source of infection through their droppings because they carry the virus in their intestines. Free-roaming domestic fowl are at more risk from wild bird droppings than housed flocks. Both food and water supplies can be contaminated by droppings or sharing with wild birds. At first it was thought that wild birds spread the virus from farm to farm, but further study indicated that people and equipment probably spread the virus to domesticated flocks [113,114].

AI viruses are classified as low pathogenic and high pathogenic based on their genetic sequence and the resulting illness in birds. Low pathogenic AI has been detected in wild birds, mostly ducks, geese, and gulls, since 1975 [115]. Low pathogenic AI virus causes only ruffled feathers and a reduction in egg production. Fortunately, most AI viruses are low pathogenic; however, in six to nine months, they can mutate to high pathogenic. High pathogenic AI viruses, first noted in 1878 in Italy, are highly contagious, spread rapidly, and are almost 100% fatal. Fowl can die the same day that they first exhibit symptoms [115,116,117].

Whenever an AI virus infects a human directly, there is much concern. Humans rarely have any immunity to AI viruses. Medical resources around the world quickly mobilize when there is a case of AI that skips reassortment in swine and directly infects a human. Fowl within a 2-mile (3-kilometer) radius of the source bird/flock are killed in order to contain the virus. An AI virus in humans usually produces upper respiratory disease and conjunctivitis. The infected humans and their contacts are watched closely for secondary transmission. For a pandemic to follow, these factors are needed:

- Humans do not have immunity to the virus

- Direct transmission from bird to human

- Sustainable transmission from human to human

- Movement of infected/contagious individuals to other geographic locations

Once a new pandemic influenza virus emerges, it generally circulates for many years [113,116]. Researchers at the University of Wisconsin, Madison, have been combining H5N1 with a seasonal flu strain (H3N2). As a result, they have found such reassortment flu viruses are highly pathogenic; 22 were more pathogenic for mice than the original H5N1, and three caused extremely severe disease [118].

AVIAN INFLUENZA VIRUSES

The hemagglutinin antigens that historically have caused human influenza are H1, H2, and H3. Although all known hemagglutinin subtypes occur in birds, H5, H7, H9, and H10 have been implicated more in recent outbreaks. Various combinations with the neuraminidase antigens occur. All of these AI viruses are type A, as B and C do not infect birds. Some of the cases focused on in the past decades have included the following [111,119,120,125]:

- H5N1 – Hong Kong, 1997, first documented human infection–18 hospitalized, 6 deaths, 1.5 million chickens culled

- H9N2 – Hong Kong, 1999, 2 mild cases in children, several in mainland China

- H7N2 – Virginia, 2002, 4.7 million chickens and turkeys culled

- H7N7 – Netherlands, 2003, 80 poultry workers, 3 family members infected (79 eye infections, 6 influenza-like), one veterinarian death due to acute respiratory distress syndrome and complications

- H5N1 – Hong Kong/China, 2003, 2 ill, death

- H9N2 – Hong Kong, 2003, 1 case confirmed in a child

- H5N1 – Asia, 2004–2005 (H5N1 had been found in Asian chickens April, 2003), 112 confirmed cases, 57 deaths; too widespread to cull all fowl

- H7N3 – British Columbia, 2004, 2 ill

- H5N2 – Taiwan, 2004, low pathogenic, no human illness

- H7N2 – Delaware, 2004, no human illness

- H5N2 – Texas, 2004, no human illness

- H5N1 – Russia/Romania/Turkey/Azerbaijan/Egypt, 2006, some human illness, unknown deaths

- H7N9 – China, 2013–2017, 1,222 confirmed cases, 40% mortality rate

Fortunately, although in some of these outbreaks bird-to-human transmission did occur, human-to-human transmission has been extremely rare. Limited transmission possibly did occur between humans in the Netherlands, but no sustainable transmission occurred, so an epidemic or pandemic did not follow. There were 14 cases and 12 deaths (11 children) from H5N1 virus in Vietnam. The viruses isolated from those who expired in Vietnam were mostly resistant to amantadine and rimantadine. Studies are continuing as to the effectiveness of oseltamivir and zanamivir against H5N1 viruses. There is some evidence that the 2004 H5N1 virus in Asia is sensitive to oseltamivir [113,114,116]. However, some evidence of resistance to oseltamivir has been reported in highly pathogenic avian influenza H5N1 viruses isolated from human cases [122]. Most of the 2004 H5N1 outbreaks were controlled by veterinarian officials or spontaneously died out. However, H5N1 continues to fulminate in poultry in Egypt [123].

AVIAN INFLUENZA AND HUMANS

Most cases of AI in humans have resulted from contact with infected poultry or contaminated surfaces. It is also possible for the virus to become aerosolized and then land on exposed surfaces of the mouth, nose, or eyes. Aerosolized virus could also be inhaled directly into the lungs. Eating poultry products has not been associated with the development of AI. Influenza viruses are destroyed by adequate heat. Because of the pathogens found in poultry, all patients should be reminded to cook all poultry, including eggs, thoroughly. Chicken should be cooked until the internal temperature reaches 180 degrees F. All utensils and surfaces that have come in contact with raw poultry should be washed well with soap and water immediately following use. A separate cutting board should be used to cut raw poultry. In order to retard bacterial or viral replication, all poultry products should be defrosted in the refrigerator, not at room temperature.

Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit poultry to be imported from countries in which there were detections of AI, such as China's ban of U.S. chicken in 2015. However, the risk of AI spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or chilled. All documented transmission to date has been from live birds [124,125].

Humans have no immunity to AI viruses, so illness tends to be severe and the fatality rate high. Prevention is difficult because the viruses tend to be highly contagious. Because of the mobile nature of people and efficient, rapid transport, any virus can spread quickly around the world. The current manufacturing process of influenza vaccine requires several months. The elements are all in place for a pandemic.

In 2007, a team of scientists at the National Institute of Allergy and Infectious Diseases reported that it had developed a way to generate vaccines and therapeutic antibodies that could target constantly mutating influenza viruses, such as H5N1. The team focused on mutations that enable H5N1 hemagglutinin protein to better recognize and enter human cells and those mutations that will elicit antibodies. This information will enable researchers to consider how to design potential vaccines that will protect people from future emerging AI virus mutants, possibly helping to contain a pandemic in its early stages [126].

In order to understand how influenza viruses mutate, researchers have been working to synthesize the hemagglutinin responsible for the 1918 influenza ("Spanish flu") pandemic. The success of this endeavor was reported in 2004, and scientists have since discovered how subtle alterations enabled the virus to move from birds to people [127].

The H5N2 avian influenza virus continues to be monitored around the world by scientists. It is highly virulent but has not been transmitted person to person yet [4,112]. In 2015, H5N2 avian influenza virus (along with H5N8 and H5N1) were found in more than 200 bird samples, indicating the likelihood that 40 million farm and backyard birds had been infected in 20 states [48].

PREVENTING OR LESSENING THE EFFECTS OF A PANDEMIC

Vaccine Development

As with the development of all vaccines, the first step is to isolate the organism. In the case of AI, various research centers and companies around the world are working to make a vaccine. The first step is to isolate the virus (e.g., the H5N1 influenza A virus in 2004). Next, the virus is dismantled so the most virulent elements can be excluded. Then the virus is reassembled without those virulent elements, and attempts are made to produce it [124]. As noted, the virus has been isolated and the virulent elements have been identified to allow vaccine development to proceed. In 2006, a new recombinant H5N1 virus became available for distribution to companies interested in pandemic vaccine development [128]. In 2007, GlaxoSmithKline received a contract from the U.S. Department of Health and Human Services to manufacture 22.5 million doses of AI vaccine in addition to the 5 million doses ordered in 2006 [129]. Research to find novel media or methods (rather than using eggs) is ongoing [130].

In 2007, the FDA approved the first human vaccine for the AI virus H5N1 [131]. This vaccine is intended for individuals 18 to 64 years of age who could be at an increased risk of exposure to the H5N1 influenza virus. The vaccine is not available commercially, but rather has been purchased by the federal government to be distributed if necessary. The vaccine consists of two 1-mL IM doses given 21 to 35 days apart (optimum: 28 days). There is thimerosal in this vaccine [45,131]. Because this vaccine has been approved by the FDA and found to be safe and effective, it is no longer considered experimental. Therefore, it can be used during a pandemic without the time-consuming protocol and signed informed consent necessary for an experimental drug or vaccine [131]. In 2013, the first adjuvanted H5N1 vaccine, Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted, was approved for individuals 18 year of age and older. The vaccine is not for commercial use, but at least 20 million doses are stocked at the Strategic National Stockpile for emergency release [53].

Antiviral Stockpile

Another plan is to gather a supply of effective antiviral medications to use not only to treat AI but also to use as a preventive treatment if a vaccine is not available. As discussed, some testing of the four antivirals available has been done with the H5N1 virus, which produced mass illness in Asia in 2004. So far, only oseltamivir was shown to be effective. More research is needed [114]. Some have suggested combining probenecid and oseltamivir to enhance effectiveness and to stretch limited oseltamivir supplies [132].

It is not known if other AI strains will be sensitive to oseltamivir or to any of the other antivirals. The suggestion has been made to stockpile antivirals so they would be available in a pandemic. Logically, it would make sense to include the effective antiviral medications in the Strategic National Stockpile and use the same distribution system and overall protocol in managing them [133].

Increased Interaction Between Veterinary and Human Disease Experts

Because of the rapid spread of avian influenza among flocks in Asia in the spring of 2004, the need for more involvement and communication between animal and human experts became apparent. No reporting of animal diseases is required by the WHO. However, the Global Early Warning System combines and coordinates the disease intelligence mechanisms of the United Nations Food and Agriculture Organization, the World Organization for Animal Health, and the WHO to provide the international community with information about the prediction, prevention, and control of animal disease threats [134]. In addition, the World Organization for Animal Health monitors avian influenza outbreaks in its member countries (including the United States) [28]. Human medical practitioners are not trained in the subtle indications of animal illnesses, nor are they usually aware of early indications that an epidemic is developing. Veterinarian expertise is also needed to institute the best measures for containing the illness and limiting transmission not only to animals but to humans as well [135].

Travelers

During the outbreaks of AI in poultry in Asia during 2003–2004, people were not restricted from traveling to outbreak areas because of the limited transmission to humans. However, the following recommendations were sent to embassies and Americans living abroad [136]:

- Practice frequent and careful handwashing with soap and water or with a hand cleanser if soap and water are unavailable.

- Avoid bird markets and poultry yards where AI is most likely to be transmitted.

- All poultry and eggs should be cooked well as influenza virus is destroyed by heat.

- Masks and other personal protective equipment in public areas are not recommended.

Travelers should be immunized with the current influenza vaccine against human influenza strains before traveling and should be reminded that winter (i.e., flu season) occurs in the Southern Hemisphere when the Northern Hemisphere is experiencing summer.

Limiting Introduction of Avian Influenza to Other Countries

The CDC has developed guidelines for airline personnel with a suspected case of AI on board an international flight originating in an area in which AI has been reported [137]:

- As much as possible, airline staffs are to keep the sick person separated from close contact with others.

- A surgical or procedural mask should be provided to limit the amount of droplets coughed into the air. If the passenger cannot wear the mask, anyone assisting him/her should be masked.

- Staff should teach the passenger cough etiquette if it is not being practiced.

- Disposable gloves are to be worn for any contact with body fluids, and hands are to be washed well when gloves are removed.

The captain is to report the illness to the nearest U.S. Quarantine Station if the aircraft is coming to the United States. The Quarantine Station will coordinate appropriate medical assistance when the plane lands and will notify the appropriate CDC staff.

In addition, general precautions of handwashing and covering coughs are, as always, important. Should flight personnel or ground staff become ill and believe they have been exposed to AI, they should notify their employer. If they are away from home, they should obtain local medical help. On any visit to a medical practitioner, they should inform the staff of the possible exposure to AI [137].

Limiting Continuing Disease and Transmission Among Fowl

The major way to limit disease and transmission among domesticated fowl is to destroy all diseased birds and their flockmates. Because the virus appears to be carried by people and machines, possibly on shoes and tires, to surrounding areas, the recommendation is that all fowl in a 2-mile (3-kilometer) radius of the diseased flock be culled. Obviously, no shipping of live poultry from the infected areas should occur.

Those culling the flocks are vulnerable to infection because they will be dealing with diseased birds, exposed to their feces, or inhaling dust/dirt contaminated with the feces. Therefore, cullers must have personal protective equipment: coveralls or a surgical gown with long sleeves and an impermeable apron, heavy duty rubber gloves or disposable nitrile or vinyl gloves, rubber boots or disposable shoe covers, N95 respirator masks, and safety goggles. Frequent effective handwashing is important. All cullers should have received the current influenza vaccine so they will not acquire the circulating influenza and provide an opportunity for reassortment with the AI strain. Cullers should be monitored by the local health department and be provided information on the ways to prevent infection. They should be instructed when to call the practitioner and to always tell the practitioner that they have been exposed to AI. Persons who are at high risk for complications from influenza should not be employed as cullers. Medical personnel who have contact with cullers should make sure that the cullers have received the current influenza vaccine, understand the symptoms of the flu, realize that eye infections are common, and understand the importance of following the protective guidelines, including how to effectively wash their hands. The CDC states that treatment with an antiviral may be considered for workers involved with culling flocks of known infected birds, but does not recommend routine use of chemoprophylaxis of workers involved in culling non-infected birds as a preventative measure [31,138]. Whether personal protective equipment was used correctly, the type of exposure, and risk of complications from illness should be part of clinical decision making. Oseltamivir or zanamivir (one dose twice daily) is recommended versus the typical antiviral regimen (once-daily dose) for exposed individuals who require chemoprophylaxis [31].

Those who dispose of the carcasses and those who are cleaning and disinfecting the environment where the flocks were housed are also at risk. The viruses can survive for varying periods of time, in some cases up to weeks or months, depending upon the temperature and humidity. For personal protection, those who dispose of the carcasses should follow the same recommendations as the cullers [31,138].

All workers involved in eradication efforts should be monitored for respiratory symptoms, fever, and conjunctivitis for one week after the last involvement with the diseased birds or their environment. If they seek medical care, they should be instructed to tell the practitioner that they were working with birds that had AI. Other than seeing the practitioner, all symptomatic personnel should stay home until their temperature has been normal for 24 hours. To protect their families, they should cover all coughs and dispose of the tissues safely, wash their hands well, and try to limit any face-to-face contact with others [151].

In handling environmental cleanup, it is important to note that the virus is killed by heating to 56 degrees C (132.8 degrees F) for three hours or to 60 degrees C (140 degrees F) for 30 minutes. Formalin and iodine compounds will also kill AI. When the temperature is cool, the virus can survive for three months in contaminated manure. It can survive for four days at 22 degrees C (71.6 degrees F) in water and for more than 30 days at 0 degrees C (32 degrees F) [116].

The culling of millions of birds has an economic impact on the owners and countries in which the culling must be done. However, the more widespread the virus is in any country or countries, the more opportunity there is for transmission to humans. Each AI in a human increases the possibility that co-infection with a human influenza virus can occur leading to reassortment of the antigens and a new virulent influenza virus that can be transmitted person-to-person [116].

Limiting Transmission of Influenza by Medical Treatment

If a patient is known to have or is suspected of having respiratory AI, he or she should be segregated in the waiting room, be provided with a surgical or procedural mask, be given tissues and a way to dispose them, and not be kept in the waiting room for an extended period.

A nasopharyngeal swab or aspirate should be collected and sent to the local public health laboratory. It is important to keep the local health authorities aware of any such suspected illness so that the full use of available resources can be made, if necessary. The specimen should then be forwarded to the state laboratory for reverse transcription-polymerase chain reaction (RT-PCR) for influenza A analysis and, if possible, for H1 and H3 analysis. Should the state not have the capacity to perform these tests, or if the tests are positive, the specimen should be sent to the CDC. Only a level 3+ laboratory should attempt to isolate the virus. Blood should be collected and stored locally for an acute (within one week of symptom onset) and convalescent (after three weeks of symptom onset) specimen to test for AI antibodies [38].

Medical practitioners should also be alert to ask all patients with respiratory symptoms and fever if they have traveled to any area in which AI is reported [139].

Increase Detection and Surveillance Systems

Early detection is another way to handle AI so that proper containment procedures can be initiated as soon as possible. As discussed, both the CDC and the WHO are working to increase surveillance in countries around the world [134,140]. Hopefully, all countries will be able to detect and acknowledge the presence of a disease before it becomes widespread and the death toll escalates [116].

13. SWINE INFLUENZA

As discussed, pigs represent an important link in the interspecies transmission of influenza and in the creation of new virus types. In addition, swine influenza has the potential to cause significant disease in humans, although it is difficult to predict the potential impact of swine influenza in humans. Because most individuals, with the possible exception of those with regular contact with pigs, do not have immunity to these viruses, the potential for pandemic exists.

Swine influenza is usually caused by the H1N1 subtype, but other swine influenza A viruses do occur, including H1N2, H3N1, and H3N2 [141]. Although swine flu viruses do not normally infect humans, sporadic human infections have occurred. When this occurs, these viruses are called "variant viruses" and are denoted by adding the letter "v" to the virus subtype designation. Human infections with H1N1v, H3N2v, and H1N2v viruses have been detected in the United States [141]. Pigs may become infected with more than one virus subtype simultaneously; in these cases, genes from the viruses may mix and create a new "reassortment" virus [142]. The main swine influenza viruses circulating in U.S. pigs in the past decade include triple reassortant (tr) H1N1, trH3N2, and trH1N2 [141].

Among pigs, swine influenza is a highly contagious acute respiratory disease. In many countries, including the United States, swine populations are routinely vaccinated against the prevalent subtypes. Vaccination of pigs, while not sufficient to produce sterilizing immunity, can reduce the levels of virus shed by the animals and reduce the potential for human exposure and infection [143].

In 2009, an outbreak of H1N1 influenza A (hereafter referred to as 2009 H1N1), popularly referred to as the "swine flu," occurred. Tests showed this virus was similar to influenza viruses normally occurring in pigs in North America. However, with more extensive testing, scientists learned that there were two genes present that typically occur in pigs in Europe and Asia. In addition, there were also avian and human genes. A quadruple reassortment virus was the result [11,144].

It should be noted that the so-called Spanish Influenza of 1918–1919 was also an H1N1 virus. The hemagglutinin gene in 2009 H1N1 influenza apparently descended from the avian-origin 1918 pandemic influenza virus; however, laboratory testing showed that 2009 H1N1 did not have any 1918-like markers that had been associated with increased risk of severe disease, nor did it have genetic markers that were previously associated with high death rates in people infected with the avian influenza A (H5N1) virus in other countries [144].

The 2009 H1N1 virus was first detected in the United States in April 2009. Laboratory testing at the CDC confirmed infection with the virus in two patients, 8 and 10 years of age, who lived 130 miles apart, who had no contact with pigs, and who had no known connection to one another. Sporadic reports of human infection with North American-lineage swine influenza virus in the United States had been reported from December 2005 to January 2009, but the detection of infection in the two children raised concern that a novel swine-origin influenza virus had made its way into the human population and that human-to-human transmission of the virus had occurred. By September 2009, more than 99% of the circulating viruses were 2009 H1N1 [144].

The 2009 H1N1 virus was not a new subtype, but many humans had no pre-existing antibody to it (especially those younger than 65 years of age). The virus quickly spread worldwide, and on June 11, 2009, the WHO declared it a worldwide pandemic [144]. The 2009 H1N1 virus remained the predominant circulating virus for the entire 2009–2010 influenza season [11,145]. On June 23, 2010, the public health emergency for 2009 H1N1 expired in the United States, and the WHO declared the pandemic over on August 10, 2010 [146].

Data from past pandemics show that influenza activity occurs in waves. A second wave of 2009 H1N1 occurred in the fall of 2010 and peaked in the first three weeks of October [8]. Experts believe that 2009 H1N1 will continue to circulate for some time as a typical winter flu, as it did extensively in 2012–2013 and 2015–2016. It is included in the formulation of the 2021–2022 vaccine [8].

TRANSMISSION

Like all flu viruses, 2009 H1N1 is mainly spread among people by coughing, sneezing, talking, and occasionally via fomites. It is not spread by food or by eating pork or pork products. There have been no cases acquired from influenza-contaminated drinking water. Chlorine treatment of drinking water has been shown to inactivate the highly pathogenic H5N1 virus, and H1N1 would be similarly affected. A documented case of influenza from any water exposure (drinking or recreational) has not occurred.

Pets, such as dogs, cats, and ferrets, can be infected with H1N1 from close contact with a sick human. All available information indicates that H1N1-infected dogs, cats, and ferrets do not transmit the illness to humans. So far, there is no H1N1 vaccine for animals. Most recover with supportive care [11].

When a swine influenza virus does become a source of widespread human illness, the transmission patterns change. Instead of being mainly limited to swine contact, the virus will spread by human-to-human contact. According to the CDC, available data indicate that the 2009 H1N1 virus is transmitted in ways similar to other influenza viruses, primarily via large-particle respiratory droplet transmission [92]. Because humans have little to no immunity to influenza viruses of swine origin, transmission may be common.

H1N1 survives on surfaces, including kitchen counters, door knobs, desk tops, and other fomites, for two to eight hours. Individuals can pick up the virus when they touch contaminated objects and unconsciously then touch their eyes, mouth, or nose. Thus it is vital for people to learn to keep their hands away from their mouths, eyes, and nose and to frequently wash their hands well with soap and water or use an alcohol-based hand sanitizer. An alcohol-based product, bleach solution, or hot, soapy water can be used to clean surfaces [148]. One positive result of the H1N1 pandemic, as indicated in a study conducted in Hong Kong, was that people were washing their hands more frequently and wearing face masks when having ILI or in public areas [149].

A major transmission concern with 2009 H1N1 was regarding newborns whose mothers had the virus. The CDC and State Health Departments strongly recommended vaccination for this population because of demonstrated risks to both infants and pregnant women. However, many disregarded the recommendation. It was then decided that infant and mother should be separated until the mother had been on antivirals for at least 48 hours, was afebrile for 24 hours without antipyretics, and could control her cough and respiratory secretions. Before visiting the infant, the mother was instructed to clean her hands well with soap and water or an alcohol-based hand sanitizer, wear a face mask, and observe respiratory/cough etiquette. If her gown had been contaminated with byproducts of coughing or sneezing, she was instructed to change to a fresh gown. Following these guidelines, the mother was then allowed to hold, feed, and care for the infant [8].

PREVENTION

Like seasonal influenza, vaccination is the most important preventive measure. Other common sense preventive steps (e.g., appropriate cough cover, correct disposal of used tissues, adequate rest, good fluid intake, staying home when ill) should also be practiced.

Vaccine

The CDC identified five groups who were given first priority vaccination [144,150]:

- Pregnant women

- Persons who live with or provide care for infants younger than 6 months of age

- Healthcare and emergency medical services personnel

- Children and young adults 6 months to 24 years of age

- Persons 25 to 64 years of age at higher risk for influenza-related complications

The ACIP also recommended that local public health authorities and healthcare practitioners have flexibility to determine how quickly and when to expand vaccination to other groups [144]. The priority patients were vaccinated as soon as the vaccine was available. The CDC recommended that children younger than 10 years receive two doses of influenza vaccine [144]. For the 2018–2019 flu season, the ACIP recommends that children 6 months through 8 years of age who are receiving influenza vaccine for the first time be given two doses at least four weeks apart [8].

SYMPTOMS

Similar to seasonal flu, H1N1 symptoms include chills, fever, myalgia, fatigue, headache, cough, sore throat, and rhinitis. But unlike seasonal flu, there may be vomiting and diarrhea in some people. Others may have respiratory symptoms without fever [11,152].

DIAGNOSIS

Unless it becomes a pandemic, swine influenza infection in humans generally goes undistinguished from typical human influenza as a result of the overlapping flu seasons and the relatively mild clinical presentation. The disease is diagnosed by analysis of a sputum sample collected in the first four to five days of illness, when an individual is most likely to be shedding the virus [153]. In June 2010, the FDA authorized the CDC Influenza 2009 A (H1N1)pdm Real-Time RT-PCR panel (IVD) to detect human infections with 2009 H1N1. This test replaced the previous real-time RT-PCR diagnostic test authorized by the FDA in April 2009, just as the WHO declared that a pandemic was imminent [144,154]. There are now several RT-PCT and other molecular assays available to differentiate 2009 H1N1 [155].

In the case of the 2009 H1N1 virus, the CDC recommended that clinicians not routinely test for the virus when it was known to occur in the community, but that testing be prioritized in people who were hospitalized with suspected flu and in people for whom a diagnosis of flu would help their physician make decisions about their care [155]. As the 2009–2010 H1N1 epidemic progressed, it became apparent that those younger than 65 years of age were at greatest risk (Table 4) [8].

Table 4: DISTRIBUTION OF 2009 H1N1 AND SEASONAL INFLUENZA BY AGE GROUP

Influenza Type

0 to 17 Years

18 to 64 Years

0 to 64 Years

65 Years and Older

Cases

2009 H1N1

33%

57%

90%

10%

Seasonal

—

—

<10%

90%

Hospitalizations

2009 H1N1

32%

58%

90%

10%

Seasonal

—

—

40%

60%

Deaths

2009 H1N1

10%

77%

87%

13%

Seasonal

—

—

10%

90%

Source: [8,150]

TREATMENT

While most swine influenza cases were sufficiently mild to resolve spontaneously, antiviral medications were used if treatment was indicated. The specifically recommended agents were determined based on clinical and epidemiologic assessment of the virus. For example, in the case of the 2009 H1N1 outbreak in North America, the virus's susceptibility profile indicated that the preferred antivirals would be oseltamivir or zanamivir [156].

During the 2009–2010 H1N1 pandemic, the CDC recommended antiviral treatment for all persons with suspected or confirmed influenza requiring hospitalization [145]. In addition, early empiric treatment with oseltamivir or zanamivir was considered for persons with suspected or confirmed influenza who were at higher risk for complications, including [145]:

- Children younger than 2 years of age

- Persons 65 years of age or older

- Pregnant women and women up to two weeks postpartum (including following pregnancy loss)

- Persons of any age with certain chronic medical or immunosuppressive conditions

- Persons younger than 19 years of age who are receiving long-term aspirin therapy

The recommended treatment for adult and adolescent patients is either 75 mg oseltamivir twice per day or 10 mg (two 5-mg inhalations) of zanamivir twice daily [45,145]. Children 7 years of age and older may be treated with the adult dose of zanamivir. However, calculating oseltamivir doses for children is more complicated and has been the source of medical errors [157]. It is important to note that while healthcare providers in the United States generally write prescriptions for liquid medications in milliliters, oseltamivir is dosed in milligrams [157]. For infants 2 weeks of age or older, the oseltamivir dosage is 3 mg/kg twice daily [45]. For children between 1 and 12 years of age, dosage is based on weight [45,145]:

- <15 kg (<33 lbs.): 30 mg twice daily

- >15 kg to 23 kg (>34 lbs. to 51 lbs.): 45 mg twice daily

- >23 kg to 40 kg (>51 lbs. to 88 lbs.): 60 mg twice daily

- >40 kg (>88 lbs.): 75 mg twice daily

Treatment should continue for five days [45]. Pregnancy is not considered a contraindication to the use of oseltamivir or zanamivir.

As of 2015, 2009 H1N1 was susceptible to both oseltamivir and zanamivir, with a few exceptions [96,103]. Those resistant to oseltamivir have been sensitive to zanamivir. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, but the public health impact has been limited [103]. As of 2015, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide [103].

INVESTIGATIONAL DRUGS

A study at Utah State University examined the use of oseltamivir combined with T-705 (favipiravir), an antiviral in late-stage development by Toyama Chemical of Japan, on mice [158,160]. This combination was effective against H1N1, H3N2, and H5N1 influenzas. The study indicated that two antivirals may be a better strategy for treatment of humans with influenza. Favipiravir is a viral RNA polymerase inhibitor with a novel mechanism of action, inhibiting viral gene replication within infected cells to prevent their propagation [160].

14. INFLUENZA PANDEMIC

Should methods for containment of a new avian or swine influenza virus fail, a worldwide epidemic or pandemic could follow. Because the population has no immunity to the new strain, millions of people could be infected and several million could die. The 1918 pandemic afflicted 20% to 40% of the world's population and caused 50 million deaths, at least 675,000 of which were in the United States [161]. As a comparison, "seasonal" flu generally affects less than 20% of the population [162]. The WHO estimates that there would be 233 million outpatient visits, 5.2 million hospitalizations, and 7.4 million deaths globally within a very short period of time were a pandemic to occur [163]. Waves of the outbreak could occur in any given community for approximately six to eight weeks, then reoccur months later, affecting the global population for one to two years [161]. The resulting strain on resources would be far more severe than a terrorist attack that is localized to one or a few areas and lasting from a few minutes to hours. However, planning for a bioterrorist attack and an influenza pandemic have many similarities, and each can enhance the other [164].

Medical practitioners, emergency departments, and clinics, especially walk-in facilities, will be the first contacts in a pandemic. Having a high index of suspicion is vital to help slow the spread of the disease. Checking the CDC weekly influenza reports will help to clarify suspicions [166]. Experience during the 2004 SARS outbreak in Toronto showed that, once SARS was recognized, infection control measures worked well to protect the medical community and facilities. The public health infrastructure was active, strong, and responsive, ensuring that public health in a major urban center was also protected [167].

The WHO has defined phases for a pandemic that reflect a global risk assessment of each influenza virus with pandemic potential [168]:

- Interpandemic phase: The period between influenza pandemics

- Alert phase: Influenza caused by a new subtype has been identified in humans, and the population has little or no immunity to the virus. This may be a precursor to a pandemic.

- Pandemic phase: A period of global spread of human influenza caused by a new subtype with sustained person-to-person transmission. Multiple cases occur in the same geographic area.

- Transition phase: As assessed global risk reduces, de-escalation of global actions may occur, and reduction in response activities may be appropriate.

The CDC has developed guidelines for public response in a pandemic situation. These stress that people should stay away from crowds, avoid close contact with anyone at work or school, stay home if they or anyone in the household is sick, wash hands frequently, practice covering all coughs and sneezes, and dispose of tissues safely.

Many people think they will be protected in a crowd if they wear a mask, but there is little scientific data proving that masks protect against the flu. Industrial masks/N95 respirators should be considered for caregivers. N95 masks must fit closely (no air leaks) to be effective. Masks that become damp or wet cease to be protective. Proper disposal of a mask is imperative, as it has the potential to become a source of infection rather than protection [106,169].

PLANNING FOR A PANDEMIC

In planning for the inevitable pandemic, five areas should be covered. These include: surveillance and laboratory issues, communication, community services, medical care, and vaccines and drugs. In 2006, the California Department of Health Services developed the Pandemic Influenza Preparedness and Response Plan [170]. The plan was then revised in 2007. The 2007 plan includes sections on pandemic influenza surveillance and epidemiology, laboratory testing capacity, healthcare planning, infection control in the healthcare setting, case management, vaccine programs, antiviral drug programs, community disease control and prevention, and risk communication. These sections cover the responsibilities of the medical community (health practitioners, hospitals, and clinics) and public health departments and include prevention and mitigation plans [170].

Surveillance and Laboratory Issues

This area includes establishing global and local data collection systems in order to determine expected disease rates in humans and animals so that an increase is recognized as quickly as possible. It also includes developing laboratory infrastructure and expertise to handle specimens correctly and accurately. The CDC is a WHO Collaborating Center that plays a major role in identifying antigenically drifted seasonal and novel influenza A viruses that possibly have pandemic potential [171]. The CDC's Influenza Division conducts surveillance throughout the year and collects and analyzes influenza viruses from around the world for antigenic (immune response), antiviral susceptibility, epidemiology, and genetic characterizations.

Communication

The second planning area is communication among all those who will be involved in a response on local, state, and federal levels. The Federal Emergency Management Agency requires that all planning for various hazards/disasters/terrorist acts follow the Incident Command System (ICS) [172]. This system provides a structure for the flow of information to the participants providing the response and back to those in authority. An influenza pandemic would require multiple agencies, organizations, and community groups to effectively respond, so in many areas, they would be under the local ICS.

In addition, communication includes relaying accurate, frequent, concise, and timely information to the public by a primary spokesperson. Health experts should use interactions with media personnel to provide educational points about the transmission, prevention, and symptoms of influenza. Such points, referred to as "sound bites," are brief, accurate, in common language, and important.

Another area of communication is between individual healthcare providers and patients. Having patient educational materials prepared before the flu season will assist patients to remember what they have been told and increase their participation in preventing the flu, as well as caring for themselves or someone else with the flu. The U.S. Chamber of Commerce has also developed a pamphlet for business owners that lists steps that can be taken to protect employees and to help keep businesses operating in the case of an outbreak [173].

Community Services

One of the facets of a pandemic is the social disruption caused by the illness of so many employees. Therefore, the third area in any preparedness plan is maintenance of community services from healthcare providers, ambulance personnel, police, fire fighters, utility workers, and truck drivers—all the services that are called on daily to maintain life in our communities. This may involve providing vaccine first to healthcare professionals and those responsible for essential services in the community. Some services and work may be done via telecommuting so that more people can stay at home and lessen their exposure to the influenza virus.

Medical Care

Medical care is the fourth area that will be heavily impacted in a pandemic. The local health officer in most jurisdictions has the legal authority to isolate those with symptoms and quarantine those who have been exposed, as needed, to slow the spread of the disease. Equipment and care may have to be prioritized. In a pandemic, multiple geographic areas are impacted, so obtaining help from another area probably will not be possible. Some hospitals, health departments, and other medical facilities are developing lists of physicians and nurses who are either retired or no longer practicing but who would be available to assist during a crisis if needed [174]. Starting in the 2000–2001 flu season, Ontario, Canada, offered influenza vaccine to all its residents to lessen the impact on hospitals. This universal vaccination program reduced the number of cases by 61% and influenza mortality by 28% [8].

If all available hospital beds in the area are in use, it may be necessary to set up a shelter for medically fragile people. Local health departments have plans and agreements with the American Red Cross and other organizations to establish shelters. Normally, these shelters are for people who have been displaced/evacuated because of a natural event (e.g., fire, flood, earthquake). A shelter for medically fragile people has additional equipment and staffing needs. Such a shelter would be for people who require help with medical treatment, such as wound care, medications, and IVs. People who are too sick to care for themselves and who have no one to care for them would be appropriate referrals for a medically fragile shelter [175].

Vaccines and Drugs

The final area to be addressed is the supply and delivery of vaccines and drugs. The objectives of planning are to reduce morbidity and mortality, make sure essential services are available, reduce the economic impact, and equitably distribute the resources [164]. Those with high risk of complications from the flu are generally the first to receive the vaccine if a shortage is anticipated or production is slow. In a pandemic, the decision may be made that healthcare professionals and others providing essential services would be the first recipients of vaccine. Because the vaccine would be completely new to a person's immune system, two doses 30 days apart may be needed to produce immunity, as is the current practice for children 6 months through 8 years of age receiving influenza vaccine for the first time [8].

Nonpharmacologic Interventions

During the influenza pandemic in 1918, large public gatherings continued to be permitted in some areas, most notably in Philadelphia, which served to spread the epidemic and led to a death rate of 719 per 100,000. Cities that had enforced a shutdown of schools, churches, and other gatherings slowed the spread and experienced a death rate of 347 per 100,000. Quarantine, school closings, and public meeting bans cut peak death rates 30% to 50% [176].

In 2007, the federal government established that, in the case of a severe influenza outbreak, schools should be closed for up to three months; sports events, movies, church, and other public gatherings and events should be canceled; working hours should be staggered to decrease the number of commuters using public transportation at any one time; and the use of public transport should be discouraged [177]. Sick people and their families, even healthy members, should stay home 7 to 10 days. Issues of other gathering places, such as daycare centers and malls, will also need to be addressed. Parents should prevent their children from gathering. Measures of isolation (isolating ill patients) and quarantine (isolating exposed persons) should be used to slow the spread of influenza [178]. State borders and airports would not be closed because of the need to transport food and other supplies [177,178].

In New York City, the plan emphasizes the importance of early detection. A monitoring system that tracks 60,000 pieces of information (e.g., ambulance runs, emergency room visits, pharmacy sales) has been developed [179].

A cooperative research project between Azusa Pacific University in California and National Chung Sing University in Taiwan is researching traditional Chinese herbal treatments and their effects on influenza virus subunits to develop alternative treatments, especially for countries in which vaccines or pharmaceutical treatments will be unavailable in a pandemic [180].

CHALLENGES OF A PANDEMIC

For medical care providers, an influenza epidemic presents many challenges. These would be compounded by the increased number of cases in a pandemic. A group in Los Angeles studied the impact on emergency departments and outpatient facilities during seven influenza epidemics. Some of the lessons learned in order to better cope with an increased number of patients were that [147]:

- Elective surgery should be reduced or eliminated.

- Facilities should work with licensing agencies, fire marshals, and other regulators to relax staff-patient ratios and/or bed capacity limitations.

- Additional staff resources for epidemics should be developed.

- Walk-in influenza clinics should be established to triage and treat patients at lower cost.

- Methods to identify additional needed equipment should be developed.

During the SARS outbreak, nurses at Stanford University Medical Center set up receiving areas to prescreen hundreds of patients before they entered the emergency department. Those with ILI were diverted to negative pressure rooms for further testing. Screening questions were used to triage the patients [147]. Table 5 provides a list of questions that could be asked of patients to elicit extra information that may assist in a more rapid diagnosis. These questions should be asked in the receiving area of the hospital, clinic, or office in order to minimize the introduction of highly contagious organisms.

Table 5: ASSESSMENT OF A PATIENT WITH INFLUENZA-LIKE ILLNESS

1. Is this the time of year when influenza is expected?

2. Has the patient done any traveling in the last 10 days? If yes, find out where so the practitioner can relate to any known SARS, avian flu, or other outbreaks in the area. Did the patient travel in an airplane or on a cruise ship?

3. Can the patient pinpoint an exact time when the illness began?

4. Has the patient had any recent contact with any farm animals, such as pigs, cows, chickens, turkeys, ducks, or other birds?

5. In the last few days, has the patient been around anyone who is sick? If yes, find out who was sick, type of contact, when it was, and symptoms of the person who was sick.

6. Is the patient getting sicker or feeling just as bad as when he or she first became ill? Or perhaps feeling a bit better?

7. Has the patient been in any place in the mountains? Did he or she notice any signs warning about plague? What did the patient do there—camp, hike, etc.?

8. Has the patient consumed any raw/unpasteurized milk in the last month?

9. If ricin toxin is suspected, find out the patient's activities in the last 24 hours.

When asking a patient or family member when a symptom began, or other information that depends on recalling one's activities, it is helpful to have a calendar and to refer any symptom to some event that would be easily remembered; for example, "Your sister visited on Tuesday. Did you have the fever then?"

Source: Author

This receiving area would also be a place where educational materials could be provided for the "worried well." In an office situation, it might be possible to set up a small table outside the office door to screen patients and distribute masks and educational materials. Some public health department plans include supplying public health staff to emergency rooms to help answer questions and educate the worried well, allowing the hospital staff to assist in the care of those critically ill.

15. CONCLUSION

Influenza, with its complication, pneumonia, is the only infectious disease that remains one of the top 10 killers in the United States. An effective vaccine to prevent influenza has been available for decades but is underused by both the general public and healthcare professionals. As a result, the economic burden of influenza is billions of dollars, including the inefficient use of healthcare resources.

The threat of biologic weapons has made the control of influenza imperative as many of the possible biologic agents initially may be misdiagnosed as influenza because of similar symptoms. Added to the perils facing the world is the expected pandemic of influenza as the result of the introduction of an avian or swine influenza virus to which humans have no immunity.

16. GLOSSARY OF TERMS

Antigenic drift: Change in an influenza virus that allows it to resist the immunity developed against it. Antigenic drift is a factor behind the need for an annual influenza vaccine.

Antigenic shift: Reassortment of RNA segments involving hemagglutinin and neuraminidase antigens from two different influenza A types in one host cell to create a new influenza type.

Antiviral: A medication that will kill or weaken a virus.

Avian, or bird, influenza (AI): Influenza caused by viruses that occur naturally among wild birds. The low pathogenic variety is common in birds and causes few problems. High pathogenic AI is deadly to domestic fowl and may be transmitted to humans, resulting in high morbidity and mortality rates due to lack of immunity.

Case definition: A standardized precise description of a disease to assist in accurate data collection. Generally, there are three levels in a case definition: suspect, probable, and confirmed. Description for each level is particular to the disease being defined based on clinical symptoms and laboratory findings.

Epidemic: An increase in the expected number of cases of a particular disease. The amount of increase needed to declare an epidemic depends upon the disease involved.

Hemagglutinin: A surface antigen on the influenza A virus indicated in the name of the virus by a capital H followed by the subtype number.

Influenza: Respiratory illness with fever.

Isolation: Separation of a person with a contagious disease from the public.

Neuraminidase: A surface antigen on the influenza A virus indicated in the name of the virus by a capital N followed by the subtype number.

Quarantine: Restriction of a well person who has been exposed to a known infectious organism.

Pandemic: Epidemic of a disease that is worldwide.

Split virus: Chemical alteration of a virus for use in a vaccine. All influenza vaccine in the United States is split virus.

17. RESOURCES

Association for Professionals in Infection Control and Epidemiology

https://apic.org

Association of State and Territorial Health Officials

http://www.astho.org

Centers for Disease Control and Prevention

https://www.cdc.gov/flu

https://www.cdc.gov/vaccines

https://www.cdc.gov/flu/weekly/fluactivitysurv.htm

National Institute of Allergy and Infectious Diseases

https://www.niaid.nih.gov/diseases-conditions/influenza

U.S. Food and Drug Administration

https://www.fda.gov

U.S. Food and Drug Administration MedWatch

https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program

Vaccine Adverse Event Reporting System

https://vaers.hhs.gov

World Health Organization Global Influenza Programme

https://www.who.int/influenza/en

18. APPENDIX 1

HOME CARE OF A PATIENT WITH INFLUENZA

1. Monitor the patient for improvement or worsening of symptoms. Write down the date and time of all observations: temperature, coughing, sneezing, amount the patient has had to drink and eat.

2. Supportive care

- Over-the-counter medicines that bring fever down (no aspirin in anyone younger than 18 years of age)

- Pain relievers (e.g., medications, carefully monitored heating pads)

- Back or leg rubs

- Cough medications, as ordered and needed

- Cool cloth to the head

- Limited light in the room

- An encouraging, positive, but not overly exuberant attitude

3. Maintain the patient's fluid intake with water, juices, popsicles, ice cubes, tea, coffee, or broths. Milk may be appealing to some patients.

4. Provide any foods that are appealing to the patient. However, fluid intake is more critical than solid food intake.

5. Provide tissues and a disposal place that the patient can reach, such as a wastebasket or paper bag pinned to the bed.

6. Assist the patient to the bathroom, if needed.

7. Continue any routine medications, if possible. Check with the physician if the patient cannot take or vomits the medications or if the medication needs to be taken with food and the patient is not eating.

8. Persons on insulin should have their blood sugar carefully monitored. Blood sugar may go up because of the disease process or go down because of poor food intake.

9. Keep the patient oriented as to time of day and date by telling him/her the time (and day, if needed) whenever they awake. Napping can lead to disorientation, especially in the elderly patient. Some patients may also need to be reminded where they are.

10. Provide a way for the patient to summon help, such as a bell, whistle, or some other method.

Source: Author

19. APPENDIX 2

CARING FOR YOURSELF TO PREVENT THE FLU

1. Get the flu shot.

2. Wash your hands frequently. Use soap, make a good lather, rub lather all over your hands for 15 seconds, rinse well, and dry with a paper towel or with your own towel at home. The process should take at least 20 seconds and should be completed:

- After shaking hands

- After being around someone who is coughing/sneezing

- After caring for someone who is sick

- As soon as you get home

3. Avoid touching your mouth, nose, or eyes.

4. Wear a mask when you take care of someone with the flu.

5. Get 7 to 8 hours rest in 24 hours.

6. Drink at least six to eight glasses of water each day. Sodas do not count. If one is tiring of water, putting it in a colored glass may help. Also, room temperature water is easier to drink in quantities than cold water.

7. Eat at least five or more servings of fruits and vegetables each day.

8. If caring for someone, get away from the house for a period of time each day, even just to go to the store or take a walk.

9. Avoid alcohol and tobacco.

Source: Author

20. APPENDIX 3

WHEN TO CALL THE DOCTOR

Phone Number ___________________________________________

Usually the person with the flu gets very sick suddenly, stays very sick for a few days, and then starts to feel better. The flu can cause other problems. Below is a list of symptoms and signs that indicate that a person needs help from a physician.

As you take care of the person, write down the date and time when you take the temperature or notice a new sign or symptom. If you are having trouble getting the patient to drink fluids, write down the time the person had a drink and how much they drank. The following signs should be reported to a physician immediately.

Fever

The temperature stays above 102 degrees F in spite of the person taking medicine to bring the fever down. (Never give aspirin to anyone younger than 18 years of age.)

Breathing

The person says or looks like he or she is having trouble breathing. The person is short of breath. The child is breathing very fast. The chest between the ribs or above the collar bone retracts when the child takes a breath. The person, especially if a child, looks a little blue.

Fluids

The person will not drink water, juice, or any fluid or suck popsicles or ice. The infant has less than 6 wet diapers in 24 hours. The urine is very dark and there is not much of it. If the skin on the forearm is pinched up, it slowly returns to normal. The eyes are sunken in and the mouth is dry. The person keeps vomiting or retching.

Changes in Mental State

The person is hard to wake up. No matter what you try, the child/infant cannot be comforted. The person is confused or seeing things. The person has fainted or nearly fainted. The person has a convulsion.

Change in Condition

Any worsening of the flu symptoms, as individuals with the flu will start to feel better after 3 to 5 days. Any worsening of any health problem (e.g., chest pain, swelling of the feet).

Rash

May indicate an allergy to a medicine or a disease other than the flu.

Source: Author

Works Cited

1. Centers for Disease Control and Prevention. Disease Burden of Influenza. Available at https://www.cdc.gov/flu/about/burden/index.html. Last accessed October 14, 2019.

2. Centers for Disease Control and Prevention. Estimated Influenza Illnesses, Medical Visits, Hospitalizations, and Deaths in the United States—2017–2018 Influenza Season. Available at https://www.cdc.gov/flu/about/burden/2017-2018.htm. Last accessed October 10, 2019.

3. Atkinson W, Hamborsky J, Wolfe C (eds). Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Public Health Foundation; 2015.

4. Centers for Disease Control and Prevention. Licensure of a high-dose inactivated influenza vaccine for persons aged ≥65 years (Fluzone high-dose) and guidance for use—United States, 2010. MMWR. 2010;59(16):485-486.

5. Mao L, Yang Y, Qiu Y, Yang Y. Annual economic impacts of seasonal influenza on U.S. counties: spatial heterogeneity and patterns. Int J Health Geographics. 2012;11:16.

6. Science Daily. Universal Influenza Vaccine Tested Successfully in Humans. Available at https://www.sciencedaily.com/releases/2008/01/080124185522.htm. Last accessed October 14, 2019.

7. Heron M. Deaths: leading causes for 2017. Natl Vital Stat Rep. 2019;68(6):1-77.

8. Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, 2021–22 influenza season. MMWR. 2021;70(5);1-28.

9. Tokars JI, Olsen SJ, Reed C. Seasonal incidence of symptomatic influenza in the United States. Clin Infect Dis. 2018;66(10):1511-1518.

10. Uyeki TM. A step forward in the treatment of influenza. N Engl J Med. 2018;379:975-977.

11. Centers for Disease Control and Prevention. 2009 H1N1 Flu ("Swine Flu") and You. Available at https://www.cdc.gov/h1n1flu/qa.htm. Last accessed October 14, 2019.

12. Centers for Disease Control and Prevention. Influenza activity United States and worldwide: 2007–08 Season. MMWR. 2008;57(25):692-697.

13. National Commission on Prevention Priorities. Preventive Care: A National Profile on Use, Disparities, and Health Benefits. Available at http://www.rwjf.org/content/dam/farm/reports/reports/2007/rwjf13325. Last accessed October 14, 2019.

14. Olsen C. Influenza: Pigs, People and Public Health. Available at http://www.montanahelp.org/2004_NPB_swine_flu_factsheet.pdf. Last accessed October 14, 2019.

15. National Institutes of Health. Interregional Spread of Influenza through United States Described by Virus Type, Size of Populations and Commuting Rates and Distance. Available at https://www.nih.gov/news-events/news-releases/interregional-spread-influenza-through-united-states-described-virus-type-size-population-commuting-rates-distance. Last accessed October 14, 2019.

16. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2012–13 influenza season. MMWR. 2012;61(32):613-618.

17. Bowser A. Serious Influenza Complications Common in Children. Available at https://www.medscape.com/viewarticle/474175. Last accessed October 14, 2019.

18. Bryan CS. Infectious Diseases in Primary Care. Philadelphia, PA: W.B. Saunders; 2002.

19. Centers for Disease Control and Prevention. About Flu. Available at https://www.cdc.gov/flu/about/index.html. Last accessed October 14, 2019.

20. Centers for Disease Control and Prevention. Key Facts about Influenza (Flu). Available at https://www.cdc.gov/flu/about/keyfacts.htm. Last accessed October 14, 2019.

21. Centers for Disease Control and Prevention. Notice to readers: considerations for distinguishing influenza-like illness from inhalational anthrax. MMWR. 2001;50(44):984-986.

22. Centers for Disease Control and Prevention. Information for Clinicians on Influenza Virus Testing. Available at https://www.cdc.gov/flu/professionals/diagnosis/index.htm. Last accessed October 14, 2019.

23. Centers for Disease Control and Prevention. Information for Clinicians on Rapid Diagnostic Testing for Influenza. Available at https://www.cdc.gov/flu/professionals/diagnosis/rapidclin.htm. Last accessed October 14, 2019.

24. Centers for Disease Control and Prevention. Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection. Available at https://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm. Last accessed October 14, 2019.

25. Centers for Disease Control and Prevention. Update: influenza-associated deaths reported among children aged <18 years—United States, 2003–04 Influenza Season. MMWR. 2003;52(Dispatch):1-2.

26. Rogawski E, McGrath L, Vielot N, Westreich D. Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study. Heart. 2014;100(6):517-518.

27. Medical News Today. Baxter Reveals Interim Results on Pandemic Flu Vaccine Clinical Trial. Available at https://www.medicalnewstoday.com/articles/66602.php. Last accessed October 14, 2019.

28. World Organization for Animal Health. Update on Highly Pathogenic Avian Influenza in Animals (Type H5 and H7). Available at https://www.oie.int/animal-health-in-the-world/update-on-avian-influenza/2016. Last accessed October 14, 2019.

29. Edwards KM, Burns VE, Allen LM, et al. Eccentric exercise as an adjuvant to influenza vaccination in humans. Brain Behav Immun. 2007;21(2):209-217.

30. Kohut ML, Arntson BA, Lee W, et al. Moderate exercise improves antibody response to influenza immunization in older adults. Vaccine. 2004;22(17-18):2298-2306.

31. Centers for Disease Control and Prevention. Interim Guidance on Influenza Antiviral Chemoprophylaxis of Persons Exposed to Birds with Avian Influenza A Viruses Associated with Severe Human Disease or with the Potential to Cause Severe Human Disease. Available at https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm. Last accessed October 14, 2019.

32. U.S. Food and Drug Administration. FDA Approves Rapivab to Treat Flu Infection. Available at https://wayback.archive-it.org/7993/20170111160835/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427755.htm. Last accessed October 14, 2019.

33. Centers for Disease Control and Prevention. Update: recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010–11. MMWR. 2010;59(31):989-992.

34. Sanofi Pasteur. Fluzone Intradermal (Influenza Virus Vaccine): Facts at a Glance. Available at http://multivu.prnewswire.com/mnr/sanofipasteur/49833/docs/49833-Fluzone_ID_Fact_Sheet.pdf. Last accessed October 14, 2019.

35. Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(RR02):1-60.

36. U.S. health officials call for vigilance against influenza: vaccine supplies predicted to be ample. Nation's Health. 2003;33(9).

37. Centers for Disease Control and Prevention. Inactivated Influenza VIS. Available at https://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html. Last accessed October 14, 2019.

38. Centers for Disease Control and Prevention. Interim Guidance on Testing, Specimen Collection, and Processing for Patients with Suspected Infection with Novel Influenza A Viruses with the Potential to Cause Severe Disease in Humans. Available at https://www.cdc.gov/flu/avianflu/severe-potential.htm. Last accessed October 14, 2019.

39. U.S. Food and Drug Administration. May 9, 2011 Approval Letter—Fluzone Intradermal. Available at https://wayback.archive-it.org/7993/20170404184329/https://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm255160.htm. Last accessed October 14, 2019.

40. Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198(5):650-658.

41. Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med. 2004;351(22):2295-2301.

42. Paccalin M, Weinberger B, Nicolas J-F, Van Damme P, Mégard Y. The intradermal vaccination route—an attractive opportunity for influenza vaccination in the elderly. Eur Geriatr Med. 2010;1(2):82-87.

43. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2005;55(RR8):1-40.

44. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR7):1-60.

45. LexiComp Online. Available at https://online.lexi.com. Last accessed October 14, 2019.

46. Daily Med. FluMist Quadrivalent (Influenza Vaccine Live Intranasal) Spray. Available at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=64f300d3-e1ba-40bc-a25f-4203ffdb27cf. Last accessed October 14, 2019.

47. Centers for Disease Control and Prevention. Questions and Answers: Antiviral Drugs 2009–2010 Flu Season. Available at https://www.cdc.gov/h1n1flu/antiviral.htm. Last accessed October 14, 2019.

48. Centers for Disease Control and Prevention. Bird Infections with Highly-Pathogenic Avian Influenza A (H5N2), (H5N8), and (H5N1) Viruses: Recommendations for Human Health Investigations and Response. Available at https://emergency.cdc.gov/han/han00378.asp. Last accessed October 14, 2019.

49. Treanor J. Influenza vaccine: outmaneuvering antigenic shift and drift. N Engl J Med. 2004;350(3):218-220.

50. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children.N Engl J Med. 2007;356(7):685-696.

51. Zangwill KM, Belshe RB. Safety and efficacy of trivalent inactivated influenza vaccine in young children: a summary for the new era of routine vaccination. Pediatr Infect Dis J. 2004;23(3):189-197.

52. Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J. 2004;23(2):138-144.

53. U.S. Department of Health and Human Services. FDA Approves First Adjuvanted Vaccine for Prevention of H5N1 Avian Influenza. Available at https://wayback.archive-it.org/7993/20170111161026/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376444.htm. Last accessed October 14, 2019.

54. Lee BY, McGlone SM. Pricing of new vaccines. Hum Vaccin. 2010;6(8):619-626.

55. Semchuk KM, Love EJ, Lee RG. Parkinson's disease: a test of the multifactorial etiologic hypothesis. Neurology. 1993;43(6):1173-1180.

56. Casals J, Elizan TS, Yahr MD. Postencephalitic parkinsonism: a review. J Neural Transm. 1998;105(6-7):645-676.

57. Pahwa R, Koller WC. Defining Parkinson's disease and parkinsonianism. In: Ellenberg JH, Keller WC, Langston JW (eds). Etiology of Parkinson's Disease. New York, NY: Marcel Dekker; 1995: 1-54.

58. Reid AH, McCall S, Henry JM, Taubenberger JK. Experimenting on the past: the enigma of von Economo's encephalitis lethargica. J Neuropathol Exp Neurol. 2001;60(7):663-670.

59. Brydak LB. Neurological complication of influenza infections. Przegl Epidemiol. 2002;56(suppl 1):16-30.

60. Takahashi M, Yamada T. A possible role of influenza A virus infection for Parkinson's disease. Adv Neurol. 2001;86:91-104.

61. Advisory Committee on Immunization Practices. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2013–2014. MMWR. 2013;62(7):1-43.

62. Fiore AE, Shay DK, Haber P, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR. 2007;56(RR6):1-54.

63. Advisory Committee on Immunization Practices. ACIP Meeting Minutes Archive: June 2007 Minutes. Available at https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2007-06-508.pdf. Last accessed October 14, 2019.

64. Centers for Disease Control and Prevention. Flu Vaccination Coverage Among Pregnant Women—United States, 2015–16 Flu Season. Available at https://www.cdc.gov/flu/fluvaxview/pregnant-coverage_1516estimates.htm. Last accessed October 14, 2019.

65. Sanofi Pasteur. Fluzone Intradermal: Highlights of Prescribing Information. Available at https://www.vaccineshoppe.com/image.cfm?pi=fluID&image_type=product_pdf. Last accessed October 14, 2019.

66. Mazunder B, Almoord D, Park K, Crimmins EM, Finch CE. Lingering prenatal effects of the 1918 influenza pandemic on cardiovascular disease. J Dev Orig Health Dis. 2010;1(1):26-34.

67. Centers for Disease Control and Prevention. Recommended Immunization Schedule for Persons Age 0 through 18 Years. Available at https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html. Last accessed October 14, 2019.

68. Shrestha SS, Swerdlow DL, Borse RH, et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009–April 2010). Clin Infect Dis. 2011;52(Suppl 1):S75-S82.

69. Caban-Martinez AJ, Lee DJ, Davila EP, et al. Sustained low influenza vaccination rates in US healthcare workers. Prev Med. 2010;50:210-212.

70. Centers for Disease Control and Prevention. Health Care Personnel and Flu Vaccination, Internet Panel Survey, United States, November 2014. Available at https://www.cdc.gov/flu/fluvaxview/hcp-ips-nov2014.htm. Last accessed October 14, 2019.

71. Goetzel RZ, Long SR, Ozminkowski RJ, Hawkins K, Wang S, Lynch W. Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers. J Occup Environ Med. 2004;46(4): 398-412.

72. Associated Press. 10 Million Doses of Flu Shot to be Thrown Away: Annual Expiration Date Ensures Up-to-Date Vaccine, but at a Huge Cost. Available at http://www.nbcnews.com/id/17708169/ns/health-cold_and_flu/t/million-doses-flu-shot-be-thrown-away/#.XaUFqH97mUk. Last accessed October 14, 2019.

73. Centers for Disease Control and Prevention. National Influenza Vaccination Week. Available at https://www.cdc.gov/flu/resource-center/nivw/index.htm. Last accessed October 14, 2019.

74. Brown D. For health officials flu shot is an annual gamble. Washington Post. January 12, 2004:A3. Available at https://www.washingtonpost.com/archive/politics/2004/01/12/for-health-officials-flu-shot-is-an-annual-gamble/afc8fb2e-fffa-4867-a46c-1b3449196fc5/. Last accessed October 14, 2019.

75. Bartlett J. Infectious Diseases: February 15, 2004. Available at https://www.medscape.com/viewarticle/467518. Last accessed October 14, 2019.

76. Centers for Disease Control and Prevention. Seasonal Influenza Vaccine Supply for the U.S. 2021–2022 Influenza Season. Available at https://www.cdc.gov/flu/prevent/vaxsupply.htm. Last accessed October 12, 2021.

77. Hathaway W. Trial Flu Vaccine Produced from Caterpillar Cells. Available at https://www.courant.com/news/connecticut/hc-xpm-2004-05-04-0405040254-story.html. Last accessed October 14, 2019.

78. Hathaway W. An Insect Alternative Helps to Fight the Flu. Available at https://www.courant.com/news/connecticut/hc-xpm-2004-06-09-0406090844-story.html. Last accessed October 14, 2019.

79. Rojahn SY. Synthetic Biology Could Speed Flu Vaccine Production. Available at https://www.technologyreview.com/s/514661/synthetic-biology-could-speed-flu-vaccine-production. Last accessed October 14, 2019.

80. U.S. Food and Drug Administration. FDA Approves New Seasonal Influenza Vaccine Made Using Novel Technology. Available at https://wayback.archive-it.org/7993/20170111225529/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm335891.htm. Last accessed October 14, 2019.

81. Milián E, Kamen AA. Current and emerging cell culture manufacturing technologies for influenza vaccines. Biomed Res Int. 2015;2015:504831.

82. U.S. Department of Health and Human Services. Healthy People 2020. Available at https://www.healthypeople.gov/2020. Last accessed October 14, 2019.

83. Immunization Action Coalition. Ask the Experts: Influenza. Availalable at https://www.immunize.org/askexperts/experts_inf.asp. Last accessed October 14, 2019.

84. Centers for Disease Control and Prevention. Key Facts about Seasonal Flu Vaccine. Available at https://www.cdc.gov/flu/prevent/keyfacts.htm . Last accessed October 14, 2019.

85. American Academy of Ambulatory Care Nursing. Health Care Providers are the Key to Influenza Vaccination. Available at https://www.aaacn.org/news/health-care-providers-are-key-influenza-vaccination. Last accessed October 14, 2019.

86. Centers for Disease Control and Prevention. Seasonal Influenza (Flu): Free Resources. Available at https://www.cdc.gov/flu/resource-center/freeresources/index.htm. Last accessed October 14, 2019.

87. Black CL, Yue X, Ball SW, et al. Influenza vaccination coverage among health care personnel—United States, 2015–16 influenza season. MMWR. 2016;65:1026-1031.

88. Pearson ML, Bridges CB, Harper SA. Influenza vaccination of health care professionals. MMWR. 2006;55(RR2):1-16.

89. Bowser A. Vaccines Effective in Nursing Home Residents. Available at https://www.medscape.com/viewarticle/474119. Last accessed October 14, 2019.

90. Hennepin County Community Health Department. Infectious Diseases in Childcare Settings and Schools Manual. Available at https://www.hennepin.us/childcaremanual. Last accessed October 14, 2019.

91. Centers for Disease Control and Prevention. Handwashing: Clean Hands Save Lives. Available at https://www.cdc.gov/handwashing. Last accessed October 14, 2019.

92. Centers for Disease Control and Prevention. How Flu Spreads. Available at https://www.cdc.gov/flu/about/disease/spread.htm. Last accessed October 14, 2019.

93. Centers for Disease Control and Prevention. Healthy Habits to Prevent Flu. Available at https://www.cdc.gov/flu/prevent/actions-prevent-flu.htm. Last accessed October 14, 2019.

94. Centers for Disease Control and Prevention. CDC Says "Take 3" Actions to Fight the Flu. Available at https://www.cdc.gov/flu/prevent/preventing.htm. Last accessed October 14, 2019.

95. Centers for Disease Control and Prevention. Prevention Strategies for Seasonal Influenza in Healthcare Settings. Available at https://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm. Last accessed October 14, 2019.

96. Centers for Disease Control and Prevention. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(RR1):1-24.

97. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Available at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Last accessed October 14, 2019.

98. Editorial. New concerns about oseltamivir. Lancet. 2007;369(9567):1056.

99. Aoki FY, Allen UD, Stiver HG, Evans GA. The use of antiviral drugs for influenza: guidance for practitioners 2012/2013. Can J Infect Dis Med Microbiol. 2012;23(4):e79-e92.

100. Rothberg M, He S, Rose DN. Management of influenza symptoms in healthy adults: cost effectiveness of rapid testing and antiviral therapy. J Gen Intern Med. 2003;10(18):808-815.

101. Centers for Disease Control and Prevention. Dosage: Guidance on the Use of Influenza Antiviral Agents. Available at https://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage.htm#Tab1. Last accessed October 14, 2019.

102. Centers for Disease Control and Prevention. Treatment: Antiviral Drugs. Available at https://www.cdc.gov/flu/antivirals/whatyoushould.htm. Last accessed October 14, 2019.

103. Centers for Disease Control and Prevention. Antiviral Drug Resistance among Influenza Viruses. Available at https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm. Last accessed October 14, 2019.

104. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Available at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Last accessed October 14, 2019.

105. Centers for Disease Control and Prevention. Influenza-Related Questions and Answers by Topic. Available at https://www.cdc.gov/flu/about/flu-faq.htm. Last accessed October 14, 2019.

106. Centers for Disease Control and Prevention. Respiratory Hygiene/Cough Etiquette in Healthcare Settings. Available at https://www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm. Last accessed October 14, 2019.

107. Centers for Disease Control and Prevention. Transmission of Influenza A Viruses between Animals and People. Available at https://www.cdc.gov/flu/avianflu/virus-transmission.htm. Last accessed October 14, 2019.

108. World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A(H5N1) Reported to WHO. Available at https://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/. Last accessed October 14, 2019.

109. Centers for Disease Control and Prevention. Highly Pathogenic Avian Influenza A (H5N1) in People. Available at https://www.cdc.gov/flu/avianflu/h5n1-people.htm. Last accessed October 14, 2019.

110. Centers for Disease Control and Prevention. Viruses of Special Concern. Available at https://www.cdc.gov/flu/pandemic-resources/monitoring/viruses-concern.html. Last accessed October 14, 2019.

111. World Health Organization. Avian Influenza: Assessing the Pandemic Threat. Available at https://apps.who.int/iris/bitstream/handle/10665/68985/WHO_CDS_2005.29.pdf. Last accessed October 14, 2019.

112. Centers for Disease Control and Prevention. Public Health Threat of Highly Pathogenic Avian Influenza A (H5N1) Virus. Available at https://www.cdc.gov/flu/avianflu/h5n1-threat.htm. Last accessed October 14, 2019.

113. Centers for Disease Control and Prevention. Avian Influenza in Birds. Available at https://www.cdc.gov/flu/avianflu/avian-in-birds.htm. Last accessed October 14, 2019.

114. Hitt E. Avian Flu: What Clinicians Need to Know. Available at https://www.medscape.com/viewarticle/468007. Last accessed October 14, 2019.

115. U.S. Department of Agriculture. USDA AVIAN INFLUENZA FACT SHEET. Available at https://www.usda.gov/sites/default/files/documents/usda-avian-influenza-factsheet.pdf. Last accessed October 14, 2019.

116. World Health Organization. Frequently Asked Questions on Human Infection Caused by the Avian Influenza A(H7N9) Virus. Available at https://www.who.int/influenza/human_animal_interface/faq_H7N9/en. Last accessed October 14, 2019.

117. Centers for Disease Control and Prevention. Update: influenza activity—United States 2003–2004 season. MMWR. 2004;53(13): 284-287.

118. Li C, Hatta M, Nidom CA, et al. Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence. Proc Natl Acad Sci USA. 2010;107(10):4687-4692.

119. Centers for Disease Control and Prevention. Interim Guidance for States Conducting Avian Mortality Surveillance for West Nile Virus (WNV) and/or Highly Pathogenic H5N1 Avian Influenza Virus. Available at https://www.cdc.gov/niosh/topics/avianflu/pdfs/cdcai-wnvbirdhandling.pdf. Last accessed October 14, 2019.

120. World Health Organization. H5N1 Avian Influenza: Timeline of Major Events. Available at https://www.who.int/influenza/H5N1_avian_influenza_update_20121217b.pdf. Last accessed October 14, 2019.

121. U.S. Food and Drug Administration. FDA Approves New Drug to Treat Influenza. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-influenza. Last accessed October 14, 2019.

122. Centers for Disease Control and Prevention. Prevention and Treatment of Avian Influenza A Viruses in People. Available at https://www.cdc.gov/flu/avianflu/prevention.htm. Last accessed October 14, 2019.

123. Kayali G, Kandeil A, El-Shesheny R, et al. Avian influenza A(H5N1) virus in Egypt. Emerg Infect Dis. 2016;22(3).

124. Crispin SW, Cohen M, Mapes T. Bird-flu outbreak revives concerns stirred by SARS. Wall Street Journal. January 28, 2004. Available at https://www.wsj.com/articles/SB107524207391913268. Last accessed October 14, 2019.

125. Centers for Disease Control and Prevention. Outbreaks of North American Lineage Avian Influenza Viruses. Available at https://www.cdc.gov/flu/avianflu/north-american-lineage.htm. Last accessed October 14, 2019.

126. National Institutes of Health. NIH Scientists Target Future Pandemic Strains of H5N1 Avian Influenza. Available at https://www.nih.gov/news-events/news-releases/nih-scientists-target-future-pandemic-strains-h5n1-avian-influenza. Last accessed October 14, 2019.

127. Gamblin SJ, Haire LF, Russell RJ, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science. 2004;303(5665):1838-1842.

128. World Health Organization. Availability of New Recombinant H5N1 Vaccine Virus. Available at https://www.who.int/influenza/resources/documents/H5N1virusJune/en. Last accessed October 14, 2019.

129. GlaxoSmithKline. GlaxoSmithKline Receives New HHS Order for H5N1 Bulk Antigen. Available at http://www.biopharminternational.com/glaxosmithkline-receives-new-hhs-order. Last accessed October 14, 2019.

130. International Federation of Pharmaceutical Manufacturers and Associations. IFPMA Supports Principles of Pandemic Influenza Preparedness Decision. Available at https://www.ifpma.org/resource-centre/ifpma-supports-principles-of-pandemic-influenza-preparedness-decision. Last accessed October 14, 2019.

131. U.S. Food and Drug Administration. FDA Approves First U.S. Vaccine for Humans against the Avian Influenza Virus H5N1. Available at https://wayback.archive-it.org/7993/20170112213127/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108892.htm. Last accessed October 14, 2019.

132. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999;37(6):471-484.

133. Kirkey S. Bird flu could kill 50,000 in Canada. Ottawa Citizen. January 30, 2004.

134. Global Early Warning System. About GLEWS and GLEWS+. Available at http://www.glews.net/?page_id=1041. Last accessed October 14, 2019.

135. Altman LK. As bird flu spreads global health weaknesses are exposed. New York Times. February 3, 2004. Available at https://www.nytimes.com/2004/02/03/health/the-doctor-s-world-as-bird-flu-spreads-global-health-weaknesses-are-exposed.html?pagewanted=all&src=pm. Last accessed October 14, 2019.

136. Centers for Disease Control and Prevention. Guidelines and Recommendations: Interim Guidance about Avian Influenza (H5N1) for U.S. Citizens Living Abroad. Available at https://wwwnc.cdc.gov/travel/page/avian-flu-americans-abroad. Last accessed October 14, 2019.

137. Centers for Disease Control and Prevention. Interim Guidance for Airline Flight Crews and Persons Meeting Passengers Arriving from Areas with Avian Influenza (Updated). Available at https://wwwnc.cdc.gov/travel/page/avian-flu-arriving-from-areas. Last accessed October 14, 2019.

138. World Health Organization. WHO Interim Recommendations for the Protection of Persons Involved in the Mass Slaughter of Animals Potentially Infected with Highly Pathogenic Avian Influenza Viruses. Available at http://www.wpro.who.int/emerging_diseases/documents/docs/WHOinterimrecommendation26012004.pdf. Last accessed October 14, 2019.

139. California Department of Health Services Division of Communicable Disease Control. Avian Influenza (H5N1) Update as of January 29, 2004.

140. Centers for Disease Control and Prevention. Influenza Division International Program. Available at https://www.cdc.gov/flu/international/program/index.htm. Last accessed October 14, 2019.

141. Centers for Disease Control and Prevention. Key Facts about Human Infections with Variant Viruses. Available at https://www.cdc.gov/flu/swineflu/keyfacts-variant.htm. Last accessed October 14, 2019.

142. World Health Organization. Avian Influenza Update: Implications of H5N1 Infections in Pigs in China. Available at https://www.who.int/csr/don/2004_08_25/en/. Last accessed October 14, 2019.

143. Centers for Disease Control and Prevention. What People who Raise Pigs Need to Know about Influenza (Flu). Available at https://www.cdc.gov/flu/swineflu/people-raise-pigs-flu.htm. Last accessed October 14, 2019.

144. Centers for Disease Control and Prevention. The 2009 H1N1 Pandemic: Summary highlights, April 2009–April 2010 (Archive). Available at https://www.cdc.gov/h1n1flu/cdcresponse.htm. Last accessed October 14, 2019.

145. Centers for Disease Control and Prevention. Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009–2010 Season (Archive). Available at https://www.cdc.gov/h1n1flu/recommendations.htm. Last accessed October 14, 2019.

146. World Health Organization. H1N1 in Post-Pandemic Period. Available at https://www.who.int/mediacentre/news/statements/2010/h1n1_vpc_20100810/en/. Last accessed October 14, 2019.

147. Leighty J. Code zebra: on the frontlines, California EDs brace for action against infectious disease and bioterrorism. Nurse Week. 2004;13-15.

148. Centers for Disease Control and Prevention. Prevent Seasonal Flu. Available at https://www.cdc.gov/flu/prevent. Last accessed October 14, 2019.

149. Lau JTF, Griffiths S, Choi K-C, Lin C. Prevalence of preventive behaviors and associated factors during early phase of the H1N1 influenza epidemic. Am J Infect Control. 2010;38(5):374-380.

150. Centers for Disease Control and Prevention. Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices, 2009. MMWR. 2009;58(RR10):1-8.

151. Centers for Disease Control and Prevention. Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses Associated with Severe Human Disease and on the Use of Antiviral Medications for Chemoprophylaxis. Available at https://www.cdc.gov/flu/avianflu/novel-av-chemoprophylaxis-guidance.htm. Last accessed October 14, 2019.

152. Centers for Disease Control and Prevention. Flu Symptoms and Severity. Available at https://www.cdc.gov/flu/symptoms/symptoms.htm. Last accessed October 14, 2019.

153. Centers for Disease Control and Prevention. Influenza Symptoms and the Role of Laboratory Diagnostics. Available at https://www.cdc.gov/flu/professionals/diagnosis/labrolesprocedures.htm. Last accessed October 14, 2019.

154. Centers for Disease Control and Prevention. New CDC Test to Detect Human Infections with the 2009 H1N1 Influenza Virus Authorized for Use by FDA. Available at https://www.cdc.gov/media/pressrel/2010/r100622.htm. Last accessed October 14, 2019.

155. Centers for Disease Control and Prevention. Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection. Available at https://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm. Last accessed October 14, 2019.

156. World Health Organization. Pandemic (H1N1) 2009: Frequently Asked Questions. Available at https://www.who.int/csr/disease/swineflu/frequently_asked_questions/en/. Last accessed October 14, 2019.

157. U.S. Food and Drug Administration. FDA Public Health Alert: Potential Medication Errors with Tamiflu for Oral Suspension. Available at https://wayback.archive-it.org/7993/20170723103955/https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm183649.htm. Last accessed October 14, 2019.

158. Smee DF, Hurst BL, Wong MH, et al. Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother. 2010;54(1):126-133.

159. U.S. Food and Drug Administration. Emergency Use Authorization of Peramivir IV: Fact Sheet for Health Care Providers. Available at https://www.fda.gov/media/77787/download. Last accessed October 14, 2019.

160. BioSpace. Toyama Chemical NDA Approval of "AVIGAN Tablet 200mg" In Japan For The Anti-influenza Virus Drug. Available at https://www.biospace.com/article/releases/toyama-chemical-nda-approval-of-avigan-tablet-200mg-in-japan-for-the-anti-influenza-virus-drug-. Last accessed October 14, 2019.

161. U.S. Department of Veterans Affairs. About Pandemic Flu. Available at https://www.publichealth.va.gov/flu/pandemic. Last accessed October 14, 2019.

162. Centers for Disease Control and Prevention. Influenza (Flu). Available at https://www.cdc.gov/flu/index.htm. Last accessed October 14, 2019.

163. World Health Organization. WHO Checklist for Influenza Pandemic Preparedness Planning. Geneva: World Health Organization, Department of Communicable Disease, Surveillance and Response, Global Influenza Programme; 2005.

164. Hearne SA, Davis M, Segal LM, et al. Ready or not? Protecting the public's health in the age of bioterrorism. Biosecur Bioterror. 2004;2(1):47-50.

165. U.S. Department of Health and Human Services. Pandemic Influenza. Available at https://www.hhs.gov/about/agencies/oga/global-health-security/pandemic-influenza/index.html. Last accessed October 14, 2019.

166. Centers for Disease Control and Prevention. Weekly U.S. Influenza Surveillance Report. Available at https://www.cdc.gov/flu/weekly/index.htm. Last accessed October 14, 2019.

167. Galvani AP. Emerging infections: what have we learned from SARS? Emerg Infect Dis. 2004;10(7):1351-1352.

168. World Health Organization. Pandemic Influenza Risk Management: WHO Interim Guidance. Geneva: World Health Organization; 2013.

169. Centers for Disease Control and Prevention. Interim Guidance for the Use of Masks to Control Influenza Transmission. Available at https://www.cdc.gov/flu/professionals/infectioncontrol/maskguidance.htm. Last accessed October 14, 2019.

170. California Department of Public Health. Pandemic Influenza Preparedness and Response Plan. Available at https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/NovelInfluenza.aspx. Last accessed October 14, 2019.

171. Centers for Disease Control and Prevention. CDC's World Health Organization (WHO) Collaborating Center for Surveillance, Epidemiology and Control of Influenza. Available at https://www.cdc.gov/flu/weekly/who-collaboration.htm. Last accessed October 14, 2019.

172. Federal Emergency Management Agency. Incident Command System. Available at https://www.fema.gov/incident-command-system-resources. Last accessed October 14, 2019.

173. U.S. Chamber of Commerce. It's Not Flu as Usual: What Businesses Need to Know about Pandemic Flu Planning. Available at https://www.uschamber.com/its-not-flu-usual. Last accessed October 14, 2019.

174. Gensheimer KF, Meltzer MI, Postema AS, Strikas RA. Influenza pandemic preparedness. Emerg Infect Dis. 2003;9(12):1645-1648.

175. California Emergency Medical Services Agency. Shelter Medical Group Toolkit: Local Emergency Preparedness Planners Guide for the Care and Sheltering of the Medically Fragile. Available at https://emsa.ca.gov/wp-content/uploads/sites/71/2017/07/TOOLKIT.pdf . Last accessed October 14, 2019.

176. Bakalar N. How (and how not) to battle flu: a tale of 23 cities. The New York Times. April 17, 2007. Available at https://www.nytimes.com/2007/04/17/health/17flu.html. Last accessed October 14, 2019.

177. Centers for Disease Control and Prevention. Ethical Guidelines in Pandemic Influenza: Recommendations of the Ethics Subcommittee of the Advisory Committee to the Director, Centers for Disease Control and Prevention. Available at https://www.cdc.gov/od/science/integrity/phethics/panflu_ethic_guidelines.pdf. Last accessed October 14, 2019.

178. Markel H, Lipman HB, Navarro JA, et al. Nonpharmaceutical interventions implemented by U.S. cities during the 1918–1919 influenza pandemic. JAMA. 2007;298(6):644-654.

179. New York City Department of Health and Mental Hygiene. NYC DOHMH Pandemic Influenza Preparedness and Response Plan. Available at https://www1.nyc.gov/assets/em/downloads/pdf/hazard_mitigation/nycs_risk_landscape_chapter_4.9_pandemic_flu.pdf. Last accessed October 14, 2019.

180. Oral report from L. Bennett, member of the summer 2007 Azusa Pacific University research team.

181. Centers for Disease Control and Prevention. Influenza A (H3N2) Variant Virus. Available at https://www.cdc.gov/flu/swineflu/variant/h3n2v-cases.htm. Last accessed October 14, 2019.

182. Centers for Disease Control and Prevention. Frequently Asked Flu Questions 2019–2020 Influenza Season. Available at https://www.cdc.gov/flu/season/faq-flu-season-2019-2020.htm. Last accessed October 14, 2019.

183. National Center for Health Statistics. Influenza. Available at https://www.cdc.gov/nchs/fastats/flu.htm. Last accessed October 14, 2019.

184. Centers for Disease Control and Prevention. Flu Vaccination Coverage, United States, 2015–2016 Influenza Season. Available at https://www.cdc.gov/flu/fluvaxview/coverage-1516estimates.htm. Last accessed October 14, 2019.

185. Centers for Disease Control and Prevention. Recombinant Influenza (Flu) Vaccine. Available at https://www.cdc.gov/flu/prevent/qa_flublok-vaccine.htm. Last accessed October 14, 2019.

186. Greenhawt M, Turner PJ, Kelso JM. Administration of influenza vaccines to egg allergic recipients: a practice parameter update 2017. Ann Allergy Asthma Immunol. 2018;120:49-52.

187. Center for Infectious Disease Research and Policy. CDC Vaccine Panel Brings Back FluMist for 2018–19 Season. Available at http://www.cidrap.umn.edu/news-perspective/2018/02/cdc-vaccine-panel-brings-back-flumist-2018-19-season. Last accessed October 14, 2019.

188. U.S. Food and Drug Administration. FDA Expands Approval of Influenza Treatment to Post-Exposure Prevention. Available at https://www.fda.gov/news-events/press-announcements/fda-expands-approval-influenza-treatment-post-exposure-prevention. Last accessed January 5, 2021.

189. Olsen SJ, Winn AK, Budd AP, et al. Changes in influenza and other respiratory virus activity during the COVID-19 pandemic—United States, 2020–2021. MMWR. 2021;70(29);1013-1019.

190. Centers for Disease Control and Prevention. COCA Call: 2021-2022 Influenza Vaccination Recommendations and Guidance on Coadministration with COVID-19 Vaccines. Available at https://emergency.cdc.gov/coca/calls/2021/callinfo_090921.asp. Last accessed October 12, 2021.

Evidence-Based Practice Recommendations Citations

1. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):e1-e47. Available at https://academic.oup.com/cid/article/68/6/e1/5251935#127789601. Last accessed October 27, 2019.

2. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(2):1-64. Available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm. Last accessed October 27, 2019.

98783 • Healthcare-Associated Infections

Lori L. Alexander, MTPW, ELS, MWC

John M. Leonard, MD

www.netce.com

Copyright © 2022 NetCE, All rights reserved.

This course is structured to provide essential education regarding the epidemiology, prevention, diagnosis, and treatment of healthcare-associated infections (HAIs). The course begins with background information on the pathogenesis of bacterial infections, transmission of infection in the healthcare setting, and the development of drug resistance. The primary sources of HAIs related to the environment, patient factors, and iatrogenic factors are also discussed. The core of the course is a comprehensive description of the most common and costly HAIs: catheter-related urinary tract infections, surgical site infections, ventilator-associated pneumonia, intravascular device-related infections, and Clostridioides difficile infections. The overall incidences, related costs, risk factors, common pathogens, prevention, diagnosis, and treatment are presented for each of these infections, with the implications of drug-resistant infections also noted. An overview of the responsibilities of an infection control program in the healthcare setting is provided, with a discussion of surveillance, adherence to infection control guidelines, management of drug-resistant micro-organisms, precautions and isolation techniques, preparedness for outbreaks and epidemics, and education targeted to both healthcare workers and patients and families.

Table of Contents

98783 • Healthcare-Associated Infections

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. OVERVIEW

2. EPIDEMIOLOGY AND BACKGROUND

3. MICROBIAL PATHOGENESIS AND DEVELOPMENT OF DRUG RESISTANCE

DEVELOPMENT OF DRUG-RESISTANT MICRO-ORGANISMS

4. SOURCES OF HAIs

ENVIRONMENTAL FACTORS

ENVIRONMENTAL SOURCES OF PATHOGENS IN THE HEALTHCARE SETTING

PATIENT-RELATED FACTORS

IATROGENIC FACTORS

5. TYPES OF INFECTIONS

CATHETER-ASSOCIATED URINARY TRACT INFECTIONS

SURGICAL SITE INFECTIONS

PNEUMONIA

INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS

CLOSTRIDIOIDES DIFFICILE INFECTIONS

6. INFECTION CONTROL

SURVEILLANCE

HAND HYGIENE

INFLUENZA VACCINATION

PRECAUTIONS AND ISOLATION TECHNIQUES

PREVENTION OF ANTIBIOTIC-RESISTANT INFECTION

EDUCATION FOR HEALTHCARE PROFESSIONALS

EDUCATION FOR PATIENTS AND FAMILIES

PREPAREDNESS AND CONTROL OF OUTBREAKS

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98783 • Healthcare-Associated Infections

Education Category. Infection Control / Internal Medicine

Release Date. 02/01/2022

Expiration Date. 01/31/2025

Course Overview

This course is structured to provide essential education regarding the epidemiology, prevention, diagnosis, and treatment of healthcare-associated infections (HAIs). The course begins with background information on the pathogenesis of bacterial infections, transmission of infection in the healthcare setting, and the development of drug resistance. The primary sources of HAIs related to the environment, patient factors, and iatrogenic factors are also discussed. The core of the course is a comprehensive description of the most common and costly HAIs: catheter-related urinary tract infections, surgical site infections, ventilator-associated pneumonia, intravascular device-related infections, and Clostridioides difficile infections. The overall incidences, related costs, risk factors, common pathogens, prevention, diagnosis, and treatment are presented for each of these infections, with the implications of drug-resistant infections also noted. An overview of the responsibilities of an infection control program in the healthcare setting is provided, with a discussion of surveillance, adherence to infection control guidelines, management of drug-resistant micro-organisms, precautions and isolation techniques, preparedness for outbreaks and epidemics, and education targeted to both healthcare workers and patients and families.

Audience

This course is designed for healthcare professionals who would benefit from enhanced knowledge of healthcare-associated infections, including physicians, physician assistants, nurses, surgical technologists/assistants, and others involved with the care of patients in hospitals, long-term care facilities, or other healthcare institutions.

Course Objective

The purpose of this course is to provide physicians, nurses, microbiologists, and other healthcare professionals with an updated review of healthcare-associated infections, including evidence-based guidelines, strategies for prevention, and selection of appropriate treatment options.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the effect of healthcare-associated infections on morbidity, mortality, and cost of health care, including the importance of surveillance and prevention.

2. Discuss the pathogenesis of infection and modes of antimicrobial resistance.

3. Identify the environmental, patient-related, and iatrogenic risk factors for healthcare-associated infection.

4. Anticipate the impact of nonimplanted and implanted devices and procedures on healthcare-associated infection.

5. List the most common types of healthcare-associated infections.

6. Identify the most common pathogens and risk factors associated with catheter-related urinary tract infections, and outline the appropriate prevention measures, means of diagnosis, and treatment.

7. List the most common pathogens and causes of surgical site infections, and develop a strategy for prevention, diagnosis, and treatment.

8. Define the most common pathogens and risk factors associated with healthcare-associated pneumonia, and devise appropriate measures for prevention, diagnosis, and treatment.

9. Outline the most common pathogens and risk factors associated with intravascular device-related bloodstream infections, and discuss the appropriate prevention measures, diagnosis, and treatment.

10. Discuss the risk factors and prevention strategies for nosocomial Clostridioides difficile infection.

11. Implement an effective hand hygiene program and strategies to increase compliance.

12. Outline interventions to control influenza transmission in the healthcare setting.

13. Describe the appropriate use of precautions and isolation techniques.

14. Define additional elements of an institution's infection control program, including the education of healthcare workers and patients with respect to healthcare-associated infections and the need to address challenges in educating non-English-proficient individuals.

15. Discuss the need for hospital preparedness for potential outbreaks.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. OVERVIEW

This course is structured to provide essential education regarding the epidemiology, prevention, diagnosis, and treatment of healthcare-associated infections (HAIs). The course begins with background information on the pathogenesis of bacterial infections, transmission of infection in the healthcare setting, and the development of drug resistance. The primary sources of HAIs related to the environment, patient factors, and iatrogenic factors are also discussed. The core of the course is a comprehensive description of the most common and costly HAIs: catheter-related urinary tract infections, surgical site infections, hospital-acquired pneumonia, intravascular device-related bloodstream infections, and Clostridioides difficile infections. The overall incidences, related costs, risk factors, common pathogens, prevention, diagnosis, and treatment are presented for each of these infections, with the implications of drug-resistant infections also noted. An overview of the responsibilities of an infection control program in the healthcare setting is provided, with a discussion of surveillance, adherence to infection control guidelines, management of drug-resistant micro-organisms, precautions and isolation techniques, preparedness for outbreaks and epidemics, and education targeted to both healthcare workers and patients and families. The course content is limited to infections in adults in acute care hospitals, although many measures for prevention are applicable in all settings for all patient populations.

2. EPIDEMIOLOGY AND BACKGROUND

HAI is one of the leading causes of death and increased morbidity for hospitalized patients. About 1 in 20 patients hospitalized has at least one healthcare-associated infection, a complication estimated to affect more than 1 million patients each year who reside in hospitals or other inpatient care facilities [1,2]. Historically, these infections have been known as nosocomial infections or hospital-acquired infections because they develop during hospitalization. As health care has increasingly expanded beyond hospitals into outpatient settings, nursing homes, long-term care facilities, and even home care settings, the more appropriate term has become healthcare-acquired or healthcare-associated infection. Many factors have contributed to an increase in HAIs. Advances in medical treatments have led to more patients with decreased immune function or chronic disease. The increase in the number of these patients, coupled with a shift in health care to the outpatient setting, yields a hospital population that is both more susceptible to infection and more vulnerable once infected. In addition, the increased use of invasive devices and procedures has contributed to higher rates of infection; more than 80% of HAIs are caused by four types of infection: catheter-related urinary tract infection, intravascular device-related bloodstream infection, surgical site infection, and ventilator-associated pneumonia [1]. These HAIs, along with infections caused by C. difficile and drug-resistant micro-organisms (especially methicillin-resistant Staphylococcus aureus [MRSA]), have garnered the most attention and research because of their impact in terms of morbidity, mortality, economic costs, and potential for prevention. Based on Centers for Disease Control and Prevention (CDC)-sponsored hospital surveillance data from 2018, about 3% to 4% of inpatients are infected and an estimated 633,000 hospitalized patients develop an HAI each year [3]. These infections lead to excess mortality and add billions of dollars in total direct medical costs annually [1,4].

Prior to 2020, the prevalence of HAIs had been declining, the result of an ongoing national collaborative effort. However, an analysis of National Healthcare Safety Network (NHSN) data from acute care hospitals in 12 U.S. states found that rates of central-line-associated bloodstream infections, catheter-related urinary tract infections, and ventilator-associated events increased significantly compared with 2019, largely as a result of the COVID-19 pandemic [5]. The analysis showed that national standard infection ratios for central-line-associated bloodstream infections initially declined in the first quarter of 2020 compared with the first quarter of 2019, but then rose by 27.9%, 46.4%, and 47.0% in the second, third, and fourth quarters of the year, respectively. Ventilator-associated events rose by 44.8% in the fourth quarter of 2020 compared with the same period for 2019 [5]. While acknowledging that 2020 was an unprecedented time for hospitals, the authors of the analysis emphasized the continued need for regular review of HAI surveillance data to identify gaps in prevention [5].

The increased focus on healthcare quality over the past decade has highlighted the need to prevent HAIs as part of overall efforts to enhance patient safety as well as reduce costs, and national initiatives have been developed by healthcare quality agencies, advocacy organizations, healthcare regulating bodies, and policymakers (Table 1) [6,7,8,9,10,11,12,13,14].

Table 1: EXAMPLES OF NATIONAL INITIATIVES TO REDUCE FREQUENCY OF HEALTHCARE-ASSOCIATED INFECTIONS

Organization

Initiative(s)

Agency for Healthcare Research and Quality: Making Health Care Safer II: An Updated Critical Analysis of the Evidence for Patient Safety Practices, 2013 (22 safety practices)

Review the evidence on patient safety practices and present priorities for their adoption

Institute of Medicine: Priority Areas for National Action: Transforming Health Care Quality, 2003 (20 priority areas)

Prevent nosocomial infections and implement surveillance programs

Institute for Healthcare Improvement: 5 Million Lives Campaign, 2006 (12 safety interventions)

Prevent central line-related infections

Prevent surgical site infections

Prevent ventilator-associated pneumonia

Reduce methicillin-resistant Staphylococcus aureus (MRSA) infection

Surgical Care Improvement Project (partnership of several organizations), 2006

Reduce postoperative complications, including surgical site infections

Centers for Medicaid and Medicare Services (effective October 1, 2008)

No reimbursement for hospital costs related to catheter-associated urinary tract infections, vascular catheter-associated infections, and mediastinitis after coronary artery bypass graft surgery

U.S. Department of Health and Human Services, 2009

National Action Plan to Prevent Healthcare-associated Infections (9 targets for elimination of HAIs)

U.S. Department of Health and Human Services, 2011

Partnership for Patients: Better Care, Lower Costs

National Quality Forum: Patient Safety, 2012 (3 broad goals)

Goal 2: Reduce the incidence of adverse healthcare-associated conditions

The Joint Commission, National Patient Safety Goals, 2013 (6 broad goals)

Prevent Infection: Follow the CDC guidelines for hand hygiene and use proven guidelines to prevent bloodstream infections from central lines, to prevent infection after surgery, and to prevent catheter-related urinary tract infections

Centers for Medicaid and Medicare Services: Partnership for Patients, 2011 (9 areas of focus)

Decrease rates of HAIs

Source: [2,6,7,8,9,10,11,12,13,14,15]

In 2009, with updates made in 2013 and 2018, the U.S. Department of Health and Human Services (HHS) developed the national Action Plan to Prevent Healthcare-Associated Infections, an initiative with a steering committee that represents a host of government health-related agencies. The plan includes 5-year goals for nine specific measures of improvement in HAI prevention [2]. The HHS is currently working to update the plan with new indicator targets and data, new research and intervention efforts, and a review of the impact of the COVID-19 public health emergency on HAIs [2].

Phase I of the plan calls for reducing the rate of HAIs in acute care hospitals by the implementation of a collaborative 10-point strategy aimed at prevention [2]:

Frontline Clinicians

- Reduce inappropriate/unnecessary use of devices

- Improve adherence to hand hygiene and barrier precautions

- Implement and improve antimicrobial stewardship

Clinical Leaders, Executives, and Administrators

- Demonstrate leadership support at the highest levels of the facility

- Implement a culture of safety

Government, Advocates, Clinical Leaders, and Administrators

- Enhance financial incentives and regulatory oversight

- Implement system-based approaches/protocols/checklists

- Achieve better use of technology

- Improve public reporting of credible data

- Enhance traditional and nontraditional partnerships

Phase two of the HAI Action Plan focuses on ambulatory surgical centers, renal dialysis facilities, and influenza vaccination of healthcare personnel. Phase three is focused on long-term care facilities, and phase four is focused on antibiotic stewardship and prevention of antibiotic resistance [2].

In 2016, the HHS released targets and measures for phase one of the HAI Action Plan using data from 2015 (baseline) to 2020. The measures reflect national progress on reduction of HAIs in acute care hospitals (Table 2) [2].

Table 2: PROGRESSa: NATIONAL ACUTE CARE HOSPITAL HAIs

Measure and (Data Source)

Progress 2016

Progress 2019

Target 2020

CLABSI (NHSN)

11% reduction

31% reduction

50% reduction

CAUTI (NHSN)

7% reduction

26% reduction

25% reduction

Invasive MRSA (NHSN/EIP)

8% reduction

5% increaseb

50% reduction

Hospital-onset MRSA (NHSN)

6% reduction

18% reduction

50% reduction

Hospital-onset CDI (NHSN)

8% reduction

42% reduction

30% reduction

SSI (NHSN)b

6% reduction

7% reduction

30% reduction

Clostridioides difficile-related hospitalizations (HCUP)

4% reduction

29% reduction

30% reduction

aProgress from baseline of 2015

bCDC data for 2019 delayed for this measure due to COVID-19 within EIP data source.

CDI=Clostridioides difficile infection; CLASBI=central line-associated bloodstream infections; CAUTI=catheter-associated urinary tract infections; EIP=Emerging Infections Program; HCUP=Healthcare Cost and Utilization Project; MRSA=methicillin-resistant Staphylococcus aureus; NHSN=National Healthcare Safety Network; SSI=surgical site infection.

Source: [2]

Evidence-based guidelines are at the heart of strategies to prevent and control HAIs and drug-resistant infections and address a wide range of issues from architectural design of hospitals to hand hygiene (Table 3) [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. Adherence to individual guidelines varies but, in general, is low. For example, hand hygiene is the most basic and single most important preventive measure, yet compliance rates among healthcare workers have averaged 30% to 50% [27,40,41,42,43]. Decreasing the number of HAIs will require research to better understand the reasons behind lack of compliance with guidelines and to develop education and interventions that target those reasons.

Table 3: SAMPLE OF GUIDELINES RELATED TO PREVENTING AND MANAGING HEALTHCARE-ASSOCIATED INFECTIONS

Organization

Guideline(s)

American College of Chest Physicians/American Association for Bronchology

Consensus statement: prevention of flexible bronchoscopy-associated infection (2005)

American Institute of Architects

Guidelines for Design and Construction of Health Care Facilities (2018)

American Thoracic Society/Infectious Diseases Society of America

Management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia (2005, updated 2016)

Canadian Critical Care Trials Group/Canadian Critical Care Society

Prevention of ventilator-associated pneumonia (2004)

Centers for Disease Control and Prevention (CDC)

Prevention of catheter-associated urinary tract infections (2009)

Disinfection and sterilization in healthcare facilities (2008)

Isolation precautions (2007)

Management of multidrug-resistant organisms in healthcare settings (2006)

Prevention of healthcare-associated pneumonia (2003)

Environmental infection control in healthcare facilities (2003, updated 2014, 2018, 2019)

Hand hygiene in healthcare settings (2002)

Prevention of intravascular device-related infections (2011)

Prevention of surgical site infections (1999, updated 2017)

Infectious Diseases Society of America

Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults (2009)

Strategies to prevent catheter-associated urinary tract infection in acute care hospitals (2014)

Society for Healthcare Epidemiology of America

Prevention of nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus (2003, 2014)

Multi-society guideline for reprocessing flexible gastrointestinal endoscopes (2003, 2021)

Society for Healthcare Epidemiology of America/Infectious Diseases Society of America

Clostridioides difficile infection in adults (2010, updated 2017)

Society for Healthcare Epidemiology of America/Infectious Diseases Society of America/Joint Committee on the Prevention of Antimicrobial Resistance

Prevention of antimicrobial resistance in hospitals (1997)

Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (published as supplement to Infection Control and Hospital Epidemiology, 2008)

Strategies to prevent central line-associated bloodstream infections, ventilator-associated pneumonia, catheter-associated urinary tract infections, surgical site infections in acute care hospitals, and transmission of methicillin-resistant S. aureus and C. difficile infections

World Health Organization (WHO)

Prevention of Hospital-Acquired Infections: A Practical Guide, 2nd ed. (2002)

Source: [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]

"Zero tolerance" of HAIs became a common catch-phrase as a call to improve prevention strategies and eliminate HAIs. Zero tolerance for HAIs is a worthy goal, but the complete elimination of all HAIs is not feasible, primarily because interventions address only exogenous sources of infection and do not address many other important factors, such as host response, patient case mixes, pathogen virulence, and lack of specificity in definitions and diagnostic criteria [44,45]. Furthermore, the literature has not supported the complete elimination of HAIs with enhanced compliance to prevention protocols. The results of the CDC's Study of Efficacy of Nosocomial Infection Control (SENIC) suggested that 6% of all HAIs could be prevented by minimal infection control efforts and 32% by "well organized and highly effective infection control programs" [46,47]. A later review of 30 studies suggested that an estimated 20% of HAIs are preventable [48]. A 2011 study estimated that approximately 65% to 75% of central line-associated bloodstream infections and catheter-associated urinary tract infections were preventable using current evidence-based strategies; 55% of ventilator-associated pneumonia and surgical site infections were estimated to be preventable [49]. Furthermore, complete elimination is not needed to reap substantial benefit. The U.S. Department of Health and Human Services estimates that a 40% decrease in preventable HAIs (compared with the 2010 rate) would result in 1.8 million fewer injuries and more than 60,000 lives saved over 3 years [9]. A 70% decrease in the rate of HAIs would save an estimated $25 to $31.5 billion [1].

The results of studies evaluating strategies to prevent HAIs have shown a wide range in efficacy, particularly with respect to specific HAIs. For example, the effectiveness of strategies to prevent surgical site infections has not been consistent, with some studies showing significant improvement and other studies showing no substantial improvement [50,51,52]. Still, research has shown that strict adherence to prevention interventions has an effect; one study demonstrated a decrease of as much as 66% in the prevalence of intravascular device-related bloodstream infections with adherence to a combination of interventions [53,54,55,56,57]. Combinations of interventions, or "bundles," have been found to be the most effective for preventing HAIs, and the Institute of Healthcare Improvement (IHI) has developed how-to guides on implementing these bundles, which are available for download from the IHI website [58,59,60]. More research is needed to determine the direct impact of many guideline recommendations and the combinations of "best practices" that yield the lowest rates of individual HAIs.

Among the national initiatives to reduce the number of HAIs was a move by the Centers for Medicare and Medicaid Services (CMS) to suspend reimbursement of hospital costs related to HAIs it considers "reasonably preventable:" catheter-related urinary tract infection, central line-associated bloodstream infection, and some surgical site infections [10,11]. However, studies have shown that this policy has not been a contributor to any decrease in the rate of HAIs, and a survey indicated that adherence to only some prevention strategies has increased as a result of the policy [61,62]. The policy also has the potential to lead to increased unnecessary use of antimicrobials in an effort to prevent infections [63].

In contrast, educating healthcare personnel helps to reduce HAIs, with a systematic review showing a statistically significant decrease in infection rates after an educational intervention in 21 of 26 studies [64]. Education is one of the key elements found to be necessary for a successful HAI prevention program. When such programs at 33 diverse hospitals were evaluated, the following were found to be essential for success [2,65]:

- Educate and re-educate providers, patients, and families

- Foster change by first understanding resistance

- Engage frontline staff by involving them in the program and enlisting champions

- Commit to regular strategic communication and join a collaborative

- Start small and tailor implementation to local needs and cultures

- Convince administration to provide leadership, funds, and dedicated staff and assign accountability

- Provide timely, relevant feedback and celebrate successes

Accurate data collection is crucial for understanding trends and the burden of HAIs and for identifying emerging infectious threats. The Association for Professionals in Infection Control and Epidemiology (APIC), the Infectious Diseases Society of America (IDSA), and the Society for Healthcare Epidemiology of America (SHEA) have led efforts to establish uniform standards for surveillance of HAIs and standardized systems for collecting and reporting. The CDC's National Healthcare Safety Network (NHSN), the nation's most widely used HAI surveillance system, is a shared resource for HAI prevention. More than 25,000 hospitals and other healthcare facilities provide data to NHSN, which in turn is used for national- and state-level analyses, including for periodic HAI reports and for targeted prevention initiatives by healthcare facilities, states, regions, quality groups, and national public health agencies, including the CDC [66,67].

In response to a call for mandatory reporting of HAIs, several states passed legislation requiring the mandatory reporting of specific HAIs, and reporting requirements vary by state. The number of states with mandates for public reporting grew from 3 in 2004 to 36 (and the District of Columbia) in 2021 [68,69].

3. MICROBIAL PATHOGENESIS AND DEVELOPMENT OF DRUG RESISTANCE

A comprehensive description of the pathogenesis of infection is beyond the scope of this course. However, a broad overview of pathogen-host interaction will aid in the understanding of how infection develops in the healthcare setting. In addition, a discussion of the development of antibiotic resistance is warranted because of the substantial impact of resistant pathogens on the management of HAIs.

A healthy human body has several defenses against infection: the skin and mucous membranes form natural barriers to infection, and immune responses (nonspecific and specific) are activated to resist micro-organisms that are able to invade. The skin can effectively protect the body from most micro-organisms unless there is physical disruption. For example, the human papillomavirus can invade the skin, and some parasites can penetrate intact skin, but bacteria and fungi cannot [70]. Other disruptors of the natural barrier are lesions, injury, or, in the healthcare setting, invasive procedures or devices.

In addition to breaks in the skin, other primary entry points for micro-organisms are mucosal surfaces, such as the respiratory, gastrointestinal, and genitourinary tracts. The membranes lining these tracts comprise a major internal barrier to micro-organisms due to the antimicrobial properties of their secretions. The respiratory tract filters inhaled micro-organisms, and mucociliary epithelium in the tracheobronchial tree moves them out of the lung. In the gastrointestinal tract, gastric acid, pancreatic enzymes, bile, and intestinal secretions destroy harmful micro-organisms. Nonpathogenic bacteria (commensal bacteria) make up the normal flora in the gastrointestinal tract and act as protectants against invading pathogenic bacteria. Commensal bacteria are a source of infection only if they are transmitted to another part of the body or if they are altered by the use of antibiotics [16].

The transmission of infection follows the cycle that has been described for all diseases, and humans are at the center of this cycle [16]. In brief, a micro-organism requires a reservoir (a human, soil, air, or water), or a host, in which to live. The micro-organism also needs an environment that supports its survival once it exits the host and a method of transmission. Inherent properties allow micro-organisms to remain viable during transmission from a reservoir to a susceptible host, another essential factor for transmission of infection. The primary routes of transmission for infections are through the air, blood (or body fluid), contact (direct or indirect), fecal-oral route, food, animals, or insects. Once inside a host, micro-organisms thrive because of adherent properties that allow them to survive against mechanisms in the body that act to flush them out. Bacteria adhere to cell surfaces through hair-like projections, such as fibrillae, fimbriae, or pili, as well as by proteins that serve as adhesions [71]. Fimbriae and pili are found on gram-negative bacteria, whereas other types of adhesions are found with both gram-negative and gram-positive bacteria. Receptor molecules in the body act as ligands to bind the adhesions, enabling bacteria to colonize within the body. The virulence of the micro-organism will determine whether only colonization occurs or if infection will develop. With colonization, there is no damage to local or distant tissues and no immune reaction; with infection, bacterial toxins that break down cells and intracellular matrices are released, causing damage to local and distant tissues and prompting an immune response in the host. Bacteria continue to thrive within a host through strategies that enable them to acquire iron for nutrition and to defend against the immune response. These virulence factors enhance a micro-organism's potential for infection by interrupting or avoiding phagocytosis or living inside phagocytes [71].

A healthcare environment increases the risk of infection for two primary reasons. First, it is likely that normally sterile body sites will become exposed, allowing pathogens to cause infection through contact with mucous membranes, nonintact skin, and internal body areas. Second, the likelihood of a susceptible host is high due to the vulnerable health status of patients. Especially in an era of decreased hospital stays and increased outpatient treatments, it is the sickest patients who are hospitalized, increasing the risk not only for infection to develop in these patients but also for their infection to be more severe and to be transmitted to others.

Infection is transmitted in a healthcare environment primarily through exogenous and endogenous modes. Exogenous transmission is through patient-to-patient or staff-to-patient contact. Patients who do not have infection but have bacterial colonization can act as vectors of transmission. Staff members can also act as vectors because of colonization or contamination. Endogenous infection occurs within an individual patient through displacement of commensal micro-organisms.

In general, the spread of infectious disease is prevented by eliminating the conditions necessary for the micro-organism to be transmitted from a reservoir to a susceptible host. This can be accomplished by:

- Destroying the micro-organism

- Blocking the transmission

- Protecting individuals from becoming vectors of transmission

- Decreasing the susceptibility of potential hosts

Antiseptic techniques and antibiotics will kill micro-organisms, and proper hand hygiene will block their transmission. Gloves, gowns, and masks remove healthcare workers from the transmission cycle by protecting them from contact with micro-organisms. Contact precautions and isolation techniques help patients avoid being vectors of transmission. Lastly, ensuring that patients and healthcare workers are immune or vaccinated can help decrease the availability of potential hosts.

DEVELOPMENT OF DRUG-RESISTANT MICRO-ORGANISMS

The prevalence of drug-resistant micro-organisms has reached a critical level, and the inappropriate use of antibiotics is often cited as a primary cause of drug-resistant infections. As much as 50% of antimicrobial use is inappropriate [72]. The prophylactic use of antibiotics preoperatively and the empiric use of antibiotics have helped bacteria to develop resistance in the healthcare setting. To meet the challenge of drug resistance, the management of antibiotic use has been a priority recommendation in guidelines developed for infection control programs in healthcare institutions, and review of the antibiotic formulary is required by institutions as part of compliance with Joint Commission standards [16,24,73,74]. (Guidelines for preventing drug-resistant infections in the healthcare setting are discussed in the Infection Control section.)

Although the inappropriate use of antibiotics is a major contributor to the development of drug resistance, other factors play an important role. These other factors include the natural ability of micro-organisms to adapt through genetic plasticity and rapid replication and the lack of antibiotic discovery and development over the past decades [75]. For example, when the efficacy of antibiotics was first demonstrated in the late 1920s, their development and manufacture increased rapidly, and they began to be widely used (too widely, perhaps). However, over the next 40 years, no new class of antibiotics was developed, and the number of new antibiotics decreased substantially between 1983 and 2014 [75]. In 2009, 16 antimicrobial compounds were in late-stage clinical development (phase II or later); however, these compounds represent only incremental advances compared with currently available options, and few address the most commonly resistant pathogens [76]. A 2013 IDSA report identified seven drugs in clinical development that were not included in the 2009 list, but indicated that these agents fell short of addressing the clinically relevant spectrum of resistance [77]. Only two new antibiotics were approved between 2009 and 2013, but five new antibiotics were approved in 2014–2015. Drug resistance typically emerges first in the healthcare setting, varies according to healthcare setting and geography, and subsequently extends to the community setting [24]. The transmission and persistence of resistant strains of pathogens in a healthcare setting depends on several factors: availability of vulnerable patients, selective pressure from use of antimicrobial agents, number of patients with colonization of infection, and presence and adherence to prevention efforts [24].

Several risk factors for HAI caused by multidrug-resistant organisms have been identified [78,79]:

- Older age

- Underlying disease and severity of illness

- Transfer of patients from another institution, especially from a nursing home

- Exposure to antimicrobial drugs, especially cephalosporins

- Prolonged hospitalization

- Gastrointestinal surgery or transplantation

- Exposure to invasive devices (urinary catheter, central venous catheter)

Antimicrobial-resistant pathogens have been reported to be the source of approximately 14% to 20% of HAIs, and these HAIs are associated with higher rates of morbidity and mortality and greater economic costs than antimicrobial-susceptible infections [40,80,81,82].

The most common drug-resistant HAI is MRSA, which emerged as a significant problem in the 1980s and increased steadily in prevalence, with a rate of approximately 59% of S. aureus infections in U.S. intensive care units (ICUs) in 2004 [79]. Since that time, however, the rate of MRSA associated with HAIs has decreased, most likely because of increased preventive strategies [79,82]. Overall, the rate of HAIs attributable to antimicrobial-resistant pathogens has not changed substantially since 2010 [82]. According to data on HAIs reported to the NHSN in 2009–2010, 20% of the infections were with antimicrobial-resistant phenotypes: MRSA (8.5%); vancomycin-resistant Enterococcus (VRE) (3%); extended-spectrum cephalosporin-resistant Klebsiella pneumoniae and K. oxytoca (2%); Escherichia coli (2%); Enterobacter spp. (2%); and carbapenem-resistant Pseudomonas aeruginosa (2%) [82]. The discovery of carbapenem-resistant Enterobacteriaceae as a new threat led the CDC to issue a guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in the healthcare setting [83,84]. Data from the 2015 NHSN network survey report showed that 45% of S. aureus isolates were methicillin-resistant, and among E. coli, Enterobacter, and Klebsiella isolates, 5% were carbapenem-resistant [3].

The COVID-19 pandemic impacted surveillance for and incidence of HAIs. Although the Centers for Medicare and Medicaid Services implemented the "extraordinary circumstance exception" (ECE) policy that excused facilities from HAI surveillance and reporting via NHSN for the fourth quarter of 2019 through the second quarter of 2020, between 86% and 88% of acute care hospitals that conducted surveillance in the first half of 2019 also performed surveillance and reported data for the first half of 2020. The NHSN analysis of data from 2020 found significant increases in HAIs, including MRSA bacteremia (15% increase), compared with 2019 [85]. As previously stated, the HAI Action Plan set a target for 2020 of a 50% reduction in hospital-onset MRSA [2].

Antimicrobial-resistant HAIs are associated with substantial morbidity and mortality compared with antimicrobial-susceptible HAIs, with longer hospital stays (excess of approximately 7 to 13 days), greater attributable mortality (up to 15%), and higher costs (additional $7,000 to $15,000) [79]. Guidelines for the prevention and management of multidrug-resistant pathogens in the hospital setting have been developed by the CDC, SHEA, and IDSA, with the most recent guidelines focusing specifically on the treatment of MRSA [24,31,34,86]. More information on antimicrobial-resistant pathogens is given in the discussions of each type of HAI. In addition, prevention of MRSA infection is addressed in the Infection Control section, as prevention is an important aspect of a healthcare facility's infection control program.

4. SOURCES OF HAIs

In general, the sources of HAIs can be categorized as being related to environmental factors (air, water, architectural design), patient-related factors (age, degree of illness/immune status, length of hospital stay), and iatrogenic factors (invasive procedures, devices, and equipment).

ENVIRONMENTAL FACTORS

Factors specifically related to the healthcare environment are not common causes of HAIs [16,87,88]. However, consideration should be given to the prevention of infection with environmental pathogens, such as fungi (e.g., Aspergillus), bacteria (e.g., Legionella species), or viruses (e.g., varicella) (Table 4). CDC guidelines provide clear recommendations for infection control measures according to several environment-related categories, including air (normal ventilation and filtration, as well as handling during construction or repair), water (water supply systems, ice machines, hydrotherapy tanks and pools), and environmental services (laundry, housekeeping). The infection control program of a facility has oversight of these measures.

Table 4: ENVIRONMENTAL SOURCES OF PATHOGENS IN THE HEALTHCARE SETTING

Source

Bacteria

Viruses

Fungi

Air

Gram-positive cocci (originating from skin)

Tuberculosis

Varicella zoster (chickenpox)

Influenza

Aspergillus

Water (tap and bath)

Gram-negative bacteria (Pseudomonas aeruginosa, Aeromonas hydrophilia, Burkholderia cepacia, Stenotrophomonas maltophilia, Serratia marcescens, Flavobacterium meningosepticum, Acinetobacter calcoaceticus, and Legionella pneumophila)

Mycobacteria (Mycobacterium xenopi, Mycobacterium chelonae, or Mycobacterium avium-intracellularae)

Molluscum contagiosum

Human papillomavirus (bath water)

Noroviruses

Aspergillus

Exophiala jeanselmei

Source: [16,87,88]

ENVIRONMENTAL SOURCES OF PATHOGENS IN THE HEALTHCARE SETTING

Air

Droplets containing micro-organisms can be transmitted in the air, causing infection in patients either directly or indirectly (through contamination of devices or equipment). Cleaning activities, such as sweeping, dry mopping, dusting, or shaking linen, can contribute to the transmission of airborne micro-organisms. Bacteria in the air primarily consist of gram-positive cocci from the skin, and they can be eliminated with appropriate ventilation and circulation of air [89]. Many airborne viruses, such as influenza and other respiratory viruses and measles, do not carry far from the source; others, such as tuberculosis and varicella zoster, may be spread over long distances [16]. The most common fungal spore to be transmitted through air is Aspergillus, which is carried through dust particles, can survive for long periods, and is easily inhaled [90]. Under normal circumstances, the level of contamination with this airborne fungus' spores is not high enough to cause disease in otherwise healthy individuals. However, in the healthcare setting, the fungus causes respiratory infection, primarily pneumonia, in susceptible hosts.

The prevalence of infection with Aspergillus within a healthcare setting has been strongly associated with Aspergillus spore counts. Consequently, air conditioning systems with high-efficiency particulate air (HEPA) filters are needed to minimize contamination [91]. HEPA filters are especially needed to prevent infection with Aspergillus in patients at high risk for infection due to a suppressed immune system [92]. In one study, the risk of transplant-related mortality and overall mortality in the first 100 days after transplantation were significantly lower among patients treated in rooms with HEPA and/or laminar flow units than among patients treated in conventional isolation units [93]. In these units, the air exchange rate should be high (more than 15 exchanges per hour), rooms should be tightly sealed, and the air pressure in the rooms should be positive in relation to the hallway [91,94,95]. HEPA filters are also used in the hoods in microbiology laboratories and pharmacies, laminar flow units in ICUs, and unidirectional flow units in operating room suites [16].

Air in the Operating Room

Maintaining a high quality of air in operating rooms is an essential factor in preventing postoperative infection. The number and movement of staff within the operating room create the primary sources of airborne bacteria. Other factors influencing airborne contamination include the type of surgery, the rate of air exchange, the initial quality of the air, the quality of the staff clothing and cleaning processes, and the level of compliance with infection control practices [16].

The CDC makes several suggestions about ventilation in the operating room in its guidelines for prevention of surgical site infections [29]. The Level I recommendations include:

- Maintain positive-pressure ventilation in the operating room with respect to the corridors and adjacent areas.

- Maintain a minimum of 15 air changes per hour, of which at least three should be fresh air.

- Filter all air, recirculated and fresh, through the appropriate filters per recommendations of the American Institute of Architects.

- Introduce all air at the ceiling and exhaust near the floor.

- Do not use ultraviolet radiation in the operating room to prevent surgical site infection.

- Keep operating room doors closed except as needed for passage of equipment, personnel, and the patient.

Air During Construction

Special care must be taken to protect patients during repair or renovation of a healthcare facility, as construction work can facilitate the spread of airborne organisms such as Aspergillus species [16]. Some construction issues that contribute to the spread of infection include water-damaged building materials, disruption of duct work, open windows, and improper setting of fans or installation of filters [96].

The Joint Commission requires an inspection process for construction on a facility, and a risk assessment is part of that process [96]. Risk factors to consider include the patient population, the extent and duration of the project, the impact of the project on mechanical systems, and whether space with construction will be occupied [96]. A representative from a facility's infection control program should review any plans for construction to ensure that barriers are used as appropriate and patients, especially those with compromised immune systems, are moved to an area away from construction [89].

Water

Water is a reservoir for several types of micro-organisms, including bacteria, fungi, and viruses, with viruses accounting for only a small percentage [87,97]. The quality of water within a healthcare setting must meet standards that vary according to use. Tap water must be safe to drink and use for baths (for hygiene and therapy) according to criteria dictated by local regulations and public health standards. The water supply to the healthcare facility can be disinfected by several methods, including chlorination, thermal eradication, ultraviolet light, and metal ionization [91].

The most common pathogen identified in tap water is P. aeruginosa [79]. In one study, researchers evaluated the association between tap water from faucets in a surgical ICU and patients with colonization or infection with P. aeruginosa [98]. The pathogen was found in 58% of water samples taken from individual faucets but was not identified in the main water supply. The genotypes of the micro-organism in 21 of the 45 patients were identical to those found in the tap water from the sink in the patient's room (15 patients) or in the adjacent room (6 patients). According to epidemiologic analysis, transmission of the pathogen had occurred from faucet to patient as well as from patient to faucet. P. aeruginosa is also the primary bacterial pathogen found in bath water [99]. The effect of infection with P. aeruginosa may be mild, as in folliculitis and external otitis, but wound infection may be more severe. Greater morbidity is associated with infection in individuals who have a compromised immune system or who have another health condition, such as diabetes [16].

Legionella, which causes infection of the respiratory tract, is another micro-organism commonly found in tap water and bath water. The highest concentrations of Legionella are found in areas of water distribution systems (hot water storage, cooling towers, condensers), where it colonizes [91]. Infection with Legionella is transmitted only through water, not through person-to-person contact. Inhalation of contaminated water droplets from shower heads or faucet aerators may cause disease [87]. In addition, high humidity levels in a room (through mists produced by respiratory equipment, for example) may promote the growth of Legionella and molds [93].

The WHO suggests that there is potential risk for HAIs if tap water is used for such purposes as ice machines or devices for washing eyes or ears, or for cleaning equipment [16]. Point-of-use filtration may help to reduce the risk of HAIs related to water [97]. Ducts, humidifiers, dehumidifiers, and other areas of a ventilation system should be kept clean and dry, as micro-organisms can colonize in water that accumulates in these areas [93]. Patients at high risk for infection should not be exposed to hospital water and sterile water should be used instead [88].

Architectural Design

Another factor in the transmission of infection in the healthcare setting is the architectural design of the facility, and the Agency for Healthcare Research and Quality lists "good hospital design principles" as one of its 10 patient safety tips for hospitals [100]. When the American Institute of Architects and the Facility Guidelines Institute (FGI) updated its Guidelines for Design and Construction of Hospital and Health Care Facilities in 2006, they set single-bed private rooms as the minimum standard for new hospital construction [19]. This new standard was based on a literature review that showed, in part, that private rooms have been associated with lower rates of HAIs [101]. Among the benefits of single-patient rooms compared with multibed rooms are decreased risk of infection through contaminated surfaces (e.g., blood pressure cuffs, privacy curtains); availability of private bathrooms; greater ease of cleaning and decontamination; increased likelihood of appropriate hand hygiene between rooms (rather than between beds within a single room); and decreased risk of prolonged hospital stays and patient transfers, all of which are risk factors for HAIs [101]. Draft 2022 FGI guidelines for Design and Construction of Hospitals maintain the single-bed per room standard, but allow for two beds when the necessity of this arrangement has been demonstrated and approved by the authority having jurisdiction [102].

The WHO guidelines on infection control refer to "architectural segregation" according to risk [16]. Four areas of a healthcare facility are defined, with administrative sections considered as low-risk areas; regular patient wards as moderate-risk areas; ICUs, burn units, or isolation units as high-risk areas; and operating rooms as very high-risk areas. The WHO and others have recommended that traffic flow should be limited in higher risk areas [16].

The type of sink and the placement of sinks throughout a healthcare facility have been of critical concern because of the substantial role of handwashing in reducing the transmission of infection. As a result, sinks have been placed within easy access in each patient room. However, it is unclear that such placement promotes better hand hygiene, with no long-term clinically significant improvement in handwashing found when sinks are placed near points of clinical activity [103].

With the advent of alcohol-based handrub solutions as more effective hand hygiene, the placement of handrub dispensers has become more important than the placement of sinks [27]. The CDC guidelines on hand hygiene recommend placing dispensers in convenient locations, such as at the entrance of each patient room or at the bedside.

PATIENT-RELATED FACTORS

Patient-related risk factors for HAIs include age, general health status, and the type of procedure to be carried out, and risk can be classified as minimal, medium, or high [16]. Patients are at minimal risk if they have no significant underlying disease, have an intact immune system, and will not undergo an invasive procedure. Medium risk is assigned to older patients who are susceptible to disease for a variety of reasons, including decreased immune function, comorbid conditions, and low nutritional status. Medium risk also refers to patients who are to have a nonsurgical invasive procedure, such as a peripheral venous catheter or a urinary catheter.

Advances in medical treatments have led to longer lives for individuals of all ages who have had organ transplantation, cancer, or infection with human immunodeficiency virus (HIV), and their compromised immune system puts them at high risk for HAI. High risk is also assigned to patients with multiple trauma or severe burns, or those who have surgery or an invasive procedure that is considered to be high risk, such as endotracheal intubation or insertion of a central venous catheter.

IATROGENIC FACTORS

The primary iatrogenic factors contributing to the development of HAIs are devices (nonimplanted and implanted) and invasive procedures. As noted, the four most common HAIs—catheter-associated urinary tract infection, intravascular device-related bloodstream infection, surgical site infection, and pneumonia (ventilator-associated and hospital-acquired)—are related to the use of invasive devices or invasive procedures.

Nonimplanted Devices

HAIs have been associated with several types of devices and equipment unique to healthcare facilities. The Spaulding classification, developed in 1968, is widely used to categorize devices according to their associated risk of infection [104]. The system includes three categories:

- Critical: A device that enters normally sterile tissue or the vascular system

- Semicritical: A device that comes into contact with intact mucous membranes and does not ordinarily penetrate sterile tissue

- Noncritical: A device that does not ordinarily touch a patient or touches only intact skin

Most HAIs can be attributed to devices in the critical and semicritical categories, including intravascular catheters, surgical drains, urinary catheters, and endoscopic instruments [89]. Discussion here is limited to endoscopic instruments, as infections related to the other devices are addressed in detail later. In general, the transmission of pathogens on endoscopic devices has been attributed to noncompliance with appropriate reprocessing (cleaning, disinfection, sterilization, and drying) [17,32,105,106]. In particular, appropriate drying has been overlooked as an integral component of reprocessing, and guidelines have been inconsistent in recommendations on drying [107].

Bronchoscopes and gastrointestinal endoscopes are the primary diagnostic scopes used in healthcare settings. Both types of devices are associated with a low risk of infection transmission. Approximately 500,000 flexible bronchoscopies are done in the United States each year [17,108]. Few studies, however, have been carried out to evaluate the risk of infection; nosocomial infection related to bronchoscopy is difficult to detect and is likely under-recognized and under-reported [109]. In 2003, there were two reports of multiple pseudoinfections and true infections, primarily with P. aeruginosa, associated with bronchoscopes that had been reprocessed according to current standards [110,111]. However, in both reports, loose fittings over the valve stem for the working channel of the bronchoscope were thought to have prevented effective mechanical cleaning and disinfection [109]. Overall, the pathogens associated with bronchoscopy-related infection have been P. aeruginosa, Serratia marcescens, nontuberculous mycobacteria, and environmental fungi [109]. In 2014, the U.S. Food and Drug Administration (FDA) received 50 medical device reports that mentioned infection or device contamination associated with reprocessed flexible bronchoscopes [108]. During the course of investigating these reports, the FDA identified two recurrent themes that contributed to device contamination or device-associated infection: failure to meticulously follow the manufacturer's instructions for reprocessing (e.g., failure to perform thorough manual cleaning before high-level disinfection), and continued use of devices, despite integrity, maintenance, and mechanical issues (e.g., persistent channel kinks or bends).

More studies have evaluated the risk of infection associated with gastrointestinal endoscopy, which is performed on approximately 10 to 20 million people each year [112]. The American Society for Gastrointestinal Endoscopy (ASGE) estimates that infectious organisms are transmitted in 1 of 1.8 million gastrointestinal endoscopies [105]. Furthermore, all instances of infection during endoscopy have been the result of noncompliance with established guidelines for reprocessing of endoscopy equipment, highlighting the importance of adhering to these recommendations [32,112,113,114].

As with bronchoscopy, the pathogen with the highest rate of transmission associated with gastrointestinal endoscopy is P. aeruginosa [112,114]. As is true for other pathogens associated with endoscopy, infection with P. aeruginosa has resulted from nonadherence to reprocessing guidelines; however, this pathogen differs from the others because of its predilection for a moist environment. Many cases of infection with P. aeruginosa have been linked to the water supply to the endoscope and to failure to completely dry the endoscope channels with a 70% alcohol solution and forced air [107,112,114]. Salmonella species have also been associated with endoscopy, but no cases have been reported since the publication of the 1988 guidelines for standardized cleaning and disinfection of the devices [112,114]. Infection with Helicobacter pylori has also been related to suboptimal cleaning and disinfection [112]. Low rates of hepatitis B and C virus transmission have been reported, and most cases of infection with hepatitis C were found to be related to the inappropriate use of multiple-dose vials and/or syringes rather than to the endoscope itself [32,112].

Noncritical devices are often overlooked by healthcare workers as vectors for infection. These devices include diagnostic equipment, stethoscopes, and other commonplace items. A systematic review of 23 studies found bacterial contamination of 87% of sampled healthcare equipment, primarily stethoscope membranes, as well as diagnostic ultrasound equipment, otoscopes, and auriscopes [115]. The organisms found on healthcare equipment have primarily been S. aureus, including MRSA; Pseudomonas spp.; Acinetobacter spp.; and Pasteurella spp. [116]. Washing stethoscopes with either an ethanol-based cleanser or isopropyl alcohol pads significantly reduces bacterial growth, even that of MRSA [117,118,119].

Contamination of therapeutic ultrasound transducer heads and ultrasound gels were evaluated in another study, and the rate of contamination was 27% for the heads and 28% for the gels [120]. The transducer heads had low levels of contamination, and most of the micro-organisms were normal flora; however, high levels of contamination were found in the gels, and the micro-organisms included such pathogens as Stenotrophomonas maltophilia, S. aureus, Acinetobacter baumannii, and Rhodotorula mucilaginosa. In two other studies, contamination of dermatoscopes was evaluated. One study indicated colonization of only nonpathogenic bacteria and the other showed that use of an alcohol-based antibacterial gel as immersion fluid yielded no bacterial growth [121,122].

Ward-based computer terminals have also been shown to have low levels of contamination. In a study of two hospitals, MRSA was found on one of 13 computer terminals in one hospital and on five of 12 in another hospital. The rate of MRSA transmission was significantly higher at the hospital with the greater number of contaminated computers [123].

In summary, a high rate of micro-organism colonization has been found on equipment within the hospital setting, but contamination is usually at low levels and the risk of direct infection is low. In general, the findings of studies have suggested that adequate cleaning of equipment can prevent as many as one-third of HAIs [115].

Implanted Devices

Surgically implanted devices are a major source of HAI, and the development and use of intracardiac devices, orthopedic implants (prostheses and fixation devices), neurosurgical devices, cochlear implants, and breast and penile implants have increased over the past several years. The most common complication with all of these devices is infection [124,125,126]. The prevalence of infection associated with these devices varies, with the prevalence highest for left ventricular assist devices (Table 5) [124]. Orthopedic implants, such as joint prostheses and fracture fixation devices, are associated with the lowest rate of infection, but reported mortality rates have been as high as 18% [124].

Table 5: DEVICE-RELATED INFECTIONS

Type of Device

Prevalence

Probable Cause

Typical Duration to Occurrence after Implantation

Most Common Micro-organisms

Signs and Symptoms

Diagnosis

Treatment

Left ventricular assist devices

25% to 50%

Biofilm formation

Within 2 to 6 weeks

Methicillin-resistant staphylococcal spp., Pseudomonas spp. ,Klebsiella spp., E. coli, Enterobacter spp., Proteus spp., Serratia spp., Candida spp., Enterococcus spp.

Signs of poor healing, localized inflammation, pocket abscess, frank sepsis, new and persistent drainage

Blood cultures

Empiric therapy with vancomycin and an anti-pseudomonal agent (ceftazidime or ciprofloxacin) or empiric antifungal therapy

Cerebrospinal fluid (CSF) shunts

10%

Bacteria originating from patient's skin introduced at time of operation

Within 30 days

Staphylococcus epidermidis (40% to 45%), S. aureus (25%), Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, Acinetobacter baumanii, Corynebacterium spp., Propionibacterium spp., and streptococci/enterococci

Fever, focal pain, ventriculitis with lethargy and malaise (proximal shunts), infected intraperitoneal fluid cysts, or frank peritonitis (distal shunts)

CSF analysis (cell count, glucose, protein), gram stain, culture; abdominal ultra-sonography (distal shunts)

Antimicrobial agent effective against noted micro-organisms, modified with results of culture; removal of shunt

Prosthetic cardiac valves

3% to 5.7%

Contamination of the valve at time of implantation or transient bacteremia

Within 60 days (early)

Coagulase-negative staphylococci, specifically methicillin-resistant S. epidermidis, S. aureus

Fever, new or changing regurgitant murmurs, CHF, shock, cardiac conduction disturbances on EKG

Blood cultures, transesophageal echocardiography

Delayed antibiotic therapy until results of culture available (if subacute course and hemodynamically stable); empiric antibiotic therapy with vancomycin, gentamicin, rifampin (evidence of significant valve dysfunction); valve replacement (new or increasing murmurs, severe CHF, persistent fever)

Penile implants

2% to 8%

Contamination at time of implantation

Not available

S. epidermidis

Erythema, induration, tenderness, fever, discharge, device extrusion, prosthesis-associated pain

Culture of specimen from the operative site

Empiric antibiotic therapy with ciprofloxacin or a cephalosporin for 10 to 12 weeks; removal of implant if pain persists or recurs after antibiotic treatment or if purulent discharge

Cochlear implants

1.7% to 3.3%

Contamination at time of implantation

Within 30 to 90 days

S. aureus, Streptococcus pneumoniae, Haemophilus influenzae

Skin flap necrosis, wound dehiscence, wound infection

Not available

Antibiotic therapy, incision and drainage, local wound care; removal of device if extrusion of device or implant-related sepsis

Transvenous permanent pacemakers/automatic implantable cardioverter defibrillators

1% to 7%

Intraoperative contamination of the device or the pocket (early); contamination of pocket as a result of erosion of generator/defibrillator through skin (late)

Within 30 days (early); within 60 days (late)

S. aureus, Propionibacterium acnes, Micrococcus spp., E. coli, Klebsiella spp., Enterobacter spp., Serratia spp. (early); coagulase-negative staphylococci (late)

Erythema, pain, warmth at site ("pocket cellulitis"), draining sinus tract or erosion of overlying skin, systemic symptoms (fever, chills, malaise, nausea)

Blood cultures, transesophageal echocardiography

Prolonged antibiotic therapy, removal of all hardware; empiric therapy with vancomycin, gentamicin, or rifampin

Breast implants

1.7% to 2.5%a

Not available

Within 2 to 4 weeks

S. aureus, peptostreptococci, Clostridium perfringens

Erythema, edema, poor healing, purulent discharge, inflammatory symptoms (breast or axillary pain, paresthesia of upper extremity)

Wound or fluid culture

Empiric antibiotic therapy, local debridement

Orthopedic implants

<1% to 2%

Intraoperative contamination (early and late)

<2 to 4 weeks (early); >30 days (late)

S. aureus, coagulase-negative staphylococci, Propionibacterium spp. (early and late)

Persistent pain, fever, evidence of wound infection (early); loosening of prosthesis, sinus tract formation with discharge

Joint aspiration, complete blood count, erythrocyte sedimentation rate, C-reactive protein, imaging

Surgical exploration and debridement followed by empiric antibiotic therapy

aAfter augmentation mammoplasty; rates may be higher after mastectomy.

Source: [124]

Many implanted device-related infections are caused by contamination during insertion, but these infections are not always the result of micro-organisms transmitted in the healthcare setting. Rather, bacteria (and sometimes fungi) colonize by adhering to the surface of the implant through the development of a biofilm [124]. Biofilms present another challenge in managing infection; biofilms provide bacteria with an extremely high level of resistance to antimicrobial agents. In fact, biofilms can tolerate antibiotic concentrations of 10 to 1,000 times of that needed to destroy free-floating (planktonic) bacteria [124]. Many bacteria, including P. aeruginosa, are capable of existing in a planktonic state [114].

The CDC defines implanted device-related HAIs as those occurring within one year after implantation of a device, and the typical interval between implantation and infection varies according to the type of implant [127]. For some implants, early and late infections differ with respect to etiology and the causative micro-organisms [124].

The treatment of infections related to these devices depends on the severity of the infection and the patient's underlying condition. A multidisciplinary approach involving antibiotic therapy and surgical intervention (either debridement or removal of the device) can have a substantial impact on morbidity and mortality. For example, prosthetic valve endocarditis is associated with mortality rates of 42% to 100%, but the rate can be decreased 20-fold through an approach that combines medical and surgical therapy rather than medical therapy alone [124]. Empiric antibiotic therapy is usually appropriate once specimens have been obtained for culture, with the antibiotic agent chosen on the basis of the most common micro-organisms.

5. TYPES OF INFECTIONS

HAI is clearly defined by the CDC in the NHSN as a "localized or system condition (1) that results from adverse reaction to the presence of an infectious agent(s) or its toxin(s); and (2) that was not present or incubating at the time of admission to the hospital" [127]. Thus, an infection is considered to be healthcare associated if it is unrelated to the admitting diagnosis and develops within 48 hours after admission. The CDC notes that an infection should be considered healthcare associated if it is thought that the infection was acquired in the hospital but did not become evident until after discharge 127]. The diagnosis of infection is made on the basis of a combination of clinical findings and the results of laboratory studies or other diagnostic testing [127]. The NHSN provides comprehensive details about the criteria for infection at 13 major anatomic sites and has developed clinical and biologic criteria for 48 specific sites or types of infection [127]. The WHO has simplified the criteria to facilitate infection control in healthcare institutions with limited resources [16].

The rates of the five most common HAIs and the percentage each infection accounts for among all HAIs vary according to several factors, including time, geography, healthcare setting (including specific units within a hospital), and the data source. In general, catheter-related urinary tract infections are the most common, representing nearly one-third of all HAIs, and are the least costly; intravascular device-related bloodstream infections tend to be the most costly (in dollars); and ventilator-associated pneumonia is associated with the highest number of deaths (Table 6) [1,30,79,82,128,129,130,131,132,133,134]. Other HAIs defined in the NHNS include infection of bones and joints; the central nervous system; the cardiovascular system; the eye, ear, nose, throat, or mouth; the lower respiratory tract (other than pneumonia); the reproductive tract; skin and soft tissue; and systemic infection. Many of these other HAIs develop as complications of surgically implanted devices [124].

Table 6: CHARACTERISTICS OF THE MOST COMMON HEALTHCARE-ASSOCIATED INFECTIONS

Infection

Proportion of All HAIs

Incidence

Costs

Excess Stay

Attributable Mortality

Mean Hospital Cost per Infection (U.S. Dollars)

Catheter-associated urinary tract infection

32%

20% to 40% of patients with an indwelling catheter

10 days

1%

$1,006

Surgical site infection

22%

1% to 3% of surgical patients

7 to 10 days

3% to 5%

$25,546

Central line-associated bloodstream infection

14%

1% of patients with a central line

10 to 20 days

35%

$36,441

Ventilator-associated pneumonia

15%

10% to 65% of intubated patients

4 days

10% to 50%

$9,966

Healthcare-associated pneumonia (other than ventilator associated)

<1%

NA

NA

NA

NA

Clostridioides difficile-associated diarrhea

Not available

30% of hospitalized adults with diarrhea

3 to 6 days

6% to 7%

$9,000–$11,000

NA = Not available.

Source: [1,30,38,79,82,129,130,131,132,133,134]

The risk factors for each of these HAIs have been delineated in many studies (Table 7) [20,79,135,136,137,138,139,140,141,142]. Yet, predicting which patients are at risk can be difficult. In one study, physicians in a surgical ICU were asked to assess at admission the individual risk of major HAI during the patient's stay in the unit. The investigators found that the physicians could not accurately predict risk, with positive predictive values that ranged from 8.4% to 14.5% and negative predictive values that ranged from 92.1% to 100% [143].

Table 7: RISK FACTORS FOR HEALTHCARE-ASSOCIATED INFECTIONS

Infection

Patient-Related Factors

Iatrogenic Factors

Urinary tract infection

Older age

Female gender

Diabetes mellitus

Renal insufficiency

Other site of infection

Urethral stent

Use of catheter to measure output

Disconnection of catheter from drainage tube

Duration of catheterization

Retrograde flow of urine from drainage bag

Surgical site infection

Nutritional status

History of smoking

History of alcohol use disorder

Obesity

Diabetes

Hypovolemia

Poor tissue perfusion

Compromised immune system

Pre-existing infection (local or other site)

Anesthesia score

Nonviable tissue in wound

Hematoma

Dead space

Wound classification

Foreign material (including drains and sutures)

Skin antisepsis

Duration of operation

Length of time sterile tray left open

Intraoperative contamination

Duration of preoperative hospital stay

Hypothermia during operation

Duration of surgical scrub

Antimicrobial prophylaxis

Preoperative preparation (wash/shave)

Surgical technique

Central line-associated bloodstream infection

Severity of illness

Burns or surgical wounds

Compromised immune system

Nutritional status

Heavy colonization on skin at site of insertion

Location in internal jugular or femoral vein

Length of time in place

Contamination of catheter hub

Type of infusate

Total parenteral nutrition

Location of insertion

Ventilator-associated pneumonia

Older age

Severity of illness

Chronic pulmonary disease

Head trauma

Elevated gastric pH

Upper abdominal or thoracic surgery

Reintubation

Supine position

Aspiration of gastric contents

Nasogastric tube

Sedation

Duration of mechanical ventilation

Hospital-acquired pneumonia (not associated with a ventilator)

Older age

Chronic pulmonary disease

Surgery

ASA class 2 or higher

Functional dependence

Congestive heart failure

History of tobacco use

Duration of operation

Emergency surgery

Surgical site

Sedation

Enteral nutrition

Clostridioides difficile-associated diarrhea

Age

Severity of illness

Compromised immune system

Gastrointestinal surgery or manipulation

Debilitation

Length of stay

Antibiotic use

Nasogastric intubation

ASA = American Society of Anesthesiologists.

Source: [20,79,135,136,137,138,139,140,141,142]

HAIs are predominantly caused by bacteria. Between January 2015 and December 2017, 355,633 pathogens (311,897 HAIs) were reported to the NHSN [144]. Surgical site infections contributed to the highest proportion of HAIs (42.4%), followed by catheter-associated urinary tract infections (29.7%), central-line associated bloodstream infections (25.3%), and ventilator-associated pneumonia (2.6%). E. coli was the most common pathogen across all HAIs, accounting for nearly 18% of reported pathogens. Approximately 69% of the reported pathogens belonged to one of nine main pathogen groups [144]:

- E. coli (17.5%)

- Enterococcus spp. (14.8%)

- S. aureus (11.8%)

- Selected Klebsiella spp. (8.8%)

- P. aeruginosa (8.0%)

- Coagulase-negative staphylococci (6.8%)

- Enterobacter spp. (4.6%)

- Proteus spp. (3.2%)

- Candida albicans (3.1%)

The micro-organisms causing HAIs vary according to several factors, including the type of infection; in the overviews of the HAIs that follow, the most common micro-organisms specific to each infection are noted. Infectious agents also vary among healthcare facilities and even units within a single institution. Knowledge of trends in the pathogens responsible for HAIs is important in determining appropriate empiric therapy. This information changes frequently, and healthcare professionals should remain up to date with the pathogens identified in their own healthcare facilities and even on specific units within the facility. The IDSA/SHEA recommends computer-based surveillance (level II, B) as part of an overall antimicrobial stewardship program [72].

CATHETER-ASSOCIATED URINARY TRACT INFECTIONS

The IDSA defines a catheter-associated urinary tract infection as an infection occurring in a patient with an indwelling urinary catheter either currently in place or in place within the previous 48 hours [30]. Approximately 15% to 25% of inpatients will have a urinary catheter inserted at some time during the hospital stay, and a urinary tract infection will develop in 20% to 40% of them [21,30]. The risk of infection varies from 3% to 8% per day when an indwelling catheter is in place [30].

The NHSN survey in 2013 found the rate of catheter-associated urinary tract infections to be 7.4 to 11.5 infections per 1,000 catheter-days [145]. Catheter-associated urinary tract infections account for approximately 40% of all HAIs annually, with 75% to 80% of these attributable to indwelling urethral catheters [146]. The most recent NHSN survey observed a significant reduction in catheter-associated urinary tract infections in 2015, compared with 2011, and the national status report the following year showed a 7% reduction over that reported in 2015 [3,67]. This improvement has been attributed in part to a reduction in urinary catheter use and to the implementation of a Comprehensive Unit Based Safety Program (focused on prevention of urinary infection) in 603 U.S. hospitals between 2011 and 2013 [3]. As discussed, the COVID-19 pandemic affected the rate of HAIs across U.S. healthcare institutions. For example, data from acute care hospitals for the fourth quarter of 2020 indicate a 19% overall increase in catheter-associated urinary tract infections, with ICUs experiencing a 30% increase [85].

Risk Factors

The duration of catheterization is the most important risk factor for infection [30]. Studies have shown that catheterization for more than 2 days is a significant risk factor for urinary tract infection as well as increased 30-day mortality [147]. Other risk factors for catheter-related urinary tract infection include no treatment with systemic antimicrobial agents, positive results on culture of the urethral meatus, microbial colonization of the urinary drainage bag, insertion of the catheter outside the operating room, and nonadherence to guidelines for appropriate catheter care. Patient-related risk factors include female gender, older age, diabetes, and an elevated level of serum creatinine at the time of catheterization [30].

Transmission and Common Pathogens

Urinary tract infections can be caused by both endogenous and exogenous transmission. Normal flora from the gastrointestinal tract can spread to the urinary tract, or pathogens can be transmitted by caregivers carrying out tasks related to the catheter or drainage bag. Occasionally, pathogens are transmitted through urologic equipment that has not been adequately disinfected. Extraluminal ascension of bacteria along the catheter-urethral mucosa interface is the most common pathway of infection, accounting for approximately two-thirds of infections [30].

According to NHSN data for 2015–2017, the pathogens most commonly isolated from catheter-related urinary tract infections are E. coli (42%), followed by Klebsiella spp. (18%), P. aeruginosa (16%), and Enterococcus species (15%) [144]. Infections related to short-term catheterization is usually caused by a single agent, whereas infections related to long-term catheterization (30 days or more) is typically caused by multiple pathogens. P. mirabilis, Morganella morganii, and P. stuartii are additional common pathogens in infections related to long-term catheterization [30].

With regard to antimicrobial-resistant pathogens, the percentage of S. aureus infections resistant to oxacillins decreased in 2015–2017 (41% vs. 59% in 2009–2010) [144]. The percentage of Enterococcus faecium resistant to vancomycin increased, to 82% (from 80% in 2007–2008), as did the percentage of vancomycin-resistant E. faecalis (approximately 12% vs 6% in 2007–2008). The prevalence of multidrug-resistance among E. coli, Klebsiella, and Enterobacter spp., previously reported as having increased from 3% in 2007–2008 increased 10%, 13%, and 7%, respectively in 2015–2017 [144].

Prevention

The principles of care required for prevention of catheter-associated urinary tract infection are well established: appropriate use, sterile catheter placement, maintenance of a closed drainage system, avoidance of back-flow, and minimal duration of catheter insertion. In addition to these technical aspects, a systems approach that standardizes care, educates, and fosters an interprofessional culture of attentiveness is also necessary for optimal preventive care [21,148].

The evidence-based guidelines for prevention of catheter-associated urinary tract infections were published by the CDC in 2009 (Table 8). The IDSA has published evidence-based clinical practice guidelines on the prevention, diagnosis, and treatment of catheter-associated urinary tract infections in 2010 [21,30]. According to both guidelines, the most important principles for prevention are:

- Limit the use of indwelling urinary catheters.

- Use aseptic technique and sterile equipment when inserting a catheter.

- Secure the catheter properly.

- Use a closed sterile drainage system.

- Maintain unobstructed urine flow.

- Remove the catheter as soon as feasible.

Table 8: SUMMARY OF LEVEL I RECOMMENDATIONS FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) FOR THE PREVENTION OF CATHETER-ASSOCIATED URINARY TRACT INFECTIONa

Appropriate Urinary Catheter Use

Insert catheters only for appropriate indications, and leave in place only as long as needed.

Minimize urinary catheter use and duration of use in all patients, particularly those at higher risk for infection or mortality from catheterization, such as women, individuals older than 65 years of age, and patients with impaired immunity.

Avoid use of urinary catheters in patients and nursing home residents for management of incontinence.

Use urinary catheters in operative patients only as necessary, rather than routinely.

For operative patients who have an indication for an indwelling catheter, remove the catheter as soon as possible postoperatively, preferably within 24 hours, unless there are appropriate indications for continued use.

Proper Techniques for Urinary Catheter Insertion

Perform hand hygiene immediately before and after insertion or any manipulation of the catheter device or site.

Ensure that only properly trained persons (e.g., hospital personnel, family members, or patients themselves) who know the correct technique of aseptic catheter insertion and maintenance are given this responsibility.

In the acute care hospital setting, insert urinary catheters using aseptic technique and sterile equipment.

Use sterile gloves, drape, sponges, an appropriate antiseptic or sterile solution for periurethral cleaning, and a single-use packet of lubricant jelly for insertion.

Properly secure indwelling catheters after insertion to prevent movement and urethral traction.

If intermittent catheterization is used, perform it at regular intervals to prevent bladder overdistension.

Proper Techniques for Urinary Catheter Maintenance

Following aseptic insertion of the urinary catheter, maintain a closed drainage system.

If breaks in aseptic technique, disconnection, or leakage occur, replace the catheter and collecting system using aseptic technique and sterile equipment.

Maintain unobstructed urine flow.

Keep the catheter and collecting tube free from kinking.

Keep the collecting bag below the level of the bladder at all times. Do not rest the bag on the floor.

Empty the collecting bag regularly using a separate, clean collecting container for each patient; avoid splashing, and prevent contact of the drainage spigot with the nonsterile collecting container.

Use Standard Precautions, including the use of gloves and gown as appropriate, during any manipulation of the catheter or collecting system.

Unless clinical indications exist (e.g., presence of bacteriuria when catheter is removed after urologic surgery), do not use systemic antimicrobial agents routinely to prevent catheter-associated urinary tract infection for patients requiring either short-term or long-term catheterization.

Do not clean the periurethral area with antiseptics to prevent infection while the catheter is in place. Routine hygiene (e.g., cleansing of the meatal surface during daily bathing or showering) is appropriate.

Quality Improvement Programs

Implement quality improvement programs or strategies to enhance appropriate use of indwelling catheters and to reduce the risk of catheter-associated urinary tract infections based on a facility risk assessment. The purposes of quality improvement programs should be to: ensure appropriate utilization of catheters; identify and remove catheters that are no longer needed (e.g., daily review of their continued need); and ensure adherence to hand hygiene and proper care of catheters.

Administrative Infrastructure

Provide and implement evidence-based guidelines that address catheter use, insertion, and maintenance.

Ensure that healthcare personnel and others who take care of catheters are given periodic in-service training regarding techniques and procedures for urinary catheter insertion, maintenance, and removal. Provide education about catheter-associated urinary tract infections, other complications of urinary catheterization, and alternatives to indwelling catheters.

aLevel I recommendations are supported by high-to-moderate quality evidence suggesting net clinical benefits or harms, or by low-quality evidence suggesting net clinical benefits or harms, or an accepted practices supported by low-to-very low quality evidence.

Source: [21]

As with prevention of all HAIs, handwashing is an essential element of aseptic technique and care of patients with catheters. In addition, healthcare staff should be educated and trained in proper techniques of catheter insertion and care.

Alternatives to indwelling catheters have been evaluated as an approach to preventing catheter-related urinary tract infections. The IDSA guidelines note that a suprapubic catheter may be considered as an alternative to short-term catheterization (level III, C), but use of this type of catheter is limited because an invasive procedure is needed for insertion [30]. Intermittent catheterization may also be considered as an alternative to short-term (level I, C) or long-term (level III, A) catheterization, and, for men who have minimal postvoid residual urine, condom catheterization can be considered as an alternative to short-term (level II, A) or long-term (level II, B) catheterization in those who are not cognitively impaired [30].

The use of catheters coated with an antimicrobial surface has been evaluated, especially those coated with silver, a highly effective antibacterial substance. In one study, the addition of silver did not reduce the incidence of bacteriuria when compared with silicone-based, hydrogel-coated urinary catheters with and without silver impregnation [149]. One meta-analysis (12 trials; 13,392 patients or catheters) showed that antimicrobial-coated catheters prevented or delayed the onset of bacteriuria in select patients, but the magnitude of the effect varied substantially according to several variables, including catheter type and publication year [150]. A subsequent systematic review (eight studies) found a favorable trend toward a lower rate of infection with silver alloy (vs uncoated) catheters, but the quality of some studies was poor and there was significant heterogeneity among the studies [151]. The 2009 CDC guidelines state that antimicrobial/antiseptic-impregnated catheters can be considered if the rate of catheter-associated urinary tract infections does not decrease after a comprehensive prevention strategy has been implemented [21]. The guidelines add that further research is needed to determine the effect of these catheters in reducing the risk of symptomatic infection, their inclusion among the primary interventions, and the patient populations most likely to benefit from them [21].

Similarly, the IDSA states that catheters coated with an antimicrobial surface may be considered to reduce the risk of infection for patients who are to have short-term catheterization (level II, B), but notes that the data on the effectiveness of this strategy are insufficient [30].

The IDSA guidelines note several prevention strategies that should not be used routinely, primarily because of insufficient data [30]:

- Systemic antimicrobials in patients with short-term (level III, A) or long-term (level II, A) catheterization

- Antimicrobials or antiseptics added to the drainage bag (level I, A)

- Catheter irrigation with antimicrobials (level II, A) or normal saline (level II, B)

- Enhanced meatal care (level I, A)

- Cranberry products

- Methenamine salts (although prophylaxis with methenamine salts may be considered after gynecologic surgery for women who have a catheter for less than 1 week) (level 1, C)

Diagnosis

The CDC and the IDSA classify catheter-associated urinary tract infections as symptomatic urinary tract infection, asymptomatic bacteriuria, or other infection of the urinary tract. Urine samples for urinalysis and quantitative urine culture (using a clean catch technique or catheterization) are necessary for accurate diagnosis [30,127].

Evidence Based Practice Recommendation

According to the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), signs and symptoms compatible with catheter associated-urinary tract infection include new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause; flank pain; costovertebral angle tenderness; acute hematuria; pelvic discomfort; and in those whose catheters have been removed, dysuria, urgent or frequent urination, or suprapubic pain or tenderness.

https://academic.oup.com/cid/article/50/5/625/324341

Last Accessed: January 20, 2022

Strength of Recommendation/Level of Evidence: AIII (Good evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees)

The IDSA notes that catheter-associated urinary tract infection is defined by the presence of signs or symptoms compatible with a urinary tract infection with no other identified source, and at least one bacterial species at a count of ≥103 cfu/mL in one urine specimen (level III, A) [30]. This threshold differs from that defined by the CDC (≥105 cfu/mL), which is intended for infection control surveillance rather than detection of infection in an individual patient [127]. In addition, the 2009 CDC guidelines define the criteria for symptomatic catheter-associated urinary tract infection as symptoms plus a positive urine culture at the threshold of ≥105 cfu/mL; if the urine culture result is between ≥103 and ≤105 cfu/mL, a positive urinalysis is needed to meet the diagnostic criteria [21].

Urine specimens for culture should not be obtained from the drainage bag; instead, a sample should be taken through the catheter port with use of aseptic technique [30]. If there is no port, a needle and syringe can be used to puncture the catheter tubing and collect the specimen [30]. For patients with a long-term indwelling catheter, the IDSA recommends replacing the catheter and collecting the specimen from the newly placed catheter [30].

Signs and symptoms suggestive of catheter-associated urinary tract infections include fever (new or worsening), flank pain, hematuria, pelvic discomfort, altered mental status, and malaise or lethargy not attributable to another cause; among patients without a current indwelling catheter, dysuria, urgency, and frequent urination are other symptoms [30]. However, studies have shown that the classic symptoms of urinary tract infection are uncommon among patients with a catheter-associated infection [30]. Pyuria is not diagnostic of catheter-associated urinary tract infection in patients with an indwelling catheter [30].

Asymptomatic bacteriuria is defined as the presence of significant bacteriuria with no signs or symptoms referable to the urinary tract [30].

Treatment

The presence of bacteriuria (as defined by a positive urine culture) in a patient with a chronic indwelling catheter should be interpreted with caution. Often, this represents poor culture technique or may reflect an asymptomatic infection that need not be treated until the catheter can be removed or unless there is fever, flank pain, or worsening renal function. The IDSA recommends that in the absence of such signs these infections not be treated, as treatment has not been found to be beneficial [30,152,153]. However, for symptomatic infection, the results of urine culture and antibiotic sensitivities are an essential guide to effective treatment [30]. For patients with a catheter in place, the catheter should be discontinued, if possible, and the urine specimen should be one that is voided midstream (level III, A) [30]. If the catheter has been in place for more than 2 weeks and continued catheterization is necessary, the catheter should be replaced (level I, A) and the urine specimen should be collected from the newly placed catheter (level II, A) [30].

The IDSA guidelines do not specify which antimicrobial to use for treatment but do recommend duration of treatment. Treatment for 7 days is recommended for patients in whom symptoms resolve promptly, and treatment for 10 to 14 days is recommended for patients in whom symptom response is delayed (level III, A) [30]. The guidelines note that a five-day regimen of levofloxacin may be considered for patients who are not severely ill (level III, B) [30].

Guideline Adherence and Quality Improvement

It has been suggested that catheter-associated urinary tract infection is the most preventable HAI [49]. Some studies have noted an increase in adherence to strategies to prevent catheter-associated urinary tract infection [53]. The greatest adherence has been to guidelines for wearing gloves (97%), using appropriate hand hygiene (89%), and maintaining a sterile barrier (81%) [154]. However, adherence to appropriate catheterization (in terms of both initial indication and duration) has been suboptimal, with studies demonstrating the following [30,147,148,155,156]:

- No justifiable indication or an inappropriate indication (such as incontinence) for more than 50% of catheterizations

- Lack of awareness of catheterization in 25% of physicians

- Catheterization for more than two days among 50% of postoperative patients

- No system for monitoring which patients had insertion of catheters in 56% of hospitals

- No system for monitoring duration of catheterization in 74%

- Policy for nurse-initiated discontinuation of catheterization in 10% of hospitals

Use of alternatives to catheterization is also low, ranging from 14% to 20% [155,156].

The use of provider reminder systems—alone or in combination with base strategies—has a moderate strength of evidence [1]. In one study, the combination of prompts in a computerized order-entry system and handheld bladder scanners led to an 81% decrease in the use of catheters and a 73% reduction in HAIs [157]. For hospitals without order-entry systems, a handwritten reminder that the patient has a catheter has been effective in reducing the rate of infection [158]. However, the use of reminder systems has been reported to be 9% to 12% [155,156].

The use of bundled interventions (e.g., staff education, electronic daily checklist, a nurse-driven removal protocol for indwelling urinary catheters) for reducing the rate of catheter-associated urinary tract infections was examined in a population of critically ill patients 18 years of age and older who were admitted to the ICU of one hospital [159]. The hospital had previously reported 13 catheter-associated urinary tract infections during one year (6 in the ICU), which exceeded the institution's goal of four or fewer such events annually. Researchers set objectives of a 30% reduction in reported catheter-associated urinary tract infections, a 20% reduction in urinary catheter days, and a 75% compliance rating in catheter-related documentation in the ICU. During the intervention phase, no catheter-associated urinary tract infections were reported, which reduced the rate by 1.33 per 1,000 catheter days. Documentation compliance increased significantly from 50.0% before intervention to 83.3% during intervention. The increase in catheter days (10.5%) was not statistically significant [159].

Despite the lack of adherence to prevention guidelines, some progress has been made in reducing this HAI; the rate of symptomatic catheter-associated urinary tract infections decreased 19% to 67% between 2000 and 2007 in ICUs [160]. Compliance with a nurse-driven evidence-based checklist led to a decrease in infections from 2.88/1,000 catheter days to 1.46/1,000 catheter days [161].

The CDC guidelines note that the following are effective elements of a quality improvement program [21]:

- A system of alerts or reminders to identify all patients with urinary catheters and assess the need for continued catheterization

- Guidelines and protocols for nurse-directed removal of unnecessary urinary catheters

- Education and performance feedback regarding appropriate use, hand hygiene, and catheter care

- Guidelines and algorithms for appropriate perioperative catheter management (such as procedure-specific guidelines for catheter placement and postoperative catheter removal and protocols for management of postoperative urinary retention, such as nurse-directed use of intermittent catheterization and use of bladder ultrasound scanners)

SURGICAL SITE INFECTIONS

According to National Hospital Discharge Survey data, 51.4 million inpatient surgical procedures were performed in 2010, creating a large population at risk for surgical site infections [162]. The CDC healthcare-associated infection (HAI) prevalence survey found that there were an estimated 157,500 surgical site infections associated with inpatient surgeries in 2011 [163]. Infection will develop postoperatively in approximately 2.6% of all patients who have surgery [164]. During 2015–2017, surgical site infections contributed the highest proportion of pathogens (43%) compared with all other HAIs [144]. The rate has decreased since the 1990s, but the lower rate is not thought to be an accurate representation because of the increased number of operations done on an outpatient basis; a decrease in the length of the postoperative hospital stay; and a wound infection incubation period of 5 to 7 days [40]. This potential for underestimation of the number of surgical site infections is reflected in the findings of a study in which one-third of healthcare-associated wound infections were detected after the patient had been discharged [165]. Surgical site infections are associated with extended lengths of stay, a high rate of readmissions, excess hospital costs, and a mortality rate of 3%, with a higher mortality rate reported for patients 70 years of age and older [166,167].

The NHSN program enables the CDC to monitor the distribution, etiology, and antimicrobial resistance pattern of infections in relation to the category of surgical procedure. The number of surgical site infections reported through NHSN increased from 10,778 in 2007–2008 to 16,019 in 2009–2010 [82]. However, this may in part be a measure of improved surveillance, as the CDC reported a 19% decrease in infection associated with 10 select procedures performed between 2008 and 2013 [168]. The 2016 NHSN progress report showed a further 6% decrease in surgical site infections for 10 procedures tracked during the previous year [67]. Table 9 shows the distribution of procedure-associated infections and common pathogens, by type of surgery, as reported to NHSN for 2015–2017 [144]. Please note that the distribution percentage is primarily a reflection of the frequency (commonality) with which the given category of surgery is performed and not an indication of the actual rate, or risk, of infection from the specific procedure itself. It may be seen that, with the exception of abdominal procedures, S. aureus (of which 49% of isolates were MRSA) accounted for the majority of these infections [144].

Table 9: DISTRIBUTION OF SURGICAL SITE INFECTION AND MOST COMMON PATHOGENS ACCORDING TO TYPE OF SURGERY: DATA REPORTED TO THE NATIONAL HEALTHCARE SAFETY NETWORK, 2015–2017

Type of Surgery

Percentage of Reported Surgical Site Infections

Most Common Pathogens

Orthopedic

24%

Staphylococcus aureus (39%), coagulase-negative staphylococci (13%), Pseudomonas aeruginosa (6%)

Abdominal

54%

Escherichia coli (20%), Enterococcus faecalis (10%), S. aureus (7%)

Cardiac

6%

S. aureus (27%), coagulase-negative staphylococci (15%), Pseudomonas aeruginosa (8%)

Obstetric/gynecologic

13%

S. aureus (15%), E. coli (14%), Enterococcus faecalis (9%)

Neurologic

1%

Not reported

Vascular

1%

Not reported

Prostate

0.1%

Not reported

Source: [144]

The category of surgery and the duration of the procedure are factors affecting the incidence of post-procedure surgical site infection. The rate of infection by type of surgery varies across facilities; for example, in a multicenter Veterans Administration study, the overall rate of surgical site infection was 6%, with the highest rate (11.3%) following colorectal procedures and the lowest (1.3%) following orthopedic procedures [169].

Risk Factors

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends that a basic nutritional assessment should be considered on all patients undergoing surgery as malnutrition is a known risk factor for decreased wound healing and increased surgical site infections.

https://www.icsi.org/wp-content/uploads/2019/01/Periop.pdf

Last Accessed: January 20, 2022

Level of Evidence: Consensus Statement/Expert Opinion

Several patient-related and surgery-related factors increase the risk for surgical site infection. Patient-related factors include [29,136,140,170]:

- Older age (≥65 years)

- Obesity

- Poor nutritional status

- Low serum albumin concentration

- History of smoking

- History of alcohol use disorders

- Existing infection

- Diabetes mellitus

- Trauma

- Blood transfusion

- Hypothermia, hypoxia, or hyperglycemia

Among the most common surgery-related factors are anesthesia score, duration of the operation, the use of drains, and inadequate aseptic technique [89]. In a study to determine the influence of risk factors on complications after colorectal surgery, body mass index, duration of the operation, and the surgeon who performed the operation were the three most important factors influencing surgical site infections [171].

Transmission and Common Pathogens

Surgical site infections arise from both endogenous and exogenous transmission. The microbial sources of surgical site infections vary according to the type of surgery, and the micro-organism reported as being the most common in 2015–2017 was S. aureus, which accounted for nearly half of all reported orthopedic surgical site infections [144]. Other common causative pathogens were coagulase-negative staphylococci, Enterococcus faecalis, and E. coli [144].

Among the facilities reporting data on surgical site infections to the NHSN in 2015–2017, the percentage of resistant phenotypes was low for pathogens most often associated with surgical site infections [144]. The percentage resistance for most pathogens decreased compared with data for 2007–2008; for example, 42% of S. aureus infections were resistant to oxacillins, a significant decrease from 48% in 2007–2008. The percentage of vancomycin-resistant E. faecium decreased from 62% in 2009–2010 to 56% in 2015–2017, and the percentage of vancomycin-resistant E. faecalis decreased from 6.2% to 3.4% in 2015–2017 [144]. Rates of resistance of E. coli to extended-spectrum cephalosporins (18%) and of P. aeruginosa to aminoglycosides (6%) increased [144].

Prevention

The CDC guideline for preventing surgical site infections, published in 1999, addresses a wide variety of issues, including preoperative preparation of the patient, antisepsis of the surgical team, management of surgical personnel with colonization or infection, antimicrobial prophylaxis, ventilation, cleaning and disinfection of environmental surfaces, microbiologic sampling, sterilization of surgical instruments, surgical attire and drapes, asepsis and surgical technique, postoperative incision care, and surveillance. The CDC's current guideline for prevention of surgical site infection was published in 2017 [29,172]. The guidelines recommend a combination of key components as a strategy to prevent surgical site infection (Table 10).

Table 10: LEVEL IA and IB RECOMMENDATIONS FOR THE PREVENTION OF SURGICAL SITE INFECTIONSa

1999 Guideline

2017 Additions

Preoperative

Whenever possible, identify and treat all infections remote to the surgical site before elective operation, and postpone elective operations on patients with remote site infections until the infection has resolved. Do not remove hair preoperatively unless the hair at or around the incision site will interfere with the operation. If hair is removed, remove immediately before the operation, preferably with electric clippers. Adequately control serum blood glucose levels in all diabetic patients and particularly avoid hyperglycemia perioperatively. Encourage tobacco cessation. At minimum, instruct patients to abstain for at least 30 days before elective operation from smoking cigarettes, cigars, pipes, or any other form of tobacco consumption (e.g., chewing/dipping). Do not withhold necessary blood products from surgical patients as a means to prevent surgical site infection. Thoroughly wash and clean at and around the incision site to remove gross contamination before performing antiseptic skin preparation. Use an appropriate antiseptic agent for skin preparation.

Implement perioperative glycemic control; use serum blood glucose target (upper) level <200 mg/dL in diabetic and nondiabetic patients.

Maintain perioperative normothermia. Perform intraoperative skin preparation with an alcohol-based antiseptic agent, unless contraindicated.

Antimicrobial Prophylaxis

Administer a prophylactic antimicrobial agent only when indicated, and select it based on its efficacy against the most common pathogens causing surgical site infection for a specific operation and published recommendations. Administer by the intravenous route the initial dose of prophylactic antimicrobial agent, timed such that a bactericidal concentration of the drug is established in serum and tissues when the incision is made. Maintain therapeutic levels of the agent in serum and tissues throughout the operation and until, at most, a few hours after the incision is closed in the operating room. Before elective colorectal operations, in addition to above recommendation, mechanically prepare the colon by use of enemas and cathartic agents. Administer nonabsorbable oral antimicrobial agents in divided doses

In all cesarean sections, administer the appropriate parenteral prophylactic antimicrobial agent prior to skin incision.

In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain.

Do not apply antimicrobial agents (i.e., ointments, solutions, powders) to the surgical incision for the prevention of surgical site infection.

Oxygenation

__

For patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation, administer increased FiO_2 both intraoperatively and postextubation in the immediate postoperative period. To optimize tissue oxygen delivery, maintain perioperative normothermia and adequate volume replacement.

Postoperative Incision Care

Protect with a sterile dressing for 24 to 48 hours postoperatively an incision that has been closed primarily. Wash hands before and after dressing changes and any contact with the surgical site.

__

aLevel I recommendations are supported by high-to-moderate quality evidence suggesting net clinical benefits or harms, or by low-quality evidence suggesting net clinical benefits or harms, or are accepted practices supported by low-to-very low quality evidence.

Source: [29]

Before surgery, patients should be advised to shower or bathe (full body) with soap (antibacterial or non-antibacterial) or an antiseptic agent on at least the night before the operative day [29]. Antimicrobial prophylaxis should be administered only when indicated based on published clinical practice guidelines and timed such that a bactericidal concentration of the agents is established in the serum and tissues when the incision is made [29]. Antibiotic prophylaxis need not be maintained longer than a few hours after the incision has been closed. Additional guidance is provided in reference to specific surgical procedures and specialty operations (e.g., prosthetic joint arthroplasty) [29].

The CDC guidelines reference appropriate antibiotics on the basis of the type of surgery [29,172]. Meta-analyses have demonstrated lower rates of infection with a single-dose (long-acting) antibiotic and broader spectrum antibiotics, such as third-generation cephalosporins [173]. However, a complication of perioperative antibiotic prophylaxis is an increased frequency of adverse events, the most serious of which is infection with C. difficile, and this risk may be higher in association with a broad-spectrum antibiotic [173].

Systematic reviews reported in the mid-2000s showed that two previously recommended measures for preventing postoperative infection have no effect on the rate of surgical site infection. One review involved six trials in which preoperative washing was evaluated in a total of 10,007 patients. There was no significant difference in the rate of surgical site infections when 4% chlorhexidine gluconate was compared with placebo or no washing [174]. The other review involved 11 randomized controlled trials in which preoperative hair removal practices were evaluated. Comparison of razor, depilatory cream, or no hair removal showed no significant difference in the rate of surgical site infection [175,176]. However, when shaving was compared with clipping, there were significantly more surgical site infections after shaving. No difference was found in the rate of surgical site infections between clipping 1 day preoperatively or on the day of surgery. On the basis of these findings, preoperative antiseptic washing and shaving are no longer recommended.

Attention should also be directed at strategies to prevent surgical site infections with MRSA. The use of an MRSA prevention bundle—adherence to the guidelines for hand hygiene, decontamination of environment and equipment, active surveillance cultures, and contact precautions for patients with MRSA infection or colonization—led to significant decreases in the overall rate of surgical site infections in one study, with a 1% decrease in surgical site infections after cardiac surgery and a 65% decrease after orthopedic surgeries [177].

Diagnosis

IDSA guidelines on the diagnosis and management of skin and soft tissue infections include a section on surgical site infections [164,178]. The guidelines note that the most reliable diagnostic information is the physical appearance of the site; local signs of infection include pain, swelling, erythema, and purulent drainage [164,178]. Clinical manifestations of a surgical site infection do not occur for at least 5 days postoperatively, with many infections not becoming apparent for as long as 2 weeks [164,178]. The IDSA notes that most postoperative fevers are not associated with a surgical site infection [164,178].

Surgical site infections are classified as superficial incisional, deep incisional, and organ/space infections. Strict criteria and standardized definitions are used in reporting infections and in surveillance programs [29,173]. The CDC described the criteria for each type of infection in its guidelines for the prevention of surgical site infections and defined the infections in the NHSN system according to this classification [29,127,179].

Superficial Incisional Classification

Infection occurs within 30 days after the operative procedure and involves only skin and subcutaneous tissue of the incision and at least one of the following:

- Purulent draining from the superficial incision

- Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision

- At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon, unless incision is culture-negative

- Diagnosis of superficial incisional surgical site infection by the surgeon or attending physician

Deep Incisional Classification

Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and involves deep soft tissues (e.g., fascial and muscle layers) of the incision and at least one of the following:

- Purulent drainage from the deep incision but not from the organ/space component of the surgical site

- Deep incision spontaneously dehisces or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: fever (>38 degrees Centigrade) or localized pain or tenderness, unless incision is culture-negative

- Abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathologic or radiographic examination

- Diagnosis of a deep incisional surgical site infection by a surgeon or attending physician

Organ/Space Classification

Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if the implant is in place and the infection appears to be related to the operative procedure and infection involves any part of the body, excluding the skin incision, fascia, or muscle layers, that is opened or manipulated during the operative procedure and at least one of the following:

- Purulent drainage from a drain that is placed through a stab wound into the organ/space

- Organisms isolated from an aseptically obtained culture or fluid or tissue in the organ/space

- Abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiographic examination

- Diagnosis of an organ/space surgical site infection by a surgeon or attending physician

Treatment

Based on expert opinion, the IDSA recommends opening an infected surgical site, removing the infected material, and continuing dressing changes until the wound heals by secondary intention [164]. Although treatment with antibiotics is commonly started when a surgical site infection is diagnosed, the IDSA notes that little evidence has supported this approach [164]. A short course (24 to 48 hours) of antibiotics may be indicated for patients with a temperature higher than 38.5 degrees Centigrade or a pulse rate of more than 100 beats/min [164]. The guidelines add that treatment is usually empirical but may be selected according to results of wound culture [164]. IDSA offers guidance on the selection of antibiotics according to the operative site [164].

Intestinal or Genital Tract

Single agents: ticarcillin/clavulanate, piperacillin/tazobactam, imipenem/cilastatin, meropenem, ertapenem

Combination agents: ceftriaxone/metronidazole, ciprofloxacin/metronidazole, levofloxacin/metronidazole, ampicillin-sulbactam/gentamicin ampicillin-sulbactam/tobramycin

Trunk and Extremities (away from axilla or perineum)

Oxacillin, nafcillin, cefazolin, cephalexin, SMX-TMP, vancomycin

Axilla or Perineum

Metronidazole/ciprofloxacin, levofloxacin, ceftriaxone

For surgical site infections after implantation of a joint prosthesis, the approach depends on the duration of infection, stability of the implant, antimicrobial susceptibility of the pathogen, and condition of the surrounding soft tissue [180]. In this setting, rifampin has shown excellent activity against adherent staphylococci and may be useful in combination with beta-lactams, glycopeptides, fluoroquinolones, minocycline, trimethoprim, or fusidic acid [181].

Guideline Adherence and Quality Improvement

The effect of prevention strategies—primarily the appropriate use of prophylactic antibiotics—on the rate of surgical site infection has been evaluated in several studies, and the results have been conflicting. For example, 56% adherence to this measure significantly reduced the incidence of surgical site infections in one study of patients who had colorectal surgery, with the rate decreasing from 22% to 3.5% [182]. There was no significant difference in the rate of surgical site infection between compliant and noncompliant prophylactic antibiotics [182]. In a retrospective review of 605 patients who had colorectal surgery with intestinal anastomosis showed that early administration of antibiotic prophylaxis and a nonstandard antibiotic were significantly associated with a greater risk of surgical site infection [183]. However, the timely administration of prophylactic antibiotics did not improve the rate of surgical site infections among nearly 9,200 elective major surgeries (all types); the rate was 5% for patients who received timely antibiotics compared with 6% for patients who received antibiotic prophylaxis outside of the recommended time [51].

More recent studies have analyzed adherence to the Surgical Care Improvement Project (SCIP) quality measures, with analysis of individual measures as well as groups of measures. Some studies have indicated that an increase in compliance with SCIP measures leads to a decrease in the rate of surgical site infection; the rate decreased from nearly 26% to 16% in one study and in another study, increasing compliance with SCIP measures from 38% to 92% led to a decrease in the rate of superficial surgical site infections from 13% to 8% [50,184]. Among patients who had laparotomy related to trauma (gunshot wound, stab wound, or blunt trauma), adherence to SCIP measures related to antibiotic prophylaxis resulted in a significantly lower rate of surgical site infection (17% vs 33%) as well as a shorter hospital stay (14 vs 19 days), even after controlling for several factors [185].

However, these data have not been consistent. In a study of nearly 500 patients who had colorectal surgery, compliance with all SCIP measures improved—from 40% to 68%—but the rate of surgical site infections remained essentially the same (approximately 19%) [52]. In addition, a retrospective review of 60,853 surgeries done over a five-year period at 112 Veterans Administration (VA) hospitals showed that improving adherence to five SCIP measures did not significantly lower the odds of surgical site infection [169].

Many have been critical of the SCIP strategy, noting that the evidence has not indicated that adherence to these quality measures alone has had an effect on reducing the overall risk of surgical site infection [186]. The quality measures do not factor in the skill of the surgeon, and other factors, such as state-of-the-art skin antisepsis and innovative antimicrobial technology, should be included in quality improvement programs [186,187].

Ways to help increase adherence to effective prevention strategies are the use of computerized standard orders for antibiotics, reminders and checklists, and auditing of the rates for individual physicians, with feedback [29]. A study demonstrated that point-of-care prompts increased compliance with timely antibiotic prophylaxis from 62% to 92%, with a corresponding decrease in the incidence of surgical site infections, from 1.1% to 0.7% [188]. In an extensive systematic review, there was moderate strength of evidence for the use of audit and feedback, with or without provider reminder systems, for improving adherence to appropriate timing of prophylactic antibiotics [1]. The IHI how-to guide for the prevention of surgical site infection outlines practical steps to help healthcare professionals ensure that prevention strategies are carried out (Table 11) [189].

Table 11: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT SURGICAL SITE INFECTIONS

Appropriate Use of Prophylactic Antibiotics

Use preprinted or computerized standing orders specifying antibiotic, timing, dose, and discontinuation. Develop pharmacist- and nurse-driven protocols that include preoperative antibiotic selection and dosing based on surgical type and patient-specific criteria (e.g., age, weight, allergies, renal clearance). Change operating room drug stocks to include only standard doses and standard drugs, reflecting national guidelines. Reassign dosing responsibilities to anesthesia or holding area nurses to improve timeliness. Involve pharmacy, infection control, and infectious disease staff to ensure appropriate timing, selection, and duration. Verify administration time during "time-out" or preprocedural briefing so action can be taken if not administered.

Appropriate Hair Removal

Ensure adequate supply of clippers and train staff in proper use. Remove all razors throughout the hospital. Work with the purchasing department to ensure that razors are no longer purchased by the hospital. Use signs or posters as reminders. Educate patients about not shaving preoperatively.

Maintaining Adequate Glycemic Control

Implement one standard glucose control protocol (sliding scale or insulin drip). Regularly check preoperative blood glucose levels on all patients. Assign responsibility and accountability for blood glucose monitoring and control.

Maintaining a Warm Body Temperature

Use hats and booties on patients preoperatively. Use warmed forced-air blankets preoperatively, during surgery, and in the recovery room. Use warmed intravenous fluids. Use warming blankets under patients on the operating table.

Maintaining a Warm Body Temperature

Prevent hypothermia at all phases of the surgical process. Use hats and booties on patients perioperatively. Use warmed forced-air blankets preoperatively, during surgery, and in the recovery room. Use warmed intravenous fluids. Use warming blankets under patients on the operating table. Adjust engineering controls so that operating rooms and patient areas are not permitted to become excessively cold overnight, when many rooms are closed. Measure temperature with a standard type of thermometer.

Source: [189]

PNEUMONIA

Pneumonia associated with healthcare facilities is classified in three categories: hospital-acquired, ventilator-associated, and healthcare-associated. Hospital-acquired pneumonia refers specifically to pneumonia that develops 48 hours after hospital admission (usually occurring postoperatively), and ventilator-associated pneumonia refers to pneumonia that develops 48 to 72 hours after tracheal intubation [190]. Healthcare-associated pneumonia develops in individuals in healthcare facilities outside hospitals, such as long-term care facilities and outpatient settings.

Hospital-acquired pneumonia, also referred to as post-procedure pneumonia, is not included in most discussions of HAIs because it represents less than 1% of all such infections; although this type of pneumonia is not reportable to NHSN, 23 cases were reported in 2009–2010 [82]. Still, hospital-acquired pneumonia can increase the length of stay by more than 1 week and is associated with increased mortality and financial cost [191].

The rate of ventilator-associated pneumonia is higher than that for hospital-acquired pneumonia, with a reported rate of 1 to 4 cases per 1,000 ventilator-days, and rates as high as 10 cases per 1,000 in some neonatal and surgical populations [18,192]. An estimated 10% of patients requiring mechanical ventilation will develop pneumonia as a complication, and the mortality rate directly attributable to ventilator-associated pneumonia is estimated at 13% [18]. Excess cost of care resulting from prolongation of hospital stay is estimated to range from $30,000 to $40,000 per patient [18].

Risk Factors

Hospital-Acquired Pneumonia

In a systematic review, the American College of Physicians found several patient-related and surgery-related factors that increased the risk of postoperative pulmonary complications. The most common patient-related factors were the presence of COPD and an age older than 60 years [141]. Other significant factors were an American Society of Anesthesiologists (ASA) class 2 (defined as a patient with mild systemic disease) or higher, functional dependence, and congestive heart failure. Cigarette use was associated with a modest increase in risk, and obesity and mild or moderate asthma were not found to increase risk [141]. Use of a PPI or histamine-2 receptor antagonist is also thought to be a risk factor [142]. Surgery-related factors included prolonged duration of surgery (more than three to four hours), emergency surgery, and surgical site, with abdominal surgery, thoracic surgery, neurosurgery, head and neck surgery, vascular surgery, and aortic aneurysm repair being associated with the greatest risks [141].

Ventilator-Associated Pneumonia

The risk of ventilator-associated pneumonia correlates with the duration of intubation; the risk has been estimated to be 3% per day during the five-day period after intubation, decreasing to 2% per day for days 5 through 10 and to 1% per day for longer durations [193]. Nearly half of all cases of ventilator-associated pneumonia develop within the first four days of mechanical ventilation [190]. In addition to duration of ventilation, several other risk factors among adults have been identified, including a supine head position; use of a nasogastric tube, paralytic agents, or PPI or histamine-2 receptor antagonists; patient age; chronic lung disease; and head trauma [20,142]. In one study, ventilator-associated pneumonia was most frequently associated with ICU admission diagnoses of postoperative care, neurologic conditions, sepsis, and cardiac complications [194].

Transmission and Common Pathogens

Gram-negative enteric bacilli and Pseudomonas spp. rarely colonize the upper respiratory tract of healthy individuals, but often do so in persons with an underlying disease, such as alcohol use disorder, and in those who are hospitalized or reside in nursing homes. Most cases of pneumonia that develop in a healthcare facility are caused by aspiration of oropharyngeal or gastric secretions colonized with hospital bacterial flora. Consequently, the prevalent causation as well as the antibiotic sensitivity pattern of resident pathogens will vary from region to region in relation to the type of facility and burden of antimicrobial usage. The selection of initial antibiotic therapy in these cases is based on the patient's risk factors for infection with a multidrug-resistant organism, such as MRSA, P. aeruginosa, K. pneumoniae, or Acinetobacter. The infectious disease and pulmonary specialty societies (IDSA and American Thoracic Society [ATS]) list the following risk factors for multidrug-resistant pathogens in patients presenting with hospital-acquired or ventilator-associated pneumonia [18]:

- Prior intravenous antibiotic use within 90 days

- Septic shock at time of ventilator-associated pneumonia

- Acute respiratory distress syndrome prior to onset of ventilator-associated pneumonia

- High frequency of antibiotic resistance in the community of residence or the hospital unit of residence

- Five or more days of hospitalization prior to onset of pneumonia

- Home infusion therapy

- Chronic dialysis within 30 days

- Family member with multidrug-resistant infection

- Immunosuppression

Approximately 50% of all cases of healthcare-associated pneumonia develop following surgical procedures, of which cardiac, abdominal, and orthopedic surgery confer the greatest risk. Viral and fungal pathogens are rare causes of hospital-acquired and ventilator-associated pneumonia in immunocompetent adults. Outbreaks of viral pneumonia may occur during influenza season, and influenza, parainfluenza, adenovirus, and respiratory syncytial virus (RSV) are involved in about 70% of those cases [18]. During the coronavirus disease (COVID-19) pandemic, SARS-CoV-2 has superseded the usual viral respiratory pathogens. Candida spp. and Aspergillus fumigatus may cause pneumonia in patients who have had organ transplantation or who have a compromised immune system and neutropenia.

Hospital-Acquired Pneumonia

Among adults with no previous antibiotic exposure, the most common bacterial causes of hospital-acquired pneumonia are S. aureus, S. pneumoniae, H. influenzae, E. coli, and K. pneumoniae [18,190,191,195]. Gram-negative bacilli resistant to first-generation cephalosporins also frequently develop in late-onset hospital-acquired pneumonia. When patients who have previously received antibiotics develop late-onset hospital-acquired pneumonia, the likelihood of causation by a multidrug-resistant pathogen, such as P. aeruginosa, A. baumannii, or MRSA, approaches 40% [191]. In a study of more than 3,600 patients admitted to an ICU, Pseudomonas spp. was the cause of pneumonia in 25% of patients; MRSA in 18%; and Acinetobacter spp. in 6% [195]. Other studies have shown that S. aureus is common among patients who are in a coma or have diabetes or renal failure; P. aeruginosa is common among patients who have had a prolonged stay in the ICU, have received prior antibiotics or corticosteroids, or who have structural lung disease; and Legionella is usually found in patients who have compromised immune systems [195].

Ventilator-Associated Pneumonia

In 2015–2017, the most common pathogens reported with ventilator-associated pneumonia in adults were S. aureus (29%) and P. aeruginosa (13%), followed by K. pneumonia/oxytoca (10%), Enterobacter spp. (8%), and H. influenzae (6%) [144]. Almost half of all cases of ventilator-associated pneumonia are caused by infection with more than one pathogen [190]. As with other forms of HAI, the percentage of S. aureus resistant to methicillin has decreased in recent years [3,163]. The percentage of vancomycin-resistant E. faecium has remained stable, but the percentage of vancomycin-resistant E. faecalis decreased from 10% in 2009–2010 to 7% in 2015–2017 [144]. In 2015–2017, the rates of resistance among Klebsiella spp. for extended-spectrum cephalosporins, carbapenems, multidrug were 21%, 7%, and 13%, respectively, and the rate of multidrug-resistant E. coli increased to nearly 10% [144].

Prevention

The CDC has published guidelines for the prevention of hospital-acquired and ventilator-associated pneumonia, with a focus on strategies to decrease or eliminate modifiable risk factors [25]. These strategies are related to preoperative and postoperative care and measures to reduce the risk of transmission of etiologic pathogens. In addition, steps to prevent the spread of influenza virus are essential, especially during influenza season.

Hospital-Acquired Pneumonia

For many years, preventing postoperative pneumonia has been a part of initiatives to decrease complications among patients who have surgery. The Respiratory Risk Index was developed to classify patients as being at low, medium, or high risk for postoperative respiratory failure [191]. The factors in the index include the complexity of the surgery, the ASA status, and comorbidities.

Smoking triples the risk for pulmonary complications after surgery, and smoking cessation for at least 8 weeks before surgery, when possible, is recommended for current smokers [191]. The risk for complications in patients with respiratory disease or congestive heart failure can be ameliorated by optimum treatment before surgery (e.g., treatment with steroids for patients with COPD or asthma) [191].

Effective pain management after surgery can also help decrease the risk of pulmonary complications. For postoperative patients who are not mechanically intubated, the ability to cough and clear secretions is important for preventing pulmonary complications [191]. The use of incentive spirometry and deep breathing exercises are recommended, especially for people at high risk for pulmonary complications, as are frequent coughing and early movement (in bed and/or walking) [25,141,191]. Fair evidence supports the selective (rather than routine) use of a nasogastric tube after abdominal surgery [141].

Ventilator-Associated Pneumonia

Two guidelines were developed to focus specifically on the prevention of ventilator-associated pneumonia; one was jointly developed by the SHEA and IDSA, and the other was jointly developed by the Canadian Critical Care Trials Group and the Canadian Critical Care Society [20,36]. In addition, prevention of ventilator-associated pneumonia is addressed in the CDC's guidelines for preventing healthcare-associated pneumonia and in the IDSA/ATS guidelines on the management of healthcare-associated pneumonias [18; 25]. All of these agencies suggest a multicomponent strategy for prevention of pneumonia. Compliance with guidelines, however, has been slow; nursing surveys demonstrate rates of adherence to specific preventive measures ranging from 15% to 50% [192,196]. All of these agencies suggest a multicomponent strategy for prevention of pneumonia. Compliance with guidelines, however, has been slow; nursing surveys demonstrate rates of adherence to specific preventive measures ranging from 15% to 50% [192,196]. Education is beneficial, and training sessions are a proven means to enhance knowledge and practice among healthcare professionals caring for intubated patients [197].

The Institute for Healthcare Improvement (IHI) found that implementation of its ventilator bundle, a collection of five prevention strategies drawn from these guidelines, led to a 45% reduction in the incidence of ventilator-associated pneumonia [198]. The bundle includes the following interventions [198]:

- Assessment of readiness to extubate and daily interruptions of sedation

- Elevation of the head of the bed

- Daily oral care with chlorhexidine

- Prophylaxis of peptic ulcer disease

- Prophylaxis of deep vein thrombosis

Assessment of Readiness to Extubate

Because of the increasing risk of infection as the duration of ventilation increases, the primary goal is to extubate patients as early as possible. Thus, assessment of the readiness for extubation and weaning protocols are key aspects in the preventive approach [18,195]. Daily interruption of sedation until the patient is awake has been shown to significantly decrease the number of days on mechanical ventilation, from 7.3 days to 4.9 days in one study [199]. There are risks to this approach, such as the potential for increased pain, anxiety, and desaturation. However, the use of sedation interruption has been further demonstrated to reduce the complications of prolonged mechanical ventilation [200]. The SHEA/IDSA guidelines recommend daily assessment of the readiness to wean and the use of weaning protocols [36].

Elevation of the Head of the Bed

Reducing the risk of aspiration and contamination with gastric secretions also helps to prevent the development of ventilator-associated pneumonia. The risk of aspiration has been significantly reduced by positioning the patient with the head of the bed at an angle of 30 to 45 degrees [20,201,202]. In one randomized controlled trial, there were 18% fewer cases of ventilator-associated pneumonia among intubated patients in the group assigned to the recumbent position (45 degrees) compared with the group assigned to the supine position [202]. In another study, elevation of the head of the bed at 30 degrees was the most effective measure among a group of preventive interventions, resulting in a 52% variance in the rate of ventilator-associated pneumonia [203]. Both the ATS/IDSA and SHEA/IDSA guidelines recommend maintaining the head of the bed at a 30- to 45-degree angle [18,36].

Daily Oral Care with Chlorhexidine

Oral care interventions have been suggested by some, in part because of an association between a high level of dental plaque and a high rate of colonization with aerobic pathogens, including S. aureus, gram-negative bacilli, and P. aeruginosa [204]. Research has shown that oral decontamination with chlorhexidine leads to a significant reduction in the colonization of pathogens in the oropharynx; in most studies, the intervention has not had a significant effect on the rate of ventilator-associated pneumonia or associated mortality, but more recent studies have shown significant decreases in the rate of ventilator-associated pneumonia [205,206,207]. Including tooth brushing with chlorhexidine does not seem to add benefit [208,209]. Regular oral care with an antiseptic solution or chlorhexidine is recommended in the ATS/IDSA and SHEA/IDSA guidelines [18,36].

Prophylaxis of Peptic Ulcer Disease

Prophylaxis of peptic ulcer disease has evolved with some conflicting views. Antacids, histamine-2 antagonists, and sucralfate have been traditionally given to patients receiving mechanical ventilation to prevent the formation of ulcers. However, reducing the amount of gastric acid can increase the risk of colonization of gram-negative bacilli in the stomach. As a result, WHO recommended avoiding the use of these agents [16]. The CDC noted that there was insufficient evidence on the use of peptic ulcer prophylaxis and included no recommendations in this regard in its guidelines [25]. The ATS/IDSA guidelines stated that the risks and benefits of prophylaxis should be weighed carefully [18]. The most recent guidelines, developed by SHEA/IDSA, notes that histamine-2 receptor antagonists and PPIs should be avoided in patients who are not at high risk for developing a stress ulcer or stress gastritis [36].

Prophylaxis of Deep-Vein Thrombosis

There is no clear relation between prophylaxis of deep-vein thrombosis and ventilator-associated pneumonia, but the American College of Chest Physicians reported a decrease in the rate of ventilator-associated pneumonia when such prophylaxis was implemented as part of a package of interventions and included this measure in its clinical practice guidelines [210].

Other Measures

In addition to these interventions, other measures have been recommended to help prevent ventilator-associated pneumonia. One such measure is selective decontamination of the digestive tract, which involves the use of either topical antiseptic, oral antibiotics, or a brief course of systemic antibiotics [191]. A meta-analysis (28 studies) showed that selective decontamination of the digestive or respiratory tract with use of topical antiseptic or antimicrobial agents helped reduce the frequency of ventilator-associated pneumonia in the ICU [211]. The estimate of efficacy in prevention was 27% for antiseptics and 36% for antibiotics. Neither had an effect on mortality. This intervention is recommended in the SHEA/IDSA guidelines [36].

Other preventive measures are targeted primarily to the care and use of ventilator equipment and practices in direct patient care. Meticulous attention to aseptic care of the equipment is necessary, and all reusable components, such as nebulizers, should be disinfected or sterilized. Tubing circuits should be replaced after more than 48 hours, or earlier if there are signs of malfunction or contamination [25]. Changes in the design of the endotracheal tube have also been evaluated; for example, a tube with a suction port above the cuff allows for continuous aspiration of subglottic secretions. Use of this specially designed endotracheal tube has led to significantly lower rates of ventilator-associated pneumonia, as well as shorter durations of ventilation and shorter stays in the ICU [212,213]. Among patients who had major cardiac surgery, the greatest benefit was found for patients who received ventilation for more than 48 hours [213]. The cost of the tube is higher than traditional tubes but is offset by overall cost savings in preventing ventilator-associated pneumonia [212]. In one meta-analysis, subglottic secretion drainage was significantly associated with a decreased incidence of ventilator-associated pneumonia, shorter time on mechanical ventilation, and longer time to the development of ventilator-associated pneumonia [214]. The CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend subglottic secretion drainage with this tube when possible [18,25,36].

The use of noninvasive ventilation is another measure that has reduced the incidence of ventilator-associated pneumonia [25,215,216]. In one study, the incidence decreased from 20% to 8% when noninvasive ventilation was used routinely for critically ill patients with acute exacerbation of chronic obstructive pulmonary disease or severe cardiogenic pulmonary edema [217]. Again, the CDC, the ATS/IDSA, and the SHEA/IDSA guidelines recommend the use of noninvasive ventilation when possible [18,25,36].

Diagnosis

The difficulty in diagnosing hospital-acquired or ventilator-associated pneumonia has been well established [18,193,218]. The clinical signs can resemble those of other, noninfectious conditions, and the specificity of clinical criteria is low [190]. According to the CDC definition, the diagnosis in adults is made on the basis of clinical signs and symptoms and results of laboratory testing or imaging and must meet one of two criteria [219,220].

Criterion 1

For any patient, at least one of the following:

- Fever (>38°C or >100.4°F)

- Leukopenia (<4,000 WBC/mm^3) or leukocytosis (≥12,000 WBC/mm^3)

- For adults ≥70 years of age, altered mental status with no other recognized cause

AND at least two of the following:

- New onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased suctioning requirements

- New onset or worsening cough, or dyspnea, or tachypnea

- Rales or bronchial breath sounds

- Worsening gas exchange (e.g., oxygen desaturations [e.g., PaO_2/FiO_2 ≤240 mm Hg], increased oxygen requirements, or increased ventilator demand)

Criterion 2

Two or more serial chest radiographs showing at least one of the following:

- New or progressive and persistent infiltrate

- Consolidation

- Cavitation

- Pneumatoceles, in infants 1 year of age or younger

In patients without underlying pulmonary or cardiac disease (e.g., respiratory distress syndrome, pulmonary edema, chronic obstructive pulmonary disease), one definitive chest radiograph is acceptable.

There are no compelling data to recommend a specific approach to diagnosing hospital-acquired or ventilator-associated pneumonia. For patients who are not receiving mechanical ventilation, collection of a sputum specimen should be attempted before antibiotic therapy is begun [195,221]. Specimens for culture can be obtained by bronchoscopy with a protected specimen brush to limit contamination or by bronchoalveolar lavage. The latter method has been found to lead to higher rates of treatment than that based on the CDC definition, and one study showed that preferential sampling of the right lung improved the diagnostic accuracy of bronchoalveolar lavage [195,222,223]. However, the invasive procedure has disadvantages, including high cost, need for technical expertise, and potential for false-negative results [195,222].

The 2016 IDSA/ATS guidelines recommend collecting specimens from the lower respiratory tract for culture, preferably by noninvasive techniques and reliance on semiquantitative culture technique [18]. Noninvasive methods to obtain respiratory samples in patients with hospital-acquired (but not ventilator-associated) include spontaneous expectoration, sputum induction, nasotracheal suctioning (in a patient unable to produce a sample), and endotracheal aspiration in a patient who subsequently requires mechanical ventilation [18]. A 2012 meta-analysis (and a 2014 update) found no evidence that the use of quantitative cultures of respiratory secretions resulted in decreased mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change compared with qualitative cultures in patients with ventilator-associated pneumonia [224,225]. In addition, there was no difference in mortality, whether invasive or noninvasive methods were used to obtain specimens.

Treatment

Treatment is complicated by two divergent needs: the need for empiric therapy with a broad-spectrum antibiotic, to aid in reducing mortality rates, and the need to avoid the indiscriminate use of antibiotics, to avoid the development of resistance. To address this complex issue, the strategy of de-escalation therapy was developed. With this treatment approach, a broad-spectrum antibiotic targeted to likely pathogens is administered, and the antibiotic regimen is altered, if necessary, after the results of cultures are known [226,227]. This strategy has reduced the mortality rate while achieving an overall objective of a more judicious use of antibiotics [226,228,229]. In one study, de-escalation therapy led to a significantly lower mortality rate compared with either escalation therapy or therapy that was neither escalated nor de-escalated (17% compared with 43% and 24%, respectively) [194].

It has been emphasized that this approach, and empiric treatment of healthcare-acquired pneumonia in general, calls for knowledge of the infection history of the healthcare facility and of individual patient units [190,195,230]. Microbiology laboratory reports can provide such details, and physicians should prescribe initial antibiotics that are likely to be active against these pathogens.

Evidence Based Practice Recommendation

In patients with suspected ventilator-associated pneumonia, the IDSA and the American Thoracic Society recommend including coverage for S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli in all empiric regimens.

https://www.idsociety.org/practice-guideline/hap_vap

Last Accessed: January 20, 2022

Strength of Recommendation/Level of Evidence: Strong recommendation, low-quality evidence

The IDSA/ATS guidelines provide several recommendations for the management of both hospital-acquired and ventilator-associated pneumonia [18]:

- Obtain sputum samples from the lower respiratory tract for culture before beginning antibiotic therapy. Do not delay initiation of therapy for critically ill patients in order to obtain specimens.

- Begin treatment promptly, selecting an empiric antibiotic regimen that coversS. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli.

- In selecting coverage for S. aureus, choose an agent active against MRSA (vancomycin or linezolid) for patients with any of the following:

- Risk factor for antimicrobial resistance

- Treatment in hospital or units where >10% of isolates are methicillin-resistant

- Patients in settings where the prevalence of MRSA is unknown

- In selecting coverage for P. aeruginosa, one antibiotic active against this pathogen is satisfactory if the patient has no risk factors for antimicrobial resistance and <10% of gram-negative isolates from the patient's unit are resistant to the agent chosen; otherwise, prescribe two antipseudomonal antibiotics from different classes.

- Consider de-escalation of antibiotics after the results of cultures and sensitivities are known and the clinical response is satisfactory.

- When an optimal antibiotic regimen is confirmed, a seven-day course of therapy is recommended, provided the rate of improvement of clinical, radiographic, and laboratory parameter is satisfactory.

- It is suggested to use serum procalcitonin levels plus clinical criteria to guide discontinuation of antibiotic therapy, rather than clinical criteria alone.

Specific treatment depends on the timing of onset and the presence or absence of risk factors for infection with multidrug-resistant organisms. For early-onset pneumonia and/or patients with no such risk factors, limited-spectrum antibiotic therapy is recommended (Table 12) [18]. For late-onset pneumonia and/or patients at increased risk for multidrug-resistant bacteria, a broad-spectrum antibiotic therapy is recommended.

Table 12: RECOMMENDED ANTIBIOTIC THERAPY FOR HEALTHCARE-ASSOCIATED PNEUMONIA ACCORDING TO SITE OF CARE

Site of Care

Recommended Regimen

General ward

Antipseudomonal cephalosporin, antipseudomonal carbapenem, or extended-spectrum ß-lactam/ß-lactamase inhibitor and antipseudomonal fluoroquinolone or aminoglycoside and anti-MRSA agent (vancomycin or linezolid)

Intensive care unit

Empiric MRSA and double coverage of Pseudomonas pneumonia

Source: [18]

Evidence Based Practice Recommendation

For patients with ventilator-associated pneumonia, the IDSA and the American Thoracic Society recommend a seven-day course of antimicrobial therapy rather than a longer duration. There exist situations in which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters.

https://www.idsociety.org/practice-guideline/hap_vap

Last Accessed: January 20, 2022

Strength of Recommendation/Level of Evidence: Strong recommendation, moderate-quality evidence

Ventilator-associated pneumonia is often caused by MRSA and gram-negative bacilli such as Acinetobacter spp. and Pseudomonas. Vancomycin has been considered the first choice for treatment of MRSA infections [226]. However, the ATS/IDSA guidelines note that linezolid may have advantages over vancomycin for ventilator-associated pneumonia caused by MRSA [18]. Linezolid has been compared with vancomycin for the treatment of pneumonia caused by MRSA in many studies and has been found to improve survival and to be more cost-effective [231,232,233,234]. In one study, the rate of early microbiologic cure was not significantly higher for linezolid than for vancomycin, although there were trends favoring linezolid in several secondary clinical outcomes, such as clinical cure; duration of ventilation, hospitalization, and stay in ICU; survival time not on a ventilator; and overall survival [235]. The findings led the authors to suggest that the benefit of linezolid may be related to factors other than bacterial clearance.

According to a meta-analysis, a short fixed-course (7 or 8 days) of antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days) for patients with ventilator-associated pneumonia not caused by non-fermenting gram-negative bacilli [236]. The short course reduced the recurrence rate of ventilator-associated pneumonia caused by multiresistant organisms without adversely affecting other outcomes. Among patients with non-fermenting gram-negative bacilli, recurrence was greater after the short course. The authors confirmed these findings in a follow-up study published in 2015 [237].

Role of Inhaled Antibiotic Therapy

For cases of ventilator-associated pneumonia caused by gram-negative bacilli that are susceptible only to aminoglycosides or polymyxins the suggestion is to use both inhaled and systemic antibiotics, rather than systemic antibiotics alone [18]. It is also reasonable to consider adjunctive inhaled antibiotic treatment as a last resort for patients who are not responding to intravenous antibiotics alone, whether the infecting organism is or is not multidrug resistant.

Guideline Adherence and Quality Improvement

Adherence to guidelines for the prevention of ventilator-associated pneumonia is low, with surveys of nurses demonstrating rates of adherence to specific preventive measures ranging from 15% to 50% [192,196]. Adherence to a bundle of prevention strategies (head-of-bed elevation, oral chlorhexidine gel, sedation holds, and a weaning protocol), with 70% compliance, led to a significant reduction in ventilator-associated pneumonia, from 32 cases per 1,000 ventilator-days to 12 cases per 1,000 ventilator-days [54]. The IHI how-to guide on preventing ventilator-associated pneumonia provides several practical recommendations, and posting compliance with the ventilator bundle in a prominent place in the ICU can encourage and motivate staff (Table 13) [198].

Table 13: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT VENTILATOR-ASSOCIATED PNEUMONIA

Elevation of the Head of the Bed

Include the intervention on nursing flow sheets and discuss at multidisciplinary rounds. Encourage respiratory therapy staff to notify nursing staff if the head of the bed is not elevated or empower respiratory therapy staff to place the bed in this position with help of nursing staff. Include the intervention on order sets for initiation and weaning of mechanical ventilation, delivery of tube feedings, and provision of oral care.

Sedative Interruptions and Assessment of Readiness to Extubate

Implement a protocol to lighten sedation daily at an appropriate time to assess for neurologic readiness to extubate. Include precautions to prevent self-extubation, such as monitoring and vigilance, during the trial. Include a sedative interruption strategy in the overall plan to wean the patient from the ventilator; add the strategy to the weaning protocol, if available. Assess compliance each day on multidisciplinary rounds. Consider implementation of a sedation scale, such as the Richmond Agitation Sedation Scale (RASS) scale, to avoid oversedation.

Prophylaxis of Peptic Ulcer Disease

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form. Include intervention as an item for discussion on daily multidisciplinary rounds. Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Prophylaxis of Deep Venous Thrombosis

Include intervention as part of the intensive care unit admission order set and ventilation order set. Make application of prophylaxis the default value on the form. Include intervention as an item for discussion on daily multidisciplinary rounds. Empower pharmacy staff to review orders for patients in the intensive care unit to ensure that some form of prophylaxis is in place at all times for patients.

Source: [198]

The use of physician-led multidisciplinary rounds with team decision making, checklists, and a focus on the ventilator bundle has led to significant reductions in ventilator-associated pneumonia [238,239,240]. Moderate strength evidence has shown that the use of audit and feedback and reminder systems improve adherence to an overall ventilator-associated pneumonia bundle as well as reduce infection rates [1]. Education sessions have also led to enhanced knowledge and practice among healthcare professionals caring for intubated patients [197].

The lack of adherence to guideline-directed treatment of pneumonia cases associated with healthcare facilities is evidenced by wide variations in practice. For example, one study showed that more than 100 different antibiotic regimens had been prescribed as initial treatment and that de-escalation therapy was used for only 22% of patients [194]. Adherence rates for treatment of pneumonia associated with healthcare facilities have been reported to be lower than rates of adherence to guidelines for treatment of community-acquired pneumonia. In one survey, guideline-recommended antibiotics were used 9% of the time for healthcare-associated pneumonia compared with 78% of the time for community-associated pneumonia [241]. This lack of adherence was not due to unfamiliarity or disagreement with the guidelines; 71% of the survey respondents said they were aware of the guidelines, and 79% said they agreed with and practiced according to them. It is reasonable to expect that strategies used to enhance adherence to guidelines in the community-acquired pneumonia setting would also be effective in the setting of hospital-acquired and ventilator-associated pneumonia. Such strategies include feedback on performance, reminder systems, standardized order sets, and education emphasizing outcomes and cost-effectiveness.

INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS

Bloodstream infections, such as septicemia and bacteremia, can develop from other types of HAIs or infections at other sites in the body, but about 25% are caused by intravascular devices, primarily central venous catheters [144]. It has been estimated that 5.3 infections occur per 1,000 catheter-days in the ICU [28,40,242]. The number of infections reported to NHSN has increased substantially, with 78,896 reported in 2015–2017, compared with 27,766 reported in 2009–2010, perhaps in part a consequence of improved surveillance [144]. These infections are also the most costly, with a mean cost of more than $50,000 per infection [243]. As stated, data from the NHSN indicated that rates of central-line-associated bloodstream infections increased significantly compared with 2019, largely as a result of the COVID-19 pandemic [5]. The analysis showed that national standard infection ratios for central-line-associated bloodstream infections initially declined in the first quarter of 2020 compared with the first quarter of 2019, but then rose by 27.9%, 46.4%, and 47.0% in the second, third, and fourth quarters of the year, respectively [5]. While acknowledging that 2020 was an unprecedented time for hospitals, the authors of the analysis emphasized the continued need for regular review of HAI surveillance data to identify gaps in prevention [5].

Risk Factors

There are several types of intravascular catheters, and the risk of intravascular device-related bloodstream infections varies according to type. These catheters include:

- Peripheral venous catheters

- Peripheral arterial catheters

- Midline catheters

- Nontunneled central venous catheters

- Pulmonary artery catheters

- Pressure monitoring system catheters

- Peripherally inserted central venous catheters

- Tunneled central venous catheters

- Totally implantable devices

The nontunneled central venous catheter accounts for the majority of all intravascular device-related bloodstream infections [28]. Peripheral catheters (arterial and venous) are rarely associated with bloodstream infections, and totally implantable catheters are associated with the lowest risk [28]. A systematic review of 200 prospective studies of intravascular device-related bloodstream infections indicated that the level of risk associated with various types of devices can vary substantially depending on whether risk is expressed as the number of infections per 100 intravascular device-days or 1,000 intravascular device-days [244]. The risks associated with peripheral intravenous catheters were much higher when expressed over 1,000 intravascular device-days, pointing to the need for prevention strategies targeted to all types of devices [244].

Other risk factors are the length of time the catheter is in place and factors related to the patient's health status (severity of illness, presence of burns or surgical wounds, compromised immune system, nutritional status) [28,35].

Transmission and Common Pathogens

Intravascular device-related bloodstream infections are transmitted by both endogenous and exogenous routes. The most common cause of infection related to short-term catheters is migration of skin organisms at the site of insertion, with the organisms traveling along the surface of the catheter and colonization at the catheter tip [28]. Direct contamination of the catheter or catheter hub by contact with hands or contaminated fluids or devices is another cause [28]. Hematogenous seeding from another focus of infection is a less common cause, and contamination of infusion fluid is rare [28].

The most commonly reported pathogens for intravascular device-related bloodstream infections in 2015-2017 were S. aureus (16%), Enterococcus spp. (13%), Candida spp. (13%), coagulase-negative staphylococci (11%), Klebsiella spp. (10%), E. coli (7%), and Candida glabrata (5%) [144].

The percentage of resistant S. aureus was 48% in 2015–2017 compared with 55% in 2009–2010 [144]. Among the drug-resistant pathogens with the greatest increases compared with data for 2007–2008 were multidrug-resistant E. coli (10% vs. 4%), extended spectrum cephalosporin-resistant E. coli (21% vs. 19%), and aminoglycoside-resistant P. aeruginosa (14% vs 10%) [144].

Prevention

The CDC guidelines on the prevention of intravascular device-related bloodstream infections were published in 2002 and updated in 2011 and 2017 [28]. The most recent guidelines emphasize the following points [28]:

- Using maximal sterile barrier precautions during central venous catheter insertion

- Using a >0.5% chlorhexidine skin preparation with alcohol for antisepsis

- Avoiding routine replacement of central venous catheters as a strategy to prevent infection

- Using antiseptic/antibiotic impregnated short-term central venous catheters and chlorhexidine-impregnated sponge dressings if the rate of infection is not decreasing despite adherence to other strategies

- Educating and training healthcare providers who insert and maintain catheters

The CDC guidelines define maximal sterile barrier precautions as the use of a cap, mask, sterile gloves, sterile gown, and a sterile full-body drape during insertion of an intravascular device (level IB) [28]. A sterile sleeve should also be used to protect pulmonary artery catheters during insertion (level IB) [28].

The CDC guidelines recommend use of an antiseptic of 70% alcohol, tincture of iodine, or chlorhexidine gluconate solution with alcohol before insertion of peripheral venous catheters (level IB) and a >0.5% chlorhexidine preparation with alcohol before insertion of central venous catheters or peripheral artery catheters and during dressing changes (category IA) [28]. The guidelines note that chlorhexidine preparations with alcohol have not been compared with povidone iodine in alcohol and thus no recommendation can be made in this regard [28]. In a meta-analysis of eight studies (4,143 catheters, primarily central line catheters), the chlorhexidine solution was found to reduce the risk for bloodstream infection by 49% [245]. In a subsequent study, use of this solution led to a 1.6% decrease in the rate of bloodstream infection, a 0.23% decrease in the incidence of death, and a cost savings of $113 per catheter used compared with povidone-iodine solutions [246].

Most intravascular device-related bloodstream infections develop at the site of insertion, due to the density of skin flora [28]. Rates of infection vary according to insertion site, with catheters in the internal jugular vein being associated with a greater risk of infection than catheters in the subclavian vein [28,247,248]. A 2005 study indicated that the site of insertion was not a risk factor for infection when experienced or trained healthcare workers inserted the catheters [249]. However, such experience will not always be the norm, and the subclavian vein has been recommended by the CDC as the preferred site when possible [28].

Another strategy to prevent infection has been the development of central venous catheters with antimicrobial coatings. These coatings have included a combination of chlorhexidine and silver sulfadiazine and a combination of minocycline and rifampin [250]. Both types of catheters are associated with a significantly lower rate of infection than that associated with standard catheters. When compared with each other, catheters impregnated with minocycline and rifampin were 12 times less likely to cause bloodstream infections than those coated with chlorhexidine and silver sulfadiazine [251]. The chlorhexidine-silver sulfadiazine coating has since been enhanced, and these second-generation catheters have significantly reduced bacterial colonization, with a trend toward fewer bloodstream infections [252,253,254]. Each coating adds to the cost of the catheter, and cost-effective analyses are necessary.

On the basis of studies of intravascular device-related bloodstream infections, a bundle consisting of five preventive measures has been recommended:

- Compliance with appropriate hand hygiene

- Use of maximal barrier precautions

- Use of 2% chlorhexidine solution for skin antisepsis

- Selection of optimal site for the catheter, with the subclavian vein as the preferred site for nontunneled catheters

- Daily review of the need for the line, with prompt removal if line is deemed unnecessary

Diagnosis

As defined by the CDC, bloodstream infections fall into two categories: laboratory-confirmed infection and clinical sepsis. Clinical sepsis is no longer used in reporting on adults and children and is restricted to use for neonates and infants [127]. For a diagnosis of laboratory-confirmed bloodstream infection, one of the two following criteria must be met [219].

Criterion 1

Recognized pathogen found on one or more blood cultures and organism cultured from blood is not related to an infection at another site

Criterion 2

At least one of the following signs or symptoms:

- Fever (>38 degrees Centigrade)

- Chills (with no other recognized cause)

- Hypotension (with no other recognized cause)

and signs and symptoms and positive laboratory results are not related to an infection at another site and common skin contaminant (e.g., diphtheroids, Bacillus spp., Propionibacterium spp., coagulase-negative staphylococci, viridans group streptococcus, Aerococcus spp., or Micrococcus spp.) is cultured from two or more blood cultures drawn on separate occasions. Criterion elements must occur within a timeframe that does not exceed a gap of one calendar day [255].

There are several approaches to diagnosing an intravascular device-related bloodstream infection. A meta-analysis of 51 studies published between 1966 and 2004 was designed to identify which method was the most accurate [256]. The studies had involved the eight most commonly used diagnostic methods: culture (qualitative, semiquantitative, or quantitative) of a catheter segment; culture (qualitative or quantitative) of blood obtained through the catheter; paired quantitative cultures (blood obtained through the catheter as well as from a peripheral site); differential time to positivity (monitoring of cultures of blood obtained through the catheter and from a peripheral site); and acridine orange leukocyte cytospin. The paired cultures method was the most accurate, with a pooled specificity of 99%, followed by qualitative culture of blood drawn through the catheter and acridine orange leukocyte cytospin [256].

Treatment

The management of an intravascular device-related bloodstream infection does not always include removal of the device. Authors of consensus-based treatment guidelines advise that the decision to remove a tunneled catheter or implanted device suspected to be the source of bacteremia or fungemia should be based on the following factors [257]:

- Underlying health status of the patient

- Type of catheter

- Strength of the evidence that the catheter is the source of the infection

- Responsible pathogens

- Presence of local or systemic complications

Evidence Based Practice Recommendation

The Centers for Disease Control and Prevention recommends using a chlorhexidine/silver sulfadiazine- or minocycline/rifampin-impregnated central venous catheter in patients whose catheter is expected to remain in place longer than five days if, after successful implementation of a comprehensive strategy to reduce rates, the central line-associated bloodstream infection rate is not decreasing.

https://www.cdc.gov/hai/pdfs/bsi-guidelines-2011.pdf

Last Accessed: January 20, 2022

Strength of Recommendation/Level of Evidence: IA (Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies)

Nontunneled central venous catheters should be removed in most cases of bacteremia or fungemia [257]. Antibiotic therapy alone has resolved 80% of infections caused by coagulase-negative staphylococcal bacteria, but in cases of infection with S. aureus or Candida, infection has persisted when the catheter has been maintained [257,258].

One strategy was developed in an attempt to retain the catheter. With so-called antibiotic lock therapy, antibiotics are instilled through the catheter after injection of an anticoagulant, locking a high concentration of the antibiotic in the lumen [258]. This approach is used in combination with systemic antibiotic therapy, and the antibiotics used have included vancomycin, cefazolin, and clindamycin. Fluconazole and amphotericin B have been used occasionally for infection with Candida spp., and another flush solution (low concentrations of minocycline and EDTA) has demonstrated activity against staphylococci, gram-negative bacilli, and Candida spp. [258]. Early empiric antifungal therapy is important if infection with Candida is suspected, as delayed treatment has been associated with higher mortality [259].

The guidelines for treatment of intravascular device-related bloodstream infection suggest antimicrobial selection according to the known or suspected pathogen (Table 14) [257]. Empiric antibiotic therapy should be selected according to clinical features and context, with due consideration for the local prevalence of resistant pathogens. Vancomycin is recommended as initial treatment for coagulase-negative staphylococci and for S. aureus until the sensitivity to methicillin is determined, at which point treatment should be changed to semisynthetic penicillin if the identified pathogen is sensitive [257]. Vancomycin should not be used as a front-line treatment for infections with methicillin-sensitive S. aureus.

Table 14: TREATMENT OF INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS IN ADULTS

Pathogen

Preferred Antimicrobial Agent

Staphylococcus aureus

Sensitive to methicillin

Resistant to methicillin

Resistant to vancomycin

Penicillinase-resistant penicillin

Vancomycin

Daptomycin or linezolid

Coagulase-negative staphylococci

Sensitive to methicillin

Resistant to methicillin

Penicillinase-resistant penicillin

Vancomycin

Enterococcus spp.

Sensitive to ampicillin

Resistant to ampicillin/sensitive to vancomycin

Resistant to ampicillin/resistant to vancomycin

Ampicillin or (ampicillin or penicillin) + aminoglycoside

Vancomycin + aminoglycoside

Linezolid or daptomycin

Escherichia coli and Klebsiella spp.

ESBL negative

ESBL positive

Third-generation cephalosporin

Carbapenem

Enterobacter spp. and Serratia marcescens

Carbapenem

Acinetobacter baumannii

Ampicillin/sulbactam or carbapenem

Pseudomonas aeruginosa

Fourth-generation cephalosporin or carbapenem or antipseudomonal beta-lactam plus aminoglycoside

Burkholderia cepacia

SMZ-TMP or carbapenem

Candida albicans or Candida spp.

Echinocandin or fluconazole

Corynebacterium spp.

Vancomycin

Mycobacterium spp.

Susceptibility varies by species

SMZ-TMP: sulfamethoxazole/trimethoprim.

Source: [257]

If fever or other signs of infection persist after removal of the catheter, the patient should be evaluated for complications such as septic phlebitis, distant abscess, and endocarditis. Bacterial endocarditis has been found in 25% of patients with intravascular device-related bloodstream infection caused by S. aureus[258]. The findings of one study suggested that patients with MRSA bacteremia and underlying chronic liver disease were at higher risk for endocarditis [260].

Guideline Adherence and Quality Improvement

As is the case with guidelines for other HAIs, adherence to prevention guidelines is suboptimal. A survey of more than 500 hospitals showed that, while adherence to the two most strongly recommended prevention strategies—maximal sterile barrier precautions and antisepsis with chlorhexidine gluconate—was good at VA hospitals (84% and 91%, respectively), the rates were lower at non-VA hospitals (71% and 69%) [261]. Adherence to a combination of maximal sterile barrier precautions, chlorhexidine gluconate, and avoidance of central line changes was even lower: 62% and 44%, respectively [261]. In another study, central venous catheters were routinely changed to prevent infection in about 15% of hospitals [262].

Implementing a prevention bundle has significantly reduced intravascular device-related bloodstream infections: the decrease was from 5.9 per 1,000 catheter-days to 3.1 per 1,000 in one study and from 7.7 per 1,000 catheter-days to 1.4 per 1,000 in another [57,238]. A how-to guide developed by the IHI provides practical suggestions for implementing the bundle (Table 15) [263]. A checklist should be developed for use when inserting a catheter to ensure adherence to all prevention strategies [35].

Table 15: PRACTICAL STEPS IN FOLLOWING GUIDELINES TO PREVENT INTRAVASCULAR DEVICE-RELATED BLOODSTREAM INFECTIONS

Hand Hygiene

Include hand hygiene as part of the checklist for placement of central lines. Keep soap/alcohol-based hand hygiene dispensers prominently placed, and make universal precautions equipment, such as gloves, available only near hand sanitation equipment. Post reminder signs at the entry and exits to patient rooms. Initiate a campaign using posters including photos of celebrated hospital physicians/employees recommending hand hygiene. Create an environment in which reminding each other about hand hygiene is encouraged.

Maximal Barrier Precautions

Include maximal barrier precautions as part of the checklist for placement of central lines. Keep equipment stocked in a cart for central line placement to avoid the difficulty of finding necessary equipment to institute maximal barrier precautions. If a full-size drape is not available, apply two drapes to cover the patient or consult with the operating room staff to determine how to obtain full-size sterile drapes, as they are used routinely in surgical settings.

Chlorhexidine Skin Antisepsis

Include chlorhexidine antisepsis as part of the checklist for placement of central lines. Include chlorhexidine antisepsis kits in carts or grab bags storing central line equipment. (Many prepared central line kits include povidone-iodine kits, and these must be avoided.) Ensure that the solution dries completely before attempting to insert the central line.

Selection of Optimal Insertion Site

Include optimal site selection as part of the checklist for placement of central lines, with room to note appropriate contraindications (e.g., bleeding risks).

Daily Review of Need for Central Line

Include daily review of the need for the central line as part of multidisciplinary rounds. Include assessment for removal of central lines as part of daily goal sheets. Record time and date of line placement for record-keeping purposes and evaluation by staff to aid in decision making.

Source: [263]

Adherence to appropriate postinsertion care has been the focus of some studies. In one study, there were breaches in postinsertion care in 45% of cases [264]. The primary breaches were non-intact dressing (158 breaches per 1,000 catheter-days) and incorrectly placed caps and taps (156 breaches per 1,000 catheter-days) [264]. The rate of intravascular device-related bloodstream infection during the study period was 5.5 per 1,000 catheter-days [264]. In another study, nursing staff used a postinsertion care bundle that consisted of the following: daily inspection of the insertion site; site care if the dressing was wet, soiled, or had not been changed for 7 days; documentation of ongoing need for the catheter; proper application of a chlorhexidine gluconate-impregnated sponge at the insertion site; appropriate hand hygiene before handling the intravenous system; and application of an alcohol scrub to the infusion hub for 15 seconds before each entry [265]. Adherence to this bundle led to a significant decrease in intravascular device-related bloodstream infections, from 5.7 per 1,000 catheter-days to 1.1 per 1,000 catheter-days [265].

The availability of policies regarding prevention strategies is also lacking. Although 80% of 25 ICUs (10 hospitals) had written policies for insertion of central venous catheters, only 28% had a policy requiring maximal sterile barrier precautions, and 36% and 60% of the units required hand hygiene before accessing a central venous catheter or treating the exit site, respectively [262]. A formal educational program on catheter insertion was in place at 52% of the units [262]. Education, in the form of self-study modules with pretest and post-test, along with didactic lectures and integration of evidence-based guidelines have been associated with increases in adherence to recommended practices and decreases in bloodstream infections [266]. One systematic review included 27 interventional studies of central line insertion or maintenance or both in adult ICU settings with documentation of central line-associated bloodstream infection incidence per 1,000 catheter days [267]. Statistical significance was found in 26 of the 27 studies in terms of infection reduction, despite large variations in the length or type of educational intervention. The authors suggest that providing continuing education on infection prevention measures may improve post-insertion outcomes [267].

A systematic review demonstrated moderate strength of evidence for audit and feedback and provider reminder systems, along with base strategies [1].

CLOSTRIDIOIDES DIFFICILE INFECTIONS

C. difficile is the most common cause of infectious diarrhea among adults in healthcare settings [33]. Colonization with the inactive spore is much more prevalent in the healthcare setting than in the community. Studies show that the rate of asymptomatic colonization is approximately 2% to 3% in the community, 3% to 26% among adult inpatients in acute care hospitals, and 5% to 7% among elderly patients in long-term care facilities [33]. In contrast, the prevalence of C. difficile in the stool of asymptomatic adults without recent healthcare facility exposure is <2% [33]. Although colonization with C. difficile is relatively common among patients in healthcare facilities, clinical illness emerges only when there is production of toxins (A and B) that cause inflammation, secretion of mucous and fluid, and damage to the mucosa, resulting in diarrhea or colitis [268]. Disease can further progress to toxic megacolon, sepsis with or without intestinal perforation, and death [269,270].

The incidence of C. difficile-associated diarrhea has increased dramatically in recent decades. The incidence more than tripled between the 1990s and 2005 (from 30 to 40 cases per 100,000 individuals to 131 per 100,000), and in 2011, the incidence was reported to be 147.2 cases per 100,000 [271,272]. During this same time, some bacterial strains have become more virulent and perhaps more resistant [273]. As with other HAIs, C. difficile infection in the healthcare setting has been associated with increased length of stays, increased mortality, and higher costs [133,274,275,276,277].

Beginning in 2009, the CDC has conducted ongoing surveillance of C. difficile infection in the community and healthcare environment through the Emerging Infections Program, a sentinel network of 10 reporting sites in 35 counties of 10 states. Data from 2018 showed a total of 15,591 C. difficile infections reported within this population group of 11,982,926 persons, for a total annual rate of 130 incident infections per 100,000 population [278]. The rate of C. difficile HAI was 64 cases per 100,000, compared with the community-based incidence of 66 per 100,000. The risk increases with age, and the elderly are especially vulnerable. Among persons older than 65 years of age the rate of HAI caused by this pathogen was 367 cases per 100,000 patients [278]. Serial surveys show that C. difficile accounts for 15% of all HAIs, and the incidence has remained stable during the period 2011 to 2015. When extrapolated to the nation at large, CDC data analysis shows that C. difficile causes more than 430,000 incident infections in the United States each year and is associated with approximately 20,500 deaths [279]. The 2020 HAI progress report showed a more positive trend, with about an 11% decrease in C. difficile infections reported from acute care hospitals between 2019 and 2020 [85].

Risk Factors

The primary risk factors for infection with C. difficile are antibiotic use, older age, and hospitalization [33]. Exposure to antibiotic agents is the most modifiable risk factor, an association reported in more than 96% of hospitalized patients in one study [280]. Antibiotics increase the risk by suppressing or altering normal bowel microflora, thereby facilitating overgrowth of relatively dormant C. difficile organisms. Many antibiotics have been implicated, but fluoroquinolones, cephalosporins, carbapenems, and clindamycin have been found to confer high risk [33]. The likelihood of infection increases with longer hospitalizations, with a 15% to 45% risk of colonization among patients hospitalized for one to three weeks [280].

Transmission

C. difficile is an exogenous infection that is transmitted person-to-person through the fecal-oral route and possibly via contact with contaminated environmental surfaces (e.g., bedding, commodes, bath tubs).

Prevention and Control

Guidelines developed by SHEA/IDSA in 2010, and updated in 2017 and 2021, offer recommendations for prevention, diagnosis, and management of C. difficile[33,281]. (The scope of the 2021 focused update is restricted to adults and includes new data for fidaxomicin and for bezlotoxumab, a monoclonal antibody targeting toxin B produced by C. difficile [281].)

Control measures include restriction of antibiotic use; isolation precautions for healthcare workers, patients, and visitors; and environmental cleaning and disinfection (Table 16) [33]. The guidelines note that the use of antibiotics should be minimized and that an antibiotic stewardship program should be developed and implemented by all hospitals [33]. Appropriate hand hygiene is essential, and soap and water should be used rather than alcohol-based handrubs, as alcohol is not effective at killing C. difficile spores [33]. Gowns, gloves, and contact precautions for the duration of diarrhea are also recommended. The guidelines suggest that removing environmental sources of C. difficile, such as replacing rectal thermometers with disposable ones, can help reduce the incidence of C. difficile infection. The guidelines also note that the following are not recommended: routine environmental screening for C. difficile (level III, C); routine identification of asymptomatic carriers for infection control purposes (level III, A); and use of probiotics to prevent infection (level I, B) [33].

Table 16: SHEA/IDSA GUIDELINES FOR INFECTION CONTROL MEASURES FOR CLOSTRIDIOIDES DIFFICILE

Restriction of Antibiotic Use

- Minimize the frequency and duration of antibiotic therapy and the number of antibiotic agents prescribed (level II, A).

- Implement an antibiotic stewardship program (level II, A). Antibiotic to be targeted should be based on the local epidemiology and the C. difficile strains present, but restricting the use of fluoroquinolones, cephalosporin and clindamycin (except for surgical antibiotic prophylaxis) may be particularly useful (level III, C).

Measures for Healthcare Workers, Patients, and Visitors

- Healthcare personnel and visitors must use gloves (level I, A) and gowns (level III, B) on entering the room of a patient with C. difficile infection.

- Emphasize compliance with appropriate hand hygiene (level II, A).

- Instruct visitors and healthcare personnel to wash hands with soap (or antimicrobial soap) and water before and after caring for or contacting patients with C. difficile infection (level III, B).

- Use a private room with contact precautions for patients with C. difficile infection (level III, B); cohort patients if single rooms are not available, and provide a dedicated commode for each patient (level III, C).

- Maintain contact precautions until 48 hours after diarrhea has resolved (level III, C).

Environmental Cleaning and Disinfection

- Identify and remove environmental sources of C. difficile, to reduce the incidence of infection (level II, B).

- Use chlorine-containing cleaning agents or other sporicidal agents to address environmental contamination in areas associated with increased rates of C. difficile infection (level II, B).

Source: [33]

Diagnosis

Evidence Based Practice Recommendation

According to the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), patients with at least three unexplained and new-onset unformed stools in 24 hours are the preferred target population for testing for Clostridioides difficile infection (CDI).

https://www.idsociety.org/practice-guideline/clostridium-difficile

Last Accessed: January 20, 2022

Strength of Recommendation/Level of Evidence: Weak recommendation, very low quality of evidence

Infection with C. difficile is diagnosed on the basis of clinical findings and the results of laboratory testing [33]. C. difficile infection is defined as (1) the presence of diarrhea (passage of three or more unformed stools in up to 24 consecutive hours) and (2) positive results on stool testing for the presence of toxigenic C. difficile or its toxins or findings of pseudomembranous colitis on colonoscopy or histopathologic evaluation [33]. Diarrhea may be absent in up to 20% of patients with fulminant colitis or postoperative ileus [280]. Other symptoms include fever, nausea, vomiting, abdominal pain or tenderness, and loss of appetite, but these symptoms are found in about half of patients with the infection [33,268].

Diagnostic stool testing should be done only on unformed stool (level II, B), and testing for asymptomatic patients is not useful (level III, B) [33]. Repeat testing during the same episode of diarrhea is discouraged, as it does not provide clinically useful information (level II, B) [33].

Several diagnostic tests are available to detect C. difficile, and they vary in terms of sensitivity, specificity, and turnaround times. Stool culture is the most sensitive test, but it is not clinically practical because of the slow turnaround time [33]. The sensitivity of cell cytotoxicity assay has been reported to range from 67% to 100%, whereas enzyme immunoassay testing for toxins A and B has a sensitivity ranging from 63% to 94% and a specificity of 75% to 100% [33]. Enzyme immunoassay testing is rapid and less expensive than other tests but it is a suboptimal choice compared with cell cytotoxicity assay (level II, B) [33]. The SHEA/IDSA guidelines note that polymerase chain reaction testing appears to be rapid, sensitive, and specific, but more data on its usefulness are needed before it can be recommended for routine use (level II, B) [33].

Treatment

Evidence Based Practice Recommendation

According to the IDSA and the SHEA, fidaxomicin is recommended over vancomycin for an initial episode of C. difficile infection. Vancomycin remains an acceptable alternative.

https://www.idsociety.org/practice-guideline/clostridioides-difficile-2021-focused-update

Last Accessed: January 20, 2022

Level of Evidence: Consensus Statement/Expert Opinion

The most important step in treating C. difficile-associated diarrhea is to discontinue the inciting antibiotic as soon as possible [33]. This approach alone will lead to resolution of diarrhea in approximately 15% to 25% of patients with mild infection [268,280]. Antibiotic treatment of the diarrhea should not begin until the culture or toxin assay results are known, as approximately 30% of hospitalized patients with antibiotic-associated diarrhea will have C. difficile infection [33]. However, if severe or complicated C. difficile infection is suspected, empirical treatment should be started as soon as the diagnosis is suspected (level III, C) [33]. The SHEA/IDSA guidelines recommend fidaxomicin rather than a standard course of vancomycin for an initial episode of C. difficile gastrointestinal infection, whether mild or moderately severe. Implementation of this recommendation depends upon available resources. Vancomycin remains an acceptable alternative [281]. For an initial episode of C. difficile, a dosage of fidaxomicin 200 mg orally twice daily for 10 days is recommended. Vancomycin 125 mg orally four times per day for 10 days is the recommended alternative regimen [281]. Table 17 outlines the guideline recommendations for treatment according to severity of illness [281].

Table 17: SHEA/IDSA GUIDELINES FOR THE TREATMENT OF CLOSTRIDIOIDES DIFFICILE INFECTION ACCORDING TO SEVERITY OF DISEASE

Severity of Disease

Preferred Treatment

Mild to severe (WBC ≤15,000)

Fidaxomicin 200 mg twice daily for 10 days (Conditional/Moderate)

Alternative: Vancomycin 125 mg orally four times daily for 10 days

Alternative (if above agents are not available): Metronidazole 500 mg orally three times daily for 10 to 14 days

Severe (WBC >15,000, serum creatinine >1.5 mg/dL)

Vancomycin PO 125 mg, four times per day for 10 days OR fidaxomicin 200 mg twice daily for 10 days (Strong/High)

Fulminant (hypotension, ileus, or megacolon)

Vancomycin 500 mg, four times per day by mouth or nasogastric tube

If ileus, add rectal administration of vancomycin and intravenous metronidazole 500 mg every 8 hoursa (Strong/Moderate)

Recurrent

First recurrence

Second recurrence or more

Vancomycin PO 125 mg four times daily for 10 days if metronidazole was used for initial treatment; fidaxomicin 200 mg twice daily for 10 days if vancomycin was used initially

Vancomycin in a prolonged tapered and pulsed regimen OR vancomycin standard 10-day regimen followed by rifaximin 400 mg three times daily for 20 days

aIf ileus is present, vancomycin may be given per rectum as a retention enema, at a dose of 500 mg/100 mL normal saline, every 6 hours.

Source: [281]

For patients with a recurrent episode of C. difficile (within the last six months), the SHEA/IDSA panel conditionally recommends using bezlotoxumab as a co-intervention with standard-of-care antibiotics, rather than antibiotics alone [281]. Bezlotoxumab has been shown to be effective in preventing C. difficile infection when administered at any time before ending antibacterial treatment [282]. Patients with a primary episode and other risk factors for recurrence (e.g., 65 years of age and older, immunocompromised, severe C. difficile, C. difficile infection in the last six months) may benefit from receiving bezlotoxumab [281]. Bezlotoxumab was approved by the FDA in 2016 and was the first humanized monoclonal antibody effective against C. difficile toxin B. It is approved for the prevention of recurrent C. difficile infection in high-risk adults [281,283]. Bezlotoxumab is administered as a one-time infusion at a recommended dose of 10 mg/kg over 60 minutes [281,283]. In patients with a history of congestive heart failure, the FDA warns that bezlotoxumab should be reserved for use when the benefit outweighs the risk [281,283].

Surgical management may be necessary for severe, fulminant cases of C. difficile colitis. In such cases, subtotal colectomy with preservation of the rectum is advisable; alternatively, a diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes may lead to improved outcomes [33].

In addition to infection-directed antibiotics, treatment of C. difficile infection also includes fluid replacement, and electrolyte normalization [284]. The use of antiperistaltic agents should be avoided, as they may obscure symptoms, lead to retained toxin, and precipitate toxic megacolon (level III, C) [33]. The use of probiotics has been suggested as an adjunct to antibiotic treatment, but a systematic review found insufficient data to support probiotics as adjunct therapy and no evidence to support its use alone [285].

6. INFECTION CONTROL

The development of formal infection control programs in hospitals and other healthcare facilities was spurred by the Joint Commission accreditation standards for infection control, published in 1976. According to the standards, accredited facilities must have a program for the surveillance, prevention, and control of HAIs [89]. In 1974, the CDC designed the Study on the Efficacy of Nosocomial Infection Control project to determine if infection surveillance and infection control programs could reduce the number of HAIs [286]. The nationwide study evaluated rates of HAIs in hospitals before and after the implementation of infection control programs; the researchers noted that programs with four components were associated with a one-third reduction in the rate of HAIs: an effective hospital epidemiologist, one infection control practitioner for every 250 beds, active surveillance mechanisms, and ongoing control efforts [287]. With the increased focus on prevention of HAIs, infection control professionals have come to be known as infection preventionists [288].

An infection control program is usually overseen by a committee chaired by an infectious disease physician and consisting of staff representing departments throughout the facility, such as nursing, pharmacy, surgery, clinical microbiology, central sterilization services, housekeeping, maintenance, food services, and laundry services. Among the responsibilities of an infection control program are to:

- Conduct surveillance of HAIs

- Develop policies regarding prevention and control, such as hand hygiene and precautions

- Ensure adherence to standards for environmental services

- Establish a program to monitor and evaluate antimicrobial therapy

- Provide education to healthcare workers about adherence to infection control policies

- Develop guidelines for outbreak preparedness

The policies and procedures in each of these areas, as well as guidelines for adherence, should be documented in an infection control manual.

All physicians and staff within a healthcare facility have responsibility for helping to advance infection control goals. Physicians should assume the following responsibilities [16]:

- Protect their patients from other infected patients or staff

- Comply with the practices approved by the infection control committee

- Obtain appropriate microbiologic specimens when infection is suspected or present

- Notify the infection control committee about confirmed cases of HAIs

- Comply with the institution's recommendations regarding the use of antibiotics

- Educate patients, visitors, and staff about techniques to prevent the transmission of infection.

As direct providers of care in a healthcare facility, the nursing staff plays a substantial role in carrying out infection control practices. Nursing administrators should promote the development and enhancement of nursing techniques, review nursing policies regarding aseptic techniques, and offer educational training programs on best practices [16]. Nurses on patient care units have the following responsibilities [16]:

- Comply with established infection control practices

- Monitor aseptic techniques, including handwashing and use of isolation precautions

- Report evidence of infection immediately to the attending physician

- Initiate patient isolation and order culture specimens when infection is suspected and a physician is not immediately available

- Limit patient exposure to infections from others (visitors, hospital staff, other patients, or equipment used for diagnosis or treatment)

Community hospitals have had success with participating in an infection control network. In 12 community hospitals in North Carolina and Virginia that joined such a network (the Duke Infection Control Outreach Network), there were significant decreases in the annual rates of healthcare-associated bloodstream infections, infection and colonization with MRSA, ventilator-associated pneumonia, and exposure of staff to bloodborne pathogens [289]. After network participation for five years, the average decrease in the number of device-related infections and HAIs due to MRSA decreased by an average of 50% [290]. The cost savings was approximately $100,000 per hospital, and in total, an estimated 52 to 105 deaths related to ventilator-associated pneumonia or intravascular device-related infection were prevented [290].

Most prevention and control policies focus on general measures, such as surveillance; adherence to guidelines for hand hygiene, influenza vaccination, precautions and isolation techniques, management of drug-resistant micro-organisms, and standards for environmental services; and education of healthcare workers as well as patients and families.

SURVEILLANCE

Surveillance is an essential component of an infection control program. The infection control team has traditionally conducted surveillance through open communication with the nursing staff and physicians and meticulous review of patient records and microbiology results. The infections most commonly targeted for surveillance are those associated with substantial costs in terms of morbidity, mortality, or economics, and those difficult to treat. In addition, infections with a predilection for epidemics are a focus. The data gathered should be evaluated in relation to regional and national norms, and temporal trends should also be noted. Continuing analysis of the data allows the infection control team to evaluate the efficacy of programs designed to enhance compliance with hospital-wide strategies to prevent HAIs.

HAND HYGIENE

Hand hygiene is the most important preventive measure in hospitals, and the Joint Commission mandates that hospitals and other healthcare facilities comply with the Level I recommendations in the CDC guidelines for hand hygiene [27]. The CDC guidelines state the specific indications for washing hands, the recommended hand hygiene techniques, and recommendations about fingernails and the use of gloves (Table 18) [27]. The guidelines also provide recommendations for surgical hand antisepsis, selection of hand-hygiene agents, skin care, educational and motivational programs for healthcare workers, and administrative measures.

Table 18: SUMMARY OF CDC RECOMMENDATIONS FOR HAND HYGIENE

Indications for Hand Hygiene

Wash hands with nonantimicrobial or antimicrobial soap and water when they are visibly dirty, contaminated, or soiled. If hands are not visibly soiled, use an alcohol-based handrub for routinely decontaminating hands.

Specific Indications

Wash hands before patient contact and before putting on gloves for insertion of invasive devices that do not require surgery (e.g., urinary catheters or intravascular devices).

Wash hands after:

Contact with a patient's skin

Contact with body fluids or excretions, nonintact skin, or wound dressings

Removing gloves

Recommended Handrub Technique

Apply to palm of one hand, rub hands together, covering all surfaces until dry.

Recommended Handwashing Techniques

Wet hands with water, apply soap, and rub hands together for at least 15 seconds.

Rinse and dry with disposable towel.

Use towel to turn off faucet.

Fingernails and Artificial Nails

Keep tips of natural nails to a length of ¼ inch. Do not wear artificial nails during direct contact with high-risk patients (e.g., patients in intensive care unit or operating room).

Use of Gloves

Use gloves when there is potential for contact with blood or other potentially infectious materials, mucous membranes, or nonintact skin. Change gloves after use for each patient.

Source: [27]

Despite the simplicity of the intervention, its substantial impact, and wide dissemination of the guidelines, compliance with recommended hand hygiene has ranged from 16% to 81%, with an average of 30% to 50% [27,40,41,42,43]. A 2010 systematic review of studies on compliance with hand-hygiene guidelines in hospital care found an overall median compliance rate of 40%, with lower rates in ICUs (30% to 40%) than in other settings (50% to 60%), lower rates among physicians than among nurses (32% and 49%, respectively), and lower rates before (21%) rather than after (47%) patient contact [291]. Among the reasons given for the lack of compliance are inconvenience, understaffing, and damage to skin [27,41,89]. The development of effective alcohol-based handrub solutions addresses these concerns, and studies have demonstrated that these solutions, as well as performance feedback and accessibility of materials, have increased compliance [42,291,292,293]. The CDC guidelines recommend the use of handrub solutions on the basis of several advantages, including [27]:

- Better efficacy against both gram-negative and gram-positive bacteria, mycobacteria, fungi, and viruses than either soap and water or antimicrobial soaps (such as chlorhexidine)

- More rapid disinfection than other hand-hygiene techniques

- Less damaging to skin

- Time savings (18 minutes compared with 56 minutes per 8-hour shift)

The guidelines suggest that healthcare facilities promote compliance by making the handrub solution available in dispensers in convenient locations (such as the entrance to patients' room or at the bedside) and provide individual pocket-sized containers [27]. The handrub solution may be used in all clinical situations except for when hands are visibly dirty or are contaminated with blood or body fluids. In such instances, soap (either antimicrobial or nonantimicrobial) and water must be used.

However, there are many other reasons for lack of adherence to appropriate hand hygiene, including denial about risks, forgetfulness, and belief that gloves provide sufficient protection [27,41]. These reasons demand education for healthcare professionals to emphasize the importance of hand hygiene. Also necessary is research to determine which interventions are most likely to improve hand-hygiene practices, as no studies have demonstrated the superiority of any intervention [294,295]. Single interventions are unlikely to be effective [294,295].

Several single-institution studies have demonstrated that appropriate hand hygiene reduces overall rates of HAIs, including those caused by MRSA and VRE [43,292,293]. However, rigorous evidence linking hand hygiene alone with the prevention of HAIs is lacking, making it difficult to evaluate the true impact of hand hygiene alone in reducing HAIs [57]. One challenge in evaluating the impact of hand hygiene is that a variety of methodologies have been used to assess compliance (e.g., surveys, direct observation, measurement of product use), each with its own advantages and disadvantages [296]. Measuring the effect of appropriate hand hygiene alone is also difficult because the intervention is often one aspect of a multicomponent strategy to reduce infection [43]. Lastly, as noted previously, the development of HAIs is complex, with many contributing factors. Although more research is needed to assess the individual impact of appropriate hand hygiene, this basic prevention measure is the essential foundation of an effective infection control strategy and an element of every infection control guideline.

INFLUENZA VACCINATION

The vaccination status of healthcare workers has been found to have a direct effect on transmission of the influenza virus to patients. Outbreaks of influenza in healthcare settings have been associated with low rates of vaccination among healthcare workers, and lower rates of nosocomial influenza have been related to higher vaccination rates among healthcare workers [297,298]. Because of these findings, several organizations have addressed the need for vaccination. The CDC and the Advisory Committee on Immunization Practices recommends annual influenza vaccination for all healthcare workers [299]. CDC guidelines include four Level I recommendations to help increase rates of vaccination [300]:

- Offer influenza vaccine annually to all eligible healthcare workers.

- Provide influenza vaccination to healthcare workers at the work site and at no cost as one component of employee health programs. Use strategies that have been demonstrated to increase influenza vaccine acceptance, including vaccination clinics, mobile carts, vaccination access during all work shifts, and modeling and support by institutional leaders.

- Monitor influenza vaccination coverage and declination of healthcare workers at regular intervals during influenza season and provide feedback of ward-, unit-, and specialty-specific rates to staff and administration.

- Educate healthcare workers about the benefits of influenza vaccination and the potential health consequences of influenza illness for themselves and their patients, the epidemiology and modes of transmission, diagnosis, treatment, and nonvaccine infection control strategies, in accordance with their level of responsibility in preventing healthcare-associated influenza.

In addition, the Joint Commission began including vaccination programs in its accreditation standards in 2007 [301].

Note: As of January 1, 2021, the Joint Commission eliminated its requirement that select healthcare facilities set a goal toward achieving a 90% vaccination rate. However, while the goal of 90% was retired, the rest of the standard remains in effect, and organizations are encouraged to "continue to strive to increase compliance with influenza vaccinations and take action to improve vaccination rates" [302].

Despite these guidelines, not all healthcare personnel are being vaccinated for influenza. Overall, 75.9% of healthcare personnel reported receiving influenza vaccination during the 2020–2021 season, which was lower than in the previous season in which 80.7% reported vaccination [303]. By occupation, vaccination rates were highest among physicians (91.3%), pharmacists (90.3%), and nurses (90.3%). Vaccination coverage was higher among personnel working in hospitals (91.6%) than for those working in long-term care facilities (66.0%) [303]. Healthcare workers have given many reasons for not being vaccinated, and the reasons vary among categories of healthcare professionals [304]. Across all categories, shortage of the vaccine is the primary reason for not being vaccinated; other reasons include concern about side effects, inconvenience, and forgetfulness [304]. Many reasons for receiving the vaccine have also been identified, including [299,304]:

- Fear of getting influenza

- Fear of transmitting influenza to patients

- Belief that the vaccine is safe

- Belief that the vaccine is effective

- Convenience

The CDC reports that vaccination rates are highest (98%) among healthcare personnel whose employers require that they be vaccinated, compared with personnel whose employers who do not recommend or have a policy recommending vaccination (42.0%%) [305]. Efforts to increase the vaccination rate among healthcare workers are ongoing. The APIC issued a position paper acknowledging the problem and highlighting suggestions to improve vaccination rates [306]. Additionally, the CDC has provided resources to healthcare employers to increase vaccination rates among healthcare personnel [305].

PRECAUTIONS AND ISOLATION TECHNIQUES

The CDC guidelines for isolation precautions in hospitals, updated in 2007, synthesize a variety of recommendations for precautions based on the type of infection, the route of transmission, and the healthcare setting [23]. As defined by the CDC, Standard Precautions represent measures that should be followed for all patients in a healthcare facility, regardless of diagnosis or infection status. Standard Precautions apply to blood; all body fluids, secretions, and excretions except sweat, regardless of whether or not they contain visible blood; nonintact skin; and mucous membranes [23]. For patients who are known to have or are highly suspected to have colonization or infection, Contact Precautions should be followed. This type of precaution is designed to reduce exogenous transmission of micro-organisms through direct or indirect contact from healthcare workers or other patients. Airborne Precautions are used for patients who have or are highly suspected of having infection that is spread by airborne droplet nuclei, such as tuberculosis, measles, or varicella. Droplet Precautions target infections that are transmitted through larger droplets generated through talking, sneezing, or coughing, such as invasive Haemophilus influenzae type b disease, diphtheria (pharyngeal), pertussis, group A streptococcal pharyngitis, influenza, mumps, and rubella [23].

The CDC guidelines include descriptions of all the elements involved in the four types of precautions, including hand hygiene; the use of personal protection equipment (gloves, gown, and face protection); handling of patient-care equipment; environmental services and occupational health; and placement of the patient. New elements of Standard Precautions added to the 2007 guidelines are respiratory hygiene/cough etiquette and safe injection practices [23]. Recommendations in this area address the importance of educating healthcare workers about adherence to measures to control the transmission of respiratory pathogens, especially during seasonal outbreaks of viral respiratory tract infections. In addition, the guidelines state that efforts should be made to contain respiratory secretions in patients and other individuals who have signs and symptoms of a respiratory infection, beginning at the point of initial encounter in a healthcare setting. Signs should be posted to instruct patients and visitors with symptoms of respiratory infection to cover their mouths/noses when coughing or sneezing, to use and dispose of tissues, and to perform hand hygiene after contact with respiratory secretions. Masks should be offered to coughing patients and other individuals with symptoms, and such persons should be encouraged to maintain an ideal distance of at least 3 feet from others in common waiting areas. The safe injection practices element was included as a result of breaches in infection control practice that contributed to four large outbreaks of hepatitis B and C viruses among patients in ambulatory care facilities [23]. These outbreaks could have been prevented by adherence to basic principles of aseptic technique, including the use of a sterile, single-use disposable needle and syringe for each injection. A survey of U.S. healthcare workers who provide medication through injection found that 1% to 3% reused the same needle and/or syringe on multiple patients [23].

PREVENTION OF ANTIBIOTIC-RESISTANT INFECTION

Managing the problem of emerging drug-resistant microbial infection is a crucial aspect of an institution's infection control program. Any use of an antibiotic exerts selective pressure that can lead to the development of drug-resistance. The growing prevalence of antibiotic resistance is a serious problem for hospitals and for public health. Studies show that treatment indication, choice of antibiotic, or duration of therapy can be incorrect in up to 30% of instances in which antibiotics are prescribed. The national effort to promote antibiotic stewardship is intended to slow the development of resistance, help prevent untreatable infection, and extend the useful lifetime of the most urgently needed antibiotics [2].

Updated guidelines for the management of MRSA and other drug-resistant micro-organisms were published by the CDC in 2006 and the SHEA in 2014; the guidelines focus on the prevention of drug-resistant infections and the judicious use of antibiotics (antimicrobial stewardship) (Table 19) [23,31,39,73].

Table 19: SUMMARY OF STRATEGIES FOR PREVENTION OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS AND OTHER DRUG-RESISTANT MICRO-ORGANISMS

Conduct MRSA risk assessment and implement an MRSA monitoring programa

System to identify patients with MRSA colonization or infection

Feedback of information to cliniciansa

Education

Hand hygiene

Environmental decontamination

Dedicated equipment

Contact precautions

Masksb

Cohortingc

Antimicrobial stewardship

Active surveillance testingc

Decolonization therapyd

Compliance with hand hygiene

Compliance with cleaning protocolse

Compliance with Contact Precautionsa

aNot discussed in the guidelines by the Society for Healthcare Epidemiology of America (SHEA).

bRecommended in SHEA guidelines but not in guidelines by the Centers for Disease Control and Prevention (CDC).

cRecommended by the CDC only for specific subpopulations or circumstances.

dRecommended by both CDC and SHEA only for specific subpopulations or circumstances.

eNot discussed in the SHEA guidelines and recommended by the CDC only for specific subpopulations or circumstances.

Source: [23,31,39,73]

The CDC's Be Antibiotics Aware program provides fact sheets, pocket cards, posters, and slide sets for a variety of patient populations, including hospitalized adults, individuals to have surgery, patients receiving dialysis, long-term care patients, and hospitalized children [307]. All of the resources are available on the CDC website at https://www.cdc.gov/antibiotic-use/week/toolkit.html.

The IHI defines five components of a program to reduce the risk of infection with drug-resistant micro-organisms [308]:

- Hand hygiene

- Decontamination of the environment and equipment

- Active surveillance

- Contact precautions for infected and colonized patients

- Bundled interventions to prevent intravascular device-related bloodstream infections and ventilator-associated pneumonia

Universal surveillance of MRSA at hospital admission has been suggested as a measure to help prevent the transmission of this infection in the healthcare setting; however, the CDC guidelines state that the evidence on universal surveillance is limited and recommends surveillance only in specific subpopulations, defined in the context of the infection characteristics of the facility [23]. The guidelines additionally state that surveillance for certain epidemiologically important organisms may need to be facility-wide and that surveillance methods will continue to evolve as healthcare delivery systems change [23].

Since the publication of the guideline, conflicting data have been reported. In a prospective study of surgical patients at a Swiss teaching hospital, a rapid MRSA screening test at the time of hospital admission did not reduce the rate of MRSA infections [309]. In contrast, a universal MRSA screening program at a three-hospital organization in the United States led to a large reduction in MRSA infection during hospitalization and at 30 days after discharge [310]. Rates of MRSA infection have been reduced when universal MRSA surveillance was incorporated into a bundle of interventions that included adherence to Standard Precautions and recommendations for hand hygiene, adherence to Contact Precautions for patients who have MRSA-positive cultures, and efforts to change the environmental culture through briefings on patient care units, leadership involvement, and other similar strategies [308]. In one study, implementation of such a bundle resulted in significant decreases in transmission of MRSA (from 5.8 per 1,000 bed-days to 3.0 per 1,000) and overall MRSA HAIs (from 2.0 per 1,000 bed-days to 1.0 per 1,000), as well as a 65% decrease in MRSA surgical site infections after orthopedic operations [177]. Three independent factors have been found to correlate with previously unknown MRSA carriage: recent treatment with antibiotics, history of hospitalization, and age older than 75 years. Predictive models with these factors may enhance MRSA screening by better targeting patients at risk for MRSA carriage [311].

Antimicrobial Stewardship

The principles underlying the judicious use of antibiotics are the limitation of unnecessary antibiotics, obtaining timely culture and sensitivity data, selecting the most appropriate treatment, and prescribing the appropriate dose [312]. In addition, studies have shown that antimicrobial use can be decreased by using explicit criteria to identify patients with HAIs as well as those at highest risk for infection [313]. Antibiotic stewardship programs provide guidance to clinicians and have been shown to improve patient outcomes, reduce the burden of antibiotic resistance, and save healthcare dollars [2,314].

In their "Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship," SHEA and IDSA recommend that two core strategies of such a program are a prospective audit with intervention and feedback and formulary restriction and preauthorization [72]. Other elements of an effective antimicrobial stewardship program include [72]:

- Education to supplement interventions

- Guidelines and clinical pathways that incorporate local microbiology and resistance patterns

- Antimicrobial order forms

- Policy to avoid routine antimicrobial cycling

- Selective use of combination therapy

- Streamlining or de-escalation of therapy

- Dose optimization

- Systematic plan for parental-to-oral conversion

The goal of phase four of the CDC national HAI Action Plan is to "slow the emergence of resistant bacteria and prevent the spread of resistant infection" (Table 20) [2]. As previously stated, the HHS is working to update the plan with new indicator targets and data, new research and intervention efforts, and a review of the impact of the COVID-19 public health emergency on HAIs [2]. The CDC is coordinating stewardship activities among federal agencies, public health, and healthcare systems [2]:

- Establishment of antibiotic stewardship programs in all acute care hospitals and improved stewardship across all healthcare settings

- Reduction of inappropriate antibiotic use by 50% in outpatient settings and by 20% in inpatient settings

- Establishment of Antibiotic Resistance Prevention Programs in all 50 states

The Agency for Healthcare Research and Quality (AHRQ) Safety Program for Improving Antibiotic Use engaged in establishing or improving antimicrobial stewardship programs in 389 ambulatory care practices throughout the United States [340]. This program involves webinars, audio presentations, educational tools, and office hours to engage stewardship leaders and clinical staff to address attitudes and cultures that challenge judicious antibiotic prescribing and incorporate best practices for the management of common infections. Over the period of one year (December 2019 through November 2020), antibiotic prescribing at participating clinics was cut overall by nearly 48%, while prescribing for acute respiratory infections was reduced by 37% [340].

Table 20: CDC'S CORE ELEMENTS FOR ANTIBIOTIC STEWARDSHIP PROGRAMS IN HOSPITALS, NURSING HOMES AND OUTPATIENT FACILITIES

Core Element

Definition

Leadership commitment

Dedicating necessary human, financial and information technology resources

Accountability

Appointing a single leader responsible for program outcomes. Experience with successful programs show that a physician leader is effective.

Drug expertise

Appointing a single pharmacist leader responsible for working to improve antibiotic use

Action

Implementing at least one recommended action, such as systemic evaluation of ongoing treatment need after a set period of initial treatment (i.e., "antibiotic time out" after 48 hours)

Tracking

Monitoring antibiotic prescribing and resistance patterns

Reporting

Regular reporting of information on antibiotic use and resistance to doctors, nurses and other relevant staff

Education

Educating clinicians about resistance and optimal prescribing

Source: [2]

EDUCATION FOR HEALTHCARE PROFESSIONALS

Education on best practices is a crucial aspect of preventing HAIs and is a recommendation in all infection control guidelines. Education should highlight the effect of prevention measures on the rates of HAIs, enhance knowledge about currently available guidelines, and provide instruction on carrying out guideline recommendations. Research has also suggested that education about prevention strategies may be more effective if patterns of care and levels of risk are incorporated into recommendations [315]. Numerous studies have shown that knowledge and practices related to HAIs and guidelines are improved after educational programs. The combination of a self-study module (with pretest and post-test), inservice lectures, posters, and fact sheets on the prevention of intravascular device-related bloodstream infections and appropriate practices led to substantial reductions in the prevalence of such infections [266,316,317]. A small study showed that ICU nurses' knowledge and practices were enhanced by education on the prevention of ventilator-associated pneumonia [197]. A Canadian study demonstrated that rates of nosocomial MRSA infection significantly decreased after a mandatory infection control education program on MRSA that included discussion of hospital-specific MRSA data and case-based practice [318].

Because increasing knowledge is not sufficient for effecting behavior change, theoretical models for behavior change should be considered when designing improvement initiatives [296,319]. Among effective model-related strategies are the following [296,319]:

- Education and discussion of barriers to adherence (cognitive model)

- External reinforcements, incentives, and reminders (behavioral model)

- Consensus, leadership, and role models (social influence model)

- Quality improvement teams, process redesign, and fostering of a safety-oriented culture (organizational model)

Healthcare facilities should explore innovative ways to develop quality improvement initiatives. In an effort to enhance adherence to the CDC guidelines on hand hygiene, a group of three hospitals used the Six Sigma approach with success. Six Sigma is a process established in the business world to achieve and sustain excellence in general operations and service [320]. The healthcare facility used the process to organize the knowledge, opinions, and actions of physicians, nurses, and other staff in four ICUs at the facilities, resulting in an increase in compliance from 47% to 80% [321].

Given the suboptimal rates of influenza vaccination among healthcare workers, education on the importance of this measure is also needed. Two literature reviews have shown high rates of misconceptions or lack of knowledge about influenza, the role of healthcare professionals in transmitting influenza to patients, and the importance and risks of vaccination [322,323]. Education on vaccination should be targeted to address these attitudes and beliefs. In addition, some studies have indicated that self-protection is a primary reason healthcare professionals decide to be vaccinated, and education that focuses on this aspect may help improve vaccination rates [323].

EDUCATION FOR PATIENTS AND FAMILIES

Education for patients and families is an important component of an overall prevention strategy, and the U.S. Department of Health and Human Services notes that such education is a critical part of the national effort on preventing HAIs [2]. Many national-level initiatives have been launched to encourage individuals to become more active in their health care and to be their own advocates, and patients, family members, and hospital visitors should be encouraged to become partners in preventing the transmission of infection in the healthcare setting [23].

Hospitals should engage patients in their own care by discussing infection control measures for hand hygiene practices, respiratory hygiene practices, and contact precautions (according to the patient's condition) with the patient and his or her family members on the day the patient enters the hospital or as soon as possible thereafter. For patients who are to have surgery, healthcare professionals should describe the measures that will be taken to prevent adverse events. This information may be provided in any form of media, and the patient's understanding of the information should be evaluated and documented.

Physicians and other healthcare professionals should educate patients and families about ways to prevent infection, especially with regard to their specific factors (e.g., surgery, insertion of a urinary catheter). Clinicians should also explain the importance of the appropriate use of antibiotics, including the need to complete the recommended antibiotic treatment course; the relationship between the inappropriate use of antibiotics and the increasing prevalence of drug-resistant bacteria; and the implications of drug-resistant bacteria. Patients should be encouraged to help promote adequate hand hygiene by asking their healthcare providers if they have washed their hands. The IHI has addressed this topic with the "It's OK to Ask" campaign, and patient educational pamphlets can be downloaded from the IHI website (http://www.ihi.org). The CDC has developed a video for newly admitted patients on the topic of hand hygiene, which is available on its website (https://www.cdc.gov/handhygiene/campaign/index.html).

The ability to understand health information and make informed health decisions, known as health literacy, is integral to good health outcomes [324]. Yet, the National Assessment of Adult Literacy estimated that only 12% of adults have "proficient" health literacy and 14% have "below basic" health literacy [325]. Rates of health literacy are especially low among ethnic minority populations and individuals older than 60 years of age [324]. Compounding the issue of health literacy is the high rate of individuals with limited English proficiency. According to the U.S. Census Bureau data from 2019, more than 67.8 million Americans speak a language other than English in the home, with more than 25.5 million of them (8.2% of the population) speaking English less than "very well" [326].

Clinicians should assess their patients' literacy level and understanding and implement interventions as appropriate. Healthcare professionals should use plain language in their discussions with patients who have low literacy or limited English proficiency. They should ask them to repeat pertinent information in their own words to confirm understanding. Reinforcement with the use of low-literacy or translated educational materials may be helpful.

Translation services should be provided for patients who do not understand the clinician's language. "Ad hoc" interpreters (family members, friends, bilingual staff members) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, clinicians should check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [327]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [327]. Individuals with limited English language skills have actually indicated a preference for professional interpreters rather than family members [328]. Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [329,330,331].

The American Medical Association offers several health literacy resources for healthcare professionals on its website (https://www.ama-assn.org), and the U.S. Department of Health and Human Services offers valuable information on cultural competency from the Health Resources and Services Administration (HRSA) (https://www.hrsa.gov/about/organization/bureaus/ohe/health-literacy/culture-language-and-health-literacy), the Office of Minority Health (https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=1&lvlid=6), and the National Center for Cultural Competence (https://nccc.georgetown.edu).

PREPAREDNESS AND CONTROL OF OUTBREAKS

Another responsibility of an infection control team is establishing response plans for outbreaks and epidemics and controlling them should they occur. An outbreak is defined by the WHO as "the occurrence of cases of disease in excess of what would normally be expected in a defined community, geographical area, or season" [332]. The number of individuals affected can vary from a few to 100 or more. Outbreaks and epidemics account for approximately 5% to 10% of HAIs, and most hospitals lack adequate equipment, isolation space, and staff to treat a large increase in the number of patients with an infectious disease [40,89]. The two primary concerns are to confirm the existence of the outbreak and to establish control measures to confine the spread [332].

An outbreak should be identified and investigated as early as possible to prevent morbidity and mortality. Any healthcare professional who suspects an outbreak should notify infection control staff, and an outbreak team should be established. Investigating an outbreak involves [16,333]:

- Establishing the existence of an outbreak

- Verifying the diagnosis

- Defining and identifying cases

- Describing and orienting the data in terms of time, place, and person

- Developing and evaluating hypotheses

- Refining hypotheses and carrying out additional studies

- Implementing control and prevention measures

- Communicating findings

The outbreak team should collaborate with all appropriate healthcare workers to identify either the carriers or the common sources of the infection and to review aseptic practices and disinfectant use for a breach in compliance. Data on potential cases should be reviewed and a case definition should be developed. The case definition should include [16,333]:

- Unit of time and place

- Specific biologic and/or clinical criteria

- Inclusion/exclusion criteria

- Gradient of definition (definite, probable, or possible)

- Differentiation between colonization and infection

- Specific criteria to identify the index case, if relevant information is available

Data should be collected from all available sources, such as patient charts, microbiology reports, pharmacy reports, and log books from patient units. Describing the outbreak in terms of individuals, place, and time helps to create an epidemic curve, which shows the distribution of cases by time of onset [16]. An attack rate can then be defined as the number of people at risk who are infected compared with the total number of people at risk.

Developing and evaluating hypotheses will yield the source of the outbreak and/or the index case. The data should be reviewed carefully to evaluate the characteristics and similarities among affected individuals. The team must then determine the extent of the outbreak. Cohort isolation is implemented as needed (Table 21) [23,334]. Throughout the investigation, the team should communicate routinely with hospital administration. At completion, data on the outbreak should be documented and published, as the information can provide valuable education to the healthcare community at large and can help staff prepare for future outbreak investigations [335].

Table 21: TYPE AND DURATION OF PRECAUTIONS REQUIRED FOR INFECTIONS WITH POTENTIAL FOR OUTBREAKS

Infection/Condition

Precaution Type

Precaution Duration

Notes

Anthrax (cutaneous or pulmonary)

Standard

Ongoing

Use Contact Precautions if there is large amount of uncontained drainage from lesions.

Aspergillosis

Standard

Ongoing

Use Contact Precautions and Airborne Precautions if there is massive soft-tissue infection with copious drainage.

Botulism

Standard

Ongoing

Not transmitted person-to-person.

Diphtheria (cutaneous or pharyngeal)

Contact, Droplet

Until antibiotic therapy is completed and two cultures taken at least 24 hours apart are negative

—

Ebola (viral hemorrhagic fever)

Standard, Contact, Droplet

Duration to be determined on case-by-case basis, in conjunction with local, state, and federal health authorities

Single patient room with the door closed preferred. Maintain log of all people entering the patient's room. Use barrier protection against blood and body fluids upon entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields). Use additional protective wear (double gloves, leg and shoe coverings) during final stages of illness when hemorrhage may occur. Use dedicated disposable (preferred) medical equipment for patient care. Clean/disinfect all nondedicated, nondisposable equipment. Limit use of needles, sharps as much as possible. Limit procedures, tests. Avoid aerosol-generating procedures. Notify public health officials immediately if Ebola is suspected.

Clostridioides difficile gastroenteritis

Contact

Duration of illness

Discontinue antibiotics if appropriate. Use soap and water for hand-washing, as antiseptic handrubs lack sporicidal activity. Do not share equipment (e.g., electronic thermometers). Ensure consistent environmental cleaning and disinfection.

Influenza, seasonal

Droplet

5 days after onset of symptoms

Single patient room preferred or cohort. Use mask on patient when he or she is transported out of room. Use gown and gloves according to Standard Precautions. The duration of precautions for immunocompromised patients cannot be defined. Refer to CDC guidance (https://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm).

Influenza, pandemic

Droplet

5 days after onset of symptoms

Refer to CDC guidance (https://www.cdc.gov/flu/pandemic-resources).

Influenza, avian

Droplet

Duration of illness

Refer to CDC guidance (https://www.cdc.gov/flu/avianflu).

Malaria

Standard

Ongoing

Install screens in windows and doors in endemic areas.

Measles (rubeola), all presentations

Airborne

4 days after onset of rash (duration of illness for immunocompromised patients )

Use Airborne Precautions for exposed susceptible patients. Susceptible healthcare staff should not enter the room if immune caregivers are available. Exclude susceptible healthcare staff from duty from day 5 after first exposure to day 21 after last exposure, regardless of post-exposure vaccine.

Meningitis (Haemophilus influenzae or Neisseria meningitidis [meningococcal] known or suspected)

Droplet

Until 24 hours after initiation of effective therapy

—

Meningococcal pneumonia

Droplet

Until 24 hours after initiation of effective therapy

—

Norovirus

Standard

Duration of illness

Cohorting of affected patients to separate airspaces and toilet facilities may help interrupt transmission during outbreaks. Use Contact Precautions for diapered or incontinent persons for the duration of illness or to control outbreaks. Ensure consistent environmental cleaning and disinfection, with focus on restrooms even when apparently unsoiled. Persons who clean heavily contaminated areas may benefit from wearing masks as virus can be aerosolized.

Plague, bubonic

Standard

Ongoing

—

Plague, pneumonic

Droplet

Until 48 hours after initiation of effective therapy

Antimicrobial prophylaxis should be given to exposed healthcare staff.

Pneumonia caused by:

Adenovirus

Legionella

Meningococcal

Mycoplasma (primary atypical pneumonia)

Droplet, Contact

Standard

Droplet

Droplet

Duration of illness

Ongoing until 24 hours after initiation of effective therapy

Duration of illness

—

Scabies

Contact

Until 24 hours after initiation of effective therapy

—

Staphylococcus aureus, skin, wound, or burn

Major: no dressing or dressing does not contain drainage adequately

Minor or limited: dressing covers and contains drainage adequately

Contact

Standard

Duration of illness

Ongoing

—

Group A streptococci, skin, wound, or burn (major: no dressing or dressing does not contain drainage adequately)

Contact, Droplet

Until 24 hours after initiation of effective therapy

—

Toxoplasmosis

Standard

Ongoing

—

Toxic shock syndrome (staphylococcal or streptococcal disease)

Standard

Ongoing

—

Tuberculosis, extrapulmonary (draining lesion)

Airborne, Contact

Only when therapy is effective, patient is clinically improving, and the cultures of 3 consecutive sputum smears, collected on different days, are negative

Examine for evidence of active pulmonary tuberculosis. (If evidence exists, additional precautions are necessary.)

Tuberculosis, extrapulmonary (no draining lesion, meningitis)

Standard

Ongoing

Examine for evidence of pulmonary tuberculosis. (If evidence exists, additional precautions are necessary.)

Tuberculosis, pulmonary or laryngeal disease (confirmed)

Airborne

Only when therapy is effective, patient is clinically improving, and the cultures of 3 consecutive sputum smears, collected on different days, are negative

—

Tuberculosis, pulmonary or laryngeal disease (suspected)

Airborne

Only when the likelihood of infectious disease is negligible and the cultures of 3 consecutive sputum smears, collected on different days, are negative

—

Tuberculosis, latent (skin-test positive with no evidence of current pulmonary disease)

Standard

Ongoing

—

Varicella zoster (chickenpox)

Airborne, Contact

Until all lesions are crusted (10 to 21 days). Susceptible healthcare staff should not enter the room if immune caregivers are available.

Whooping cough (pertussis)

Droplet

Until 5 days after initiation of effective therapy

—

Source: [23,334]

Case Example

The following case outlines an investigative process and illustrates that the source of an outbreak may be unusual [336].

A cardiac surgeon noticed a cluster of cases of sternal wound dehiscence among his patients who had had surgery. Specimens from the wounds were obtained for culture. Microbiologic evaluation indicated that the infections were predominantly caused by Enterobacter cloacae, and molecular typing and serotyping demonstrated that the isolates were similar. No infections had developed after operations the surgeon had performed at other hospitals. No breach in aseptic technique was identified. All of the infected patients had been operated on in the same operating room, and the environment was screened. No source was found. Further questioning of the surgeon's operative practice revealed one difference from other cardiac surgeons: he used semi-frozen sodium lactate solution to achieve cardioplegia. Swabbing of the freezer used for the solution identified E. cloacae of the same typing as that found in the wound infections. The hypothesis was that contamination of the freezer led to contamination of the ice/slush solution, and the micro-organism was transmitted to the patients. The freezer was replaced, a rigorous cleaning schedule was instituted, and no further cases have occurred.

Potential Outbreaks

The following are overviews of selected potential outbreaks. Identification and early action in the case of any of these outbreaks will limit the adverse effects.

Group A Streptococci

Most outbreaks of group A streptococci involve surgical wounds, and the source can usually be traced to an asymptomatic carrier in the operating room or on the wound care team [89,337]. Standard Precautions are sufficient if the wound is minor; if it is major, Contact Precautions should be instituted and followed for 24 hours after initiation of effective therapy [23]. The healthcare worker should receive antimicrobial therapy as appropriate and leave the setting until completion of therapy.

Pulmonary Tuberculosis

Dealing with pulmonary tuberculosis involves prompt identification of the disease and determining the susceptible individuals who were exposed to the patient before isolation [89]. Airborne Precautions should be instituted and remain in place until the patient is receiving effective therapy, is improving clinically, and the culture results for three consecutive sputum specimens, collected on different days, are negative. Comprehensive information is available in the CDC guidelines for preventing the transmission of tuberculosis in healthcare facilities [338].

Legionella

The source of HAI with Legionella pneumonia is usually contaminated water [89]. Implementation of Standard Precautions for the patient is sufficient [23]. Laboratory-based surveillance for nosocomial Legionella should be performed, and samples of tap water should be obtained for culture. If the culture is positive, it is best to obtain cultures from patients who have healthcare-associated pneumonia. There are more than 40 known types of Legionella species, but most outbreaks are caused by Legionella pneumophila serotypes 1 and 6.

Antibiotic-Resistant Micro-Organisms

Outbreaks of antibiotic resistance have involved MRSA, VRE, and, most recently, vancomycin-resistant S. aureus [339]. In such outbreaks, it is important to identify patients with colonization or infection early and isolate them or cohort them. Contact Precautions should be implemented and carried out until antibiotic therapy has been completed and cultures are negative [23]. The importance of adhering to proper hand hygiene and other elements of Contact Precautions should be emphasized. Healthcare workers who were involved with patients before isolation should be evaluated for colonization and infection and treated appropriately.

Other Outbreaks

The potential for other outbreaks or epidemics vary, and the CDC website, http://www.bt.cdc.gov, offers resources on emergency preparedness for outbreaks or epidemics caused by potential agents of bioterrorism, including anthrax and viral hemorrhagic fever. A Bioterrorism Readiness Plan template is also available (https://emergency.cdc.gov/bioterrorism/pdf/13apr99APIC-CDCBioterrorism.pdf). Many aspects should be considered when planning for bioterrorism preparedness, and each department of a healthcare facility can play an important role.

7. CONCLUSION

Infections acquired in the healthcare setting raise a great risk for patients, leading to high rates of morbidity and mortality. Many of the deaths caused by HAIs could be prevented by following evidence-based guidelines and consensus statements on prevention strategies. Several institutions have implemented campaigns to enhance the quality of health care and patient safety by focusing on measures to reduce the most common HAIs: catheter-associated urinary tract infection, surgical site infection, pneumonia, intravascular device-related bloodstream infection, and C. difficile infection. The single most effective infection control measure is appropriate hand hygiene, and all efforts to reduce the rate of HAIs must focus on enhancing compliance with this measure in conjunction with other prevention strategies. Along with hand hygiene, meticulous attention to aseptic technique when preparing for invasive procedures or using invasive devices is also essential for reducing the prevalence of HAIs. Prevention measures specific for each of the most common types of HAIs have been recommended in evidence-based guidelines and consensus statements (Table 22).

Table 22: SUMMARY OF PREVENTION MEASURES FOR THE MOST COMMON HEALTHCARE-ASSOCIATED INFECTIONS

Type of Infection

Evidence-Based Recommended Measures

Other Suggestions

All infections

Appropriate hand hygiene

Meticulous aseptic technique for devices and equipment

—

Catheter-associated urinary tract infection

Indwelling catheters only when needed

Proper securing of catheter

Closed sterile drainage system

Unobstructed urine flow

Removal of catheter as soon as possible

Alternative to indwelling catheter (suprapubic, condom)

Antimicrobial-coated catheter

Hand-held bladder scanners

Pneumonia (without mechanical intubation)

Deep breathing

Frequent coughing

Early movement (in bed and/or walking)

Limited use of narcotic agents

Incentive spirometry (for patients at high risk)

—

Ventilator-associated pneumonia

Elevation of the head of the bed (30 degrees)a

Daily interruptions of sedation and assessment of readiness to extubatea

Prophylaxis of peptic ulcer diseasea

Prophylaxis of deep venous thrombosisa

Endotracheal tube with a dorsal lumen

Noninvasive ventilation

Surgical site infection

Appropriate antibiotic prophylaxis

Avoidance of preoperative shaving

Maintaining adequate glycemic control

Maintaining a warm body temperature

Performance feedback to surgeons

Intravascular device-related bloodstream infections

Maximal barrier precautionsa

2% chlorhexidine solution for skin antisepsisa

Selection of optimal site for the catheter (subclavian vein preferred for nontunneled catheters)a

Daily review of the need for the line, with prompt removal if line is deemed unnecessarya

Catheter with antimicrobial coating

Performance feedback to personnel

Clostridioides difficile-associated diarrhea

Judicious use of antibiotics

Barrier precautions (gowns and gloves, dedicated or disposable equipment, cohorting of patients and/or staff)

Handwashing with soap and water (alcohol is not effective against C. difficile spores)

Appropriate disinfectant for surfaces and devices

—

aComponent of a bundle of interventions that, when implemented together, has lowered the rate of infection.

Source: Compiled by Author

The common pathogens, diagnosis, and treatment vary among these infections and even within each type of infection. The CDC has detailed diagnostic criteria for each type of infection, and consensus statements and guidelines have also proposed such criteria. The treatment of HAIs varies according to the pathogen and the anatomic site. The prevailing principle is to use antibiotics judiciously, as the inappropriate use of antibiotics has led to an increasing number of resistant strains of bacteria. When using empiric antibiotic therapy, physicians should select an antibiotic on the basis of known pathogens in the healthcare facility as a whole, as well as on the specific unit within the facility.

An effective infection control team is critical to reducing the incidence of HAIs in a healthcare facility. All departments within a healthcare facility should be represented on this team to ensure widespread adherence to prevention measures. The responsibilities of an infection control team are to conduct surveillance of infections; ensure compliance with infection control guidelines, including those for management of drug-resistant organisms; and establish response and control plans for outbreaks and epidemics. Most important is the development of an organizational culture that fosters a focus on patient safety and emphasizes education on HAIs and infection control for healthcare workers and patients and their families.

Works Cited

1. Rothenberg BM, Marbella A, Pines E, et al. Prevention of Healthcare-Associated Infections. Closing the Quality Gap: Revisiting the State of the Science. Evidence Report/Technology Assessment No. 208. Rockville, MD: Agency for Healthcare Research and Quality; 2012.

2. Office of Disease Prevention and Health Promotion. HAI National Action Plan. National Action Plan to Prevent Health Care-Associated Infections: Road Map to Elimination. Available at https://www.hhs.gov/oidp/topics/health-care-associated-infections/hai-action-plan/index.html. Last accessed January 11, 2022.

3. Magill SS, O'Leary E, Janelle SJ, et al. Changes in prevalence of health care-associated infections in U.S. hospitals. N Engl J Med. 2018;379:1732-1744.

4. Scott RD II. The Direct Medical Costs of Healthcare-Associated Infections in U.S. Hospitals and the Benefits of Prevention. Available at https://www.cdc.gov/HAI/pdfs/hai/Scott_CostPaper.pdf. Last accessed January 11, 2022.

5. Weiner-Lastinger LM, Pattabiraman V, Konnor RY, et al. The impact of coronavirus disease 2019 (COVID-19) on healthcare-associated infections in 2020: a summary of data reported to the National Healthcare Safety Network. Infect Control Hosp Epidemiol. 2021;362:1-14.

6. Shekelle PG, Wachter RM, Pronovost PJ, et al (eds). Making Health Care Safer II: An Updated Critical Analysis of the Evidence for Patient Safety Practices. Comparative Effectiveness Review No. 211. Rockville, MD: Agency for Healthcare Research and Quality; 2013.

7. Adams K, Corrigan JM (eds). Priority Areas for National Action: Transforming Health Care Quality. Washington, DC: The National Academies Press; 2003.

8. McCannon CJ, Hackbarth AD, Griffin FA. Miles to go: an introduction to the 5 Million Lives Campaign. Jt Comm J Qual Patient Safe. 2007;33(8):477-484.

9. Office of Disease Prevention and Health Promotion. National Action Plan to Prevent Healthcare-Associated Infections: Road Map to Elimination. Available at https://www.healthypeople.gov/2020/tools-resources/evidence-based-resource/national-action-plan-prevent-health-care-associated. Last accessed January 11, 2022.

10. Centers for Medicare & Medicaid Services. Medicare program; hospital inpatient prospective payment systems for acute care hospitals and the long-term care hospital prospective payment system and policy changes and fiscal year 2022 rates: final rule. Fed Regist. 2021;86(154):44774-45615.

11. Centers for Medicare & Medicaid Services. CMS Improves Patient Safety for Medicare and Medicaid By Addressing Never Events. Available at https://www.cms.gov/newsroom/fact-sheets/cms-improves-patient-safety-medicare-and-medicaid-addressing-never-events. Last accessed January 11, 2022.

12. National Quality Forum. Patient Safety. Available at http://www.qualityforum.org/Topics/Patient_Safety.aspx. Last accessed January 11, 2022.

13. The Joint Commission. 2022 National Patient Safety Goals. Available at https://www.jointcommission.org/standards/national-patient-safety-goals/.NPSG_HAP.pdf. Last accessed January 11, 2022.

14. Bratzler DW, Hunt DR. The surgical infection prevention and surgical care improvement projects: national initiatives to improve outcomes for patients having surgery. Clin Infect Dis. 2006;43(3):322-330.

15. Centers for Medicare and Medicaid Services. Partnership for Patients. Available at https://innovation.cms.gov/innovation-models/partnership-for-patients. Last accessed January 11, 2022.

16. World Health Organization. Prevention of Hospital-Acquired Infections:A Practical Guide. 2nd ed. Geneva: WHO Press; 2002.

17. Mehta AC, Prakash UB, Garland R, et al. American College of Chest Physicians and American Association for Bronchology consensus statement: prevention of flexible bronchoscopy-associated infection. Chest. 2005;128(3):1742-1755.

18. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis.2016;63(5):e61-e111.

19. Facility Guidelines Institute and American Society for Healthcare Engineer. Guidelines for Design and Construction of Hospitals and Outpatient Facilities. Lakewood, CO: American Hospital Association; 2018.

20. Dodek P, Keenan S, Cook D, et al., for the Canadian Critical Care Trials Group and the Canadian Critical Care Society. Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann Intern Med. 2004;141(4):305-313.

21. Gould CV, Umscheid CA, Agarwal RK, Kuntz G, Pegues DA. Guideline for prevention of catheter-associated urinary tract infections 2009. Infect Control Hosp Epidemiol. 2010;31:319-326.

22. Rutala WA, Weber DJ, Healthcare Infection Control Practices Advisory Committee. Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008. Available at https://www.cdc.gov/infectioncontrol/pdf/guidelines/disinfection-guidelines-H.pdf. Last accessed January 11, 2022.

23. Siegel JD, Rhinehart E, Jackson M, Chiarello L, and the Healthcare Infection Control Practices Advisory Committee. 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings. Available athttps://www.cdc.gov/infectioncontrol/pdf/guidelines/isolation-guidelines-H.pdf. Last accessed January 11, 2022.

24. Siegel JD, Rhinehart E, Jackson M, Chiarello L, the Healthcare Infection Control Practices Advisory Committee. Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006. Available at https://www.cdc.gov/infectioncontrol/pdf/guidelines/mdro-guidelines.pdf. Last accessed January 11, 2022.

25. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R. Guidelines for preventing health-care-associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR. 2004;53(RR03):1-36.

26. Sehulster L, Chinn RYW. Guidelines for environmental infection control in health-care facilities. MMWR. 2003;52(RR10):1-42.

27. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings. MMWR. 2002;51(RR16):1-44.

28. O'Grady NP, Alexander M, Burns LA, et al. Guidelines for the Prevention of Intravascular Catheter-Related Infections, 2011. Available at https://www.cdc.gov/infectioncontrol/pdf/guidelines/bsi-guidelines-H.pdf. Last accessed January 11, 2022.

29. Berrios-Torres SI, Umscheid CA, Bratzler DW, et. al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784-791.

30. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663.

31. Muto CA, Jernigan JA, Ostrowsky BE, et al. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and Enterococcus. Infect Control Hosp Epidemiol. 2003;24(5):362-386.

32. Day LW, Muthusamy VR, Collins J, et al. Multisociety guideline on reprocessing flexible GI endoscopes and accessories. Gastrointest Endosc. 2021;93(1):11-33.

33. McDonald C, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.

34. Shlaes DM, Gerding DN, John JF Jr, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Infect Cont Hosp Epidemiol. 1997;18(4):275-291.

35. Marschall J, Mermel LA, Classen D, et al. Strategies to prevent central-line-associated bloodstream infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(Suppl 1):S62-S80.

36. Coffin SE, Klompas M, Classen D, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(Suppl 1):S22-S30.

37. Lo E, Nicolle L, Classen D, et al. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S41-S50.

38. Anderson DJ, Kaye KS, Classen D, et al. Strategies to prevent surgical site infections in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S51-S61.

39. Calfee DP, Salgado CD, Classen D, et al. Strategies to prevent transmission of methicillin-resistant Staphylococcus aureus in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29:S62-S80.

40. Burke JP. Infection control: a problem for patient safety. N Engl J Med. 2003;348(7):651-656.

41. Clark AP, Houston S. Nosocomial infections: an issue of patient safety: part 2. Clin Nurse Spec. 2004;18(2):62-64.

42. Pittet D, Hugonnet S, Harbarth S, et al. Effectiveness of a hospital-wide programme to improve compliance with hand hygiene. Lancet. 2000;356(9238):1307-1312.

43. Larson EL, Quiros D, Lin SX. Dissemination of the CDC's Hand Hygiene Guideline and impact on infection rates. Am J Infect Control. 2007;35(10):666-675.

44. Craven DE, Hjalmarson K. Prophylaxis of ventilator-associated pneumonia: changing culture and strategies to trump disease. Chest. 2008;134(5):898-900.

45. Brown J, Doloresco F III, Mylotte JM. "Never events:" not every hospital-acquired infection is preventable. Clin Infect Dis. 2009;49:743-746.

46. Haley RW. Managing Hospital Infection Control for Cost-Effectiveness. Chicago, IL: American Hospital Association; 1986.

47. Babcock HM, Woeltie KF. The development of infection surveillance and control programs. In: Bennett JV, Brachman PS (eds). Hospital Infections. Philadelphia, PA: Lipincott, Williams, and Wilkins; 2014: 57-62.

48. Harbarth S, Sax H, Gastmeier P. The preventable proportion of nosocomial infections: an overview of published reports. J Hosp Infect. 2003;54(4):258-266.

49. Umscheid CA, Mitchell MD, Doshi JA, et al. Estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs. Infect Control Hosp Epidemiol. 2011;32(2):101-114.

50. Hedrick TL, Heckman JA, Smith RL, Sawyer RG, Friel CM, Foley EF. Efficacy of protocol implementation on incidence of wound infection in colorectal operations. J Am Coll Surg. 2007;205(3):432-438.

51. Hawn MT, Itani KM, Gray SH, Vick CC, Henderson W, Houston TK. Association of timely administration of prophylactic antibiotics for major surgical procedures and surgical site infection. J Am Coll Surg. 2008;206(5):814-819.

52. Pastor C, Artinyan A, Varma MG, Kim E, Gibbs L, Garcia-Qquilar J. An increase in compliance with the Surgical Care Improvement Project measures does not prevent surgical site infection in colorectal surgery. Dis Colon Rectum. 2010;53(1):24-30.

53. Krein SL, Kowalski CP, Hofer TP, Saint S. Preventing hospital-acquired infections: a national survey of practices reported by U.S. hospitals in 2005 and 2009. J Gen Intern Med. 2012;27(7):773-779.

54. Morris AC, Hay AW, Swann DG, et al. Reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle. Crit Care Med. 2011;39(10):2218-2224.

55. Zack J. Zeroing in on zero tolerance for central line-associated bactermia. Am J Infect Control. 2008;36(10):S176:e1-e2.

56. Galpern D, Guerrero A, Tu A, Fahoum B, Wise L. Effectiveness of a central line bundle campaign on line-associated infections in the intensive care unit. Surgery. 2008;144(4):492-495.

57. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU.N Engl J Med. 2006;355(26):2725-2732.

58. Yokoe DS, Classen. Improving patient safety through infection control: a new healthcare imperative. Infect Control Hosp Epidemiol. 2008;29(Suppl 1):S3-S11.

59. Curtis LT. Prevention of hospital-acquired infections: review of non-pharmacological interventions. J Hosp Infect. 2008;69(3):204-219.

60. Institute for Healthcare Improvement. 5 Million Lives Campaign. Available at http://www.ihi.org/Engage/Initiatives/Completed/5MillionLivesCampaign/Pages/default.aspx. Last accessed January 11, 2022.

61. Lee GM, Kleinman K, Soumerai SB, et al. Effect of nonpayment for preventable infections in U.S. hospitals. N Engl J Med. 2012;367(15):1428-1437.

62. Lee GM, Hartmann CW, Graham D, et al. Perceived impact of the Medicare policy to adjust payment for health care-associated infections. Am J Infect Control. 2012;40(4):314-319.

63. Edmond M, Eickhoff TC. Who is steering the ship? External influences on infection control programs. Clin Infect Dis. 2008;46(11):1746-1750.

64. Safdar N, Abad C. Educational interventions for prevention of healthcare-associated infection: a systematic review. Crit Care Med. 2008;36(3):933-940.

65. Welsh CA, Flanagan ME, Hoke SC, Doebbeling BN, Herwaldt L, Reducing health care-associated infections (HAIs): lessons learned from a national collaborative of regional HAI programs. Am J Infect Control. 2012;40(1):29-34.

66. Centers for Disease Control and Prevention. National Healthcare Safety Network (NHSN). Available at https://www.cdc.gov/nhsn/. Last accessed January 11, 2022.

67. Centers for Disease Control and Prevention. Current HAI Progress Report. Available at https://www.cdc.gov/hai/data/portal/progress-report.html. Last accessed January 11, 2022.

68. Centers for Disease Control and Prevention, Association of State and Territorial Health Officials. Eliminating Healthcare-Associated Infections. State Policy Options. Arlington, VA: Association of State and Territorial Health Officials; 2011.

69. Centers for Disease Control and Prevention. State-Based HAI Prevention Activities. Available at https://www.cdc.gov/hai/state-based/index.html. Last accessed January 11, 2022.

70. Porter RS. The Merck Manual of Diagnosis and Therapy. 19th ed. Merck and Co., Inc.; 2011.

71. Pier G. Molecular mechanisms of microbial pathogenesis. In: Kasper D, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J (eds). Harrison's Principles of Internal Medicine. 19th ed. New York: McGraw Hill; 2015.

72. Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.

73. Calfee DP, Salgado CD, Milstone AM, et al. Strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(7):772-796.

74. Joint Commission Accreditation. Comprehensive Accreditation Manual 2015: Standards of Elements of Performance Scoring Accreditation Policies (Comprehensive Accreditation Manual for Hospitals [CAMH]). Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2014.

75. Spellberg B, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(2):155-164.

76. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12.

77. Boucher HW, Talbot GH, Benjamin DK Jr, et al. 10 x '20 progress—development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(12):1685-1694.

78. Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant Staphylococcus aureus, Enterococcus, gram-negative bacilli, Clostridium difficile, and Candida. Ann Intern Med. 2002;136(11):834-844.

79. Sydnor ERM, Perl TM. Hospital epidemiology and infection control in acute-care settings. Clin Microbiol Rev. 2011;24(1):141-173.

80. Raymond DP, Pelletier SJ, Crabtree TD, Evans HL, Pruett TL, Sawyer RG. Impact of antibiotic-resistant gram-negative bacilli infections on outcome in hospitalized patients. Crit Care Med. 2003;31(4):1035-1041.

81. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49(8):1175-1184.

82. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010. Infect Control Hosp Epidemiol. 2013;34(1):1-14.

83. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. JAMA. 2008;300(24):2911-2913.

84. Lledo W, Hernandez M, Lopez E, et al. Guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. MMWR. 2009;58(10):256-260.

85. Centers for Disease Control and Prevention. Healthcare-Associated Infections. Current HAI Progress Report. 2020 National and State Healthcare-Associated Infections Progress Report: Executive Summary. Available at https://www.cdc.gov/hai/data/portal/progress-report.html. Last accessed January 11, 2022.

86. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-e55.

87. Clark AP, John LD. Nosocomial infections and bath water: any cause for concern? Clin Nurse Spec. 2006;20(3):119-123.

88. Anaissie EJ, Penzak SR, Dignani MC. The hospital water supply as a source of nosocomial infections: a plea for action. Arch Intern Med. 2002;162(13):1483-1492.

89. Weinstein R. Hospital-acquired infections. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J (eds.)Harrison's Principles of Internal Medicine. 19th ed. New York: McGraw Hill; 2015.

90. Perdelli F, Cristina ML, Sartini M, et al. Fungal contamination in hospital environments. Infect Cont Hosp Epidemiol. 2006;27(1):44-47.

91. Noskin GA, Peterson LR. Engineering infection control through facility design. Emerg Infect Dis. 2001;7(2):354-357.

92. Kimura SI. Invasive aspergillosis in hematological patients. Med Mycol J. 2016;57(2):J77-J88.

93. Passweg JR, Rowlings PA, Atkinson KA, et al. Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia. Bone Marrow Transplant. 1998;21(12):1231-1238.

94. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR. 2000;49(RR1-10):1-125.

95. Yokoe D, Casper C, Dubberke E, et al. Infection prevention and control in health-care facilities in which hematopoietic cell transplant recipients are treated. Bone Marrow Transplant. 2009;44(8):495-507.

96. Streifel AJ, Hendrickson C. Assessment of health risks related to construction: minimizing the threat of infection from construction-induced air pollution in health-care facilities. HPACEngineering. 2002:27-32.

97. Ortolano GA, McAlister MB, Angelbeck JA, et al. Hospital water point-of-use filtration: a complementary strategy to reduce the risk of nosocomial infection. Am J Infect Control. 2005;33(5 Suppl 1):S1-S19.

98. Reuter S, Sigge A, Wiedeck H, Trautmann M. Analysis of transmission pathways of Pseudomonas aeruginosa between patients and tap water outlets. Crit Care Med. 2002;30(10):2222-2228.

99. Pier GB, Ramphal R. Pseudomonas aeruginosa. In: Mandell GL, Bennett JE, Dolin R (eds). Principles and Practices of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2010.

100. Agency for Healthcare Research and Quality. 10 Patient Safety Tips for Hospitals. Available at https://www.ahrq.gov/patients-consumers/diagnosis-treatment/hospitals-clinics/10-tips/index.html. Last accessed January 11, 2022.

101. Detsky ME, Etchells E. Single-patient rooms for safe patient-centered hospitals. JAMA. 2008;300(8):954-956.

102. 2.2 Specific Requirements for General Hospitals. Available at https://fgiguidelines.org/wp-content/uploads/2020/06/2022-Draft-H-2.2-General-Hospitals-sections-1-2.pdf. Last accessed January 11, 2022.

103. Whitby M, McLaws ML. Handwashing in healthcare workers: accessibility of sink location does not improve compliance. J Hosp Infect. 2004;58(4):247-253.

104. Favero MS, Bond WW. Disinfection of medical and surgical materials. In: Block SS (ed). Disinfection, Sterilization, and Preservation. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 881-917.

105. American Society for Gastrointestinal Endoscopy. Infection control during gastrointestinal endoscopy. Gastrointest Endosc. 2008;67(6):781-790.

106. Spach DH, Silverstein FE, Stamm WE. Transmission of infection by gastrointestinal endoscopy and bronchoscopy. Ann Intern Med. 1993;118(2):117-128.

107. Muscarella LF. Inconsistencies in endoscope-reprocessing and infection-control guidelines: the importance of endoscope drying.Am J Gastroenterol. 2006;101(9):2147-2154.

108. U.S. Food and Drug Administration. Infections Associated with Reprocessed Flexible Bronchoscopes: FDA Safety Communication. Available at https://wayback.archive-it.org/7993/20170404182158/https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm462949.htm. Last accessed January 11, 2022.

109. Culver DA, Gordon SM, Mehta AC. Infection control in the bronchoscopy suite: a review of outbreaks and guidelines for prevention. Am J Respir Crit Care Med. 2003;167(8):1050-1056.

110. Srinivasan A, Wolfenden LL, Song X, et al. An outbreak of Pseudomonas aeruginosa infections associated with flexible bronchoscopes. N Engl J Med. 2003;348(3):221–227.

111. Kirschke DL, Jones TF, Craig AS, Chu PS, Mayernick GG, Patel JA, Schaffner W. Pseudomonas aeruginosa and Serratia marcescens contamination associated with a manufacturing defect in bronchoscopes. N Engl J Med. 2003;348(3)214-220.

112. Nelson DB, Muscarella LF. Current issues in endoscope reprocessing and infection control during gastrointestinal endoscopy.World J Gastroenterol. 2006;12(25):3953-3964.

113. Leung JW. Reprocessing of flexible endoscopes. J Gastroenterol Hepatol. 2000;15(Suppl):G73-G77.

114. Kovaleva J, Peters FTM, van der Mei H, Degener JE. Transmission of infection by flexible gastrointestinal endoscopy and bronchoscopy. Clin Microbiol Rev. 2013;26(2):231-254.

115. Schabrun S, Chipchase L. Healthcare equipment as a source of nosocomial infection: a systematic review. J Hosp Infect. 2006;63(3):239-245.

116. Bernard L, Kereveur A, Durand D, et al. Bacterial contamination of hospital physicians' stethoscopes. Infect Control Hosp Epidemiol. 1999;20(9):626-628.

117. Lecat P, Cropp E. McCord G, Haller NA. Ethanol-based cleanser versus isopropyl alcohol to decontaminate stethoscopes. Am J Infect Control. 2009;37(3):241-243.

118. Schroeder A, Schroeder MA, D'Amico F. What's growing on your stethoscope? (And what you can do about it). J Fam Pract. 2009;58(8):404-409.

119. Russell A, Secrest J, Schreeder C. Stethoscopes as a source of hospital-acquired methicillin-resistant Staphylococcus aureus. J Peranesth Nurs. 2012;27(2):82-87.

120. Schabrun S, Chipchase L, Rickard H. Are therapeutic ultrasound units a potential vector for nosocomial infection? Physiother Res Int. 2006;11(2):61-71.

121. Hausermann P, Widmer A, Itin P. Dermatoscope as vector for transmissible diseases-no apparent risk of nosocomial infections in outpatients. Dermatology. 2006;212(1):27-30.

122. Kelly SC, Purcell SM. Prevention of nosocomial infection during dermoscopy? Dermatol Surg. 2006;32(4):552-555.

123. Devine J, Cooke RP, Wright EP. Is methicillin-resistant Staphylococcus aureus (MRSA) contamination of ward-based computer terminals a surrogate marker for nosocomial MRSA transmission and handwashing compliance? J Hosp Infect. 2001;48(1):72-75.

124. Vinh DC, Embil JM. Device-related infections: a review. J Long-Term Effects Med Implants. 2005;15(5):467-488.

125. Harris LG, Richards RG. Staphylococci and implant surfaces: a review. Injury. 2006;37(Suppl 2):S3-S14.

126. Schierholz JM, Beuth J. Implant infections: a haven for opportunistic bacteria. J Hosp Infect. 2001;49(2):87-93.

127. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-332.

128. Anderson DJ, Podgomy K, Berrios-Torres SI, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(6):605-627.

129. Mittmann N, Koo M, Daneman N, et al. The economic burden of patient safety targets in acute care: a systematic review. Drug, Healthcare Patient Safe. 2012;4:141-165.

130. Dubberke ER, Butler AM, Yokoe DS, et al. Multicenter study of Clostridium difficile infection rates from 2000 to 2006. Infect Control Hosp Epidemiol. 2010;31(10):1030-1037.

131. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis. 2012;55(Suppl 2):S88-S92.

132. Mitchell BG, Gardner A. Mortality and Clostridium difficile infection: a review. Antimicrob Resist Infect Control. 2012;1(1):20.

133. McGlone SM, Bailey RR, Zimmer SM, et al. The economic burden of Clostridium difficile. Clin Microbiol Infect. 2012;18(3):282-289.

134. Weber DJ, Sickbert-Bennett EE, Gould CV, Brown VM, Huslage K, Rutala WA. Incidence of catheter-associated and non-catheter-associated urinary tract infections in a healthcare system. Infect Control Hosp Epidemiol. 2011;32:822-823.

135. Lo E, Nicolle LE, Coffin SE, et al. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(5):464-479.

136. Falagas ME, Kompoti M. Obesity and infection. Lancet Infec Dis. 2006;6(7):438-446.

137. Chen HS, Wang FD, Lin M, Lin YC, Huang LJ, Liu CY. Risk factors for central venous catheter-related infections in general surgery. J Microbiol Immunol Infect. 2006;39(3):231-236.

138. Mukhtar RA, Throckmorton AD, Alvarado MD, et al. Bacteriologic features of surgical site infections following breast surgery.Am J Surg. 2009;198(4):529-531.

139. Dalstrom DJ, Venkatarayappa I, Manternach AL, Palcic MS, Heyse BA, Prayson MJ. Time-dependent contamination of opened sterile operating-room trays. J Bone Joint Surg Am. 2008;90(5):1022-1025.

140. de Wit M, Goldberg S, Hussein E, Neifeld JP. Health care-associated infections in surgical patients undergoing elective surgery: are alcohol use disorders a risk factor? J Am Coll Surg. 2012;215(2):229-236.

141. Qaseem A, Snow V, Fitterman N, et al. Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the American College of Physicians. Ann Intern Med. 2006;144(8):575-580.

142. Eom C-S, Jeon CY, Cho E-G, Park SM, Lee K-S. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ. 2011;183(3):310-319.

143. Merle V, Hallais C, Tavolacci MP, et al. Validity of medical staff assessment at admission of patient's risk of nosocomial infection: a prospective study in a surgical intensive care unit. Intensive Care Med. 2006;32(6):915-918.

144. Weiner-Lastinger LM, Abner S, Edwards JR, et al. Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: summary of data reported to the National Healthcare Safety Network, 2015-2017. Infection Control Hospital Epidemiology. 2019;41(1):1-18.

145. Dudeck MA, Edwards JR, Allen-Bridson K, Gross Cet al. National Healthcare Safety Network (NHSN) report, data summary for 2013, device-associated module. Am J Infect Cont. 2015;43(3):206-221.

146. Institute for Healthcare Improvement. Catheter-Associated Urinary Tract Infection. Available at http://www.ihi.org/Topics/CAUTI/Pages/default.aspx. Last accessed January 11, 2022.

147. Wald HL, Ma A, Bratzler DW, et al. Indwelling urinary catheter use in the postoperative period: analysis of the National Surgical Infection Prevention Project data. Arch Surg. 2008;143(6):551-557.

148. Huang SS. Catheter-associated urinary tract infection: turning the tide. N Engl J Med. 2016;374(22):2168-2169.

149. Srinivasan A, Karchmer T, Richards A, Song X, Perl TM. A prospective trial of a novel, silicone-based, silver-coated Foley catheter for the prevention of nosocomial urinary tract infections. Infect Control Hosp Epidemiol. 2006;27(1):38-43.

150. Johnson JR, Kuskowski MA, Witt TJ. Systematic review: antimicrobial urinary catheters to prevent catheter-associated urinary tract infection in hospitalized patients. Ann Intern Med. 2006;144(2):116-126.

151. Beattie M, Taylor J. Silver alloy vs. uncoated urinary catheters: a systematic review of the literature. J Clin Nurs. 2011;20(15-16):2098-2108.

152. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaffer A, Hooton TM. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40(5):643-654.

153. Buonanno AP Jr, Damweber BJ. Review of urinary tract infection. US Pharm. 2006;31(6):HS26-HS36.

154. Fink R, Gilmartin H, Richard A, et al. Indwelling urinary catheter management and catheter-associated urinary tract infection prevention practices in Nurses Improving Care for Healthsystem Elders hospitals. Am J Infect Control. 2012;40(8):715-720.

155. Saint S, Kowalski CP, Kaufman SR, et al. Preventing hospital-acquired urinary tract infection in the United States: a national study. Clin Infect Dis. 2008;46(2):243-250.

156. Conway LJ, Pogorzelska M, Larson E, Stone PW. Adoption of policies to prevent catheter-associated urinary tract infections in United States intensive care units. Am J Infect Control. 2012;40(8):705-710.

157. Topal J, Conklin S, Camp K, Morris V, Balcezak T, Herbert P. Prevention of nosocomial catheter-associated urinary tract infections through computerized feedback to physicians and a nurse-directed protocol. Am J Med Qual. 2005;20(3):121-126.

158. Saint S, Kaufman SR, Thompson M, Rogers MA, Chenoweth CE. A reminder reduces urinary catheterization in hospitalized patients. Jt Comm J Qual Patient Saf. 2005;31(8):455-462.

159. Shadle HN, Sabol V, Smith A, Stafford H, Thompson JA, Bowers M. A bundle-based approach to prevent catheter-associated urinary tract infections in the intensive care unit. Crit Care Nurse. 2021;41(2):62-71.

160. Burton DC, Edwards JR, Srinivasan A. Fridkin SK, Gould CV. Trends in catheter-associated urinary tract infections in adult intensive care units—United States, 1990–2007. Infect Control Hosp Epidemiol. 2011;32(8):748-756.

161. Fuchs MA, Sexton DJ, Thornlow DK, Champagne MT. Evaluation of an evidence-based, nurse-driven checklist to prevent hospital-acquired catheter-associated urinary tract infections in intensive care units. J Nurse Care Qual. 2011;26(2):101-109.

162. Centers for Disease Control and Prevention. FastStats: Hospital Utilization (in non-Federal Short-Stay Hospitals). Available at https://www.cdc.gov/nchs/fastats/hospital.htm. Last accessed January 11, 2022.

163. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. New Engl J Med. 2014;370:1198-1208.

164. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-e52.

165. Nan DN, Fernandez-Ayala M, Farinas-Alvarez C, et al. Nosocomial infection after lung surgery: incidence and risk factors. Chest. 2005;128(4):2647-2652.

166. de Lissovoy G, Fraeman K, Hutchins V, et al. Surgical site infection: incidence and impact on hospital utilization and treatment costs. Am J Infect Control. 2009;37(5):387-397.

167. McGarry SA, Engemann JJ, Schmader K, Sexton DJ, Kaye KS. Surgical-site infection due to Staphylococcus aureus among elderly patients: mortality, duration of hospitalization, and cost. Infect Control Hosp Epidemiol. 2004;25(6):461-467.

168. Centers for Disease Control and Prevention. Current HAI Progress Report. Available at https://www.cdc.gov/hai/data/portal/progress-report.html. Last accessed January 11, 2022.

169. Hawn MT, Vick CC, Richman J, et al. Surgical site infection prevention: time to move beyond the surgical care improvement program. Ann Surg. 2011;254(3):494-499.

170. Cheadle W. Risk factors for surgical site infection. Surg Infect(Larchmt). 2006;7(Suppl 1):s7-s11.

171. Manilich E, Vogel JD, Kiran RP, Church JM, Seyidova-Khoshknabi D, Remzi FH. Key factors associated with postoperative complications in patients undergoing colorectal surgery. Dis Colon Rectum. 2013;56(1):64-71.

172. Berrios-Torres SI, Umscheid CA, Bratzler DW, et al. Draft Guidelines for the Prevention of Surgical Site Infection. Available at http://www.jscva.org/files/CDC-SSI_Guideline_Draft2014.pdf. Last accessed January 11, 2022.

173. Auerbach AD. Prevention of surgical site infections. In: Shojania KG, Duncan BW, McDonald KM, Wachter RM (eds).Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Evidence Report/Technology Assessment, No. 43. Rockville, MD: Agency for Healthcare Research and Quality; 2001.

174. Webster J, Osborne S. Preoperative bathing or showering with skin antiseptics to prevent surgical site infection. Cochrane Database Syst Rev. 2015;20(2):CD004985.

175. Tanner J, Woodings D, Moncaster K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev. 2006;19(2):CD004122.

176. Tanner J, Norrie P, Melen K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev. 2011;9(11):CD004122.

177. Awad SS, Palacio CH, Subramanian A, et al. Implementation of a methicillin-resistant Staphylococcus aureus (MRSA) prevention bundle results in decreased MRSA surgical site infections. Am J Surg. 2009;198(5):607-610.

178. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373-1406.

179. Centers for Disease Control and Prevention. Surgical Site Infection (SSI) Event. Available at https://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf. Last accessed January 11, 2022.

180. Trampuz A, Widmer AF. Infections associated with orthopedic implants. Curr Opin Infect Dis. 2006;19(4):349-356.

181. Trampuz A, Zimmerli W. Antimicrobial agents in orthopaedic surgery: prophylaxis and treatment. Drugs. 2006;66(8):1089-1105.

182. Nguyen N, Yegiyants S, Kaloostian C, et al. The Surgical Care Improvement Project (SCIP) initiative to reduce infection in elective colorectal surgery: which performance measures affect outcome? Am Surg. 2008;74(10):1012-1016.

183. Ho VP, Barie PS, Stein SL, et al. Antibiotic regimen and the timing of prophylaxis are important for reducing surgical site infection after elective abdominal colorectal surgery. Surg Infect(Larchmt). 2011;12(4):255-260.

184. Berenguer CM, Ochsner MG Jr, Lord SA, Senkowski CK. Improving surgical site infections: using National Surgical Quality Improvement Program data to institute Surgical Care Improvement Project protocols in improving surgical outcomes. J Am Coll Surg. 2010;210(5):734-741.

185. Smith BP, Fox N, Fakhro A, et al. "SCIP"ping antibiotic prophylaxis guidelines in trauma: the consequences of noncompliance.J Trauma Acute Care Surg. 2012;73(2):452-456.

186. Edmiston CE, Spencer M, Lewis BD, et al. Reducing the risk of surgical site infections: did we really think SCIP was going to lead us to the promised land? Surg Infect (Larchmt). 2011;12(3):169-177.

187. Awad SS. Adherence to Surgical Care Improvement Project measures and post-operative surgical site infections. Surg Infect (Larchmt). 2012;13(4):234-237.

188. Schwann NM, Bretz KA, Eid S, et al. Point-of-care electronic prompts: an effective means of increasing compliance, demonstrating quality, and improving outcome. Anesth Analg. 2011;113(4):869-876.

189. Institute for Healthcare Improvement. How-to Guide: Prevent Surgical Site Infections. Cambridge, MA: Institute for Healthcare Improvement; 2012.

190. Kollef MH. What is ventilator-associated pneumonia and why is it important? Respir Care. 2005;50(6):714-721.

191. Kieninger AN, Lipsett PA. Hospital-acquired pneumonia: pathophysiology, diagnosis, and treatment. Surg Clin North Am. 2009;89(2):439-461.

192. Pogorzelska M, Stone PW, Furuya EY, et al. Impact of the ventilator bundle on ventilator-associated pneumonia in intensive care unit. Int J Qual Health Care. 2011;23(5):538-544.

193. Kollef MH. Antibiotic management of ventilator-associated pneumonia due to antibiotic-resistant gram-positive bacterial infection. Eur J Clin Microbiol Infect Dis. 2005;24(12):794-803.

194. Kollef MH, Morrow LE, Niederman MS, et al. Clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia. Chest. 2006;129(5):1210-1218.

195. Flanders SA, Collard HR, Saint S. Nosocomial pneumonia: state of the science. Am J Infect Control. 2006;34(2):84-93.

196. van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med. 2006;34(2):396-402.

197. Tolentino-DelosReyes AF, Ruppert SD, Shiao S-YPK. Evidence-based practice: use of the ventilator bundle to prevent ventilator-associated pneumonia. Am J Crit Care. 2007;16(1):20-27.

198. Institute for Healthcare Improvement. How-To Guide: Prevent Ventilator-Associated Pneumonia. Cambridge, MA: Institute for Healthcare Improvement; 2012.

199. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477.

200. Schweickert WD, Gehlbach BK, Pohlman AS, Hall JB, Kress JP. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32(6):1272-1276.

201. Bearman GML, Munro C, Sessler CN, Wenzel RP. Infection control and the prevention of nosocomial infections in the intensive care unit. Semin Respir Crit Care Med. 2006;27(3):310-324.

202. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet. 1999;354(9193):1851-1858.

203. Shay A, O'Malley P. Blue Ribbon Abstract Award: Clinical outcomes of a ventilator associated pneumonia prevention program. Am J Infect Control. 2006;34(5):E19-E20.

204. El-Solh AA, Pietrantoni C, Bhat A, et al. Colonization of dental plaques: a reservoir of respiratory pathogens for hospital-acquired pneumonia in institutionalized elders. Chest. 2004;126(5):1575-1582.

205. Zhao T, Wu X, Zhang Q, Li C, Worthington HV, Hua F. Oral hygiene care for critically ill patients to prevent ventilator-associated pneumonia. Cochrane Database Syst Rev. 2020;12(12):CD008367.

206. Jackson L, Owens M. Does oral care with chlorhexidine reduce ventilator-associated pneumonia in mechanically ventilated adults? Br J Nurs. 2019;28(11):628-689.

207. Veitz-Keenan A, Ferraiolo DM. Oral care with chlorhexidine seems effective for reducing the incidence of ventilator-associated pneumonia. Evid Based Dent. 2017;18(4):113-114.

208. Lorente L, Lecuona M, Jimenez A, et al. Ventilator-associated pneumonia with or without toothbrushing: a randomized controlled trial. Eur J Clin Microbiol Infect Dis. 2012;31(10):2621-2629.

209. Alhazzani W, Smith O, Muscedere J, Medd J, Cook D. Toothbrushing for critically ill mechanically ventilated patients: a systematic review and meta-analysis of randomized trials evaluating ventilator-associated pneumonia. Crit Care Med. 2013;41(2):646-655.

210. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.

211. Pileggi C, Bianco A, Flotta D, Nobile CG, Pavia M. Prevention of ventilator-associated pneumonia, mortality and all intensive care unit acquired infections by topically applied antimicrobial or antiseptic agents: a meta-analysis of randomized controlled trials in intensive care units. Crit Care. 2011;15(3):R155.

212. Dezfulian C, Shojania K, Collard HR, Kim HM, Matthay MA, Saint S. Subglottic secretion drainage for preventing ventilator-associated pneumonia: a meta-analysis. Am J Med. 2005;118(1):11-18.

213. Bouza E, Perez MJ, Munoz, Rincon C, Barrio JM, Hortal J. Continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in the postoperative period of major heart surgery. Chest. 2008;134(5):938-946.

214. Wang F, Bo L, Tang L, et al. Subglottic secretion drainage for preventing ventilator-associated pneumonia: an updated meta-analysis of randomized controlled trials. J Trauma Acute Care Surg. 2012;72(5):1276-1285.

215. Osmon S, Kollef MH. Prevention of pneumonia in the hospital setting. Clin Chest Med. 2005;26(1):135-142.

216. Isakow W, Kollef MH. Preventing ventilator-associated pneumonia: an evidence-based approach of modifiable risk factors. Semin Respir Crit Care Med. 2006;27(1):5-17.

217. Girou E, Brun-Buisson C, Taille S, Lemaire F, Brochard L. Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA. 2003;290(22):2985-2991.

218. Davis KA. Ventilator-associated pneumonia: a review. J Intensive Care Med. 2006;21(4):211-226.

219. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-332.

220. National Healthcare Safety Network. Pneumonia (Ventilator-associated [VAP] and Non-ventilator-associated Pneumonia [PNEU]) Event. Available at https://www.cdc.gov/nhsn/pdfs/pscmanual/6pscvapcurrent.pdf. Last accessed January 11, 2022.

221. Porzecanski I, Bowton DL. Diagnosis and treatment of ventilator-associated pneumonia. Chest. 2006;130(2):597-604.

222. Miller PR, Johnson JC 3rd, Karchmer T, Hoth JJ, Meredith JW, Chang MC. National nosocomial infection surveillance system: from benchmark to bedside in trauma patients. J Trauma. 2006;60(1):98-103.

223. Zaccard CR, Schell RF, Spiegel CA. Efficacy of bilateral bronchoalveolar lavage for diagnosis of ventilator-associated pneumonia.J Clin Microbiol. 2009;47(9):2918-2924.

224. Berton D, Kalil AC, Teixeira PJ. Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst Rev. 2012;1:CD006482.

225. Berton DC, Kalil AC, Zimermann Teixeira PJ. Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst Rev. 2014;30(10):CD006482.

226. Depuydt P, Myny D, Blot S. Nosocomial pneumonia: aetiology, diagnosis and treatment. Curr Opin Pulm Med. 2006;12(3):192-197.

227. Micek ST, Heuring TJ, Hollands JM, Shah RA, Kollef MH. Optimizing antibiotic treatment for ventilator-associated pneumonia. Pharmacotherapy. 2006;26(2):204-213.

228. Rello J, Vidaur L, Sandiumenge A, et al. De-escalation therapy in ventilator-associated pneumonia. Crit Care Med. 2004;32(11):2183-2190.

229. Kaye KS. Antimicrobial de-escalation strategies in hospitalized patients with pneumonia, intra-abdominal infections, and bacteremia. J Hosp Med. 2012;(7 Suppl 1):S13-S21.

230. Sligl W, Taylor G, Brindley PG. Five years of nosocomial gram-negative bacteremia in a general intensive care unit: epidemiology, antimicrobial susceptibility patterns, and outcomes. Int J Infect Dis. 2006;10(4):320-325.

231. Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intensive Care Med. 2004;30(3):388-394.

232. Mullins D, Kuznik C, Shaya FT, Obeidat NA, Levine AR, Liu LZ, Wong W. Cost-effectiveness analysis of linezolid compared with vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Ther. 2006;28(8):1184-1198.

233. Shorr AF, Susla GM, Kollef MH. Linezolid for treatment of ventilator-associated pneumonia: a cost-effective alternative to vancomycin. Crit Care Med. 2004;32(1):137-143.

234. Patel DA, Michel A, Stephens J, Weber B, Petrik C, Charbonneau C. An economic model to compare linezolid and vancomycin for the treatment of confirmed methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Germany. Infect Drug Resist. 2014;7:273-280.

235. Wunderink RG, Mendelson MH, Somero MS, et al. Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus. Chest. 2008;134(6):1200-1207.

236. Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev. 2011;10:CD007577.

237. Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults. Cochrane Database Syst Rev. 2015;8:CD007577.

238. Jain M, Miller L, Belt D, King D, Berwick DM. Decline in ICU adverse events, nosocomial infections and cost through a quality improvement initiative focusing on teamwork and culture change. Qual Saf Health Care. 2006;15(4):235-239.

239. Stone MJ, Snetman D, O'Neill A, et al. Daily multidisciplinary rounds to implement the ventilator bundle decreases ventilator-associated pneumonia in trauma patients: but does it affect outcome? Surg Infect (Larchmt). 2011;12(5):373-378.

240. Cachecho R, Dobkin E. The application of human engineering interventions reduces ventilator-associated pneumonia in trauma patients. J Trauma Acute Care Surg. 2012;73(4):939-943.

241. Seymann GB, Di Francesco L, Sharpe B, et al. The HCAP gap: differences between self-reported practice patterns and published guidelines for health care-associated pneumonia. Clin Infect Dis. 2009;49(12):1868-1874.

242. Blot SI, Depuydt P, Annemans L, et al. Clinical and economic outcomes in critically ill patients with nosocomial catheter-related bloodstream infections. Clin Infect Dis. 2005;41(11):1591-1598.

243. Hollenbeak CS. The cost of catheter-related bloodstream infections: implications for the value of prevention. J Infus Nurs. 2011;34(5):309-313.

244. Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin Proc. 2006;81(9):1159-1171.

245. Chaiyakunapruk N, Veenstra DL, Lipsky BA, Saint S. Chlorhexidine compared with povidone-iodine solution for vascular catheter-site care: a meta-analysis. Ann Intern Med. 2002;136(11):792-801.

246. Chaiyakunapruk N, Veenstra DL, Lipsky BA, Sullivan SD, Saint S. Vascular catheter site care: the clinical and economic benefits of chlorhexidine gluconate compared with povidone iodine. Clin Infect Dis. 2003;37(6):764-771.

247. Mermel LA, McCormick RD, Springman SR, Maki DG. The pathogenesis and epidemiology of catheter-related infection with pulmonary artery Swan-Ganz catheters: a prospective study utilizing molecular subtyping. Am J Med. 1991;91(3B):197S-205S.

248. Merrer J, De Jonghe B, Golliot F, et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA. 2001;286(6):700-707.

249. Deshpande KS, Hatem C, Ulrich HL, et al. The incidence of infectious complications of central venous catheters at the subclavian, internal jugular, and femoral sites in an intensive care unit population. Crit Care Med. 2005;33(1):13-20.

250. Maki DG, Knasinski V, Halvorson K, Tambyah PA. A novel silver-hydrogel-impregnated indwelling urinary catheter reduces CAUTIs: a prospective double-blind trial [abstract]. Infect Control Hosp Epidemiol. 1998;19:682.

251. Darouiche RO, Raad II, Heard SO, et al. A comparison of two antimicrobial-impregnated central venous catheters. N Engl J Med. 1999;340(1):1-8

252. Brun-Buisson C, Doyon F, Sollet JP, Cochard JF, Cohen Y, Nitenberg G. Prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial. Intensive Care Med. 2004;30(5):837-843.

253. Wang H, Tong H, Liu H, et al. Effectiveness of antimicrobial-coated central venous catheters for preventing catheter-related bloodstream infections with the implementation of bundles: a systematic review and network meta-analysis. Ann Intensive Care. 2018;8(1):71.

254. Cobrado L, Silva-Dias A, Azevedo MM, Rodrigues A. Anti-Candida activity of antimicrobial impregnated central venous catheters. Antimicrob Resist Infect Control. 2017;6:110.

255. National Healthcare Safety Network. Bloodstream Infection Event (Central Line-Associated Bloodstream Infection and Non-central Line Associated Bloodstream Infection. Available at https://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf. Last accessed January 11, 2022.

256. Safdar N, Fine JP, Maki DG. Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection. Ann Intern Med. 2005;142(6):451-466.

257. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45.

258. Raad I. Management of intravascular catheter-related infections. J Antimicrob Chemother. 2000;45(3):267-270.

259. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother. 2005;49(9):3640-3645.

260. Hsu RB. Risk factors for nosocomial infective endocarditis in patients with methicillin-resistant Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol. 2005;26(7):654-657.

261. Krein SL, Hofer TP, Kowalski CP, et al. Use of central venous catheter-related bloodstream infection prevention practices by U.S. hospitals. Mayo Clin Proc. 2007;82(6):672-678.

262. Warren DK, Cosgrove SE, Kiekema DJ, et al. A multicenter intervention to prevent catheter-associated bloodstream infections. Infect Control Hosp Epidemiol. 2006;27(7):662-669.

263. Institute for Healthcare Improvement. How-to Guide: Prevent Central Line-Associated Bloodstream Infections. Cambridge, MA: Institute for Healthcare Improvement; 2012.

264. Shapey IM, Foster MA, Whitehouse T, et al. Central venous catheter-related bloodstream infections: improving post-insertion catheter care. J Hosp Infect. 2009;71(2):117-122.

265. Guerin K, Wagner J, Rains K, Bessesen M. Reduction in central line-associated bloodstream infections by implementation of a postinsertion care bundle. Am J Infect Control. 2010;38(6):430-433.

266. Warren DK, Yokow DS, Climo MW, et al. Preventing catheter-associated bloodstream infections: a survey of policies for insertion and care of central venous catheters from hospitals in the Prevention Epicenter Program. Infect Cont Hosp Epidemiol. 2006;27(1):8-13.

267. Foka M, Nicolaou E, Kyprianou T, et al. Prevention of central line-associated bloodstream infections through educational interventions in adult intensive care units: a systematic review. Cureus. 2021;13(8):e17293.

268. Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges from an established pathogen. Clev Clin J Med. 2006;73(2):187-197.

269. McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from U.S. short-stay hospitals, 1996–2003. Emerging Infect Dis. 2006;12(3):409-415.

270. McDonald LC. Clostridium difficile: responding to a new threat from an old enemy Infect Cont Hosp Epidemiol. 2005;26(8):672-675.

271. Zilberberg MD, Shorr AF, Kollef MH. Increase in adult Clostridium difficile-related hospitalizations and case-fatality rate, United States, 2000–2005. Emerg Infect Dis. 2008;14(6):929-931.

272. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044.

273. Gerding DN, Muto CA, Owens RC Jr. Treatment of Clostridium difficile infection. Clin Infect Dis. 2008;46(Suppl 1):S32-S42.

274. Dubberke ER, Gerding DN, Classen D, Arias KM. Strategies to prevent Clostridium difficile infections in acute care hospitals.Infect Control Hosp Epidemiol. 2008;29(Suppl 1):S81-S92.

275. Dubberke ER, Reske KA, Olsen MA, McDonald LC, Fraser VJ. Short- and long-term attributable cost of Clostridium difficile-associated disease in non-surgical patients. Clin Infect Dis. 2008;46(4):497-504.

276. Song X, Bartlett JG, Speck K, Naegeli A, Carroll K, Perl TM. Rising economic impact of Clostridium difficile-associated disease in adult hospitalized patient population. Infect Control Hosp Epidemiol. 2008;29(9):823-828.

277. Lipp MJ, Nero DC, Callahan MA. Impact of hospital-acquired Clostridium difficile. J Gastroenterol Hepatol. 2012;27(11):1733-1737.

278. Centers for Disease Control and Prevention. 2018 Annual Report for the Emerging Infections Program for Clostridium difficile Infection. Available at https://www.cdc.gov/hai/eip/Annual-CDI-Report-2018.html. Last accessed January 11, 2022.

279. Guh AY, Winston LG, Johnston H, et al. Trends in U.S. burden of Clostridioides difficile infection and outcomes. N Engl J Med. 2020;382(14):1320-1330.

280. Leclair M-A, Allard C, Lesur O, Pépin J. Clostridium difficile infection in the intensive care unit. J Intensive Care Med. 2010;25(1):23-30.

281. Solanki D, Kichloo A, El-Amir Z, et al. Clostridium difficile infection hospitalizations in the United States: insights from the 2017 National Inpatient Sample. Gastroenterol Res. 2021;14(2):87-95.

282. Birch T, Golan Y, Rizzardini G, et al. Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection. J Antimicrob Chemother. 2018;73:2524-2528.

283. Lexicomp Online. Available at https://online.lexi.com. Last accessed January 11, 2022.

284. Halsey J. Current and future treatment modalities for Clostridium difficile-associated disease. Am J Health Syst Pharm. 2008;65(8):705-715.

285. Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;(1):CD004611.

286. Haley RW, Quade D, Freeman HE, Bennett JV. Study on the efficacy of nosocomial infection control (SENIC Project): summary of study design. Am J Epidemiol. 1980;111(5):472-485.

287. Haley RW, Culver DH, White JW, et al. The efficacy of infection surveillance and control programs in preventing nosocomial infections in U.S. hospitals. Am J Epidemiol. 1985;121(2):182-205.

288. Association for Professionals in Infection Control and Epidemiology. Infection Prevention and You. Available at http://www.apic.org/Resource_/TinyMceFileManager/IP_and_You/IPandYou_SmallFlyer_download_hiq.pdf. Last accessed January 11, 2022.

289. Kaye KS, Engemann JJ, Fulmer EM, Clark CC, Noga EM, Sexton DJ. Favorable impact of an infection control network on nosocomial infection rates in community hospitals. Infect Control Hosp Epidemiol. 2006;27(3):228-232.

290. Anderson DJ, Miller BA, Chen LF, et al. The network approach for prevention of healthcare-associated infections: long-term effect of participation in the Duke Infection Control Outreach Network. Infect Control Hosp Epidemiol. 2011;32(4):315-322.

291. Erasmus V, Daha TJ, Brug H, et al. Systematic review of studies on compliance with hand hygiene guidelines in hospital care.Infect Control Hosp Epidemiol. 2010;31(3):283-294.

292. Johnson PDR, Rhea M, Burrell LJ, et al. Efficacy of an alcohol/chlorhexidine hand hygiene program in a hospital with high rates of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection. Med J Aust. 2005;183(10):509-514.

293. Gordin FM, Schultz ME, Huber RA, Gill JA. Reduction in nosocomial transmission of drug-resistant bacteria after introduction of an alcohol-based handrub. Infect Control Hosp Epidemiol. 2005;26(7):650-653.

294. Gould DJ, Moralejo D, Drey N, Chudleigh JH. Interventions to improve hand hygiene compliance in patient care. Cochrane Database Syst Rev. 2010;(9):CD005186.

295. Gould DJ, Moralejo D, Drey N, Chudleigh JH, Taljaard M. Interventions to improve hand hygiene compliance in patient care. Cochrane Database Syst Rev. 2017;9(9):CD005186.

296. The Joint Commission. Measuring Hand Hygiene Adherence. Overcoming the Challenges. Oakbrook Terrace, IL: The Joint Commission; 2009.

297. Salgado CD, Giannetta ET, Hayden FG, Farr BM. Preventing nosocomial influenza by improving the vaccine acceptance rate of clinicians. Infect Control Hosp Epidemiol. 2004;25(11):923-928.

298. Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination on health-care workers on mortality of elderly people in long-term care: a randomized controlled trial. Lancet. 2000;355(9198):93-97.

299. Centers for Disease Control and Prevention. Influenza: Seasonal Influenza Vaccination Resources for Health Professionals. Available at https://www.cdc.gov/flu/professionals/vaccination/index.htm. Last accessed January 11, 2022.

300. Pearson ML, Bridges CB, Harper SA. Influenza vaccination of health-care personnel. MMWR. 2006;55(RR02):1-16.

301. Nichol K. Improving influenza vaccination rates among adults. Cleve Clin J Med. 2006;73(11):1009-1015.

302. The Joint Commission. Re Report Issue 3: Influenza Vaccination. Available at https://www.jointcommission.org/standards/r3-report/r3-report-issue-3---influenza-vaccination/. Last accessed January 11, 2022.

303. Center for Disease Control and Prevention. Influenza. Influenza Vaccination Coverage Among Health Care Personnel—United States, 2020–2021 Influenza Season. Available at https://www.cdc.gov/flu/fluvaxview/hcp-coverage_1920-21-estimates.htm. Last accessed January 11, 2022.

304. Christini AB, Shutt KA, Byers KE. Influenza vaccination rates and motivators among healthcare worker groups. Infect Control Hosp Epidemiol. 2007;28(2):171-177.

305. Center for Disease Control and Prevention. Influenza. Increase Influenza Vaccination Coverage Among Your Health Care Personnel. Available at https://www.cdc.gov/flu/toolkit/long-term-care/plan.htm. last accessed January 11, 2022.

306. Dash GP, Fauerbach L, Pfeiffer J, et al. APIC position paper: improving health care worker influenza immunization rates. Am J Infect Control. 2004;32(3):123-125.

307. Centers for Disease Control and Prevention. Be Antibiotics Aware. Available at https://www.cdc.gov/antibiotic-use/week/toolkit.html. Last accessed January 11, 2022.

308. Institute for Healthcare Improvement. How-to Guide: Reduce MRSA Infection. Available at http://www.ihi.org/resources/Pages/Tools/HowtoGuideReduceMRSAInfection.aspx. Last accessed January 11, 2022.

309. Harbarth S, Fankhauser C, Schrenzel J, et al. Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA. 2008;299(10):1149-1157.

310. Robicsek A, Beaumont JL, Paule SM, et al. Universal surveillance for methicillin-resistant Staphylococcus aureus in 3 affiliated hospitals. Ann Intern Med. 2008;148(6):409-418.

311. Harbarth S, Sax H, Uckay I, et al. A predictive model for identifying surgical patients at risk of methicillin-resistant Staphylococcus aureus carriage on admission. J Am Coll Surg. 2008;207(5):683-689.

312. Raymond DP, Pelletier SJ, Sawyer RG. Antibiotic utilization strategies to limit antimicrobial resistance. Semin Respir Crit Care Med. 2002;23(5):497-501.

313. Wibbenmeyer L, Danks R, Faucher L, et al. Prospective analysis of nosocomial infection rates, antibiotic use, and patterns of resistance in a burn population. J Burn Care Res. 2006;27(2):152-160.

314. Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clin Proc. 2011;86(11):1113-1123.

315. Raboud J, Saskin R, Wong K, et al. Patterns of handwashing behavior and visits to patients on a general medical ward of healthcare workers. Infect Control Hosp Epidemiol. 2004;25(3):198-202.

316. Warren DK, Zack JE, Cox MJ, Cohen MM, Fraser VJ. An educational intervention to prevent catheter-associated bloodstream infections in a nonteaching, community medical center. Crit Care Med. 2003;31(7):1959-1963.

317. Coopersmith CM, et al. Effect of an education program on decreasing catheter-related bloodstream infections in the surgical intensive care unit. Crit Care Med. 2002;30(1):59-64.

318. Lee TC, Moore C, Raboud JM, et al. Impact of a mandatory infection control education program on nosocomial acquisition of methicillin-resistant Staphylococcus aureus. Infect Control Hosp Epidemiol. 2009;30(3):249-256.

319. Grol R, Grimshaw J. From best evidence to best practice: effective implementation of change in patients' care. Lancet. 2003;362(9391):1225-1230.

320. Pande PS, Neuman RP, Cavanagh RR. The Six Sigma Way: How GE, Motorola, and Other Top Companies are Honing their Performance. New York, NY: McGraw Hill; 2000.

321. Eldridge NE, Woods SS, Bonello RS, et al. Using the Six Sigma process to implement the Centers for Disease Control and Prevention guideline for hand hygiene in 4 intensive care units. J Gen Intern Med. 2006;21(Suppl 2):S35-S42.

322. Hofmann F, Erracin C, Marsh G, Dumas R. Influenza vaccination of healthcare workers: a literature review of attitudes and beliefs. Infection. 2006;34(3):142-147.

323. Hollmeyer HG, Hayden F, Poland G, Buchholz U. Influenza vaccination of health care workers in hospitals: a review of studies on attitudes and predictors. Vaccine. 2009;27(30):3935-3944.

324. Committee on Health Literacy Board on Neuroscience and Behavioral Health. Health Literacy: A Prescription to End Confusion. Washington, DC: The National Academies Press; 2004.

325. Kirsch I, Jungeblut A, Jenkins L, Kolstad A. Adult Literacy in America: A First Look at the Results of the National Adult Literacy Survey (NALS). Washington, DC: National Center for Education Statistics, U.S. Department of Education; 1993.

326. U.S. Census Bureau. Selected Social Characteristics in the United States: 2019:ACS 1-Year Estimates Data Profiles. Available at https://data.census.gov/cedsci/table?q=DP02#. Last accessed January 11, 2022.

327. Sevilla Matir J, Willis DR. Using bilingual staff members as interpreters. Fam Pract Manag. 2004;11(7):34-36.

328. Ngo-Metzger Q, Massagli MP, Clarridge BR, et al. Linguistic and cultural barriers to care: perspectives of Chinese and Vietnamese immigrants. J Gen Intern Med. 2003;18(1):44-52.

329. Flores G. Language barriers to health care in the United States. N Engl J Med. 2006;355(3):229-231.

330. Flores G. The impact of medical interpreter services on the quality of health care: a systematic review. Med Care Res Rev. 2005;62(3):255-299.

331. Karliner L, Jacobs EA, Chen AH, Mutha S. Do professional interpreters improve clinical care for patients with limited English proficiency? A systematic review of the literature. Health Serv Res. 2007;42(2):727-754.

332. World Health Organization. Disease Outbreaks. Available at http://www.emro.who.int/health-topics/disease-outbreaks/index.html. Last accessed January 11, 2022.

333. Centers for Disease Control and Prevention. Steps of an Outbreak Investigation. Available at https://www.cdc.gov/csels/dsepd/ss1978/lesson6/section2.html. Last accessed January 11, 2022.

334. Centers for Disease Control and Prevention. Infection Prevention and Control Recommendations for Hospitalized Patients Under Investigation (PUIs) for Ebola Virus Disease (EVD) in U.S. Hospitals. Available at https://www.cdc.gov/vhf/ebola/clinicians/evd/infection-control.html. Last accessed January 11, 2022.

335. Gastmeier P, Stamm-Balderjahn S, Hansen S, et al. How outbreaks can contribute to prevention of nosocomial infection: analysis of 1,022 outbreaks. Infect Cont Hosp Epidemiol. 2005;26(4):357-361.

336. Breathnach AS, Riley PA, Shad S, et al. An outbreak of wound infection in cardiac surgery patients caused by Enterobacter cloacae arising from cardioplegia ice. J Hosp Infect. 2006;64(2):124-128.

337. Felkner M, Pascoe N, Shupe-Ricksecker K, Goodman E. The wound care team: a new source of group A streptococcal nosocomial transmission. Infect Control Hosp Epidemiol. 2005;26(5):462-465.

338. Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR. 2005;54(RR17):1-141.

339. Henderson DK. Managing methicillin-resistant staphylococci: a paradigm for preventing nosocomial transmission of resistant organisms. Am J Med. 2006;119(6 Suppl 1):S45-S52, S62-S70.

340. Keller SC, Caballero TM, Tamma PD, et al. Assessment of changes in visits and antibiotic prescribing during the Agency for Healthcare Research and Quality Safety Program for Improving Antibiotic Use and the COVID-19 pandemic. JAMA Netw Open. 2022;5(7):e2220512.

Evidence-Based Practice Recommendations Citations

1. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(5):625-663. Available at https://academic.oup.com/cid/article/50/5/625/324341. Last accessed January 20, 2022.

2. Card R, Sawyer M, Degnan B, et al. Perioperative Protocol: Health Care Protocol. Bloomington, MN: Institute for Clinical Systems Improvement; 2019. Available at https://www.icsi.org/wp-content/uploads/2019/01/Periop.pdf. Last accessed January 20, 2022.

3. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. Available at https://www.idsociety.org/practice-guideline/hap_vap. Last accessed January 20, 2022.

4. O'Grady NP, Alexander M, Burns LA, et al. Guidelines for the Prevention of Intravascular Catheter-Related Infections, 2011. Atlanta, GA: Centers for Disease Control and Prevention; 2011. Available at https://www.cdc.gov/hai/pdfs/bsi-guidelines-2011.pdf. Last accessed January 20, 2022.

5. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48. Available at https://academic.oup.com/cid/article/66/7/e1/4855916. Last accessed January 20, 2022.

6. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-1044. Available at https://www.idsociety.org/practice-guideline/clostridioides-difficile-2021-focused-update. Last accessed January 20, 2022.