|Use these tools to enrich your learning experience!|
|View the Evidence-Based Practice Recommendations to determine the validity or relevance of the information.|
Assess your retention of the subject matter with these
See your score at the end. This self-assessment is optional.
|Use this objective-based question and answer exercise to enhance your course knowledge.|
|Download this course as a PDF to avoid shipping charges and mail time. Print or save at any time!|
|Download this course for your eReader to access the content immediately, anywhere!|
Choosing an antibacterial agent can be challenging, given the wide array of drugs available. Learning the important properties and uses of these drugs is made easier by the fact that they are grouped in classes based on their biochemical structure. Members of a drug class share characteristics such as clearance, mechanism of action, absorption, and side effects; knowing these shared properties makes it easier to choose the appropriate agent for a particular patient. In addition, it is easier to quickly grasp the strengths and weaknesses of a newly marketed antibiotic if you understand the general pharmacology of its class. A good grasp of the use of specific agents to target specific bacteria leads to improved clinical response to treatment and a decrease in the likelihood of the development of microbial resistance. This course is intended as an overview of the general characteristics of the major antibiotic classes, with a brief discussion of the individual agents and indications, giving greater perspective to the actions and characteristics of antibiotics. Due to the large number of antibiotics available, this course focuses on 8 major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines.
Education Category Pharmacology
Release Date 02/01/2012
Expiration Date 01/31/2015
This course is designed for healthcare providers who prescribe and administer antibiotics to patients, including physicians, physician assistants, nurses, and nurse practitioners.
CME Resource is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME Resource is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. CME Resource is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. CME Resource is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. CME Resource has been accredited as an Authorized Provider by the International Association for Continuing Education and Training (IACET), 1760 Old Meadow Road, Suite 500, McLean, VA 22102. In obtaining this approval, CME Resource has demonstrated that it complies with the ANSI/IACET Standard which is widely recognized as the Standard of good practice internationally. As a result of their Authorized Provider accreditation status, CME Resource is authorized to offer IACET CEUs for its programs that qualify under the ANSI/IACET 1-2013 Standard. CME Resource is approved as a provider of online continuing education for certified nursing assistants through the California Department of Public Health Licensing and Certification Division. Nurse Aide Certification (NAC) Provider #7005.
CME Resource designates this enduring material for a maximum of 5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. CME Resource designates this continuing education activity for 5 ANCC contact hour(s). CME Resource designates this continuing education activity for 5 pharmacology contact hour(s). CME Resource designates this continuing education activity for 6 hours for Alabama nurses. This continuing education activity is approved for 6.5 CE credits by the Association of Surgical Technologists, Inc., for continuing education for the Certified Surgical Technologist and Certified Surgical First Assistant. This recognition does not imply that AST approves or endorses any product or products that are discussed or mentioned in the CE course. This home study course is approved by the Florida Board of Nursing Home Administrators for 5 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 5 hour(s) of continuing education credit - NHAP#1622005-2933/P. California NHAs may only obtain a maximum of 10 hours per course. AACN Synergy CERP Category A. CME Resource is authorized by IACET to offer 0.5 CEU(s) for this program.
In addition to states that accept ANCC, CME Resource is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through December 12, 2017); California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10671; Florida, Provider #50-2405; Iowa, Provider #295; Kentucky, Provider #7-0054 through 12/31/2017.
This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.
The purpose of this course is to provide a review of the classes of antibiotics and their characteristics as well as an overview of the individual antibiotics that are currently available for use by the practitioner.
Upon completion of this course, you should be able to:
Donna Coffman, MD, attended medical school at the University of Louisville and completed her residency in Family Practice at St. John's Mercy Medical Center in St. Louis, Missouri. She is board-certified in Family Medicine and currently on staff at John Cochran VAMC in St. Louis.
Contributing faculty, Donna Coffman, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
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.
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.
Table of Contents
Supported browsers for Windows include Microsoft Internet Explorer 7.0 and up, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Supported browsers for Macintosh include Safari, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Other operating systems and browsers that include complete implementations of ECMAScript edition 3 and CSS 2.0 may work, but are not supported.
The number of antibiotic agents available is remarkable, and new agents are frequently added. This course is intended as an overview of the general characteristics of the major antibiotic classes, with a brief discussion of the individual agents and indications, giving greater perspective to the actions and characteristics of antibiotics. Due to the large number of antibiotics available, this course focuses on 8 major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines. Many very useful and commonly used antibiotics are unique and do not fit in these classes and are outside of the scope of this course.
It is beyond the scope of this course to define all of the possible side effects, recommended uses, and off-label uses of the antibiotics. Before using a specific antimicrobial, review the manufacturer's package insert and dosing recommendations for the drug.
There are some characteristics that all antibiotics share. All antibiotics can elicit allergic responses, although some are more allergenic than others. Allergic reactions can range from mild, annoying rashes to life-threatening reactions like anaphylaxis and Stevens-Johnson syndrome. In some cases, there is a cross-sensitivity between agents in different classes. In addition, all antibiotics affect normal body flora as well as pathogens, which may result in overgrowth of Candida and pathogenic bacteria such as Clostridium difficile. Overgrowth of C. difficile is a serious complication of antimicrobial therapy that can produce symptoms ranging from mild diarrhea to severe, life-threatening complications, such as pseudomembranous colitis . Most cases resolve with supportive care and discontinuation of the offending antibiotic, but many require treatment. In addition, diarrhea and pseudomembranous colitis can develop weeks after antimicrobial therapy has been discontinued. A high degree of suspicion and judicious use of laboratory testing are the keys to recognizing and managing these complications.
Bacteria develop resistance to antibiotics in a variety of ways, including methods that may decrease the intracellular concentrations of the antibiotic, deactivate the antibiotic, change the binding sites for the antibiotic, and develop adaptations that bypass the need for the binding site targeted by the antibiotic .
Methods that decrease intracellular concentrations of the antibiotic include changes in the cell wall to increase the efflux of the antibiotic from the cell. This is seen in tetracycline and quinolone resistance. Another method is to decrease the cell membrane permeability, which is seen as a bacterial defense in beta-lactam and quinolone resistance. In addition, bacteria can prevent influx of the antibiotic by decreasing cytoplasmic membrane transport, as seen with the use of aminoglycosides. Examples of enzymes that deactivate the antibiotic are the lactamases, which deactivate beta-lactams, and the phosphotransferases and acetyltransferases, which deactivate aminoglycosides.
There are numerous methods for altering or bypassing the binding site targeted by the antibiotic. In one method, the target of the antibiotic may be altered in such a way that the antibiotic can no longer bind to and deactivate it. Examples of this method include alterations in the deoxyribonucleic acid (DNA) gyrase that prevent the binding of quinolones, and methylation of ribosomal ribonucleic acid (rRNA) that prevents the binding of macrolides. An example of an adaptation that bypasses a binding site is the ability of some bacteria to use an alternate metabolic route in folate synthesis, avoiding the effects of trimethoprim .
These resistances may be acquired through mutations in the genes that encode for the target or affected transport proteins. As the bacterial cells without the adaptive mutations are killed as a result of an antibiotic, the cells that have the mutation continue to replicate, replacing the original population with a resistant one.
These resistances may also be acquired as a result of the transfer of plasmids or transposons and similar agents. These agents are small segments of DNA that are readily exchanged between bacteria. A plasmid that contains a gene for an adaptive mutation can be shared with a large number of nearby bacteria, which may or may not be the same species. In this manner, resistance can quickly spread from species to species .
Many strategies have been used in an attempt to circumvent the multiple mechanisms of resistance that have developed in bacteria. Adding beta-lactamase inhibitors to penicillin drugs, chemically altering cephalosporins to create the additional generations of the drugs, and combining sulfa drugs with pyrimethamine, trimethoprim, and erythromycin are examples of these strategies.
In addition, new categories of antibiotics are being created in an attempt to stay ahead of the rapid evolution of bacterial resistance. Linezolid, the first oxazolidinone, is an example of this. Linezolid is a unique drug that prevents formation of the 70S protein synthesis complex in bacteria, and it may be useful in the treatment of vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. Nonetheless, development of resistance in bacteria is relentless.
In light of the efficient means by which bacteria develop resistances, it is important to avoid practices that contribute to the process. The Centers for Disease Control and Prevention (CDC) has issued a position paper outlining recommendations for minimizing nosocomial infection and the emergence of resistant organisms . In this paper, the CDC recommended a multistep approach.
The first step recommended by the CDC is to prevent infection. Many infections in hospitalized or institutionalized patients are the direct result of indwelling urinary catheters, central venous catheters, and intubation. These invasive medical devices should be avoided unless they are clearly indicated. In addition, proper vaccination of medical staff and patients is an effective method to prevent the spread of Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
The next step is to tailor medical treatment to fit the infection. Antimicrobial therapy should be based on the likely pathogens or culture results, so broad-spectrum antibiotics may be avoided when possible. Consideration should be given to pathogens common to the area of infection (e.g., skin, intra-abdominal) and to pathogens common in the environment locally (e.g., hospital environment). Prolonged treatment regimens may allow more time for the development of resistance, so the duration of therapy must be considered as well.
The last step is to prevent the transmission of resistant bacteria between patients. A simple, effective method of infection containment is hand washing. As noted in the CDC position paper, participation in hospital infection control programs is also necessary . A coordinated effort to contain pathogens within hospital infection control guidelines makes it easier to prevent the spread of multidrug-resistant bacteria.
Despite the remarkable rate of the development of new antibiotics, the emergence of drug-resistant bacteria continues unabated. Therefore, it is important to use antibiotics wisely to maintain their usefulness for the future.
Obtaining a detailed patient history is a vital aspect of the appropriate prescription of antibiotics, particularly in empirical treatment. Furthermore, communication with patients regarding treatment regimens and compliance depends on clear communication between the patient and clinician. 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. The interpreter should be considered an active agent in the diagnosis and/or treatment processes, negotiating between two cultures and assisting in promoting culturally competent communication and practice .
Penicillin was discovered by Alexander Fleming in 1928. After observing that Penicillium colonies inhibited the growth of staphylococci on agar plates, Fleming made an extract from the mold and proved that it inhibited bacterial growth. Penicillin became available for general use in the 1940s .
Penicillin is bactericidal, killing bacterial cells by impairing cell wall synthesis. It impairs cell wall synthesis by preventing cross-binding of the peptidoglycan polymers necessary for cell wall formation and by binding the penicillin-binding proteins (PBPs) (carboxypeptidases, endopeptidases, and transpeptidases) that participate in cell wall synthesis . Although the exact mechanisms involved are not known, the end result is that the cell wall is structurally weakened and lyses, leading to cell death.
The basic form of penicillin is structured around the beta-lactam ring (a thiazolidine ring) and can be altered by substituting side chains. By doing so, the antimicrobial spectrum, absorption characteristics, and resistance to beta-lactamase deactivation can be altered.
Bacterial resistance to penicillins may take different forms. The most significant is the bacterial production of beta-lactamases, which can destroy the beta-lactam ring by means of hydrolysis, effectively preventing antimicrobial activity by the agent . In addition, some bacteria are able to prevent binding to the PBPs by various means, including altered binding sites for the penicillins .
Various strategies have been employed to circumvent these microbial adaptations. Altering the structure of the penicillins to produce agents that are more resistant to the hydrolysis from the beta-lactamases has resulted in the development of the extended-spectrum penicillins.
Another strategy has been to combine penicillins with other agents that either block bacterial beta-lactamases or have an alternate method for killing bacteria that are resistant to penicillin. Examples include amoxicillin plus clavulanic acid, ampicillin plus sulbactam, piperacillin plus tazobactam, and ticarcillin plus clavulanic acid. Clavulanic acid is produced by Streptomyces clavuligerus. Sulbactam and tazobactam are derived from the basic penicillin ring. These agents have little intrinsic antimicrobial activity, but they bind irreversibly to many beta-lactamases, preventing hydrolytic activity against the beta-lactam ring.
Penicillins can be separated into groups based on their pharmacokinetics and antibacterial activity. These groups are the natural penicillins, the aminopenicillins, the penicillinase-resistant penicillins, and the antipseudomonal penicillins .
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|Penicillin G benzathine||1.2–2.4 MU||
|IM||Rash, GI upset||
|Penicillin G benzathine or penicillin G procaine||2.4 MU in one dose||
|IM||Rash, GI upset|
|Penicillin G (parenteral/aqueous)||Up to 24 MU per day||
|IM, IV||Rash, GI upset|
|Penicillin V potassium||250–500 mg 2 to 4 times daily||
|PO||Rash, GI upset||No longer recommended for dental procedure prophylaxis.|
|Amoxicillin||250–500 mg every 8 hrs, or 500–875 mg twice daily||
|Amoxicillin and clavulanate||250–500 mg every 8 hrs, or 875 mg every 12 hrs||
|PO||Rash, diarrhea||Dosing for amoxicillin/ clavulanate is based on the amoxicillin component; the ES formulation of amoxicillin/clavulanate is not interchangeable with the regular suspension and requires product specific dosing.|
|Ampicillin||250–500 mg every 6 hrs||
|PO, IV, IM||Rash, GI symptoms (very common)||The IV form can be given in divided doses or in a continuous infusion.|
|Ampicillin and sulbactam||1.5–3 g every 6 hrs IV||
|IV, IM||Rash, diarrhea, local pain at injection or infusion site (very common with IM use)||Dosing for ampicillin/ sulbactam is based on the ampicillin component.|
|Dicloxacillin||125–500 mg every 6 hrs||
|PO||Rash, diarrhea||Not recommended for use in neonates.|
|Nafcillin||IV: 0.5–2 g every 4 to 6 hrs IM: 0.5 g every 4 to 6 hrs||
|IV, IM||Phlebitis at IV site, neutropenia, rash||Tissue necrosis can occur with IV extravasation.|
|Oxacillin||0.25–2 g every 4 to 6 hrs||
|IV, IM||Phlebitis at IV site, hepatitis, rash||Drug-induced hepatitis is usually reversible if drug is discontinued. Neonatal dosing may require the use of alternate container system/dosage forms.|
|Piperacillin or piperacillin/tazobactam||
|IV, IM||Rash, GI upset, phlebitis at infusion site||Piperacillin/tazobactam doses are based on the piperacillin component.|
|Ticarcillin or ticarcillin/clavulanate||
|IV||Rash, GI upset||Potential warfarin interaction. Ticarcillin/clavulanate doses are based on the ticarcillin component.|
The natural penicillins include various penicillin G preparations and penicillin V potassium. Penicillin G is very unstable in stomach acid and must be given parenterally. Penicillin V potassium was developed to be more stable in stomach acid and is typically given orally.
The natural penicillins are active against gram-positive organisms, such as many staphylococci, many streptococci, Enterococcus faecalis, and Listeria monocytogenes. They are also active against anaerobic species, such as Bacteroides species and Fusobacterium species. The natural penicillins are effective against some gram-negative bacteria, such as Escherichia coli, H. influenzae, Neisseria gonorrhoeae, Treponema pallidum, and susceptible Pseudomonas species, and they are indicated for use in infections caused by penicillin-sensitive organisms. The sensitivity should be proven for moderate-to-severe infections if resistant organisms are likely. Labeled uses include treatments for infections of the upper and lower respiratory tract, throat, skin, and genitourinary tract and prophylaxis of recurrent rheumatic fever and pneumococcal infections .
The aminopenicillins have about the same activity as the natural penicillins, plus improved coverage of gram-negative cocci and Enterobacteriaceae. These agents are not active against Treponema species or Actinomyces species, but amoxicillin/clavulanic acid and ampicillin/sulbactam have better coverage against H. influenzae and Klebsiella species than the natural penicillins and the aminopenicillins alone.
The aminopenicillins include ampicillin and amoxicillin. Ampicillin can be given parenterally or orally; indications include endocarditis, meningitis, and urinary tract infection . Amoxicillin was specifically designed to be stable in stomach acid, and its absorption is considerably better than that of ampicillin. Improved absorption also means that amoxicillin causes less diarrhea than other oral penicillins. Labeled uses include endocarditis prophylaxis and as a component of a multi-drug H. pylori eradication regimen . Amoxicillin is also investigational for postexposure anthrax prophylaxis.
The penicillinase-resistant penicillins were developed in response to the discovery of resistant staphylococcal bacteria that could deactivate available penicillins. These penicillins are resistant to hydrolysis by the lactamase produced by the staphylococci, and they include nafcillin and oxacillin, which are parenteral formulations, and dicloxacillin, which is given orally. Methicillin and cloxacillin are no longer available in the U.S .
While the penicillinase-resistant penicillins are effective against many of the same gram-positive organisms that the natural penicillins are effective against, they are not effective against gram-negative or anaerobic organisms. They are, however, notable for their usefulness against penicillin-resistant Staphylococcus and Streptococcus species.
The antipseudomonal penicillins are often also referred to as extended-spectrum penicillins; these include ticarcillin and piperacillin (both of which are parenteral). Mezlocillin, which was also parenteral, and carbenicillin, which was oral, are no longer available in the U.S.
These agents retain much of their activity against gram-positive bacteria, but they also have more activity against gram-negative bacteria and are much more active against Pseudomonas aeruginosa than ampicillin. Additional gram-negative species that are treated by these agents include H. influenzae, Serratia species, and Klebsiella species. These agents are not active against T. pallidum or Actinomyces species.
Clavulanic acid, sulbactam, and tazobactam increase the spectrum of activity of the drug with which they are compounded. They are generally active against the beta-lactamases produced by H. influenzae, Moraxella catarrhalis, and S. aureus. However, their activity is variable against some of the gram-negative bacteria, such as some species of Pseudomonas, Enterobacter, E. coli, Klebsiella, and Serratia, due to resistance to these beta-lactamase inhibitors .
While most penicillins can be absorbed via the oral route, the bioavailability varies considerably, and food may interfere with absorption. Penicillin V, amoxicillin, ampicillin, and dicloxacillin can be given orally; the remaining penicillins are too unstable in the acidic environment of the stomach and must be given parenterally.
Once absorbed, these agents are widely distributed throughout the body. Therapeutic concentrations of penicillins are readily achieved in tissues and secretions (e.g., joint fluid, pleural fluid, pericardial fluid, and bile). Low concentrations are found in prostatic secretions, brain tissue, intraocular fluid, and phagocytes. Cerebrospinal fluid (CSF) concentrations vary but are less than 1% of serum concentration when the meninges are normal. When the meninges are inflamed, CSF concentrations may rise to 5% and can be increased by co-administration of probenecid (500 mg 4 times daily) [11,149]. Concentration in urine is high due to renal secretion.
Penicillins are eliminated rapidly by the kidneys as a result of glomerular filtration and renal tubular secretion. Probenecid markedly reduces the tubular secretion of the penicillins and decreases the apparent volume of distribution, resulting in higher serum levels. All of the penicillins are excreted to some degree in the bile, but biliary excretion is most important for antipseudomonal penicillins and nafcillin .
In patients with mild renal insufficiency, dosage adjustment is not needed, except with the use of ticarcillin . If the creatinine clearance is less than 10 mL/min, then dosage adjustments should be made to avoid excess serum levels. Nafcillin undergoes extensive hepatic metabolism, and the dosage must be adjusted for severe renal and hepatic insufficiency.
These drugs are usually well tolerated. However, gastrointestinal (GI) disturbances may occur with all oral penicillins.
Allergy to any of the penicillins is the only absolute contraindication to use of a penicillin agent. Allergic reactions occur in up to 10% of patients, with 0.001% dying from anaphylaxis . The allergic responses vary and can include a mild rash (the most common) and urticaria. Rarely, serum sickness, exfoliative dermatitis, and Stevens-Johnson syndrome may develop [12,149]. These allergic responses develop in response to the beta-lactam ring and its derivatives; therefore, it should be noted that the penicillins are cross-reactive. Cross-reactions with cephalosporins have been noted in patients with true penicillin allergy .
Rarely, penicillins may cause hematologic reactions with neutropenia due to reversible bone marrow suppression. Abnormal platelet aggregation may occur, particularly with ticarcillin . Other rare reactions include hepatitis, seizures, interstitial nephritis, and hypokalemia due to local effects in the renal tubules.
The penicillins should not be given concurrently with tetracycline or other bacteriostatic agents. Penicillin works in cells that are actively synthesizing cell wall components, and if metabolism is prevented, then the actions of penicillin may be impaired. The antipseudomonal penicillins also may affect warfarin metabolism. Therefore, the prothrombin time, using the international normalized ratio (INR), should be monitored .
The penicillins are pregnancy category B, indicating no adverse events noted in animal studies . These agents are secreted in breastmilk, and breastfeeding should be avoided if the infant is allergic to any of the penicillins . Use while breastfeeding may cause modifications of normal intestinal flora and allergic sensitization in the infant .
The first cephalosporin was discovered in 1948 by Giuseppe Brotzu, who observed that the fungus Cephalosporium acremonium produced a substance that inhibited the growth of S. aureus and other bacteria. The initial substance was identified and modified to create the cephalosporins that are now used. The cephamycins were created by adding a methoxy group on the beta-lactam ring of the original compound, based on the structure of cefoxitin, produced by Streptomyces lactamdurans. By altering the chemical groups substituted on the basic molecule, greater antimicrobial activity and longer half-lives have been obtained .
Like penicillins, the cephalosporins are beta-lactams in which the beta-lactam ring is joined to a dihydrothiazine ring. Their antimicrobial effect is based on the same mechanism of action that occurs in the penicillins. The cephalosporins inhibit bacterial cell wall synthesis by blocking the transpeptidases and other PBPs involved in the synthesis and cross-linking of peptidoglycan [20; 21].
Because each bacterial species has a unique chemical structure in its cell wall, the cephalosporins may have different mechanisms of action by which they inhibit cell wall synthesis.
As with penicillins, resistance to the action of cephalosporins may result from mutations in the penicillin-binding proteins (preventing the cephalosporins from binding to them) and from the production of extended-spectrum beta-lactamases that deactivate the drug . An additional source of resistance in gram-negative bacteria is alteration in the cell-membrane porins that normally allow passage of the cephalosporins .
Of these mechanisms, the production of beta-lactamase is the most clinically significant. This form of resistance may occur through mutations or may be carried on plasmids .
The cephalosporins have been classified in different ways, based on chemical structure and pharmacologic activities. The most commonly used classification system groups the agents into "generations" based on their similarities in antimicrobial coverage.
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|Cefadroxil||1–2 g/day in 2 divided doses||
|PO||Rash, diarrhea||Can interfere with some urine glucose tests.|
|IV, IM||Phlebitis at infusion site, rash, diarrhea||Can interfere with some urine glucose tests.|
|>1 yr: 25–100 mg/kg/day in 3 to 4 divided doses||PO||GI upset, rash||Can interfere with some urine glucose tests.|
|Cefaclor||250–500 mg every 8 hrs||
|PO||Rash, GI upset||Can interfere with some urine glucose tests.|
|Not studied for pediatric use||IV, IM||Phlebitis at infusion site, rash, GI upset||Disulfiram-like reaction with alcohol. Can interfere with some urine glucose tests.|
|>3 mos: 80–160 mg/kg/day in 4 to 6 divided doses||IV, IM||Phlebitis at infusion site, rash||IM injection is painful. Can interfere with some urine glucose tests.|
|Cefprozil||250–500 mg every 12 to 24 hrs||
|PO||Rash, GI upset, elevated liver enzymes||Avoid use in phenylketonuria. Can interfere with some urine glucose tests.|
|Phlebitis at infusion site, rash, GI upset||
|Cefdinir||300 mg every 12 hrs, or 600 mg every 24 hrs||14 mg/kg/day in 1 or 2 doses||PO||Rash, diarrhea||Iron and antacids can reduce absorption. Can interfere with some urine glucose tests.|
|Cefditoren pivoxil||200–400 mg every 12 hrs||Not studied for patients <12 yrs||PO||GI upset, headache||Interaction with proton-pump inhibitors, H2 blockers, antacids. Contraindicated with milk protein allergy.|
|Cefixime||400 mg/day in 1 or 2 doses||
|PO||Diarrhea, rash||Can interfere with some urine glucose tests.|
|Cefotaxime||1–2 g every 4 to 12 hrs||1 mo to 12 yrs (<50 kg): 50–200 mg/kg/day in 3 to 4 divided doses||IV, IM||Phlebitis at infusion site, rash, GI upset||Single dose can be given for GC. Transient arrhythmias have developed after administration of this agent through central venous catheter.|
|Cefpodoxime||100–400 mg every 12 hrs||
|PO||Diarrhea, nausea, vomiting||Decreased absorption with antacids and H2 blockers. Can be given as a single dose for GC.|
|Ceftazidime||0.5–2 g every 8 to 12 hrs||
|IV, IM||Phlebitis at infusion site, rash, GI upset||Can interfere with some urine glucose tests. The L-arginine formulation should not be used in children.|
|Ceftibuten||400 mg every 24 hrs||
|PO||Rash, GI upset, headache||Can interfere with some urine glucose tests.|
|Ceftriaxone||IV, IM:1–2 g every 12 to 24 hrs||
|IV, IM||Phlebitis at infusion site, rash||Avoid in neonates with hyperbilirubinemia. Higher doses are used for meningitis. A ceftriaxone-calcium salt can precipitate in the gallbladder, causing sonographically detectable abnormalities.|
|IV, IM||Phlebitis at infusion site, GI upset||Can interfere with some urine glucose tests.|
|Ceftaroline fosamil||600 mg every 12 hours||Not studied for pediatric use||IV||Phlebitis at infusion site, GI upset, headache||Slow IV infusion over 60 minutes. Can interfere with some urine glucose tests.|
The first-generation cephalosporins are most active against aerobic gram-positive cocci. These agents include cefazolin, cephalexin, and cefadroxil, and they are often used for skin infections caused by S. aureus and Streptococcus. They have activity against E. coli and some activity against H. influenzae and Klebsiella species, but because of the limited gram-negative coverage, they are not first-line agents for infections that are likely to be caused by gram-negative bacteria.
The second-generation cephalosporins are more active against gram-negative organisms, such as Moraxella, Neisseria, Salmonella, and Shigella. Cefoxitin and cefotetan, which are included in this group under this classification system although they are technically cephamycins, also have more coverage against anaerobic bacteria. The true cephalosporins that are also part of this class are cefprozil, cefuroxime, cefaclor, cefoxitin, and cefotetan. These drugs are used primarily for respiratory tract infections because they are better against some strains of beta-lactamase producing H. influenzae.
The third-generation cephalosporins have the most activity against gram-negative organisms, including Neisseria species, M. catarrhalis, and Klebsiella, while ceftazidime is active against P. aeruginosa. These agents have less coverage of the gram-positive cocci, notably methicillin-sensitive S. aureus. In addition to the agent with antipseudomonas coverage, this class includes cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftibuten, and ceftriaxone. These drugs are useful for more severe community-acquired respiratory tract infections, resistant infections, and nosocomial infections (because of the high incidence of resistant organisms) .
Cefepime is classed as a fourth-generation cephalosporin because it has good activity against both gram-positive and gram-negative bacteria, including P. aeruginosa and many Enterobacteriaceae. The gram-negative and anaerobic coverage makes cefepime useful for intra-abdominal infections, respiratory tract infections, and skin infections.
Ceftaroline fosamil is the only advanced generation cephalosporin to gain FDA approval to date. While the agent is not considered active against P. aeruginosa, Enterococcus spp., and extended-spectrum beta-lactamase producing Enterobacteriaceae or AmpC mutants, it has enhanced activity against many gram-negative and gram-positive bacteria. It is active against community-acquired pneumonia infections caused by E. coli, H. influenzae, Klebsiella, S. aureus (methicillin-susceptible isolates only), and S. pneumoniae (including cases with concurrent bacteremia) and is effective and safe for treating skin infections caused by multidrug-resistant S. aureus [149,152]. Clinical cure rates for moderate-to-severe community-acquired pneumonia were higher with ceftaroline (83.3%) than with ceftriaxone (70%) in a phase III clinical trial, and the agent was well tolerated .
The orally administered cephalosporins include cefaclor, cefadroxil, cephalexin, cefprozil, cefuroxime axetil, cefixime, cefpodoxime proxetil, ceftibuten, and cefdinir. In general, the orally administered cephalosporins are absorbed rapidly. Cephalexin, cefadroxil, cefaclor, cefixime, ceftibuten, and cefdinir are nonesterified and are absorbed from the GI tract by active transport in the small intestine. Other agents, such as cefuroxime axetil and cefpodoxime proxetil, are prodrug esters and are passively absorbed. Once absorbed into the cells lining the small intestine, these agents are hydrolyzed and then excreted into the blood stream as active cephalosporins .
The presence of food or antacids may increase or decrease the absorption, depending on the drug. Cefuroxime axetil and cefpodoxime proxetil have increased absorption when taken with food. Cefaclor, cefadroxil, and cephalexin have slowed absorption when food is in the stomach. Cefixime, cefprozil, and ceftibuten are not affected by the presence of food. Cefpodoxime is the only cephalosporin whose absorption is decreased by the presence of antacids or H2 antagonists .
There is extensive distribution of the cephalosporins into body tissues and fluids. They readily cross the placenta and are also found in synovial fluid. Concentrations in bile and urine are high. Most cephalosporins do not cross into the CSF in sufficient concentration to be recommended for the treatment of meningitis, but there are some exceptions. Cefuroxime, cefotaxime, ceftriaxone, cefepime, and ceftaroline all have good penetration into the CSF [28,152].
Most cephalosporins are primarily eliminated by the kidneys. The exception in the oral cephalosporins is cefixime, half of which is excreted in the urine. The remaining half is partly metabolized to inactive metabolites and partly excreted in the bile. Cefotaxime and cephalothin are deacetylated by the liver to a bioactive metabolite and inactive forms. The deacetylated metabolites are then excreted by the kidney. Cefpiramide is excreted predominantly in the bile.
In severe hepatic insufficiency, compensatory changes in renal excretion of the hepatically metabolized drugs may occur . However, the dosage of cefotaxime may have to be adjusted. If both severe renal and hepatic insufficiency are present, dosage adjustments of both cefotaxime and ceftriaxone is necessary.
As a group, cephalosporins are relatively well tolerated . The most common complaints are GI upset, resulting in nausea, vomiting, or diarrhea. Thrombophlebitis can occur with intravenous (IV) administration. One to three percent of patients develop an allergic reaction. Rash, fever, eosinophilia, and urticaria can develop. Anaphylaxis is rare. Infrequently, there is some cross-sensitivity with true penicillin allergy (4% to 10% of cases); this occurs mostly with first-generation cephalosporins . If a patient develops urticaria, anaphylaxis, or angioedema with penicillins or a cephalosporin, avoid using any of the other cephalosporins.
Nephrotoxicity may develop . Neurotoxicity is rare. Cephalosporins that contain the methylthiotetrazole (MTT) side chain (cefotetan) may induce a disulfiram-like reaction with alcohol ingestion (e.g., flushing, tachycardia, nausea and vomiting, diaphoresis, dyspnea, hypotension, and confusion). This is due to increased circulating acetaldehyde.
Ceftriaxone has been associated with cholelithiasis due to precipitation in the bile .
Rare reactions include hematologic toxicity with resultant eosinophilia, thrombocytopenia, and leukopenia, all of which resolve after stopping treatment . Rarely, hemolytic anemia develops . Hypoprothrombinemia may occur with cephalosporins with the MTT side chain as a result of interference by the MTT moiety with the synthesis of vitamin-K-dependent clotting factors . For patients at high risk of bleeding, exogenous vitamin K may help alleviate this side effect.
False-positive glucosuria testing with a copper reduction test (Clinitest) may occur with many cephalosporins .
The serum levels of all the cephalosporins are increased with co-administration of probenecid. The effects of warfarin may be enhanced by co-administration of cefotetan, cefazolin, cefoxitin, and ceftriaxone.
Meropenem, imipenem/cilastatin, doripenem, and ertapenem are parenteral synthetic beta-lactams derived from thienamycin, an antibiotic produced by Streptomyces cattleya. They have a lactam ring, like the penicillins and cephalosporins, but have a methylene moiety in the ring.
Like other beta-lactams, the carbapenems inhibit mucopeptide synthesis in the bacterial cell wall by binding to PBPs, leading to lysis and cell death. Bacterial resistance may occur due to a specific beta-lactamase that affects carbapenems. Another significant source of resistance is a mutation that results in the absence of the outer membrane porin, thus not allowing transport of the drug into the cell . Cross-resistance may occur between the carbapenems.
Imipenem and ertapenem have a wide antimicrobial spectrum with excellent activity against anaerobic bacteria, including Bacteroides species. They also cover many gram-positive cocci, such as Enterococcus and Streptococcus, as well as many gram-negative bacteria . Meropenem has somewhat greater activity against gram-negative bacteria, which are not affected by most beta-lactamases. Doripenem has good activity against pseudomonas aeruginosa.
Imipenem and ertapenem are indicated by the U.S. Food and Drug Administration (FDA) for use in urinary tract infections, pneumonia, intra-abdominal infections, and skin and soft tissue infections . Meropenem is approved by the FDA for treatment of intra-abdominal infections, skin and skin structure infections, and meningitis in patients older than 3 months of age .
Imipenem/cilastatin, meropenem, and ertapenem are given parenterally, as they are unstable in stomach acid. Imipenem is combined with cilastatin, which inhibits dehydropeptidase I in the proximal renal tubular cells. Dehydropeptidase I inactivates imipenem by hydrolysing the beta-lactam ring, so adding the cilastatin allows increased levels of imipenem in the urine and also prevents the production of the nephrotoxic metabolites of imipenem . Meropenem, doripenem, and ertapenem do not require a dehydropeptidase I inhibitor.
Meropenem is well distributed in body tissues and fluids, including the CSF. Imipenem/cilastatin and ertapenem are distributed throughout body tissues, but with only low concentrations in the CSF .
Most of the imipenem/cilastatin dose is excreted in the urine. The remaining 20% to 25% of the dose is excreted through an unknown mechanism. Meropenem is excreted unchanged into the urine by means of glomerular filtration and tubular secretion . Ertapenem is metabolized by hydrolysis of the beta-lactam ring, and then both the metabolite and parent drug are excreted in the urine.
The carbapenems require dosage adjustment in patients with renal insufficiency. No changes in dosage are necessary for patients with hepatic insufficiency.
The carbapenems are generally well tolerated. Occasional reactions include nausea and vomiting, phlebitis at the infusion site, elevation of liver enzymes, and leukopenia. Seizures may occur. The risk is higher in patients with underlying central nervous system (CNS) disease and in patients with renal disease, which results in high serum levels of the drug . Hypersensitivity reactions may occur, and there is a high degree of cross-sensitivity with penicillins. Carbapenems are contraindicated in patients allergic to the carbapenems or penicillins.
There are few drug interactions associated with the carbapenems, but probenecid may increase the serum levels of meropenem, ertapenem, and imipenem/cilastatin and should be avoided. Ertapenem cannot be infused with dextrose or other medications. Meropenem may reduce levels of valproic acid .
Meropenem, doripenem, and ertapenem are pregnancy category B, with animal studies showing no adverse reactions . Imipenem/cilastatin is pregnancy category C, based on studies in monkeys that showed increased embryonic loss and side effects in the mother . No data is available regarding breastfeeding and carbapenem administration.
The safety of doripenem use has not been studied in children. Meropenem has been used in children and is indicated by the FDA for the treatment of pediatric meningitis but has not been studied in infants younger than 3 months of age . Ertapenem can be used in infants older than 3 months of age, and imipenem can be used from birth; these agents are useful for treating complicated infections in pediatric patients (e.g., complicated urinary tract infections).
Monobactams have a single beta-lactam core, distinguishing them from the other beta-lactam drugs . Aztreonam is the only available example of this class of drugs. Aztreonam was originally extracted from Chromobacterium violaceum. It is now manufactured as a synthetic antibiotic.
THE OTHER BETA-LACTAMS
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|Doripenem||500 mg every 8 hours||Not studied for pediatric use||IV||Headache, rash, nausea, vomiting, diarrhea, phlebitis||Dosage adjustment necessary for renal impairment. Cannot be used in patients with known hypersensitivity to any beta-lactam antibiotic. Seizure risk in patients with CNS disorders.|
|IV, IM||Diarrhea, nausea, phlebitis at infusion site||Seizure risk in patients with CNS disorders|
|Imipenem and cilastatin||
|IV||Phlebitis at infusion site, rash||
|Meropenem||1.5–6 g/day in 3 divided doses||
|IV||Diarrhea, nausea, inflammation at the injection site, headache||Can cause elevated LFTs. Seizure risk in patients with CNS disorders.|
|IV, IM||Rash, nausea, vomiting, phlebitis at infusion site||Rare cross-sensitivity with allergy to other beta-lactams.|
As with other beta-lactams, aztreonam inhibits mucopeptide synthesis in the bacterial cell wall by binding to the penicillin-binding proteins of gram-negative bacteria, leading to cell lysis and death. Aztreonam is resistant to most beta-lactamases. Treatment in combination with an aminoglycoside appears to be synergistic against Pseudomonas.
Aztreonam does not have significant activity against gram-positive or anaerobic bacteria and is primarily used against gram-negative aerobic bacteria, including P. aeruginosa and Klebsiella. It is indicated for use in pneumonia, soft-tissue infections, urinary tract infections, and intra-abdominal and pelvic infections that are caused by gram-negative aerobic bacteria.
Aztreonam is absorbed rapidly after intramuscular (IM) dosing, but it cannot be given orally due to instability in stomach acid. It is distributed widely in body tissues and fluids, including inflamed meningeal tissue . Aztreonam is mainly excreted in the urine as an unchanged drug, although there is also minimal hepatic metabolism . Doses must be adjusted for renal insufficiency based on glomerular filtration rate .
Frequent adverse reactions include elevations of liver enzymes and transient eosinophilia. Less common reactions include phlebitis at the infusion site, rash, diarrhea, and nausea .
There have been a few reports of cross-allergy reactions in patients who are allergic to ceftazidime, but patients with penicillin and cephalosporin allergy can usually tolerate aztreonam . Aztreonam is contraindicated in patients with prior allergic reactions to it or to any component of the formulation.
No drug interactions have been reported with aztreonam .
Aztreonam is pregnancy category B, based on animal studies that have shown no ill effects of the drug. There is no human data available .
Aztreonam is secreted in breastmilk in low concentrations; breastfeeding is not recommended because the effects of the drug have not been studied in young infants.
Aztreonam has not been studied for use in children younger than 1 month of age but appears safe in children older than 1 month of age. It has been shown to be very useful in children with respiratory symptoms of cystic fibrosis .
The aminoglycosides were developed during the 1940s. Actinomycetes were studied for possible antimicrobial by-products, and it was found that Micromonospora and Streptomyces produced useful agents. Streptomycin is derived from Streptomyces griseus and was the first of the aminoglycosides that was developed.
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|Amikacin||5–7.5 mg/kg every 8 hrs||5–7.5 mg/kg every 8 hrs||IV, IM||Renal failure, vestibular nerve damage, auditory nerve damage||Predisposition to auditory/vestibular nerve damage may be genetic; check family history. Check serum levels. Doses are based on lean body mass; maintenance dose is based on calculation with creatinine clearance. Additional dose adjustments are needed in renal failure.|
|Gentamicin||1–2.5 mg/kg every 8 to 12 hrs, or 4–7 mg/kg once daily||
|15 mg/kg/day in 2 to 3 divided doses||IV, IM|
|Neomycin||500–2000 mg every 6 to 8 hrs, or 4–12 g/day in 4 to 6 divided doses||50–100 mg/kg/day in 3 to 4 divided doses||PO, topical||Systemic absorption is possible, resulting in the same side effects as amikacin.||Used as a bowel prep for surgery. Is also formulated in some topical eye, ear, and skin preparations.|
|Streptomycin||15–30 mg/kg/day or 1g every 12 hours||
|IM||Renal failure, vestibular nerve damage, auditory nerve damage||This is the most ototoxic of aminoglycosides; levels must be monitored closely.|
|Tobramycin||1–2.5 mg/kg every 8 to 12 hrs, or 4–7 mg/kg once daily dose||
|IV, IM inhalation solution, ophthalmic drops||Renal failure, vestibular nerve damage, auditory nerve damage||Effects of nondepolarizing muscle relaxants can be increased.|
The basic structure of the aminoglycosides is an aminocyclitol ring. Different members of the family have different glycosidic linkages and side groups.
The aminoglycosides have at least two effects on the bacterial cell that ultimately result in cell death. These agents bind negative charges in the outer phospholipid membrane, displacing the cations that link the phospholipids together. This leads to disruption in the wall and leakage of cell contents. In addition, they inhibit protein synthesis by binding to the 30S subunit of the ribosome, causing miscoding and termination .
Although resistance to aminoglycosides is less common than with many other antibiotics, it can develop as a result of three known mechanisms. The most common pattern of resistance is through modification of the aminoglycoside molecule itself by enzymes produced by some bacteria. After the aminoglycoside is altered, it cannot bind as well to the ribosomes. The genes that encode for these enzymes are carried on plasmids, allowing rapid transfer of resistance between bacteria. Of note, amikacin has an S-4 amino 2-hydroxybutyryl (AHB) side chain that protects it against deactivation by many bacterial enzymes and is therefore less susceptible to this bacterial defense mechanism .
The binding site for aminoglycosides on the rRNA of the ribosome may also be altered, reducing binding. In addition, mutations that cause reduced uptake of aminoglycosides have been documented .
To combat resistances and overcome the relative natural resistance of enterococcus to aminoglycosides, other agents that target the cell wall are often used in conjunction with the aminoglycosides. Damage to the cell wall from the additional agents may be bactericidal in some cases and also makes the cell wall more permeable to the aminoglycosides .
The aminoglycosides are effective for the treatment of aerobic gram-negative bacilli, such as Klebsiella species, Enterobacter, and P. aeruginosa. There is very little activity against anaerobes and gram-positive organisms, so combination therapy with a penicillin, vancomycin, or other agents against gram-positive organisms and anaerobes is commonly used. The aminoglycosides are indicated for infections caused by susceptible organisms of the urinary tract, respiratory tract, skin and soft tissues, and sepsis due to gram-negative aerobic bacilli.
Aminoglycosides have poor oral absorption, but they are rapidly absorbed after parenteral administration. Neomycin is taken orally as a bowel decontaminant and has minimal absorption. Available parenteral aminoglycosides include amikacin, gentamicin, kanamycin, streptomycin, and tobramycin. They may also be administered directly into intrapleural and intraperitoneal fluid, with rapid absorption. Tobramycin is used for pulmonary infections in cystic fibrosis but must be administered as an inhaled solution to obtain adequate local drug levels .
The aminoglycosides are widely distributed in extracellular fluid, including pleural fluid, synovial fluid, abscesses, and peritoneal fluid. They are relatively insoluble in lipid, so the volume of distribution is lower in obese patients. They have poor distribution in bile, aqueous humor, bronchial secretions, sputum, and the CSF .
Aminoglycosides are excreted, unmetabolized, by the kidneys. There is no reduction of dosage necessary in liver failure, as there is no hepatic metabolism of these agents. In renal failure, the dosage must be carefully adjusted based on glomerular filtration rate and measured serum levels. Serum levels should be followed in all patients with reduced renal function .
Common side effects associated with aminoglycosides include renal failure that is usually reversible when the drug is discontinued. The exact mechanism of renal injury and how that injury results in decreased glomerular filtration is unknown . It appears that, although there is no hepatic metabolism of the aminoglycosides, concomitant liver disease increases the likelihood of the development of nephrotoxicity .
Less commonly, vestibular and auditory impairment may develop during treatment with aminoglycosides. These effects are usually reversible, and because there is some data suggesting that there is a genetic predisposition to this side effect, it should be avoided in patients who have a family history of ototoxicity with aminoglycosides .
Streptomycin is the most ototoxic of the aminoglycosides, and levels must be monitored carefully. Neomycin is too ototoxic to use parenterally, so it is used orally to decontaminate the bowel in the treatment of hepatic encephalopathy and in combination therapy to prepare the bowel for surgery.
Neuromuscular blockage has also been observed as a side effect. Aminoglycosides may aggravate muscle weakness in patients with neuromuscular disorders, such as myasthenia gravis and Parkinson's disease, due to a curare-like effect on neuromuscular function .
Hypersensitivity reactions are not common with aminoglycosides, but rash, fever, urticaria, angioneurotic edema, and eosinophilia may occur. Very rare reactions include optic nerve dysfunction, peripheral neuritis, arachnoiditis, encephalopathy, pancytopenia, exfoliative dermatitis, and amblyopia. Bronchospasm and hoarseness have been known to occur with tobramycin inhalation solution .
The aminoglycosides are contraindicated in patients with hypersensitivity to the drug. Cross-sensitivity between aminoglycosides does occur. Streptomycin also contains metabisulfite and should be avoided if the patient is allergic to sulfites (more common in asthmatics) .
There are numerous drug interactions that should be taken into consideration when using the aminoglycosides. Nephrotoxicity may be increased with co-administration with other drugs that are nephrotoxic. Loop diuretics (e.g., furosemide) and other ototoxic drugs may increase the incidence of ototoxicity. Respiratory depression may occur if aminoglycosides are given with nondepolarizing muscle relaxants. Neomycin may affect digoxin levels by altering the bowel flora that are responsible for the metabolism of digoxin in the GI tract. Gentamicin may also cause increased serum digoxin levels .
In vitro deactivation of penicillins due to acylation has been observed, so the drugs should not be mixed in vitro. Tobramycin inhalation solution cannot be mixed in the nebulizer with dornase alfa .
Amikacin, streptomycin, tobramycin, and kanamycin are pregnancy category D due to eighth cranial nerve toxicity that has occurred in the fetus with some aminoglycosides. Gentamicin is pregnancy category C due to animal studies that show dose-related nephrotoxicity. Ototoxicity has not been reported with gentamicin, but it may occur. Neomycin is pregnancy category C due to minimal systemic absorption of the oral dose. Despite these categorizations by the manufacturers, some authorities think that these agents may be used if the benefit outweighs the potential risk .
Traces of aminoglycosides are excreted in breastmilk, but the AAP considers this compatible with breastfeeding because aminoglycosides are very poorly absorbed from the GI tract . However, they may cause alterations in the normal bowel flora of the infant.
Half-life alterations occur in patients at extremes of age. The half-life in neonates and low-birth-weight infants may be considerably prolonged. The elderly may also have a longer aminoglycoside half-life due to an age-related decrease in renal function . Geriatric dosing should be based on ideal body weight estimates .
The original macrolide, erythromycin, was discovered in 1952 by J.M. McGuire. It is produced by Saccharopolyspora erythrae (formerly known as Streptomyces erythreus). Semisynthetic derivatives (clarithromycin, azithromycin) have been produced from the original erythromycin, with modifications that improve acid stability, antibacterial spectrum, and tissue penetration.
THE MACROLIDES AND TELITHROMYCIN
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|PO, IV||GI upset||One dose of 1 g given PO can be used for non-GC urethritis/cervicitis. Interaction with pimozide/cyclosporine.|
|Clarithromycin*||250–500 mg every 12 hrs, or 1 g/day extended-release formulation||7.5 mg/kg every 12 hrs||PO||GI upset, metallic taste||Inhibits liver CYP 450 enzyme 3A4, resulting in multiple significant drug interactions. Special dosing combined with omeprazole and amoxicillin is one regimen used for H. pylori treatment.|
|PO, IV, topical ophthalmic solution||GI intolerance (common), phlebitis at IV infusion site||Inhibits liver CYP 450 enzymes 3A4 and 1A2, resulting in multiple significant drug interactions.|
|Telithromycin||800 mg every 24 hrs||
|PO||Nausea, diarrhea||Occasionally causes visual changes (reversible). Inhibits liver CYP 450 enzyme 3A4, resulting in multiple significant drug interactions.|
The macrolides are bacteriostatic, inhibiting protein synthesis by binding at the 50S ribosomal unit and by blocking transpeptidation and translocation. At high concentrations or with rapid bacterial growth, the effects may be bactericidal .
Telithromycin is technically a ketolide, but it is structurally related to the macrolides. It also functions by binding the ribosomal subunit with subsequent inhibition of bacterial protein synthesis. By binding in two places, telithromycin remains active against bacteria that produce methylases, which alter binding at the domain V site on the ribosomal subunit .
Many bacteria that are resistant to the penicillins are also resistant to erythromycin. Bacterial resistance may result from decreased permeability of the cell membrane; in addition, an increase in active efflux of the drug may occur by incorporating a transporter protein into the cell wall . The gene for this mechanism is transferred on plasmids between bacteria. Mutations of the 50S ribosomal receptor site may also develop, preventing binding of the erythromycin. Lastly, bacterial enzymes have been described that may deactivate erythromycin . It is likely that this form of resistance is also transferred on plasmids.
Many strains of H. influenzae are resistant to erythromycin alone but are susceptible to a combination with a sulfonamide . Erythromycin ethylsuccinate and sulfisoxazole are manufactured as suspensions for use in treating acute otitis media in children older than 2 months of age. They are useful for targeting H. influenzae, one of the common pathogens in otitis media in this age group.
Erythromycin has a wide spectrum of activity. Gram-positive bacteria that are usually susceptible to erythromycin include the Streptococcus species. Erythromycin is a second-line agent for gram-negative bacteria, such as H. influenzae and M. catarrhalis. Macrolides are particularly useful for their coverage of atypical bacteria, such as Mycoplasma and Chlamydia. Some spirochetes and mycobacteria are also susceptible to the macrolides. These drugs are indicated for upper respiratory tract infections, such as sinusitis, otitis media, pharyngitis, and bronchitis. They are also useful in the treatment of pertussis, Legionnaires' disease, and diphtheria. Telithromycin is indicated for community-acquired pneumonia .
Erythromycin base is deactivated by gastric acid, so it is formulated in enteric-coated tablets or capsules that protect the drug until it reaches the duodenum, where it is absorbed. Eating increases stomach acid secretion and may slow absorption as a result. The ester forms of the erythromycin base (stearate, estolate, and ethylsuccinate) were all formulated to improve absorption. The estolate is the best absorbed of the three after eating; the ethylsuccinate form is best absorbed in the fasting state . Erythromycin may also be given intravenously.
Clarithromycin and azithromycin have excellent absorption after oral dosing. Clarithromycin and telithromycin may be given with food, but for azithromycin, the presence of food in the stomach causes significant delays in absorption .
All the macrolides have extensive tissue distribution, with less than adequate penetration into the brain tissue and the CSF . Erythromycin and azithromycin are primarily excreted unchanged into the bile. Clarithromycin is excreted in the bile and in the urine, both unchanged and as the hydroxy metabolite. Telithromycin undergoes hepatic metabolism and is eliminated mainly in the bile, but also in the urine .
It may be necessary to adjust the doses of the macrolides in the presence of severe hepatic insufficiency. Azithromycin and clarithromycin doses may have to be reduced in severe renal failure. Because telithromycin is eliminated by more than one mechanism, hepatic or renal insufficiency is unlikely to affect serum levels unless they are both present .
While serious side effects with the macrolides are rare, milder side effects are common. Erythromycin stimulates motility in the GI tract, and this may cause abdominal cramping, diarrhea, nausea, and vomiting. Hepatic dysfunction with or without jaundice has occasionally been reported. There have also been some reports of reversible hearing loss in patients treated with erythromycin in high doses or in the presence of renal insufficiency. With IV erythromycin, prolongation of the QT interval and ventricular tachycardia may occur .
Clarithromycin may cause nausea, diarrhea, abnormal taste, dyspepsia, and headache. There have been reports of tooth discoloration that is reversible with professional cleaning. Transient CNS changes with anxiety and behavioral changes, which resolve when the drug is discontinued, have also been reported .
Side effects from telithromycin include nausea and diarrhea in up to 10% of treated patients . Occasional side effects include headache, dizziness, vomiting, reversible liver function test (LFT) elevation, and hepatitis. Reversible vision blurring and diplopia occurs in 1% of patients . Exacerbations of myasthenia gravis have been reported as well. QT interval elongation may occur, so telithromycin should be avoided in patients at risk for arrhythmias .
Allergic reactions to macrolides are rare, but may include rash and eosinophilia. Very rarely, severe reactions such as Stevens-Johnson syndrome have occurred. The drugs are contraindicated in patients with known hypersensitivity to the macrolides.
Drug interactions are extensive. Erythromycin and clarithromycin are inhibitors and substrate for the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A4). If they are given with a drug that is primarily metabolized by CYP3A, the drug serum levels may be increased and/or prolonged . Erythromycin and clarithromycin are contraindicated with concurrent use of cisapride, pimozide, astemizole, or terfenadine. Serum levels of theophylline, cyclosporine, digoxin, ergotamine, carbamazepine, benzodiazepines, warfarin, amiodarone, and tacrolimus may also be affected by concurrent administration with erythromycin and clarithromycin. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors levels may also be elevated, with increased risk for rhabdomyolysis .
Azithromycin is not likely to interact with drugs metabolized by CYP3A4. However, azithromycin interacts with pimozide, potentially resulting in QT interval prolongation and arrhythmia . Co-administration with pimozide is therefore contraindicated. Levels of cyclosporine could potentially be increased and therefore should be monitored closely .
Telithromycin is metabolized in the liver, partly by the P450 enzyme system and partly by other mechanisms. It may interact with the following drugs: cisapride, pimozide, quinidine, procainamide, dofetilide, rifampin, ergot alkaloids, itraconazole, ketoconazole, midazolam, digoxin, cyclosporine, carbamazepine, hexobarbital, phenytoin, tacrolimus, sirolimus, metoprolol, theophylline, and statins. Telithromycin is contraindicated in patients allergic to macrolides or telithromycin. It should not be given with cisapride or pimozide . An interaction between warfarin and telithromycin has also been reported .
Erythromycin is pregnancy category B, with an erythromycin estolate preparation as the preferred form because it is less likely to cause hepatotoxicity. Surveillance studies have not shown any increase in adverse outcomes. The CDC recommends the use of erythromycin for the treatment of Chlamydia during pregnancy . Azithromycin is also category B, based on animal studies. It has been used safely to treat Chlamydia in pregnant women 
Clarithromycin is pregnancy category C, based on the finding that it causes growth retardation in monkeys and adverse effects on other mammals. A postmarketing surveillance study did not find any evidence of teratogenicity, but another study found a higher rate of spontaneous abortion in those treated with clarithromycin [92,93].
Erythromycin is excreted in breastmilk, but the AAP considers it usually compatible with breastfeeding . Clarithromycin is excreted in breastmilk in lactating animals, but the effects have not been studied in humans. There have been some reports of infantile hypertrophic pyloric stenosis following treatment of newborns with erythromycin .
The first quinolone, nalidixic acid, was introduced in 1962. It was developed as a result of chloroquine synthesis. Later, derivatives with broader spectrum antimicrobial coverage were produced, leading to the current class of quinolone drugs. As with other classes of synthetic and semisynthetic antimicrobials, alterations of side chains affect antimicrobial activity and pharmacokinetics .
Quinolones cause bacterial cell death by inhibiting DNA synthesis. They inhibit DNA gyrase and DNA topoisomerase, enzymes that mediate DNA supercoiling, transcription, and repair . The exact mechanism by which this leads to cell death has not yet been determined.
Bacterial resistance develops as a result of spontaneous mutations that change the binding sites for quinolones on the DNA gyrase and the DNA topoisomerase . Mutations that decrease the ability of quinolones to cross the cell membrane also occur. Some of these resistances may be transferred from other bacteria by means of plasmids .
The quinolones are active against many gram-negative cocci, gram-negative bacilli, atypical bacteria (e.g., Legionella, Mycoplasma), and staphylococci. Activity against streptococci and anaerobes is not as strong, although newer agents, such as moxifloxacin, have better coverage for these . Gram-negative coverage includes Campylobacter, Enterobacter, E. coli, H. influenzae, Klebsiella, Salmonella typhi, Shigella, and Vibrio cholerae. Indications for the use of quinolones include urinary tract infections, N. gonorrhoeae infections of the urethra and cervix, pneumonia, sinusitis, soft tissue infections, and prostatitis. Ciprofloxacin is indicated for post-exposure prophylaxis for anthrax, and levofloxacin has an indication for the treatment of inhalation anthrax infection. The quinolones are absorbed well from the GI tract. Food may delay the time to reach peak serum concentration but does not decrease total absorption. The drugs are distributed well throughout all tissues, including the prostate, although the levels in the CSF and prostatic fluid are lower than serum levels .
Clearance mechanisms vary between the quinolones. Levofloxacin and ofloxacin are mainly cleared by renal excretion and have minimal hepatic clearance . Moxifloxacin is mainly excreted nonrenally. Moxifloxacin is metabolized, via glucuronide and sulfate conjugation in the liver, to an inactive metabolite .
Norfloxacin, ciprofloxacin, and gemifloxacin have mixed routes of elimination. Norfloxacin has some hepatic metabolism to active metabolites; the metabolites and parent drug are excreted by the kidney. About 30% of the dose of norfloxacin is excreted in the stool, in the bile, and as unabsorbed drug. As much as 50% of the ciprofloxacin dose is excreted renally, and 40% is excreted in the bile after hepatic metabolism. Approximately 60% of gemifloxacin is excreted in the feces, and the remainder is excreted in the urine.
In renal insufficiency, the quinolones that are primarily excreted renally and those with mixed routes of elimination require dosage adjustments . Moxifloxacin doses do not have to be adjusted for mild hepatic insufficiency, although this has not been studied in severe hepatic insufficiency .
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|PO, IV, topical, otic, ophthalmic||GI upset, headache||
|Gemifloxacin||320 mg/day||N/A||PO||GI upset, headache, rash|
|Levofloxacin||250–750 mg/day||N/A||PO, IV, topical||GI upset, headache, phototoxicity|
|Moxifloxacin||400 mg/day||N/A||PO, IV, topical, ophthalmic||GI upset, headache|
|Use adult dosing||Ophthalmic||Conjunctival irritation, keratitis|
|Norfloxacin||400 mg every 12 hrs, or 800 mg as a single dose for GC*||N/A||PO, ophthalmic||GI upset, headache||Antacids decrease absorption.|
|Ofloxacin||200–400 mg every 12 hrs||N/A||PO, IV, otic, ophthalmic|
The most common side effect with the use of quinolones is GI upset. Less common side effects include headache, insomnia, dizziness, peripheral neuropathy, tendon rupture, elevated liver enzymes, and interstitial nephritis [104,105]. Rarely, hematologic toxicities have occurred, resulting in hemolytic anemia (more likely to occur in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency), aplastic anemia, and agranulocytosis . Very rarely, hepatic necrosis and hepatic failure have been reported .
Although allergic reactions are not common, they may occur and range from a rash to severe reactions, such as Stevens-Johnson syndrome. Very rare cases of severe fatal hypoglycemia have been reported with concurrent treatment with glyburide and ciprofloxacin . Use quinolones with caution in patients with medical problems that predispose the patient to seizures.
There is also a risk of disabling peripheral neuropathy associated with the use of oral or injectable fluoroquinolones . The onset of this side effect can be rapid, and patients should be advised to contact their healthcare provider if any signs or symptoms develop. In these cases, the fluoroquinolone should be stopped and an alternative non-fluoroquinolone drug used, unless the benefit of continued treatment outweighs the risk .
Drug interactions are common and vary among the quinolones. Antacids may decrease the absorption of these agents. Iron supplements and other supplements with divalent and trivalent cations cause quinolone-cation complexes and impair absorption . Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) appear to increase the risk of seizures .
Theophylline, phenytoin, warfarin, and mexiletine levels may be elevated in patients concurrently treated with ciprofloxacin. Serum levels or prothrombin time should be monitored, and the doses of these drugs should be altered as appropriate. Dosage adjustments are not typically needed with other quinolones .
Quinolones are not recommended during pregnancy. Animal studies have demonstrated arthropathy in immature animals . It is presumed that quinolones are excreted in breastmilk, and due to the risk for arthropathy, breastfeeding while taking a quinolone should be avoided.
It is unclear if these effects cause clinically significant changes in humans, so there is debate over whether it is safe to use the drugs in children . Quinolones have been used in pediatric patients with cystic fibrosis, but they should only be used in patients younger than 18 years of age if the benefits outweigh the risks .
Sulfonamides, the first true antibiotics, are derived from azo dyes. The first agent was sulfachrysoidine, used in 1935, which released sulfanilamide in vivo . Modifications were made to the sulfanilamide to reduce side effects, resulting in the development of the modern sulfonamides. Many of the sulfonamides are no longer used as parenteral agents, but they continue to be used as topical agents or for treatment in specific conditions (e.g., prophylaxis for drug-resistant malaria). Some of these agents are no longer available in the U.S. but are still commonly used in other countries.
The sulfonamides are bacteriostatic, exerting their effect as competitive antagonists of para-aminobenzoic acid (PABA). They inhibit dihydropteroate synthase from using PABA to synthesize dihydropteroic acid, a precursor of folic acid. The lack of folic acid intermediates ultimately results in impaired synthesis of nucleotides. Bacteria that use pre-formed folate are not susceptible to the bacteriostatic action. Silver sulfadiazine is one exception, as it exerts its effects on the cell membrane and cell wall and is bactericidal. The mechanism of action of mafenide is not known.
Unfortunately, bacterial resistance to sulfonamides is common, with cross-resistance between agents frequently occurring. Mutations that result in additional production of PABA or changes in the enzyme binding sites for sulfonamides are responsible for the resistance . Genes for these resistant mutations may be carried on plasmids, allowing rapid transfer to other similar bacteria and resulting in more rapid development of resistance patterns than through random mutation alone .
One method for improving bacterial activity against potentially resistant strains is the addition of trimethoprim . Trimethoprim is a competitive inhibitor of dihydrofolate reductase, another enzyme active in the synthesis of folate. Trimethoprim resistance is also common .
The sulfonamides can be divided into 4 groups based on absorption and excretion attributes. They are classified as short- to medium-acting agents, long-acting agents, agents limited to activity in the GI tract, and topical agents.
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|Short- to Medium-Acting|
|Sulfadiazine||2–4 g/day in3to 6 divided doses||>2 mos: 75–150 mg/kg/day in 4 to 6 divided doses||PO||Rash, pruritus||Multiple drug interactions. Contraindicated in infants <2 mos of age.|
|Sulfamethoxazole and trimethoprim||
|PO, IV||Rash, pruritus||Multiple drug interactions.|
|Sulfisoxazole and erythromycin||400 mg erythromycin and 1200 mg sulfisoxazole every 6 hours (based on erythromycin content)||≥2 months: 50 mg/kg/day erythromycin and 150 mg/kg/day sulfisoxazole in divided doses every 6 hours||PO||Rash, pruritus||Multiple drug interactions. Only in combination with erythromycin. Contraindicated in infants <2 mos of age.|
|Sulfadoxine/ pyrimethamine||Single dose of 3 tablets||
|PO||Folic acid deficiency, blood dyscrasias, GI upset,||For malaria prophylaxis: A single dose should be carried for self-treatment in the event of febrile illness when medical attention is not immediately available. Note: Discontinue at first sign of rash, myelosuppression, or active bacterial/fungal infection|
|Limited to GI Tract|
|>2 yrs: 40–60 mg/kg/day in 3 to 6 divided doses||PO||Anorexia, headache, GI upset||Contraindicated with hypersensitivity to salicylates, sulfasalazine, sulfonamides, or mesalamine.|
|Use adult dosing||Use adult dosing||Burning at application site, rash, allergic reaction||
|Silver sulfadiazine||Apply 1.6 mm layer to burn area once or twice daily||Use adult dosing||Cream||Rash, allergic reaction|
|Sulfacetamide||Dosage varies with the preparation.||Use adult dosing||Prepared in complex with other topical medications as a solution or ointment||Rash, local irritation||Combinations with fluorometholone, prednisolone, and phenylephrine are available, each with differing dosing, indications, and contraindications. Common for ophthalmic use.|
The first group, the short- to medium-acting agents, includes sulfisoxazole, sulfamethoxazole, and sulfadiazine. Sulfisoxazole is partly metabolized to N-acetyl sulfisoxazole; both the drug and the metabolite are excreted in the urine . Because of a limited spectrum of action, sulfisoxazole is indicated primarily for uncomplicated urinary tract infection and chloroquine-resistant malaria. Sulfamethoxazole is combined with trimethoprim and is indicated for Pneumocystis jiroveci prophylaxis and treatment, upper respiratory tract infections, and urinary tract infections. The only FDA indication for sulfadiazine is toxoplasmosis .
The long-acting agents have been associated with severe allergic reactions and for the most part been replaced in use by the less-toxic sulfonamides. The only long-acting agent still available is sulfadoxine, which is given as a combination with pyrimethamine. This drug is reserved for use for the treatment of drug-resistant malaria and may be used for treatment of Toxoplasma gondii. Pyrimethamine inhibits dihydrofolate reductase in Plasmodium species during the erythrocytic stage .
Sulfadoxine/pyrimethamine is absorbed quickly from the small intestine and, like the shorter acting agents, is widely distributed in tissue and body fluids .
The agents limited to the GI tract are very poorly absorbed and have been used for reducing bacterial flora in the bowel before surgery. The only available agent in this class is sulfasalazine, which is used in the treatment of ulcerative colitis. Although absorption of sulfasalazine from the intact intestine is very low, inflammation in the bowel may result in significant absorption of the metabolite sulfapyridine.
The topical sulfonamides include mafenide acetate and silver sulfadiazine, which are used in the treatment of burns. Mafenide is used less often because it may cause a metabolic acidosis as a result of carbonic anhydrase inhibition. An additional topical agent is sulfacetamide, which is used in ophthalmic and lotion formulations. Topical sulfonamides may be absorbed systemically, and if large burn areas are treated, absorption may be significant .
The sulfonamides are quickly absorbed after administration unless they have been altered to stay in the lumen of the intestine (e.g., sulfasalazine). After absorption, they are acetylated in the liver into a toxic but inactive form. The acetylated form is mostly excreted in the urine, with a small amount excreted in bile. These drugs are widely distributed throughout body tissue and fluids, including the CSF and peritoneal fluid .
The sulfonamides undergo acetylation and glucuronidation in the liver. Both the unchanged and metabolized forms are excreted in the urine through glomerular filtration and renal tubular secretion.
Mafenide may be used in renal failure, but monitoring of acid-base balance is recommended. Dosage and frequency of administration of other sulfonamides must be adjusted in renal failure based on serum levels. No data is available on dosing in hepatic insufficiency.
Allergic reactions with rash and itching are relatively common. Nausea, vomiting, diarrhea, headache, and photosensitivity may occur. Rare but severe hypersensitivity reactions, including vasculitis, anaphylaxis, serum sickness, and Stevens-Johnson syndrome, may occur . Sulfacetamide lotion also contains metabisulfite, which may cause an allergic reaction in patients allergic to sulfites.
Sulfonamide ophthalmic preparations may cause local irritation. The topical mafenide may cause pain or burning locally. Systemic reactions may develop during treatment with ophthalmic and topical preparations of sulfonamides due to systemic absorption.
Less common reactions include metabolic acidosis that may occur with absorption of mafenide due to a by-product, (rho) carboxybenzenesulfonamide, that inhibits carbonic anhydrase. Very rare reactions with sulfonamides include blood dyscrasias (agranulocytosis, aplastic anemia, thrombocytopenia, hemolytic anemia), hepatitis and hepatocellular necrosis, and toxic nephrosis due to crystalluria . Hemolysis is more likely to develop in patients with G6PD deficiency .
Sulfonamides are contraindicated in patients who are known to be allergic to sulfa drugs and in cases where there have been previous adverse effects to sulfonamides.
Warfarin, phenytoin, and sulfonylureas may all be potentiated due to displacement of the drugs from serum albumin by the sulfonamides . Cyclosporine levels may be decreased, and levels should be monitored . Administration of PABA may antagonize the effects of sulfa drugs.
Sulfa drugs should be avoided in pregnancy near term due to the increased potential for kernicterus in the newborn . Animal studies with sulfamethoxazole show bone abnormalities and a higher incidence of cleft palate.
Mafenide, sulfacetamide ophthalmic drops, and sulfadiazine are pregnancy category C. Sulfacetamide lotion has not been studied in pregnancy. Silver sulfadiazine is pregnancy category B, based on animal studies that showed no ill effects .
Sulfonamides are excreted in breastmilk. Sulfamethoxazole and sulfisoxazole are considered compatible with breastfeeding by the AAP, although they should be avoided if hyperbilirubinemia or G6PD deficiency is present . Sulfacetamide lotion and silver sulfadiazine have not been studied in breastfeeding but would presumably also be excreted in breastmilk; use with caution in breastfeeding women .
Because of the risk of neonatal kernicterus, use of sulfonamides should be avoided in the newborn. Sulfacetamide eye drops have not been studied in children younger than 2 months of age .
Chlortetracycline, the first tetracycline, was developed in 1948 as a product of Streptomyces aureofaciens. Chlortetracycline was altered to produce tetracycline. Doxycycline and minocycline are semisynthetic derivatives.
Tetracyclines bind to the 30S ribosomal subunit, blocking the binding of aminoacyl transfer-RNA . This results in inhibition of protein synthesis, with bacteriostatic effects.
Bacterial resistance is typically the result of mutations that either prevent entrance of tetracyclines into the cell or increase the export of tetracycline out of the cell . The resistance may be transmitted by plasmids .
The tetracyclines have a broad range of antibacterial effects, covering gram-positive, gram-negative, aerobic, and anaerobic bacteria. In addition, they also have activity against spirochetes and atypical bacteria, such as Mycoplasma and Chlamydia species .
The tetracyclines may be divided into three groups based on their pharmacokinetic traits. These groups are the short-acting group, intermediate-acting group, and long-acting group. The varying half-lives are the result of different rates of renal excretion .
|Agent||Adult Dosing Range||Pediatric Dosing Range||Route||Common Side Effects||Comments|
|Tetracycline||250–500 mg every 6 hrs||25–50 mg/kg/day in 4 divided doses||PO||Photosensitivity, tooth enamel deformities in children <8 yrs of age||Polyvalent cations decrease absorption.|
|≥8 years:8–12 mg/kg/day in 2 to 4 divided doses||PO||GI upset, tooth enamel deformities in children <8 yrs of age||Polyvalent cations decrease absorption. Use caution if used with warfarin.|
|Doxycycline||100–200 mg/day in 1 to 2 divided doses||
|PO IV||Photosensitivity, tooth enamel deformities in children <8 yrs of age||Polyvalent cations decrease absorption. Use caution if used with warfarin.|
|Initial: 4 mg/kg Maintenance: 2 mg/kg every 12 hrs||PO||GI upset, tooth enamel deformities in children <8 yrs of age|
The short-acting tetracyclines include oxytetracycline and tetracycline, the namesake of the class. Frequent dosing is needed because of the very short half-life of these agents. Oxytetracycline is no longer available in the United States . Tetracycline has a broad spectrum of activity, with coverage of many aerobic gram-negative bacilli, atypical bacteria (such as Chlamydia trachomatis, Chlamydia psittaci, and Mycoplasma pneumoniae), and spirochetes, such as Borrelia burgdorferi. Tetracycline is also a second-line agent for T. pallidum. It is indicated by the FDA for treatment of rickettsial infections, typhus, Rocky Mountain spotted fever, trachoma, nongonococcal urethritis, and lymphogranuloma venereum. It is also commonly used for the treatment of acne .
The only intermediate-acting agent available in the U.S. is demeclocycline. Demeclocycline is no longer used as an antibiotic but rather is used to treat the syndrome of inappropriate antidiuretic hormone (SIADH) .
The long-acting tetracycline agents, doxycycline and minocycline, are the more recently developed drugs. The main difference between these and the short-acting agents is that these may be dosed less frequently. The spectrum of bacterial coverage is essentially the same and the indications are the same, with the additional indication for the treatment of inhalation anthrax as part of a multidrug regimen.
Tetracycline is well absorbed after an oral dose taken in the fasting state. Doxycycline and minocycline are well absorbed after an oral dose and may be given with or without food.
The tetracyclines are well distributed throughout body tissues and fluids; distribution in the CSF is adequate for the treatment of some infections [133,134]. The excellent tissue penetration results in the ability of the drug to cross into the dentin, where the tetracycline permanently chelates with the calcium .
Most of the tetracycline dose is excreted unchanged into the urine by glomerular filtration, although there is some biliary excretion as well. Doxycycline and minocycline are mostly excreted by nonrenal, possibly hepatic, routes. Only 20% to 26% of doxycycline and 4% to 19% of minocycline is excreted in the urine .
Tetracycline should be avoided in the presence of renal insufficiency, because it accumulates rapidly in the serum in the presence of decreased renal function. Doxycycline may be used in renal failure, as it will be excreted into the bile .
Because tetracyclines have been known to cause hepatic toxicity, they should not be used in patients with hepatic insufficiency .
Tetracyclines commonly cause GI upset, including nausea, vomiting, and diarrhea. They also cause staining and deformity of the teeth in children younger than 8 years of age. Photosensitivity, pseudotumor cerebri, esophageal ulceration, and hepatotoxicity occur rarely .
Minocycline is often associated with vertigo, nausea, and vomiting, and it may increase azotemia in renal failure. In addition, prolonged use of minocycline may cause reversible discoloration of the fingernails, the sclera, and the skin . Minocycline has been associated with a lupus-like reaction .
Allergic reactions to tetracyclines are not common but may range from mild rashes to anaphylaxis. Tetracyclines are contraindicated in patients who have shown hypersensitivity to any tetracyclines.
Several types of drug interactions result in alterations in serum levels of tetracyclines. Agents that alkalinize the urine will increase excretion of the tetracyclines. Polyvalent metal cations (calcium, aluminum, zinc, magnesium, and iron) and bismuth decrease absorption . Drugs that induce hepatic enzymes may decrease the half-life of doxycycline.
Interactions that affect the efficacy of other drugs also occur. The bactericidal effect of penicillins may be decreased by co-administration with tetracyclines. Concurrent use of oral contraceptives may make the contraceptive less effective [142,143]. The effects of warfarin are increased, probably because tetracyclines depress plasma prothrombin activity, resulting in a synergistic effect . Digoxin effects may be increased because of changes in the bowel flora that are responsible for digoxin metabolism .
Tetracycline and doxycycline are pregnancy category D because of impaired bone development in the fetus. Hypoplasia of the enamel and discoloration of fetal teeth may occur, and maternal hepatic toxicity has been reported as well [146,147].
Tetracyclines are excreted into the breastmilk in small amounts. Most exposed infants have very low blood levels of the drug and probably are not at risk . Tetracyclines should not be used in children younger than 8 years of age because of the risk for tooth deformity.
Antibiotics are commonly used drugs that are diverse in their actions and side effects. The large number of antibiotics available makes it challenging to understand the characteristics of each of these antimicrobial agents, including important information such as toxicities and indications. Knowing the general characteristics of the classes of antibiotics makes it easier to recall the specific characteristics of agents within those classes, including newly introduced and future drugs.
Understanding the indications and antimicrobial effects of the antibiotic classes also makes it easier for the practitioner to tailor antibiotic treatment. This will lessen the likelihood of the development of microbial resistances, diminish side effects, and more effectively treat infections.
It is important to remember that the indications given by the FDA are guidelines. Many antibiotics are used for off-label purposes, and they may be used in doses that differ from the recommended doses, particularly for severe and life-threatening infections or for special populations, such as premature infants, neonates, and the elderly. Before using a specific agent, carefully review the detailed information offered in the package insert.
1. Poutanen SM, Simor AE. Clostridium difficile-associated diarrhea in adults. CMAJ. 2004;171(1):51-58.
2. Kaye KS, Fraimow HS, Abrutyn E. Pathogens resistant to antimicrobial agents: epidemiology, molecular mechanisms, and clinical management. Infect Dis Clinics North Am. 2000;14(2):293-319.
3. Neu HC. Overview of mechanisms of bacterial resistance. Diagn Microbiol Infect Dis. 1989;12(4 suppl):S109-S116.
4. Normark BH, Normark S. Evolution and spread of antibiotic resistance. J Intern Med. 2002;252(2):91-106.
5. Raymond DP, Kuehnert MJ, Sawyer RG. CDC/SIS position paper: preventing antimicrobial-resistant bacterial infections in surgical patients. Surg Inf. 2002;3(4):375-385.
6. Tomasz A. The mechanism of the irreversible antimicrobial effects of penicillins: how the beta-lactam antibiotics kill and lyse bacteria. Annu Rev Microbiol. 1979;33:113.
7. Livermore DM. Beta-lactamases in laboratory and clinical resistance. Clin Microbiol Rev. 1995;8(4):557-584.
8. Georgopapadakou NH. Penicillin-binding proteins and bacterial resistance to beta-lactams. AntiMicrob Agents Chemother. 1993;37(10):2045-2053.
9. Nathwani D, Wood MJ. Penicillins. A current review of their clinical pharmacology and therapeutic use. Drugs. 1993;45(6): 866-894.
10. Bush LM, Johnson CC. Ureidopenicillins and beta-lactam/beta-lactamase inhibitor combinations. Infect Dis Clin North Am. 2000;14(2):409-433.
11. Richards ML, Prince RA, Kenaley KA, et al. Antimicrobial penetration into cerebrospinal fluid. Drug Intell Clin Pharm. 1981;15(5):341-368.
13. Watson ID, Boulton-Jones M, Stewart MJ, Henderson I, Payton CD. Pharmacokinetics of clavulanic acid-potentiated ticarcillin in renal failure. Ther Drug Monit. 1987;9(2):139-147.
15. Babiak LM, Rybak MJ. Hematological effects associated with beta-lactam use. Drug Intell Clin Pharm. 1986;20(11): 833-836.
18. Nau H. Clinical pharmacokinetics in pregnancy and perinatology. II. Penicillins. Dev Pharmacol Ther. 1987;10(3):174-198.
19. Kees F, Grobecker H. Systematics of beta-lactams: chemical properties and structure activity relationship of oral cephalosporins. Antibiot Chemother. 1995;47:1-7.
20. Fontana R, Cornaglia G, Ligozzi M, Mazzariol A. The final goal: penicillin-binding proteins and the target of cephalosporins.Clin Microbiol Infect. 2000;6(suppl 3):34-40.
21. Wise R. The pharmacokinetics of the oral cephalosporins—a review. J Antimicrob Chemother. 1990;26(suppl E):13-20.
22. Koch AL. Penicillin binding proteins, beta-lactams, and lactamases: offensives, attacks, and defensive countermeasures.Crit Rev Microbiol. 2000;26(4):205-220.
23. Hopkins JM, Towner KJ. Enhanced resistance to cefotaxime and imipenem associated with outer membrane protein alterations in Enterobacter aerogenes. J Antimicrob Chemother. 1990;25(1):49-55.
24. Gootz TD. Global dissemination of beta-lactamases mediating resistance to cephalosporins and carbapenems. Expert Rev Anti Infect Ther. 2004;2(2):317-327.
25. Neu HC. Pathophysiologic basis for the use of third-generation cephalosporins. Am J Med. 1990;88(suppl 4A):3S-11S.
26. Mazzei T, Dentico P. The pharmacokinetics of oral cephalosporins. Clin Microbiol Infect. 2000;6(suppl 3):53-54.
27. Borin MT. A review of the pharmacokinetics of cefpodoxime proxetil. Drugs. 1991;42(suppl 3):13-21.
28. Cherubin CE, Eng RH, Norrby R, et al. Penetration of newer cephalosporins into cerebrospinal fluid. Rev Infect Dis. 1989;11(4):526-548.
29. Balant LP, Dayer P, Fabre J. Consequences of renal insufficiency on the hepatic clearance of some drugs. Int J Clin Pharmacol Res. 1983;3(6):459-474.
31. Tune BM. Renal tubular transport and nephrotoxicity of beta lactam antibiotics: structure-activity relationships. Miner Electrolyte Metab. 1994;20(4):221-231.
32. Famularo G, Polchi S, De Simone C. Acute cholecystitis and pancreatitis in a patient with biliary sludge associated with the use of ceftriazone: a rare but potentially severe complication. Ann Ital Med Int. 1999;14(3):202-204.
33. Alanis A, Weinstein AJ. Adverse reactions associated with the use of oral penicillins and cephalosporins. Med Clin North Am. 1983;67(1):113-129.
34. Seltsam A, Salama A. Ceftriaxone-induced immune haemolysis: two case reports and a concise review of the literature.Intensive Care Med. 2000;26(9):1390-1394.
35. Bechtold H, Andrassy K, Jahnchen E, et al. Evidence for impaired hepatic vitamin K1 metabolism in patients treated with N-methyl-thiotetrazole cephalosporins. Thromb Haemost. 1984;51:358-361.
36. McCue JD, Gal P, Pearson RC. Interference of new penicillins and cephalosporins with urine glucose monitoring tests.Diabetes Care. 1983;6(5):504-505.
37. Fulton B, Moore LL. Antiinfectives in breastmilk. Part I: penicillins and cephalosporins. J Hum Lact. 1992; 8(3):157-158.
38. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776-789.
39. Kahan JS, Kahan FM, Goegleman R, et al. Thienamycin, a new beta-lactam antibiotic. I: discovery, taxonomy, isolation and physical properties. J Antibiot. 1979;32(1):1-12.
40. Rybak MJ. Resistance to antimicrobial agents: an update. Pharmacotherapy. 2004;24(12 pt 2):203S-215S.
42. Drusano GL, Standiford HC. Pharmacokinetic profile of imipenem/cilastin in normal volunteers. Am J Med. 1985;78(6A): 47-53.
43. Andes DR, Craig WA. Pharmacokinetics and pharmacodynamics of antibiotics in meningitis. Infect Dis Clin North Am. 1999;13(3):595-618.
44. Leroy A, Fillastre JP, Borsa-Lebas F, et al. Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment. Antimicrob Agents Chemother. 1992;36(12):2794-2798.
45. Seto AH, Song JC, Guest SS. Ertapenem-associated seizures in a peritoneal dialysis patient. Ann Pharmacother. 2005;39(2):352-356.
46. Nacarkucuk E, Saglam H, Okan M. Meropenem decreases serum level of valproic acid. Pediatr Neurol. 2004;31(3):232-234.
49. Odio CM, Puig JR, Feris JM, et al. Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime in bacterial meningitis in children. Meropenem Meningitis Study Group. Pediatr Infect Dis J. 1999;18(7):581-590.
50. Ennis DM, Cobbs CG. The newer cephalosporins: aztreonam and imipenem. Infect Dis Clin North Am. 1995(3):687-713.
51. Duma RJ, Berry AJ, Smith SM, et al. Penetration of aztreonam into cerebrospinal fluid of patients with and without inflamed meninges. Antimicrob Agents Chemother. 1984;26(5):730-733.
52. Sattler FR, Schramm M, Swabb EA. Safety of aztreonam and SQ 26992 in elderly patients with renal insufficiency. Rev Infect Dis. 1985;7(suppl 4):S622-S627.
53. Fillastre JP, Leroy A, Baudoin C, et al. Pharmacokinetics of aztreonam in patients with chronic renal failure. Clin Pharmacokinet. 1985;10(1):91-100.
55. Perez Pimiento A, Gomez Martinez M, Minguez Mena A, Trampal Gonzalez A, De Paz Arranz S, Rodriguez Mosquera M. Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity. Allergy. 1998;53(6):624-625.
58. Bosso JA, Black PG. Controlled trial of aztreonam vs. tobramycin and azlocillin for acute pulmonary exacerbations of cystic fibrosis. Pediatr Infect Dis J. 1988;7(3):171-176.
59. Moellering RC Jr. In vitro antibacterial activity of the aminoglycoside antibiotics. Rev Infect Dis. 1983;5(Suppl):S212-S232.
60. Kotra LP, Haddad J, Mobashery S. Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob Agents Chemother. 2000;44(12):3249-3256.
61. Gordon S, Swenson JM, Hill BC, et al. Antimicrobial susceptibility patterns of common and unusual species of enterococci causing infections in the United States. Enterococcal Study Group. J Clin Microbiol. 1992;30(9):2373-2378.
62. Ramsey BW, Dorkin HL, Eisenberg JD, et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med. 1993;328(24):1740-1746.
63. Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am. 2003;17(3):503-528.
64. Appel GB. Aminoglycoside nephrotoxicity. Am J Med. 1990;88(suppl 3C):S16-S20; discussion 38S-42S.
65. Lietman PS. Liver disease, aminoglycoside antibiotics and renal dysfunction. Hepatology. 1988;8(4):966-968.
66. Pandya A, Xia X, Radnaabazar J, et al. Mutation in the mitochondrial 12S rRNA gene in two families from Mongolia with matrilineal aminoglycoside ototoxicity. J Med Genet. 1997;34(2):169-172.
67. Hokkanen E. The aggravating effect of some antibiotics on the neuromuscular blockade in myasthenia gravis. Acta Neurol Scand. 1964;40:346-352.
69. Alkadi HO, Nooman MA, Raja'a YA. Effect of gentamicin on serum digoxin level in patients with congestive heart failure.Pharm World Sci. 2004;26(2):107-109.
71. Dashe JS, Gilstrap LC III. Antibiotic use in pregnancy. Obstet Gynecol Clin North Am. 1997;24(3):617-629.
72. Goldman RC, Fesik SW, Doran CC. Role of protonated and neutral forms of macrolides in binding to ribosomes from gram- positive and gram-negative bacteria. Antimicrob Agents Chemother. 1990;34(3):426-431.
74. Sun H, Maglio D, Nicolau D. Macrolide resistance in Streptococcus pneumoniae: mechanisms, patterns, and clinical implications of resistance. Conn Med. 2004;68(9):571-576.
75. Matsuoka M, Sasaki T. Inactivation of macrolides by producers and pathogens. Curr Drug Targets Infect Disord. 2004;4(3):217-240.
76. Doern GV, Jorgensen JH, Thornsberry C, et al. National collaborative study of the prevalence of antimicrobial resistance among clinical isolates of Haemophilus influenzae. Antimicrob Agents Chemother. 1988;32(2):180-185.
77. Malmborg AS. Effect of food on absorption of erythromycin. A study of two derivatives, the stearate and the base. J Amtimicrob Chemother. 1979;5(5):591-599.
78. Bahal N, Nahata MC. The new macrolide antibiotics: azithromycin, clarithromycin, dirithromycin, and roxithromycin.Ann Pharmacother. 1992;26(1):46-55.
79. Periti P, Mazzei T, Mini E, Novelli A. Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part II). Clin Pharmacokinet. 1989;16(5):261-282.
80. Zuckerman JM. Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am. 2004;18(3): 621-649.
81. Clark JP, Langston E. Ketolides: a new class of antibacterial agents for treatment of community-acquired respiratory tract infections in a primary care setting. Mayo Clin Proc. 2003;78(9):1113-1124.
82. Katapadik K, Kostandy G, Katapadi M, et al. A review of erythromycin-induced malignant tachyarrhythmia-- torsade de pointes: a case report. Angiology. 1997;48:821-826.
83. Guay DR, Patterson DR, Seipman N, Craft JC. Overview of the tolerability profile of clarithromycin in preclinical and clinical trials. Drug Saf. 1993;8(5):350-364.
85. Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmacokinet. 1985;10:63-79.
86. Kahri AJ, Valkonen MM, Vuoristo MK, Pentikainen PJ. Rhabdomyolysis associated with concomitant use of simvastatin and clarithromycin. Ann Pharmacother. 2004;38(4):719.
87. Desta Z, Soukhova N, Flockhart DA. In vitro inhibition of pimozide N-dealkylation by selective serotonin reuptake inhibitors and azithromycin. J Clin Psychopharmacol. 2002;22(2):162-168.
88. Watkins VS, Polk RE, Stotka JL. Drug interactions of macrolides: emphasis on dirithromycin. Ann Pharmacother. 1997;31(3): 349-356.
89. Kolilekas L, Anagnostopoulos GK, Lampaditis I, Eleftheriadis I. Potential interaction between telithromycin and warfarin.Ann Pharmacother. 2004;38(9):1424-1427.
90. Centers for Disease Control and Prevention. Chlamydia trachomatis infections--policy guidelines for prevention and control.MMWR. 1985;34(3-S):S53-S74.
91. Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol. 2001;9(4):197-202.
92. Drinkard CR, Shatin D, Clouse J. Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations. Pharmacoepidemiol Drug Saf. 2000;9(7):549-556.
93. Einarson A, Phillips E, Mawji F, et al. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol. 1998;15(9):523-525.
94. Hauben M, Amsden GW. The association of erythromycin and infantile hypertrophic pyloric stenosis: causal or coincidental?Drug Saf. 2002;25(13):929-942.
95. Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother. 2003;51(Suppl 1):1-11.
96. Drlica K, Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol. Biol R. 1997;61(3):377-392.
97. Willmott CJ, Maxwell A. A single point mutation in the DNA gyrase A protein greatly reduces binding of fluoroquinolones to the gyrase-DNA complex. Antimicrob Agents Chemother. 1993;37:126-127.
98. Mammeri H, Van De Loo M, Poirel L, Martinez-Martinez l, Nordmann P. Emergence of plasmid-mediated quinolone resistance in Escherichia coli in Europe. Antimicrob Agents Chemother. 2005;49(1):71-76.
99. Blondeau JM. A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new respiratory quinolones. J Antimicrob Chemother. 1999;43(suppl B):1-11.
100. Sorgel F, Kinzig M. Pharmacokinetics of gyrase inhibitors, part 1: basic chemistry and gastrointestinal disposition. Am J Med. 1993;94(3A):S44-S55.
101. Sorgel F, Kinzig M. Pharmacokinetics of gyrase inhibitors, part 2: renal and hepatic elimination pathways and drug interactions.Am J Med. 1993; 94(3A):S56-S69.
102. Moise PA, Birmingham MC, Schentag JJ. Pharmacokinetics and metabolism of moxifloxacin. Drugs Today. 2000;36(4):229-244.
103. Fillastre JP, Leroy A, Moulin B, Dhib M, Borsa-Lebas F, Humbert G. Pharmacokinetics of quinolones in renal insufficiency.J Antimicrob Chemother. 1990;26(suppl B):51-60.
104. Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother. 2001;35(12):1540-1547.
105. Zabraniecki L, Negrier I, Vergne P, et al. Fluoroquinolone induced tendinopathy: report of 6 cases. J Rheumatol. 1996;23(3): 516-520.
106. Oh YR, Carr-Lopez SM, Probasco JM, Crawley PG. Levofloxacin-induced autoimmune hemolytic anemia. Ann Pharmacother. 2003;37(7-8):1010-1013.
107. Coleman CI, Spencer JV, Chung JO, Reddy P. Possible gatifloxacin-induced fulminant hepatic failure. Ann Pharmacother. 2002;36(7-8):1162-1167.
108. Lin G, Hays DP, Spillane L. Refractory hypoglycemia from ciprofloxacin and glyburide interaction. J Toxicol Clin Toxicol. 2004;42(3):295-297.
109. Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother. 1989;33(11):1841-1844.
110. Hori S, Kizu J, Kawamura M. Effects of anti-inflammatory drugs on convulsant activity of quinolones: a comparative study of drug interaction between quinolones and anti-inflammatory drugs. J Infect Chemother. 2003;9(4):314-320.
111. Radandt JM, Marchbanks CR, Dudley MN. Interactions of fluoroquinolones with other drugs: mechanisms, variability, clinical significance, and management. Clin Infect Dis. 1992;14(1):272-284.
112. Von Keutz E, Ruhl-Fehlert C, Drommer W, Rosenbruch M. Effects of ciprofloxacin on joint cartilage in immature dogs immediately after dosing and after a 5-month treatment-free period. Arch Toxicol. 2004;78(7):418-424.
113. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J. 2003;22(12): 1128-1132.
114. Redmond A, Sweeney L, MacFarland M, Mitchell M, Daggett S, Kubin R. Oral ciprofloxacin in the treatment of pseudomonas exacerbations of paediatric cystic fibrosis: clinical efficacy and safety evaluation using magnetic resonance image scanning.J Int Med Res. 1998;26(6):304-312.
115. Woods DD. Relation of p-aminobenzoic acid to mechanism of action of sulphanilamide. Br J Exp Pathol. 1940;21:74-90.
116. Radstrom P, Fermer C, Kristiansen BE, Jenkins A, Skold O, Swedberg G. Transformational exchanges in the dihydropteroate synthetase gene of Neisseria meningitidis: a novel mechanism for acquisition of sulfonamide resistance. J Bacteriol. 1992;174(20):6386-6393.
117. Then RL. Mechanisms of resistance to trimethoprim, the sulfonamides and trimethoprim-sulfamethoxazole. Rev Infect Dis. 1982;4(2):261-269.
118. Bushby SRM. Trimethoprim-sulfamethoxazole: in vitro microbiologic aspects. J Infect Dis. 1973;128(suppl):442-462.
120. Hekster CA, Vree TB. Clinical pharmacokinetics of sulphonamides and their N4-acetyl derivatives. Antibiot Chemother. 1982;31:118-122.
121. Foltzer MA, Reese RE. Trimethoprim-sulfamethoxazole and other sulfonamides. Med Clin North Am. 1987;71(6):1177-1194.
122. Lawson DH, Paice BJ. Adverse reactions to trimethoprim-sulfamethoxazole. Rev Infect Dis. 1982;4(2):429-433.
123. Keisu M, Wiholm BE, Palmblad J. Trimethoprim-sulphamethoxazole-associated blood dyscrasia: ten years experience of the Swedish spontaneous reporting system. J Intern Med. 1990;228(4):353-360.
124. Markowitz N, Saravolatz LD. Use of trimethoprim-sulfamethoxazole in a glucose-6-phosphate dehydrogenase-deficient population. Rev Infect Dis. 1987;9:S218-S229.
125. Kaufman JM, Fauver HE Jr. Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology. 1980;16(6):601-603.
126. Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically significant drug interactions with cyclosporine: an update. Clin Pharmacokinet. 1996;30(2):141-179.
127. Springer C, Eyal F, Michael J. Pharmacology of trimethoprim-sulfamethoxazole in newborn infants. J Pediatr. 1982;100(4):647-650.
129. Craven GR, Gavin R, Fanning T. The transfer RNA binding site of the 30 S ribosome and the site of tetracycline inhibition.Cold Spring Symp Quant Biol. 1969;34:129-137.
130. Schnappinger D, Hillen W. Tetracyclines: antibiotic action, uptake, and resistance mechanisms. Arch Microbiol. 1996;165(6): 359-369.
131. Speer BS, Shoemaker NB, Salyers AA. Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance. C lin Microbiol Rev. 1992;5(4):387-399.
132. Forrest JN, Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1978;298(4):173-177.
133. Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother. 1996;40(5):1104-1107.
134. Yim CW, Flynn NM, Fitzgerald FT. Penetration of oral doxycycline into the cerebrospinal fluid of patients with latent or neurosyphilis. Antimicrob Agents Chemother. 1985;28(2):347-348.
136. Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet. 1988;15(6):355-366.
137. Houin G, Brunner F, Nebout T, Chereaoui M, Lagrue G, Tillement JP. The effects of chronic renal insufficiency on the pharmacokinetics of doxycycline in man. Br J Clin Pharmacol. 1983;16(3):245-252.
138. Vial T, Biour M, Descotes J, Trepo C. Antibiotic-associated hepatitis: update from 1990. Ann Pharmacother. 1997;31(2): 204-220.
139. Angeloni VL, Salasche SJ, Ortiz R. Nail, skin, and scleral pigmentation induced by minocycline. Cutis. 1987;40(3):229-233.
140. Byrne PA, Williams BD, Pritchard MH. Minocycline-related lupus. Br J Rheumatol. 1994;33:674-676.
141. Gugler R, Allgayer H. Effects of antacids on the clinical pharmacokinetics of drugs: an update. Clin Pharmacokinet. 1990;18(3): 210-219.
142. Bacon JF, Shenfield GM. Pregnancy attributable to interaction between tetracycline and oral contraceptives. Br Med J. 1980;280(6210):293.
143. Dickinson BD, Altman RD, Nielsen NH, Sterling ML, Council on Scientific Affairs, American Medical Association. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol. 2001;98(5 pt 1):853-860.
144. Danos EA. Apparent potentiation of warfarin activity by tetracycline. Clin Pharm. 1992;11(9):806-808.
145. Rodin SM, Johnson BF. Pharmacokinetic interactions with digoxin. Clin Pharmacokinet. 1988;15(4):227-244.
147. Allen ES, Brown WE. Hepatic toxicity of tetracycline in pregnancy. Am J Obstet Gynecol. 1966;95(1):12-18.
149. Lexi-Comp Online. Available at http://online.lexi.com. Last accessed January 11, 2012.
150. Allchin D. Penicillin and Chance. Available at http://www1.umn.edu/ships/updates/fleming.htm. Last accessed January 11, 2012.
151. Hwa-Froelich DA, Westby CE. Considerations when working with interpreters. Communication Disorders Quarterly. 2003;4(2): 78-85.
152. Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2011;52(9):1156-1163.
153. Low DE, File TM Jr, Eckburg PB, et al. FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother. 2011;66 (Suppl 3):iii33-iii44.
154. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA Requires Label Changes to Warn of Risk for Possibly Permanent Nerve Damage from Antibacterial Fluoroquinolone Drugs taken by Mouth or by Injection. Available at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM365078.pdf. Last accessed August 29, 2013.
1. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=15952. Last accessed January 19, 2012.
2. Davey P, Brown E, Fenelon L, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database System Rev. 2005;4:CD003543. Available at http://summaries.cochrane.org/CD003543/improving-how-antibiotics-are-prescribed-by-physicians-working-in-hospital-settings.. Last accessed January 19, 2012.
3. American Optometric Association. Care of the Patient with Ocular Surface Disorders. St. Louis, MO: American Optometric Association; 2010. Summary retrieved from National Guideline Clearinghouse at http://www.guideline.gov/content.aspx?id=33585. Last accessed January 19, 2012.