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 eight major classes of antibiotics: the penicillins, cephalosporins, other beta-lactams, aminoglycosides, macrolides, quinolones, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.
This course is designed for healthcare providers who prescribe and administer antibiotics to patients, including physicians, physician assistants, nurses, and nurse practitioners.
NetCE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NetCE is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is accredited by the International Association for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.
NetCE 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. NetCE designates this continuing education activity for 5 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 6 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. 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, Certified Surgical First Assistant and Associate members. This recognition does not imply that AST approves or endorses any product or products that are included in the enduring materials. 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#1622005-4773/P. California NHAs may only obtain a maximum of 10 hours per course. NetCE is authorized by IACET to offer 0.5 CEU(s) for this program. AACN Synergy CERP Category A.
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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 major classes of antibiotics and their characteristics as well as an overview of selected individual agents within each class that are most useful for today's clinical practitioner.
Upon completion of this course, you should be able to:
- Describe the general characteristics and mode of action of antibiotics commonly in use.
- Employ best practice principles for limiting the emergence and transmission of antimicrobial resistant strains within the healthcare environment.
- Discuss the mechanism of action, pharmacokinetics, and spectrum of activity of natural and extended-spectrum penicillins.
- Select the most appropriate, cost-effective cephalosporin based on "generational" characteristics and spectrum of activity.
- Describe the role of carbapenems and monobactams.
- Discuss the characteristics, expected toxicities, and indications for the use of aminoglycosides, macrolides, and sulfonamides.
- Outline the mechanism of action, pharmacokinetics, and advantages inherent to quinolones and the tetracyclines.
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.
John V. Jurica, MD, MPH
Jane C. Norman, RN, MSN, CNE, PhD
Chris Keegan, CST, MS
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.
- GENERAL CHARACTERISTICS OF ANTIBIOTICS
- ANTIBIOTIC RESISTANCE
- CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS
- MACROLIDES AND TELITHROMYCIN
- Works Cited
- Evidence-Based Practice Recommendations Citations
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#95071: Antibiotics Review
The number of antibiotic agents available is remarkable, and new agents are added regularly. This course is intended as an overview of the general characteristics of the major antibiotic classes, emphasizing mechanism of action, pharmacokinetics, and potential toxicities, with a brief discussion of the individual member agents and their clinical indications. The purpose is to enlarge clinical perspective and enhance the understanding and confidence required for the selection of appropriate therapy of bacterial infections. The goal is to improve efficacy and safety while limiting the risk for selection and transmission of antimicrobial-resistant pathogens.
Given the large array of available antimicrobial agents, the scope of this course is confined to the eight major classes of antibiotics commonly employed for acute bacterial infection: the penicillins, cephalosporins, carbapenems, aminoglycosides, quinolones, macrolides, sulfonamides, and tetracyclines. A brief discussion of vancomycin and the newer glycopeptide analogues is also included.
For the purposes of the course, it is impractical to list or describe all of the possible adverse effects, recommended uses, and off-label uses of the antibiotics discussed. Before using a specific antimicrobial, it is important to 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.
Repeated exposure to an antibiotic may lead to the emergence of selective subpopulations of the same or related bacteria now resistant to the therapeutic agent. Mechanisms of microbial resistance include altered cellular permeability (leading to greatly diminished intracellular concentration of the drug), increased efflux of the antibiotic from the cell, and elaboration of deactivating enzymes that alter the antibiotic's interaction at binding sites within the cell wall or cytoplasm .
Decreased cell membrane permeability is a common mechanism of bacterial resistance to beta-lactams and quinolones. Microbial resistance to tetracyclines and quinolones is often mediated by increased efflux of the antibiotic from the cell. Enzymatic deactivation by beta-lactamases is the common mechanism of resistance to penicillins and cephalosporins. Resistance to aminoglycosides may result from altered cytoplasmic membrane transport (influx) or from intracellular enzymes (e.g., phosphotransferases and acetyltransferases) that deactivate the drug.
There are various mechanisms by which the interaction of an antibiotic with its binding site may be altered or bypassed, resulting in loss of antimicrobial activity. One such example, affecting the target site for quinolone activity, is an acquired structural alteration of deoxyribonucleic acid (DNA) gyrase, an enzyme essential for bacterial DNA synthesis. As a result, quinolones are no longer able to bind to the enzyme and the drug loses its antimicrobial effect. Another example is the methylation of ribosomal ribonucleic acid (rRNA) that prevents the binding of macrolides. The effectiveness of trimethoprim/sulfamethoxazole, which acts through disruption of folate synthesis by the cell, may become diminished by the adaptive ability of some bacteria to utilize an alternate metabolic pathway, thereby avoiding the effects of trimethoprim .
These resistance mechanisms 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 succumb to the action of the antibiotic, the subpopulation that has the adaptive mutation continues to replicate, replacing the original population with a resistant one.
Bacterial resistance can be transferred from one bacterium to another, or from one bacterial species to related group, by means of plasmids or transposons that gain entry to the cell. 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 encountered in bacteria. Among these are the addition of beta-lactamase inhibitors to extended-spectrum penicillins, alteration of cephalosporin side chains to produce new generations of the drug with broader activity, and pairing two drugs to enhance the antimicrobial effect (e.g. sulfamethoxazole with trimethoprim).
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 resistance, 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 results of culture, 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 increase the likelihood of emerging resistance, so the duration of therapy should be carefully monitored and undue prolongation avoided.
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 .
Alexander Fleming discovered penicillin 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 susceptible bacteria by interrupting cell wall synthesis. The drug exerts its affect by preventing cross-binding of the peptidoglycan polymers necessary for cell wall formation and by binding with carboxypeptidases, endopeptidases, and transpeptidase ("penicillin-binding proteins" [PBPs]) 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 favorably modified.
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 penicillin molecule 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 block bacterial beta-lactamases. 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 spectrum of 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.|
|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 is more acid-stable and is the appropriate form for oral administration.
The natural penicillins are active against gram-positive organisms such as streptococci, Enterococcus faecalis, and Listeria monocytogenes. However, most S. aureus isolates are now resistant. They are also active against anaerobic species, such as Bacteroides species and Fusobacterium species. At serum levels achieved by parenteral administration, the natural penicillins are effective against some gram-negative bacteria, such as Escherichia coli, H. influenzae, Neisseria gonorrhoeae, and Treponema pallidum. For the treatment of moderate-to-severe infections in which resistant organisms are considered a possibility, reliance upon penicillin alone should be avoided unless the identity and sensitivity of the infecting organism have been confirmed. 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 against susceptible gram-positive organisms, plus improved coverage of selected gram-negative bacilli, including Enterobacteriaceae. 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. These agents are useful for the management of sinusitis/bronchitis, endocarditis, meningitis, susceptible urinary tract infection, and salmonellosis . Amoxicillin is the best absorbed of the oral penicillins. It is acid-stable and its absorption, unlike ampicillin, is not much affected by food. Improved absorption is also thought to provide an advantage over ampicillin in reducing the risk of antibiotic-associated diarrhea. Labeled uses include endocarditis prophylaxis and as a component of a multidrug H. pylori eradication regimen .
The penicillinase-resistant penicillins were developed in response to the emergence of penicillinase-producing S. aureus. 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 United States .
While the penicillinase-resistant penicillins are effective against many of the same gram-positive organisms that the natural penicillins are effective against, they lack significant activity against gram-negative or anaerobic organisms. They are, however, notable for their usefulness against penicillin-resistant (methicillin-sensitive) Staphylococcus 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 United States.
These agents retain much of their activity against gram-positive bacteria, but they also have more activity against gram-negative bacteria, including Pseudomonas aeruginosa. Additional gram-negative species that are treated by these agents include H. influenzae, Serratia species, and Klebsiella species.
The addition of clavulanic acid, sulbactam, or tazobactam increases the spectrum of activity of the penicillin derivative with which they are combined. 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 either too unstable in the acidic environment of the stomach or must be given intravenously in order to achieve sustained therapeutic levels.
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 excreted in the kidney by means 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 breast milk, 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 .
Giuseppe Brotzu discovered the first cephalosporin in 1948, observing 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 as that for 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 results 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 and for susceptible urinary tract infections. 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 enhanced activity and a broader spectrum against gram-negative organisms, including Neisseria species, M. catarrhalis, Klebsiella, and other Enterobacteriaceae. Of these agents, ceftriaxone has the best activity against gram-positive cocci, specifically S. pneumoniae and methicillin-sensitive S. aureus. Ceftazidime is active against P. aeruginosa. Other cephalosporins in this class include cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftibuten, and ceftriaxone. These drugs are useful for more severe community-acquired respiratory, intraabdominal, and urinary tract infections and for 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 a novel advanced-generation cephalosporin approved by the U.S. Food and Drug Administration (FDA) in 2010, for the treatment of community-acquired bacterial pneumonia and bacterial skin and soft-tissue infections. As with other beta-lactams, ceftaroline exerts its antimicrobial affect by binding to PCP and inhibiting cell wall synthesis. This agent is unique in that it also has a high affinity for PBP2a, which is associated with resistance to methicillin. Consequently, ceftaroline is highly active against methicillin-sensitive and resistant strains of S. aureus and against multidrug-resistant S. pneumoniae . It is ineffective for P. aeruginosa, and its activity against Enterobacteriaceae is variable. Beta-lactamase-producing Enterobacteriaceae and AmpC mutants are resistant. Prospective clinical trials have shown that the efficacy of ceftaroline is comparable to vancomycin plus aztreonam for the treatment of bacterial skin and soft-tissue infection (including methicillin-resistant S. aureus [MRSA]) and to ceftriaxone for the treatment of community-acquired bacterial pneumonia . Among cases of pneumonia caused by S. pneumoniae, clinical cure rates 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 eliminated by the kidney. 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 is deacetylated by the liver to a bioactive metabolite and inactive forms. The deacetylated metabolites are 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 . In the presence of severe renal and/or hepatic insufficiency, dosage adjustment of cefotaxime 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.
Although uncommon, nephrotoxicity has been reported . 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 approved by the 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 as an alternative therapy for gram-negative bacterial infections, including P. aeruginosa and Klebsiella, that are resistant to the first-line beta-lactams or carbapenems. 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.
There is no oral form of aztreonam, and intravenous is the preferred mode of parenteral administration. 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 breast milk 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 first aminoglycoside, streptomycin, was derived from Streptomyces griseus during the 1940s. Actinomycetes were studied for possible antimicrobial by-products, and it was found that Micromonospora and Streptomyces produced useful agents. As newer, safer, and more effective aminoglycosides have been developed, the use of streptomycin is now confined primarily to certain management strategies for the treatment of tuberculosis.
|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, or4–7 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, or4–12 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, or4–7 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 involves 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, 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 beta-lactam, vancomycin, or other agents active 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.
The aminoglycosides commonly used at present for treatment of systemic bacterial infection include gentamicin, tobramycin, amikacin, and kanamycin. Aminoglycosides have negligible oral absorption and thus require parenteral administration. They also can be administered directly into body cavities and have a role in the management of pleural and peritoneal infection. Tobramycin is particularly useful for treatment of recurrent Pseudomonas infection in patients with cystic fibrosis and can be administered by aerosolized inhalation to facilitate optimal local antimicrobial effect . Neomycin is often used orally as part of a pre-operative bowel decontamination protocol.
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 unchanged 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 monitored in all patients with reduced renal function .
The most common adverse effect associated with aminoglycoside usage is renal failure, which 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 ototoxicity, this drug class should be avoided in patients who have a family history of ototoxicity with aminoglycosides . When aminoglycoside therapy is expected to exceed 5 to 7 days, baseline testing of auditory function should be performed and monitored weekly for the duration of treatment.
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. The risk of nephrotoxicity may be increased with co-administration of other drugs that are nephrotoxic or in patients receiving loop diuretics (e.g., furosemide). Respiratory depression may occur if aminoglycosides are given with nondepolarizing muscle relaxants. Neomycin may affect digoxin levels by altering the bowel flora 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 breast milk, 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 erythraea (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, which has a long half-life and can be given once daily, has proved useful for the management of 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 breast milk, but the AAP considers it usually compatible with breastfeeding . Clarithromycin is excreted in breast milk 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-positive cocci, gram-negative bacilli, and atypical bacteria (e.g., Legionella, Mycoplasma). Quinolone activity against streptococci and anaerobes, at achievable serum levels, is relatively poor, although newer agents, such as moxifloxacin, have better coverage for anaerobes . 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, non-gonococcal 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 after oral administration, and peak serum levels in the elderly and those with reduced renal function approximate those achieved with intravenous usage. 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 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) appears 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 breast milk, 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 United States 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 characteristics. 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 in 3 to 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 breast milk. 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 breast milk; 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 spectrum of activity that includes aerobic gram-positive and 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 approved by the FDA for treatment of rickettsial infections, typhus, Rocky Mountain spotted fever, trachoma, nongonococcal urethritis, and lymphogranuloma venereum .
As a result of decades of clinical and agricultural use, the prevalence of resistance to tetracyclines is now high among common gram-positive and gram-negative pathogens. For this reason, and because they are bacteriostatic, the role of tetracyclines is limited for treatment of most pyogenic infections. Primary indications for this class are atypical infections (e.g. mycoplasma and chlamydia) and zoonoses (e.g. tularemia and brucellosis).
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 Rangea||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 is inexpensive but requires dosing every 6 hours for most indications. A less frequent dosage protocol is commonly used for the treatment and prevention of acne .
The only intermediate-acting agent available in the United States 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 (once or twice daily), which is an advantage in ensuring compliance. 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. Nonrenal, possibly hepatic, mechanisms account in large part for excretion of doxycycline and minocycline. 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 breast milk 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.
Vancomycin is the oldest member of the glycopeptide antibiotics class, a group of large molecules that inhibit bacterial cell wall synthesis. Glycopeptides have a high binding affinity for peptides found only in bacterial cell walls. This interaction disrupts peptidoglycan polymerization, the late-stage reaction that imparts rigidity to the cell wall . Gram-positive organisms, both cocci and bacilli, are highly susceptible to glycopeptides.
Vancomycin was developed more than 50 years ago as an alternative intravenous therapy for serious staphylococcal and streptococcal infections in patients allergic to beta-lactams. In this early period, vancomycin usage was associated with a high incidence of vestibular and renal toxicity. The cause was attributed in large part to impurities in the formulation, a problem solved in subsequent years. At present, the major role for vancomycin is in the treatment of serious infections caused by MRSA, methicillin-resistant S. epidermidis (MRSE), and ampicillin-resistant enterococci. An oral formulation is available for the treatment of C. difficile-associated diarrhea/colitis.
Vancomycin is not absorbed by the intestinal tract and must be administered by intravenous infusion. The determination of a safe, effective dosage regimen, and decisions regarding monitoring of therapy, are complex matters that require consideration of multiple factors, including the site and severity of infection, the patient's weight and renal function, the susceptibility of the infecting organism, and the anticipated duration of therapy . The usual adult dose is 15–20 mg/kg every 12 hours. The rate of infusion should be no more than 500 mg/hr, as rapid infusion causes an uncomfortable generalized erythroderma ("red man" syndrome). The red man syndrome is a histamine-mediated flushing that occurs during or immediately following infusion and does not mandate discontinuation unless slowing the infusion rate fails to mitigate the reaction.
Vancomycin is cleared almost entirely by the kidneys. Prolonged usage at excessively high therapeutic serum levels has been associated with nephrotoxicity and ototoxicity. In treating patients with invasive staphylococcal infection and MRSA, it is considered important to use the maximum dosage (target trough serum vancomycin level of 15–20 mcg/mL) in order to assure optimal therapeutic effect . The serum creatinine and trough vancomycin level (target <20 mcg/mL) should be monitored once or twice weekly in such cases, as well as in all patients who are elderly or have impaired renal function.
Apart from the (avoidable) red man syndrome, vancomycin administration is well tolerated and side effects are uncommon. As with beta-lactams and sulfonamides, vancomycin is a good sensitizing agent; allergic manifestations such as fixed drug eruptions and drug fever are relatively common.
Vancomycin nephrotoxicity does occur. The incidence is low, the exact mechanism is poorly understood, and the impact is usually reversible upon discontinuation of the drug. Risk factors for nephrotoxicity include total daily dose in excess of 3–4 grams, trough serum vancomycin levels >20 mcg/mL, pre-existing renal disease, concomitant use of other nephrotoxic drugs (e.g. aminoglycosides), and duration of therapy longer than one week .
Reversible neutropenia, presumably from bone marrow toxicity, is sometimes seen in patients receiving prolonged vancomycin therapy (e.g., for endocarditis and osteomyelitis). Oral vancomycin is not absorbed and thus imposes no risk of nephrotoxicity or ototoxicity.
In response to the increasing prevalence of multidrug resistance among clinical isolates of staphylococci and streptococci, glycopeptide analogues (lipoglycopeptides) with enhanced activity and favorable pharmacokinetics have been developed. In comparison to vancomycin, the lipoglycopeptides have greater potency against gram-positive bacteria, are active against vancomycin-resistant strains, and appear to be less likely to lead to emergence of resistant organisms [159,160]. As with vancomycin, lipoglycopeptides must be administered intravenously. The lipophilic side chain prolongs plasma half-life and helps anchor these agents to the outer structure of the bacterial cell. In animal studies, lipoglycopeptides have proven effective in treating a variety of serious gram-positive infections, including bacteremia, pneumonia, and endocarditis [159,160]. Clinical studies of efficacy in humans have been limited to date.
At present, two lipoglycopeptides, telavancin and dalbavancin, have been approved by the FDA for the treatment of acute bacterial skin and soft-tissue infection. Clinical trials have shown equivalent or superior efficacy against MRSA skin infection compared with vancomycin [160,161]. The side effect profile is mild and comparable to other effective regimens. Reported adverse effects include headache, nausea, pruritus, pain at injection site, and fever.
Dalbavancin has the advantage of a prolonged plasma half-life (6 to 10 days), allowing for weekly administration and perhaps obviating the need for an indwelling central line. In adults and children 12 to 17 years of age, the best-studied treatment protocol is 1 g IV, followed by 500 mg weekly [161,162]. In a randomized trial comparing dalbavancin (1 g IV on days 1 and 8) with vancomycin (IV for 3 days followed by the option of oral linezolid to complete 10 to 14 days) for treatment of skin infection, the clinical response outcomes were similar in both treatment arms. For patients with S. aureus infection, including MRSA, clinical success was observed in 90.6% of patients treated with dalbavancin and 93.8% of those who received vancomycin-linezolid .
Antibiotics are commonly used drugs that have diverse actions, side effects, and toxicities. The large number of antibiotics available makes it challenging to understand the characteristics of each antimicrobial class, including important information such as indications, action, dosage, and toxicities. Knowing the general characteristics by antibiotic class and having experience with one or two key agents within each class improves recall and facilitates the selection of the most appropriate antibiotic for a given bacterial infection.
An understanding of the mode of action, spectrum of activity, and potential toxicity enables the practitioner to tailor a therapeutic regimen that is specific and of appropriate duration. This in turn lessens the likelihood developing microbial resistances and reduces risk of adverse effects.
It is important to remember that the indications given by the FDA are guidelines. Many antibiotics are used for off-label purposes, and occasionally in doses that differ from those recommended for the usual indications. This may be necessary when faced with managing severe and life-threatening infections or for special populations, such as premature infants, neonates, and the elderly. Before using a specific agent, one should always consider carefully reviewing the detailed information (package insert) provided by the manufacturer.
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