Timothy H. Dellit MD1
Assistant Professor of Medicine
Thomas M. Hooton MD, FACP2
1Division of Allergy and Infectious Diseases, University of Washington School of Medicine
2University of Washington School of Medicine; Medical Director, Harborview HIV/AIDS Clinic, Harborview Medical Center
Timothy H. Dellit, M.D., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Thomas M. Hooton, M.D., F.A.C.P., has received grants for educational activities from Pfizer, Inc.
Overview of Antimicrobial Therapy
The essential feature of effective antimicrobial agents is the ability to inhibit the growth of microorganisms at concentrations tolerated by the host. Antimicrobial agents generally target anatomic structures or biosynthetic pathways unique to microorganisms.
The appropriate choice of an antimicrobial for an infection depends on five considerations: (1) the infecting organism and its antimicrobial susceptibilities; (2) the type of infection (e.g., abscess, bacteremia, meningitis, or urinary tract infection); (3) host factors (e.g., neutropenia, immune deficiencies, concurrent illnesses, age, drug allergies, and renal function); (4) factors associated with antimicrobial agents (e.g., dosage, routes of administration, drug interactions, serum levels and tissue penetration, potential toxicities, and cost); and (5) public health considerations. The widespread use of antibiotics has led to selection for highly resistant organisms that subsequently pose a risk for the patient and the community.
Identification of the Infecting Organism
Prompt identification of the causative organism is essential for the selection of appropriate antimicrobial drugs. A Gram stain of infected body fluids can provide early clues to the etiologic agent. Other relatively simple laboratory procedures, such as immunodiagnostic tests, may provide rapid identification of infecting organisms. If it is not possible to perform a Gram stain, initial decisions are based on the clinical features and the usual bacteriology of the illness, pending results of appropriate cultures. Culture results must be interpreted with full recognition of the indigenous flora on various mucosal surfaces and on the skin. Culture identification of the infecting organism and knowledge of the local antibiograms can offer clues to the likely antimicrobial susceptibilities [see Table 1]. However, even within a single institution's antibiogram, patterns of susceptibilities are influenced by patient characteristics (e.g., previous antimicrobial exposure) and location within the hospital (e.g., intensive care unit or general ward). National trends in antimicrobial resistance are tracked by the Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/drugresistance/community).
Table 1 Antimicrobial Susceptibilities of Clinical Isolates at a Representative Hospital
Determination of Bacterial Susceptibility to Specific Drugs
Determination of the in vitro susceptibility of isolated bacteria is usually performed to ensure that the empirical antimicrobial regimen is optimal. Timely availability of susceptibility data allows tailoring, when appropriate, of the antimicrobial regimen. However, the susceptibility of certain species (e.g., group A streptococci) to the drug of choice (e.g., penicillin G) has been so uniform that routine in vitro testing is unnecessary. Moreover, in vitro susceptibility data may not accurately predict the therapeutic outcome. For example,Enterobacter infections treated with third-generation cephalosporins, such as ceftazidime, may lead to induction of AmpC β-lactamases and clinical failure despite initial in vitro susceptibility.1 Similarly, Klebsiella species and Escherichia coli may harbor extended-spectrum β-lactamases (ESBLs) and still appear susceptible to cephalosporins in vitro unless the clinical microbiology laboratory actively screens for their presence. Cephalosporin treatment of such an apparently susceptible organism with an unrecognized ESBL, however, is associated with a high rate of failure.2
Disk diffusion is the classic method of testing antimicrobial susceptibility, although more automated systems are now available. When necessary, organisms can be tested by tube dilution techniques to determine the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of various antibiotics. Newer techniques include the gradient diffusion method and various nucleic acid-based tests that can detect genes conferring antimicrobial resistance in bacteria.3
The Site of Infection and Ancillary Therapy
The efficacy of antimicrobial therapy depends on drug delivery to the site of infection. Transport across the blood-brain barrier varies considerably among antibiotics.4 Intracellular parasites, such as rickettsiae and mycobacteria, require therapy with agents that can reach the intracellular milieu of the organism. Necrotic lesions, such as sequestra in bone or large abscesses, hinder penetration by antimicrobials. Drainage, debridement, or both, combined with antimicrobials, are necessary. Antimicrobial therapy for infection in or around a foreign body or prosthesis often is ineffective unless these materials are removed or replaced. Infections behind obstructing lesions, such as pneumonia that occurs behind a blocked bronchus or cholecystitis caused by biliary obstruction, will not respond to antibiotics until the obstruction is relieved.
Factors Affecting Dosage and Route of Administration
Many antimicrobials are absorbed sufficiently well via the oral route to provide effective serum levels in patients with normal gastrointestinal function.5 For some antimicrobials (e.g., fluoroquinolones, metronidazole, and linezolid), the pharmacokinetics of the oral agents are almost the same as those of the parenteral formulations, and oral therapy, when appropriate, is much less expensive. The enteral absorption of some antimicrobial agents is impeded by food and some medications (e.g., antacids); these antibiotics, such as tetracyclines, should be administered at least 1 hour before meals or several hours after meals. Certain antibiotics, such as neomycin, are essentially nonabsorbable and are used primarily for their effects on bowel flora. Intramuscular administration is used in a small number of conditions (e.g., benzathine penicillin for syphilis or ceftriaxone for gonorrhea), but most antimicrobials cannot be given intramuscularly because of local pain or necrosis at the injection site. Intravenous administration must be used in the treatment of major and life-threatening infections such as septic shock, meningitis, and endocarditis. Patients who are clinically stable after initial intravenous treatment may be ready for discharge from the hospital and may be able to receive parenteral antibiotics on an outpatient basis. Newer antimicrobial agents with long half-lives can be administered with improved intravenous catheters and delivery devices in simplified regimens. Alternatively, the enhanced bioavailability of some antimicrobials has allowed many patients to complete a course of oral antimicrobial therapy after they are discharged. Such pharmacologic advances have led to substantial economic benefits, enhanced patient comfort, and good therapeutic results with few complications.6
Patients with immunosuppressive illnesses are vulnerable to opportunistic pathogens. These patients may require broader antimicrobial coverage and combination therapy for ordinary pathogens. The same is true to a lesser extent for patients with chronic debilitating illness. Patients with renal insufficiency or liver disease may be unusually susceptible to direct drug toxicity [see Direct Drug Toxicity, below].
Many antimicrobials (e.g., penicillins, cephalosporins, aminoglycosides, vancomycin, and fluoroquinolones) are excreted primarily by the kidneys. Guidelines for dosage adjustment in patients who have severe renal failure and are undergoing dialysis or peritoneal dialysis are provided elsewhere [see 10:IX Pharmacologic Approach to Renal Insufficiency, Appendix A]. Antibiotics with nonrenal metabolism may be preferable in azotemic patients, provided that the infecting organism is susceptible. A number of antibiotics, including nafcillin, piperacillin, doxycycline, metronidazole, and rifampin, are excreted by the liver.
The administration of antimicrobials during pregnancy and in the postpartum period poses several problems. Foremost is the question of safety, both for the mother and for the fetus or neonate. Although most antibiotics cross the placenta and enter maternal milk, the concentrations to which the fetus or neonate is exposed vary widely. Because the immature liver may lack the enzymes required to metabolize certain drugs, pharmacokinetics and toxicities in the fetus are often very different from those in older children and adults. Teratogenicity is a major concern when any drug is administered during pregnancy. Finally, it may be necessary to alter the dosage schedules of drugs that appear to be safe to use during pregnancy. Increases in maternal blood volume, glomerular filtration rate (GFR), and hepatic metabolic activity often reduce the maternal serum levels of antimicrobials by 10% to 50%, especially late in pregnancy and in the early postpartum period. In some women, delayed gastric emptying may reduce the absorption of antibiotics that have been administered orally during pregnancy.
Even though 25% to 40% of women receive antibiotics during pregnancy, data regarding safety and efficacy in this setting are often scarce. Some general recommendations have been proposed, but they are intended only as a guide [see Table 2]; in all cases, therapy must be individualized, and both the indications for antibiotics and the possible risks to mother and fetus must be considered. Individual decisions are also required for lactating mothers. Although most antimicrobials appear safe for breast-fed infants, chloramphenicol, fluoroquinolones, and tetracyclines should be avoided.7
Table 2 Antibiotics in Pregnancy
Physiologic changes that occur with age can alter the pharmacokinetics of antimicrobials. For example, decreased gastric acidity and intestinal motility can impair drug absorption; increased body fat and decreased serum albumin levels can alter drug distribution; and decreased hepatic blood flow and enzymatic action can delay drug metabolism. Although these factors have not consistently affected antibiotic levels in the elderly, the decrease in GFR that occurs with age can lead to the accumulation of drugs excreted by the kidney. The high therapeutic index of the penicillins and cephalosporins obviates major changes in dosage schedules in elderly patients who have normal serum creatinine levels. However, in the case of aminoglycosides and vancomycin, decreased dosage schedules are often required. Ideally, drug levels should be measured and renal function should be monitored when these agents are given.
Complications of Antimicrobial Therapy
There are three general types of complications with antimicrobials: hypersensitivity reactions (which are not dose related), direct drug toxicity (which usually is dose related and manifests itself in a single organ or, occasionally, in several organs), and microbial superinfection (which is caused by drug-resistant organisms, such as Clostridium difficile, that flourish under the selective pressures exerted by antimicrobial therapy). In rare situations, antimicrobial therapy can lead to a worse clinical outcome. For example, antibiotic therapy has been associated with the development of hemolytic-uremic syndrome in children with gastroenteritis caused by E. coli 0157:H7.8
A history of allergies should be taken before antimicrobial therapy is initiated in any patient.9 More information is available regarding allergies to the penicillins than allergies to other agents, but skin eruptions, drug fever, and even anaphylaxis may be produced by many antibiotics. Allergic reactions occur in 1% to 10% of patients who receive penicillin. Fatal anaphylactic reactions are much less frequent [seeAllergic Reactions to β-Lactam Antibiotics, below].
Direct Drug Toxicity
Although antimicrobials can damage virtually all human organ systems, the potential for toxicity varies widely from drug to drug.10 The principal antibiotics that are directly toxic to the kidney are aminoglycosides and polymyxins. Patients with preexisting renal insufficiency are at increased risk for toxic reactions to various antibiotics, including nephrotoxicity, coagulopathies and other hematologic toxicities, seizures, and ototoxicity and other neurotoxicities.
Chloramphenicol can produce bone marrow suppression, which is usually mild and reversible, but rarely presents as an irreversible fatal aplastic anemia. Chloramphenicol, sulfonamides, nitrofurantoin, and primaquine can cause hemolytic anemia in patients who have deficiencies of erythrocyte glucose-6-phosphate dehydrogenase (G6PD). Hemolytic anemia, thrombocytopenia, and leukopenia that involve an immune mechanism can be caused by penicillins, cephalosporins, tetracyclines, and rifampin, but these reactions are uncommon. Macrolides and trimethoprim-sulfamethoxazole have been associated with agranulocytosis. Trimethoprim can produce anemia, leukopenia, and thrombocytopenia from folate deficiency, which is reversible with folinic acid. Linezolid can also produce myelosuppression, which appears to be reversible with discontinuance of the drug. Patients receiving linezolid for more than 2 weeks are at greatest risk, and the complete blood count with differential should be monitored weekly in such patients. Neutropenia can occur during therapy with penicillins, cephalosporins, or vancomycin. It may be severe but is self-limited, with recovery occurring 1 to 7 days after the antibiotic is withdrawn. Penicillins inhibit platelet aggregation by adenosine diphosphate, which may account for the bleeding that occurs in some patients receiving these antibiotics in high doses. Various cephalosporins may produce coagulopathies by prolonging the prothrombin time. The methylthiotetrazole side chain present in cephalosporins such as cefotetan appears to be responsible.
Antibiotics may produce a wide range of toxic effects on the central and peripheral nervous systems. Ototoxicity, either vestibular or auditory, can be produced by any of the aminoglycosides; neuromuscular blockade is much less common. Minocycline has occasionally been reported to produce significant vestibular reactions. Vancomycin can cause auditory neurotoxicity. Intravenous administration of penicillin and other β-lactams may produce seizures, especially when administered in very high doses or when given to azotemic patients or to patients with underlying epilepsy.
Peripheral neuropathy can occur as a complication of therapy with nitrofurantoin, particularly when renal failure is present. The neuropathy that occurs with isoniazid can be prevented by the daily administration of 50 mg of pyridoxine. Tetracycline may in rare instances produce reversible benign intracranial hypertension with headache and papilledema. Nalidixic acid may also produce intracranial hypertension and seizures in children. Metronidazole can sometimes cause ataxia, encephalopathy, seizures, or peripheral neuropathies. Ofloxacin has been reported to cause seizures, and mania has been attributed to clarithromycin. Optic neuritis, usually manifested by decreased visual acuity and decreased perception of the color green, may occur as a side effect of ethambutol.
The principal antimicrobials that produce adverse effects on the liver are those used in the treatment of tuberculosis: isoniazid, rifampin, aminosalicylic acid, and pyrazinamide. Trovafloxacin was withdrawn because of hepatotoxicity, but other fluoroquinolones have not been implicated. The tetracyclines can occasionally cause fatty liver with hepatotoxicity; this is most likely to occur in patients receiving 2 g or more daily by the intravenous route. Patients receiving high-dose β-lactam antibiotics may develop hepatitis or cholestasis, presumably as a result of hypersensitivity reactions. Nitrofurantoin may cause chronic active hepatitis in some patients. Erythromycins and sulfonamides have been associated with acute hepatitis.
GI reactions to antibiotics result either from direct irritation by the drug, the occurrence of which is usually dose related, or from bacterial overgrowth.11 Irritative GI side effects are usually produced when antibiotics are administered orally rather than parenterally. The predominant site of irritation varies from drug to drug; for example, erythromycin more commonly produces gastric irritation with epigastric distress and nausea, whereas tetracyclines may produce diarrhea and upper GI symptoms. Some qualitative and quantitative changes in the intestinal flora occur after antibiotic administration. These intestinal changes may contribute to flatulence and other lower GI symptoms, including antibiotic-associated diarrhea, which are quite common when broad-spectrum antibiotics are administered orally. An important subset of antibiotic-associated diarrhea involves the selective overgrowth of Clostridium difficile and resultant pseudomembranous colitis [see 7:V Anaerobic Infections and 4:III Diarrheal Diseases].
Antibiotics may cause various other toxicities. Erythromycin and other macrolides can cause prolongation of the QTc interval and polymorphic ventricular tachycardia. In rare instances, this toxicity occurs in the absence of predisposing factors, but it is more likely to occur in patients with significant heart disease and in patients taking terfenadine, astemizole, or cisapride. Several fluoroquinolones, particularly grepafloxacin and sparfloxacin can have similar effects on cardiac conduction.12 All fluoroquinolones can cause tendonitis and either hyperglycemia or hypoglycemia. Trimethoprim-sulfamethoxazole can cause hyperkalemia, particularly in azotemic patients. Sulfonamides, fluoroquinolones, and tetracyclines can produce photosensitivity.13
Antimicrobial therapy reduces the number of susceptible organisms from the normal flora of the skin, oropharynx, genitourinary tract, and gastrointestinal tract and exerts selective pressures that favor survival of drug-resistant organisms. Such resistant organisms can occasionally establish a superinfection (i.e., a new infection caused by a different pathogen from the one being treated) either at the site of the original infection or at remote sites. Recent reports of both the increasing incidence and severity of C. difficile infections indicate that further caution is warranted against the indiscriminant use of antimicrobials, particularly broad-spectrum cephalosporins and fluoroquinolones.14
Public Health Considerations
The extensive use of antimicrobials, especially in intensive care units15 and other health care facilities, strongly favors the selection of resistant microbial species, particularly bacterial strains harboring plasmids that confer transmissible resistance.16,17,18 The widespread use of antibiotics in animal husbandry and agriculture compounds the problem; roughly 50% of the 25,000 tons of antibiotics that are sold annually in the United States are used in agriculture and aquaculture.19 Infections from highly resistant strains of Enterococcus, Streptococcus pneumoniae, Staphylococcus, Neisseria gonorrhoeae, Salmonella, Serratia, Klebsiella, Acinetobacter, Enterobacter, Pseudomonas, and Mycobacterium have become important problems. Infections from resistant strains can spread rapidly—first within an institution, then throughout a community, and eventually even globally.20 Although antimicrobial resistance is a worldwide problem, control depends on local measures, beginning with the judicious prescription of antibiotics by individual practitioners in combination with sound infection control practices. Through the Campaign to Prevent Antimicrobial Resistance in Healthcare Settings (http://www.cdc.gov/drugresistance/healthcare), the CDC offers resources for infection control. There is national concern that the relatively small number of new antimicrobial agents in development will not keep pace with the emergence of drug resistance.
Specific Antimicrobial Agents
The simultaneous use of multiple antibiotics in a shotgun fashion should be avoided because of the problems of drug toxicity and hypersensitivity reactions, microbial superinfections, and antagonisms between certain agents. Most bacterial infections can be treated satisfactorily with a single antimicrobial agent. There are a limited number of situations, however, in which the simultaneous administration of different antimicrobials is warranted: (1) when synergism occurs between two antimicrobials against a specific infecting agent; (2) to prevent the emergence of resistance to one or more drugs; (3) for treatment of polymicrobial infections for which one antibiotic is not sufficient; and (4) for initial empirical treatment of life-threatening infections before isolation of the etiologic agent.
Although the choice of antimicrobial drugs must always be individualized, there are useful guidelines that can be followed [see Table 3].21,22
Table 3 Antimicrobial Drugs of Choice for Various Infections in Adults21
The penicillins are bactericidal antibiotics that impair synthesis of the bacterial cell wall peptidoglycan by attaching to penicillin-binding proteins located in the cell membrane. These enzymes are responsible for linking individual elements of the bacterial cell wall together. Penicillins and other β-lactam antibiotics have different affinities for the various penicillin-binding proteins.23
The penicillins may be classified into subgroups on the basis of their structure, β-lactamase susceptibility, and spectrum of action. Dosages of these agents vary according to the type and severity of infection. The penicillins are generally well tolerated. Hypersensitivity and GI reactions are the most common side effects, though granulocytopenia, hemolytic anemia, bleeding, interstitial nephritis, hepatitis, and seizures may occur. The adverse effects of penicillin are generally shared by all its derivatives. However, broad-spectrum penicillins are more likely to cause pseudomembranous colitis, and penicillins with α-carboxyl substitutions, such as ticarcillin, are more likely to impair platelet function. Patients allergic to one penicillin compound are likely to be allergic to other penicillins.
Penicillin G and penicillin V
Penicillin G, the first antibiotic to be used for systemic infections, is still the drug of choice for various infections. Resistance to penicillin has not been observed in group A streptococci and Treponema pallidum, and penicillin G is highly effective in subacute bacterial endocarditis caused by susceptible bacteria. Penicillin V (phenoxymethyl penicillin) has the same spectrum of activity as penicillin G but is more acid-stable and is thus better absorbed from the GI tract. The narrow spectra of penicillin G and V, however, limit their use to a small number of indications, and resistance to these agents is increasing, particularly with S. pneumoniae strains. Although all forms of penicillin introduced since the release of penicillin G are prescribed by weight, penicillin G is still prescribed for parenteral administration by unitage. For interconversion, 1 mg of penicillin G equals approximately 1,600 units. Procaine penicillin G and benzathine penicillin G are slowly absorbed, allowing dosing every 12 to 24 hours and weekly, respectively, for treatment of highly susceptible pathogens.
Penicillinase-resistant penicillins were developed for their activity against β-lactamase-producing S. aureus. Nafcillin and oxacillin are usually administered parenterally. Oxacillin is also available in an oral formulation, but cloxacillin and, especially, dicloxacillin are preferred for oral administration because of superior GI absorption. The emergence of methicillin-resistant S. aureus (MRSA) continues to be a major public health issue.
Penicillinase-susceptible broad-spectrum penicillins
Ampicillin has a broader spectrum of activity than penicillin G. Its spectrum encompasses not only most pneumococci, meningococci, gonococci, and various streptococci but also some gram-negative bacilli. Like penicillin G, however, ampicillin is readily cleaved by β-lactamase and is useless in the treatment of infections caused by S. aureus or other organisms producing this enzyme. Plasmids conferring ampicillin resistance have appeared in S. typhi, Haemophilus influenzae, and N. gonorrhoeae. Increasing resistance has appeared in strains of E. coli, S. pneumoniae, N. gonorrhea, and nontyphoidal Salmonella.
Amoxicillin has a spectrum of activity that is identical to that of ampicillin, but amoxicillin is more efficiently absorbed from the GI tract, and effective concentrations are present in the circulation for twice as long.
The change from an amino to a carboxyl substituent on the side chain converts ampicillin to carbenicillin. Carbenicillin has an extended spectrum of activity against gram-negative bacilli, including Pseudomonas, Proteus species other than P. mirabilis, and some strains ofEnterobacter. β-Lactamase-producing S. aureus is resistant to carboxypenicillins. The indanyl carbenicillin ester is acid stable and is suitable for oral administration in the treatment of urinary tract infections caused by susceptible gram-negative bacilli, including Pseudomonas, but serum levels are too low for use in other infections. Ticarcillin is the other carboxypenicillin; it is administered intravenously to treat serious infections caused by susceptible organisms. Ticarcillin has an extended spectrum of activity against gram-negative bacilli, including P. aeruginosa, but it is ineffective against Klebsiella. Because of the widespread use of these antibiotics, however, many strains of P. aeruginosa are now resistant to the carboxypenicillins.24
Like the carboxypenicillins, the ureidopenicillins (i.e., azlocillin, mezlocillin, and piperacillin) are ampicillin derivatives. They are active against most organisms that are susceptible to ampicillin, including many pneumococci, most streptococci, N. meningitidis, and most E. coliand P. mirabilis strains. They have extended activity against P. aeruginosa, although the prevalence of resistance is rising. β-Lactamase-producing staphylococci and H. influenzae are resistant to the ureidopenicillins.
The carboxypenicillins and ureidopenicillins also differ from ampicillin in their increased effectiveness against many anaerobes, including about 50% of Bacteroides fragilis strains. However, the major role of these drugs depends on their spectrum of activity against resistant gram-negative bacilli, which is somewhat broader for the ureidopenicillins than it is for the carboxypenicillins. Despite these in vitro differences, clinical studies have not demonstrated that the ureidopenicillins are superior to the carboxypenicillins in treating organisms susceptible to both groups. The newer cephalosporins and carbapenems, however, appear preferable for treating infections caused by resistant Klebsiella and Serratia strains.
The serum levels, tissue distribution, half-lives, and recommended dosage ranges of piperacillin, mezlocillin, and azlocillin are similar to those of ticarcillin. Unlike ticarcillin and carbenicillin, which are solely excreted by the kidneys, the ureidopenicillins are excreted in the bile and the urine and do not accumulate in patients with renal failure. The toxicities of these drugs are similar, except that the ureidopenicillins are less likely to impair platelet function or cause hypokalemia.
Penicillin-β-lactamase inhibitor combinations
The major mechanism of resistance to the penicillins is bacterial production of β-lactamase enzymes that hydrolyze the β-lactam ring, rendering the molecule inactive. Clavulanate, sulbactam, and tazobactam are β-lactam compounds that have little intrinsic antibacterial activity except for sulbactam in A. baumannii infections.25 They do, however, bind irreversibly to the β-lactamase enzymes that are produced by many bacteria, thus inactivating these enzymes and rendering the organisms susceptible to β-lactamase-susceptible penicillins.
Clavulanate is combined with amoxicillin in an oral formulation. Ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam are parenteral formulations. The combinations are active against ampicillin-susceptible organisms and various ampicillin-resistant organisms, including β-lactamase-producing strains of Moraxella catarrhalis, H. influenzae, E. coli, K. pneumoniae, some Proteus species, and S. aureus(except methicillin-resistant strains). The combinations are also active against many anaerobes, including B. fragilis. However, P. aeruginosaand many strains of Serratia and Enterobacter are resistant to amoxicillin-clavulanate and ampicillin-sulbactam. These agents are not active against bacteria resistant to the penicillin derivative when the resistance is not mediated by β-lactamase production. For example, penicillin-resistant strains of S. pneumoniae have altered penicillin-binding proteins and are not affected by the addition of a β-lactamase inhibitor.
Amoxicillin-clavulanate therapy has been used successfully to treat upper and lower respiratory tract infections, urinary tract infections, and human and animal bites. Twice-daily administration is effective. The ampicillin-sulbactam combination has been used successfully to treat gynecologic and intra-abdominal infections, as well as infections of the upper and lower respiratory tracts, urinary tract, skin and soft tissues, and bones and joints. Ticarcillin-clavulanate has been successful in the treatment of pulmonary, urinary tract, bone, soft tissue, and bloodstream infections. Piperacillin-tazobactam is very similar to ticarcillin-clavulanate in its very broad spectrum of activity, pharmacokinetics, toxicities, and expense. The recommended dosage of 3 g of piperacillin and 375 mg of tazobactam every 6 hours for adults with normal renal function is lower than the recommended dosage for piperacillin alone (18 g/day) and may not be sufficient for some serious infections caused by P. aeruginosa. An increased dose of 4 g of piperacillin and 500 mg of tazobactam is approved for nosocomial pneumonia when there is concern for infection from Pseudomonas species.
The cephalosporins and closely related cephamycins (e.g., cefoxitin and cefotetan) comprise a large family of β-lactam antibiotics. Like the penicillins, the cephalosporins are bactericidal antibiotics that inhibit bacterial cell wall synthesis and have a low intrinsic toxicity. The adverse effects of the cephalosporins are mainly hypersensitivity reactions, local pain (with intramuscular use), and thrombophlebitis (with intravenous use). Less common toxicities include GI symptoms, elevated liver enzyme levels, and renal impairment. Third- and fourth-generation cephalosporins may cause seizures, including nonconvulsive status epilepticus, in patients with renal failure.26Pseudomembranous colitis may also develop. Because the cephalosporins share immunologic cross-reactivity, patients who are allergic to one cephalosporin are likely to be allergic to others. There is also a possibility of cross-reactivity in penicillin-allergic patients.27
The cephalosporins are grouped into generations on the basis of their antibacterial spectrum28 [see Table 4]. In general, activity against gram-positive cocci diminishes from the first generation to the third generation, whereas the spectrum of activity against gram-negative organisms increases. The single fourth-generation agent, cefepime, has an extended spectrum of activity against both gram-positive and gram-negative organisms. Agents in each group exhibit pharmacologic differences in serum levels and half-lives, leading to substantial variation in dosing. Most cephalosporins are excreted primarily by the kidneys and require dose reduction in the presence of renal failure, with the notable exceptions of ceftriaxone and cefoperazone [see 10:IX Pharmacologic Approach to Renal Insufficiency, Appendix A]. Cephalosporins cross the placenta and penetrate the pericardium and joints. The third- and fourth-generation cephalosporins have good cerebrospinal fluid penetration and are effective in treating meningitis, whereas none of the first-generation drugs and only one of the second-generation agents (cefuroxime) are effective in treating meningitis.
Table 4 Properties of Cephalosporin Antibiotics
The first-generation cephalosporins are active against many gram-positive bacteria, including penicillin-susceptible pneumococci, penicillinase-producing S. aureus, and most streptococci. However, they are ineffective against MRSA, coagulase-negative staphylococci, penicillin-resistant pneumococci, enterococci, and Listeria. Although the first-generation cephalosporins are active against many strains of E. coli, K. pneumoniae, and P. mirabilis, they are ineffective against many other gram-negative species because these organisms produce β-lactamases.
The second-generation cephalosporins consist of two groups: the true cephalosporins (such as cefuroxime) and the cephamycins (such as cefoxitin, cefotetan, and cefmetazole). Because they are not as vulnerable to the β-lactamases that are produced by many of the gram-negative bacteria, the second-generation cephalosporins have enhanced activity against gram-negative bacilli, including many strains of E. coli, Klebsiella, Serratia, and Proteus that are resistant to the first-generation cephalosporins. However, second-generation cephalosporins are not effective against Pseudomonas or Enterobacter species. The second-generation cephalosporins retain some activity against gram-positive organisms that are susceptible to first-generation cephalosporins. The cephamycins have enhanced anaerobic activity, including activity against B. fragilis, and are effective in intra-abdominal and pelvic infections; however, these agents have largely been supplanted by combination therapy with pencillin and a β-lactamase inhibitor and by the carbapenems.
Third- and fourth-generation cephalosporins
The third-generation cephalosporins differ from other cephalosporins in some important respects. Their enhanced ability to resist hydrolysis by the β-lactamases of many gram-negative bacilli gives them an expanded antibacterial spectrum. Pharmacologically, these drugs also have an important advantage: unlike older cephalosporins, they achieve therapeutic levels in the cerebrospinal fluid and can be used to treat meningitis. These advantages, however, come at an increased cost, in that there is an emerging resistance to these agents and that their effect on the normal flora causes increased colonization with vancomycin-resistant Enterococcus (VRE).
Although third-generation agents are less active than the older cephalosporins against many gram-positive cocci,29 they are active against most penicillin-nonsusceptible pneumococci. Like other cephalosporins, the third-generation agents are inactive against enterococci, MRSA, and Listeria; however, they have enhanced potency against many gram-negative bacilli, including E. coli, Klebsiella, Proteus, Serratia, andCitrobacter organisms. They are also very active against penicillinase-producing and non-penicillinase-producing strains of H. influenzae and gonococci. The third-generation cephalosporins are active against most Salmonella species and have been clinically effective in the treatment of typhoid fever and other Salmonella infections. Resistant strains are now beginning to emerge in the United States, however.30Although most Enterobacter species initially appear susceptible to third-generation cephalosporins, they may rapidly develop resistance during therapy as a result of inducible cephalosporinases.1 Hence, it may be prudent to avoid using a cephalosporin as the sole therapy for these organisms. Similarly, Klebsiella species may appear susceptible by disk-diffusion testing but may harbor an ESBL, which renders therapy with a third-generation cephalosporin ineffective.2 Increased zone size around the combined ceftazidime-clavulanate disk relative to the zone size of ceftazidime alone is indicative of the presence of ESBLs.
Although third-generation cephalosporins exhibit activity against B. fragilis and other anaerobes, the cephamycins cefoxitin, cefotetan, and cefmetazole are more active. Ceftazidime has the greatest activity against P. aeruginosa. Cefoperazone also demonstrates good activity, but the other third-generation cephalosporins have been disappointing. Other nosocomial gram-negative pathogens that are resistant to these drugs include Acinetobacter and Stenotrophomonas.
Cefepime is a fourth-generation cephalosporin with broad antimicrobial activity against both aerobic gram-positive bacteria (e.g., penicillin-nonsusceptible S. pneumoniae) and methicillin-susceptible S. aureus; it is also effective against gram-negative bacteria, including H. influenzae, Neisseria, and Enterobacteriaceae. Its activity against Pseudomonas is similar to that of ceftazidime. Compared to the third-generation cephalosporins, cefepime is a weaker inducer of AmpC β-lactamase and is more stable in the presence of this enzyme.31 The clinical significance of this finding remains to be determined.
Imipenem and meropenem were the first carbapenems available for clinical use in the United States; the third, ertapenem, received Food and Drug Administration approval in 2002. Like other β-lactam antibiotics, they are bactericidal and act by inhibiting bacterial cell wall synthesis.32 Three properties account for the extraordinarily broad antibacterial spectrum of the carbapenems: the ability to penetrate the cell membrane of gram-negative bacteria; high affinity for critical penicillin-binding proteins; and resistance to hydrolysis by β-lactamases.
Imipenem is extensively hydrolyzed in the renal tubule, which results in low urinary levels of the drug and the production of a nephrotoxic metabolite. Cilastatin prevents this degradation by inhibiting the brush-border enzyme dehydropeptidase-1; cilastatin and imipenem are administered simultaneously in equal doses. Meropenem and ertapenem are not susceptible to degradation by dehydropeptidase and can therefore be administered without cilastatin. Ertapenem has a longer half-life than the other carbapenems, allowing for a single daily dose; imipenem, on the other hand, requires dosing every 6 hours, and meropenem, every 8 hours.33 The carbapenems are primarily excreted in the urine; the dosage should be reduced in azotemic patients.
The carbapenems have broader antibacterial spectra than any other β-lactam antibiotics; they are effective against most clinically important gram-positive and gram-negative bacteria, including anaerobes. Whereas imipenem tends to be more active against gram-positive cocci, meropenem appears to be more active against gram-negative bacilli. However, neither drug is active against methicillin-resistant staphylococci, E. faecium, or Stenotrophomonas. Ertapenem has a similarly broad spectrum of coverage; however, compared to the other carbapenems, ertapenem has decreased activity against Pseudomonas, Acinetobacter, and E. faecalis.
Carbapenems are extraordinarily active against gram-negative bacteria. Virtually all Enterobacteriaceae are susceptible. Haemophilus andNeisseria species are also susceptible to carbapenems but at drug concentrations somewhat higher than those of third-generation cephalosporins. Acinetobacter, which is resistant to most other β-lactam antibiotics, is usually susceptible to imipenem and meropenem, although resistance appears to be increasing. All three carbapenems retain activity against most bacterial strains expressing the inducible AmpC β-lactamase enzyme (e.g., Serratia, Citrobacter, and Enterobacter), as well as organisms containing ESBL; in fact, carbapenems are the drugs of choice for infections caused by such organisms. Gram-negative anaerobes, including B. fragilis, are susceptible. P. aeruginosais generally susceptible to imipenem and meropenem, but resistance has emerged with increased carbapenem use.
The safety of carbapenems seems comparable to that of other β-lactam antibiotics. Nausea and vomiting, local pain at injection sites, and hypersensitivity are the most common reactions. Seizures, although unusual, are a potential concern with imipenem. They have been observed in 0.9% of patients who have received the drug; risk factors for seizures include excessive dosage, preexisting CNS lesions, epilepsy, and renal insufficiency. Meropenem is less likely to provoke seizures. Transient elevations of liver enzymes and leukopenia can occur in patients who are given carbapenems. Antibiotic-associated pseudomembranous colitis has occurred.
Because the structure of the carbapenems resembles that of the penicillins and cephalosporins, there is potential for cross-reactivity in patients allergic to other β-lactam antibiotics. Clinical experience in this situation is limited, but it appears prudent to avoid carbapenems in patients who experience anaphylactic reactions to β-lactam drugs and to use carbapenems with caution in patients who have milder allergies to penicillins or cephalosporins.34
Carbapenems have been used successfully in patients with pneumonia, intra-abdominal infections, complicated skin and soft tissue infections, complicated urinary tract infections, endocarditis, bacteremia, osteomyelitis, and febrile neutropenia. The broad spectrum and apparent low toxicity of carbapenems are impressive, but they should be used with restraint and selectivity.
The monobactams are monocyclic β-lactam antibiotics that lack the thiazolidine ring found in penicillins and the dihydrothiazine ring found in cephalosporins.32 Aztreonam is currently the only available monobactam. The antibacterial activity of aztreonam depends on its ability to penetrate the outer membrane of gram-negative bacilli, as well as on its high affinity for penicillin-binding protein-3 and its resistance to hydrolysis by the β-lactamases of gram-negative bacilli.
The antibacterial activity of aztreonam is restricted to aerobic or facultative aerobic gram-negative bacteria. Most strains of H. influenzae, gonococci, and meningococci are susceptible to aztreonam, as are most enteric gram-negative bacilli, including E. coli, Klebsiella, Proteus, and Enterobacter. Most strains of P. aeruginosa are also susceptible, but somewhat higher concentrations of aztreonam are required to kill these bacteria. Acinetobacter, S. maltophilia, and B. cepacia are generally resistant to aztreonam, as are all gram-positive bacteria and anaerobes.
Excellent serum levels are achieved after intramuscular or intravenous administration, and the drug is widely distributed in body tissues and fluids, including the CSF. The serum half-life of aztreonam is about 90 minutes, and glomerular filtration is the major means by which the drug is eliminated. The dosage of aztreonam must be reduced in azotemic patients. The drug is efficiently removed by hemodialysis but not by peritoneal dialysis.
Aztreonam is well tolerated. Its toxicities resemble those of other β-lactam antibiotics; these toxicities include occasional instances of local reactions at the site of injection, rash, diarrhea, nausea, and vomiting. Neither nephrotoxicity nor ototoxicity has been reported. Aztreonam does not cross-react with serum antibodies of penicillin-allergic and cephalosporin-allergic patients, and the drug has been well tolerated in penicillin-allergic patients.
Aztreonam has been used successfully in the treatment of a wide variety of infections caused by gram-negative bacteria, including pneumonias, skin and soft tissue infections, bone and joint infections, urinary tract infections, and bacteremias. Although aztreonam achieves therapeutic concentrations in the CSF, experience in the treatment of meningitis has been very limited.
Because aztreonam combines the spectrum of activity of the aminoglycosides with the low toxicity of the β-lactam antibiotics, it is an attractive alternative for many gram-negative infections. Synergy can be demonstrated between aztreonam and aminoglycosides for some gram-negative bacilli; however, it is not synergistic with other β-lactam agents. More clinical experience is needed to determine the circumstances in which aztreonam should be substituted for or used as a supplement to the aminoglycosides.
Allergic Reactions to β-Lactam Antibiotics
Hypersensitivity is the most common adverse reaction to β-lactam antibiotics [see 2:VI Cutaneous Adverse Drug Reactions and 6:XIV Drug Allergies]. Most often, it is a delayed reaction characterized by maculopapular eruptions, fever, or both. Eosinophilia may also be present. Much less common but much more serious is immediate hypersensitivity, mediated by IgE. Manifestations may include early-onset urticaria, laryngeal edema, or anaphylaxis. Immune complexes can produce serum sickness in some patients. Hypersensitivity to β-lactam antibiotics can also cause hemolytic anemia or allergic interstitial nephritis.
Establishing Drug Allergy
As many as 10% of all patients report a history of penicillin allergy, but only 10% to 20% of those reporting allergy are actually at risk for immediate hypersensitivity reactions.35 A careful history is the best way to establish true drug allergy. A patient's recollection of rash, urticaria, arthralgias, wheezing, or anaphylaxis confirms the diagnosis of hypersensitivity, whereas treatment failure, diarrhea, vaginitis or other superinfections, or vague symptoms do not. Skin tests have a limited role in predicting true penicillin allergy, but they can help exclude IgE-mediated (anaphylactic) hypersensitivity.36 To document severe allergy, both benzylpenicilloyl polylysine (a major-determinant antigen) and the so-called minor-determinant antigens should be injected. A wheal-and-flare reaction signifies IgE-mediated allergies; negative reactions to both major and minor determinants make anaphylaxis unlikely, but small test doses of penicillin should be administered for additional safety. Facilities and equipment necessary for the treatment of anaphylaxis should always be on hand when skin testing is performed. Patients with positive skin-test responses have a 41% to 67% chance of exhibiting significant penicillin allergy if they are rechallenged with the drug. The risk to patients with negative skin-test responses is only 1% to 4%, and no life-threatening reactions have been reported. Nonetheless, because benzylpenicilloyl polylysine is no longer commercially available, the use of this diagnostic test is limited to medical centers that are able to produce their own major-determinant and minor-determinant antigens.
Patients with penicillin allergy, whether documented by history or by skin testing, should receive other antibiotics for infections. In rare cases in which there is no acceptable alternative to a penicillin (e.g., syphilis in a pregnant woman), desensitization can be attempted. Desensitization is carried out with the equipment and medications for the treatment of anaphylaxis at the bedside: a laryngoscope, oxygen, an endotracheal tube, epinephrine (1:1,000 weight in volume), sodium bicarbonate solution, and a running intravenous infusion. Penicillin doses are administered in graded increases in the forearm at a site low enough for a tourniquet to be applied proximally should a reaction occur. The initial dose of 1 unit of penicillin is applied by scratch test. If there is no wheal-and-flare reaction within 15 minutes, a dose of 2 units is injected intradermally. If no local or systemic reactions occur after another 15 minutes, a dose of 5 units is injected intradermally. If no reactions occur, successive doses that approximately double each previous dose are injected intradermally at 15-minute intervals. When the amount injected becomes large, the penicillin dose is administered subcutaneously. When a dose of 100,000 units has been injected without reaction, penicillin can be given intravenously. If an immediate local or systemic reaction occurs, it can be controlled. Use of an alternative drug is then advisable. Oral desensitization regimens are also available. Neither corticosteroids nor antihistamines will prevent anaphylaxis in an individual who is highly sensitive to penicillin.
Penicillin Allergy and Hypersensitivity to Other Drugs
Patients who are allergic to one penicillin should be considered allergic to all penicillins. However, this generalization may not be true for some children in whom a rash has developed after taking ampicillin or amoxicillin, particularly in the setting of infectious mononucleosis. Patients who are allergic to penicillin have an 8% likelihood of having an allergic reaction to a cephalosporin antibiotic27; cephalosporins are best avoided in patients who have IgE-mediated (anaphylactic) hypersensitivity to penicillin. Although there is much less experience with carbapenems (e.g., imipenem, meropenem, and ertapenem), the same guidelines apply for the use of these drugs in patients who are allergic to other β-lactams. However, monobactams (e.g., aztreonam) have not provoked cross-reactive hypersensitivity reactions. There are no reliable skin tests for cephalosporin, carbapenem, or monobactam allergies.
The aminoglycosides are bactericidal drugs that inhibit protein synthesis by binding irreversibly to the 30S ribosomal subunit of susceptible bacteria.37 They exhibit concentration-dependent activity, as well as a postantibiotic effect. Because oxygen is required to transport aminoglycosides across the outer bacterial membrane, these agents are ineffective against anaerobes and may function poorly in the acidic, anaerobic milieu of abscesses. Although various aminoglycosides display activity against a wide range of microorganisms, they are used chiefly to treat infections caused by aerobic gram-negative bacilli, including Pseudomonas. Aminoglycosides are also used in combination with cell wall-active antibiotics (e.g., penicillins and vancomycin) for the synergistic treatment of deep tissue infections caused by enterococci and coagulase-negative staphylococci. In addition, streptomycin is still used to treat tuberculosis, tularemia, and plague.38
The aminoglycosides are not absorbed from the GI tract and must be administered intravenously or intramuscularly. The drugs penetrate pleural, ascitic, and synovial fluids in the presence of inflammation, but they diffuse poorly into other body fluids, such as the CSF, respiratory tract secretions, and the aqueous humor.39 The aminoglycosides are excreted by glomerular filtration, and their dosages must be reduced in the presence of azotemia. Blood levels may be monitored to ensure proper dosing. Peak levels may be lower than anticipated in febrile patients, patients with an expanded extracellular volume, and patients with major burns. The major toxicities of the aminoglycosides include renal damage and ototoxicity, which may be vestibular or auditory.40 Other adverse reactions include rash, nausea and vomiting, and neuromuscular blockade, which is rare but may occur in patients with myasthenia gravis or in those receiving succinylcholine or similar drugs. Endotoxin-like reactions to gentamicin have been reported.
Gentamicin, netilmicin, and tobramycin have similar spectra of activity, except tobramycin is more active against P. aeruginosa. Amikacin is used principally for gentamicin-resistant gram-negative bacilli. Streptomycin is occasionally used in the multidrug treatment of tuberculosis and in synergistic therapy of gentamicin-resistant enterococci.38 Spectinomycin is used only in the treatment of gonorrhea in patients who are allergic to cephalosporins and fluoroquinolones.41
Extended-Interval Dosing of Aminoglycosides
In patients with normal renal function, aminoglycosides are conventionally administered in divided doses at 8- to 12-hour intervals. To decrease toxicity and cost, extended-interval (e.g., once-daily) dosing regimens have been widely adopted.42 In most protocols, the total doses are equivalent in the single-dose and divided-dose regimens. Meta-analyses of such trials concluded that in patients with normal renal function, extended-interval dosing is as effective as divided dosing and has a lower risk of toxicity.43 Although most trials evaluated immunocompetent adults, similar trends were noted for children and for patients with febrile neutropenia. Extended-interval dosing has not been studied adequately in pregnant women or in patients with renal dysfunction, burns, ascites, or endocarditis.
The Changing Role of Aminoglycosides
The aminoglycosides are extremely active antibiotics that are clinically effective against many serious infections caused by gram-negative bacilli, and these agents are inexpensive. These assets, however, must be weighed against the potential of aminoglycosides to produce renal and otovestibular toxicity. New efforts to improve the toxic-to-therapeutic ratio of aminoglycosides include extended-interval dosage schedules and reevaluations of the recommended therapeutic ranges. To determine the future role of aminoglycosides, the cost-effectiveness of these agents needs to be compared directly with that of the new β-lactams and the fluoroquinolones.
Polymyxins are cationic polypeptides that disrupt the bacterial cell membrane through a detergentlike mechanism. After the development of less toxic agents, such as extended-spectrum penicillins and cephalosporins, parenteral polymyxin use was largely abandoned, except for the treatment of multidrug-resistant pulmonary infections in patients with cystic fibrosis. More recently, however, the emergence of multidrug-resistant gram-negative bacteria, such as P. aeruginosa and A. baumannii, and the lack of new antimicrobial agents has led to a revival in the use of the polymyxins, particularly colistin (polymyxin E) and polymyxin B.44 Colistin is bactericidal against gram-negative bacilli, including strains of Acinetobacter, P. aeruginosa, Klebsiella, Enterobacter, E. coli, Citrobacter, Morganella, H. influenzae, and some strains of S. maltophilia. It is not active against P. mallei, B. cepacia, Proteus, Providencia, or Serratia. Colistin sulfate is available as an oral formulation for use in bowel decontamination; colistimethate sodium can be administered intravenously, intramuscularly, or by nebulization. The recommended intravenous dosage is 2.5 to 5 mg/kg/day divided into two to four equal doses; however, dosing must be reduced if renal insufficiency is present. In the largest study of colistin toxicity, which examined 317 courses of therapy, rates of renal insufficiency and neurotoxicity were 20.2% and 7.3%, respectively.45 Respiratory insufficiency and apnea were seen in 2.1% of patients.
Polymyxin B has been used extensively in topical otic and ophthalmic solutions, but it has more limited parenteral experience than colistin. Originally, colistimethate sodium was thought to be less toxic than polymyxin B; however, if the drugs are administered at comparable doses, their toxicities may be similar.
Given the concern about potential toxicity, the use of colistin and polymyxin B should be viewed as a treatment of last resort in patients who have serious infections caused by multidrug-resistant gram-negative pathogens for which no other therapeutic options exist.
Tetracyclines inhibit bacterial protein synthesis by reversibly binding to the 30S ribosomal subunit. Originally, they were widely used because of their broad spectrum of activity against both gram-positive and gram-negative bacteria; they are used less extensively now because of the availability of the more effective bactericidal penicillins, cephalosporins, and fluoroquinolones. The emergence of resistance among gram-negative bacilli, group A streptococci, and pneumococci and the increased risk of superinfection caused by drug-resistant organisms have also tended to limit their use.
Tetracyclines are the drugs of choice in the treatment of rickettsial diseases, such as Rocky Mountain spotted fever, ehrlichiosis, and Q fever; they also have activity against Francisella, Brucella, and spirochetes.46 Tetracyclines are useful in the treatment of pneumonia caused by Mycoplasma pneumoniae or Chlamydia pneumoniae47; urogenital infections caused by C. trachomatis; and other chlamydial diseases, such as psittacosis, trachoma, and lymphogranuloma venereum. They may also be used in the treatment of urinary tract infections caused by susceptible organisms. In the penicillin-allergic patient, doxycycline is an alternative therapy for syphilis, leptospirosis, and cat and dog bites infected by Pasteurella. As antimicrobial resistance continues to emerge, a new use has been found for minocycline in the treatment of MRSA. Doxycycline is active against some strains of VRE.48
Doxycycline has emerged as the favored tetracycline. It is available in oral and intravenous formulations, has a long half-life that allows administration in one or two daily doses of 100 mg, and does not accumulate in the presence of renal failure. Minocycline is available in oral and intravenous formulations and is administered at a dosage of 100 mg twice daily. The parent tetracycline is administered at a dosage of 250 to 500 mg four times daily. Concomitant ingestion of milk and antacids impairs the absorption of all tetracyclines. The tetracyclines should not be given to children younger than 9 years or to pregnant women, because permanent discoloration of teeth may result. Other potential side effects include phototoxicity, hepatotoxicity, esophageal ulceration, and, rarely, pseudotumor cerebri. In addition, minocycline has been associated with vestibular reactions and skin and mucous membrane discoloration.
Tigecycline received approval by the Food and Drug Administration in 2005 as the first member of the glycylcycline family. Tigecycline is a semisynthetic derivative of minocycline. Its mechanism of action is similar to that of minocycline in that tigecycline inhibits protein synthesis by binding to the 30S ribosomal subunit.49 Modification of position 9 in the tetracycline ring, however, allows tigecycline to overcome the two major forms of tetracycline resistance—namely, ribosomal protection and drug efflux. Tigecycline has a broad spectrum of bacteriostatic activity against gram-positive, gram-negative, and atypical bacteria (e.g., Mycoplasma, Chlamydia, and some nontuberculous mycobacteria), as well as anaerobic bacteria. It is active against multidrug-resistant bacteria, such as penicillin-resistant S. pneumoniae, MRSA, VRE, and ESBL-producing E. coli and K. pneumoniae. It is also active against some strains of Acinetobacter; however, it is not active against Pseudomonas or Proteus. Tigecycline is currently indicated in the treatment of complicated intra-abdominal infections and complicated skin and soft tissue infections.
Tigecycline is available only as an intravenous formulation; it is administered at a loading dose of 100 mg, followed by 50 mg every 12 hours. Excretion is primarily through the biliary system. Side effects are similar to those of the tetracyclines, with GI disturbances such as nausea and emesis being the most common.
The macrolides are composed of 14, 15, or 16 carbon atoms joined together in a complex circular molecule that is linked to various side chains.50 In the United States, erythromycin, clarithromycin, azithromycin, and dirithromycin are available. Macrolides inhibit bacterial protein synthesis by reversibly binding to the 50S ribosomal subunit of susceptible microorganisms.
Erythromycin is active against such gram-positive bacteria as penicillin-susceptible S. pneumoniae, C. diphtheriae, and, historically, group A streptococci. In the late 1980s, macrolide-resistant group A streptococci began to emerge worldwide. Resistance in Finland reached 19% overall and 42% in one region; however, these levels decreased to 6% to 8% after a reduction in the use of macrolides in outpatient therapy.51 Similarly, a clonal outbreak of erythromycin-resistant group A streptococci was recognized in Pittsburgh in 1998.52 Currently, 5% of group A streptococci are macrolide resistant in the United States.53 Most pneumococci that are not susceptible to penicillin are also resistant to erythromycin. Erythromycin remains active against M. pneumoniae, C. trachomatis, and some gram-negative bacilli, includingLegionella pneumophila, Campylobacter, and Bordetella pertussis. Neisseria and T. pallidum are also susceptible to erythromycin.
Erythromycin is excreted to a large extent in the bile and only to a minor degree in the urine. The dosage need not be altered in the presence of renal insufficiency. Erythromycin penetrates pleural and peritoneal fluids and crosses the placenta; this allows it to be used to treat syphilis in pregnant women who are allergic to penicillin.
Because erythromycin is active against Legionella, Mycoplasma, and Chlamydia species, it is an effective treatment for patients with atypical pneumonia [see 7:XX Pneumonia and Other Pulmonary Infections]. Erythromycin is also effective for Campylobacter gastroenteritis, for the treatment of diphtheria, and for chemoprophylaxis in pertussis carriers. In patients who cannot tolerate penicillins and cephalosporins, erythromycin is an effective alternative for the treatment of streptococcal pharyngitis, though resistance is emerging, and treatment of syphilis. Other uses of erythromycin include granuloma inguinale and chancroid, prophylaxis for elective bowel surgery (for which it is administered orally with neomycin), and acne (for which it is administered topically or orally).
Erythromycin is administered orally at a dosage of 250 mg to 1 g four times daily. Therapeutic serum levels can be achieved with any of the oral erythromycin preparations. Intravenous preparations of erythromycin are available for the treatment of severe infections, but prolonged therapy is difficult because of the frequent occurrence of thrombophlebitis at infusion sites. GI intolerance is the most common side effect. Other adverse reactions shared by the macrolides include rash, stomatitis, pseudomembranous colitis, pancreatitis, and ototoxicity. Because of the occasional occurrence of cholestatic hepatitis after administration of the estolate form, erythromycin base or stearate is preferred for adults.
Clarithromycin is a semisynthetic 14-member macrolide that is available only in oral formulation. It is acid stable and is well absorbed from the GI tract irrespective of food ingestion.50 Like erythromycin, clarithromycin achieves wide tissue penetration. Because of its longer half-life, however, clarithromycin may be administered once or twice a day, rather than four times a day, in 250 to 500 mg doses. In addition, clarithromycin produces fewer GI side effects than erythromycin; some people report a metallic taste. Clarithromycin and other macrolides can produce ventricular arrhythmias when administered with cisapride, astemizole, or disopyramide.
Clarithromycin is highly active against organisms that are sensitive to erythromycin, including streptococci, pneumococci, staphylococci,Legionella, Campylobacter, Mycoplasma, and C. pneumoniae. Clarithromycin also exhibits excellent activity against M. catarrhalis and H. influenzae; it is therefore an attractive agent for the treatment of respiratory tract infections, including sinusitis, pharyngitis, bronchitis, and pneumonia caused by susceptible organisms. Clarithromycin has been used successfully in patients who have Legionnaires disease, but azithromycin is the most active macrolide against Legionella, the etiologic agent of this community-acquired pneumonia [see Azithromycin,below]. The drug has assumed an important role in the multidrug regimens used to treat disseminated M. avium complex infections and is active against other nontuberculous mycobacteria, such as M. chelonae and M. fortuitum. It is also used as a component of some H. pyloriregimens.
Azithromycin, a 15-member macrolide, is active against the same broad range of organisms as those that clarithromycin inhibits.50 An intravenous preparation is available. Like the other macrolides, azithromycin is well absorbed from the GI tract. However, azithromycin differs from clarithromycin in that the bioavailability of azithromycin is decreased by food. As a result, azithromycin should be taken 1 hour before or 2 hours after meals. Azithromycin clears rapidly from serum and moves promptly into interstitial and intracellular tissue compartments. Tissue levels are extraordinarily prolonged, with an average terminal half-life of 68 hours. Therefore, tissue levels of azithromycin can be expected to remain in the therapeutic range from 4 to 7 days after a 5-day treatment course. These unique pharmacokinetics support the current program of administering azithromycin once daily for 5 days. Plasma and tissue levels are considerably lower, however, than those for clarithromycin. Like clarithromycin, azithromycin appears to be well tolerated and to have fewer GI side effects than erythromycin.
Azithromycin has been effective in the treatment of pharyngitis, sinusitis, bronchitis and pneumonia, and skin and soft tissue infections. Azithromycin has also assumed an important role in the treatment of Legionnaires disease and other atypical and community-acquired pneumonias [see 7:XX Pneumonia and Other Pulmonary Infections]. In addition to these indications, azithromycin has been used successfully as a single 1 g dose for urethritis and cervicitis caused by C. trachomatis. This provides a significant advantage because no other single-dose regimen now exists for these infections. Another important use for azithromycin is in the prophylaxis and treatment of M. avium complex infections in patients with AIDS.
Dirithromycin is an oral macrolide antibiotic with an antibacterial spectrum similar to that of erythromycin. It can be administered once daily but has no other advantages over erythromycin. The drugs produce similar GI side effects, and dirithromycin is substantially more expensive.
Ketolides, which are derived from erythromycin, inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit, which is similar to the action of macrolides.54 Telithromycin, the first member of the ketolide class of antimicrobials, received FDA approval in 2004. Telithromycin is predominantly active against respiratory pathogens, such as S. pneumoniae (including penicillin-resistant and macrolide-resistant strains), H. influenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, and Legionella; it also has activity against S. pyogenes and methicillin-susceptible S. aureus. However, telithromycin is inactive against Enterobacteriaceae. Telithromycin has been effective in the management of acute exacerbations of chronic bronchitis, acute bacterial sinusitis, and community-acquired pneumonia. Because telithromycin is active against macrolide-resistant S. pneumoniae, it has potential as a fluoroquinolone-sparing agent in situations in which macrolide resistance is a concern.
Telithromycin is well absorbed from the GI tract, and its bioavailability is not affected by food ingestion. Because of its long half-life, the standard dose is 800 mg once a day for 5 to 7 days. Telithromycin is well tolerated; its most adverse side effects are diarrhea, nausea, and headache.
Clindamycin inhibits bacterial protein synthesis by binding to the bacterial 50S ribosomal subunit at a site that overlaps with chloramphenicol and the macrolides; the use of clindamycin with these drugs results in antagonism.55 Clindamycin is rapidly absorbed and penetrates most tissues well, with the exception of CSF and brain. It may be administered orally (150 to 450 mg four times a day) or intravenously (600 to 900 mg every 8 hours), depending on the severity of infection. Because clindamycin is excreted primarily by the liver, no dose adjustment is necessary in patients with renal insufficiency; however, in patients with moderate to severe hepatic disease, clindamycin should be administered in half the usual dose. Clindamycin is active against most anaerobes, although resistance is seen in 10% to 20% of infections with B. fragilis, peptostreptococci, and clostridia other than C. perfringens. Clindamycin also has activity against most aerobic gram-positive bacteria, including S. aureus, S. pneumoniae, and group A and other streptococci except Enterococcus. It is also active against B. anthracis,56 but clinical experience is very limited. The emergence of clindamycin resistance during therapy for infections caused by S. aureus and β-hemolytic streptococci has led to the recommendation that a double-disk diffusion assay (i.e., the erythromycin-clindamycin D-zone test) be performed for those isolates that are resistant to erythromycin before treatment with clindamycin.57 The D-zone test can distinguish strains of S. aureus and β-hemolytic streptococci that have the potential to express inducible resistance during therapy from strains that are fully susceptible to clindamycin. Clindamycin is indicated in the treatment of serious infections caused by susceptible anaerobes, particularly those originating in the GI and female genital tracts.55 Clindamycin has also been very effective in the treatment of aspiration pneumonia and lung abscess. Because of its ability to rapidly reduce toxin production, clindamycin may be very helpful in the management of streptococcal toxic-shock syndrome and necrotizing infections caused by C. perfringens and S. pyogenes, possibly in conjunction with penicillin. Clindamycin has also been used to treat protozoan infections, such as toxoplasmosis and babesiosis.47 Because clindamycin does not readily penetrate the CNS, even when there is marked meningeal inflammation, it should not be used to treat meningitis. For acne therapy, clindamycin should be used only topically.
Nausea, vomiting, and diarrhea are the most common side effects associated with clindamycin, but hypersensitivity reactions, neutropenia, and thrombocytopenia may also occur infrequently. Although C. difficile colitis has been reported with most antimicrobials, the incidence with clindamycin may approach 10% and should limit its indiscriminate use.
Metronidazole was originally noted for its effectiveness against certain protozoa such as Trichomonas, Giardia, and Entamoeba and was later recognized for its anaerobic activity. Metronidazole undergoes a reductive process within the bacterial cell, a process culminating in the damage of bacterial DNA by the activated metabolites.55
Metronidazole is bactericidal against almost all anaerobic gram-negative bacilli and against most Clostridium species. Although true anaerobic streptococci are generally susceptible to metronidazole, microaerophilic streptococci and Actinomyces and Propionibacteriumspecies are often resistant. It has supplanted penicillin as the drug of choice for B. fragilis and C. tetani. Although metronidazole and oral vancomycin are equally effective in treating C. difficile colitis, metronidazole has become the preferred agent because of its lower cost and because of concern over the emergence of VRE. Metronidazole is also effective both orally and vaginally in the treatment of bacterial vaginosis.
When metronidazole is administered orally, it is well absorbed and is widely distributed in body tissues, including those of the CNS. For serious anaerobic infections, the drug is administered intravenously with a loading dose of 15 mg/kg, followed by 7.5 mg/kg every 6 hours until the patient is well enough to take an oral dosage. This is roughly equivalent to 500 mg every 6 to 8 hours. The dosage need not be reduced in azotemic patients, but it should be reduced in patients with hepatic insufficiency.
Side effects of metronidazole include dry mouth associated with a metallic taste and nausea. Concurrent use of alcohol may cause a reaction similar to that produced when alcohol is drunk after disulfiram ingestion. Neurologic symptoms, including peripheral neuropathy and encephalopathic reactions, and neutropenia are uncommon. Pancreatitis has been reported. Metronidazole is mutagenic for bacteria. Metronidazole is carcinogenic for rats and mice; carcinogenicity in humans has not been demonstrated but remains a concern.
Metronidazole is effective in the treatment of a variety of infections caused by anaerobes, including CNS infections, bone and joint infections, abdominal and pelvic sepsis, and endocarditis. Failures have been reported in the treatment of pleuropulmonary infection, which may reflect the polymicrobial nature of these infections.
Although chloramphenicol remains a useful antibiotic, its role has decreased as less toxic alternatives have become available.48,55 Because of the rare occurrence of aplastic anemia, clinical use of chloramphenicol should be limited to serious infections for which alternative antibiotics may be less effective. Such infections include those caused by VRE, B. fragilis, and Salmonella, as well as meningitis caused byH. influenzae, N. meningitidis, or S. pneumoniae in patients who are allergic to penicillin and cephalosporins. However, other agents are usually preferable to chloramphenicol for such infections. For example, the newer cephalosporins and fluoroquinolones should be considered for salmonellosis; second-generation and third-generation cephalosporins should be considered for ampicillin-resistant strains of H. influenzae; linezolid and quinupristin-dalfopristin should be considered for VRE; and combinations of a penicillin and a β-lactamase inhibitor, carbapenems, cefmetazole, cefoxitin, cefotetan, clindamycin, or metronidazole can be used to treat infections caused by B. fragilis.
Chloramphenicol may be administered orally or intravenously. Chloramphenicol diffuses rapidly into most tissues, CSF, ascitic fluid, and aqueous humor. The drug is lipid soluble and achieves levels in the brain up to nine times higher than in the serum. Chloramphenicol is inactivated in the liver by conjugation with glucuronic acid; blood levels may increase in patients with marked cirrhosis and jaundice.
One of the more serious and potentially fatal side effects of chloramphenicol is aplastic anemia, which can occur weeks to months after the completion of therapy. A separate dose-related suppression of the bone marrow with neutropenia, anemia, and thrombocytopenia is common during treatment and is usually reversible. Another potentially fatal adverse reaction is the gray-baby syndrome in neonates, which is caused by a diminished ability to conjugate chloramphenicol and to excrete the active form in the urine. Other adverse effects include rash, stomatitis, GI intolerance, and neurotoxic reactions.
In view of the risk of aplastic anemia and neonatal toxicity, the following guidelines should be employed in the use of chloramphenicol: (1) it should be used in the treatment of only those infections for which it is clearly indicated and for which less toxic alternatives are not feasible; (2) repeated courses should be avoided; (3) the complete blood count should be checked two or three times weekly; and (4) the patient should be observed closely for evidence of sore throat, which may be a marker of granulocytopenia.
Vancomycin is a glycopeptide that impairs cell wall synthesis of gram-positive bacteria. Its spectrum of activity includes staphylococci, streptococci, pneumococci, enterococci, clostridia, Corynebacterium species, and other gram-positive bacteria.58 It is generally bactericidal but is bacteriostatic against some strains of enterococci, coagulase-negative staphylococci, and corynebacteria.
Vancomycin is poorly absorbed when administered orally. The oral route is employed only for the treatment of staphylococcal enterocolitis and C. difficile colitis at a dosage of 125 to 250 mg every 6 hours. In adults with normal renal function, vancomycin is administered intravenously in a total daily dose of 30 mg/kg, which, in most individuals, is equivalent to 500 mg every 6 hours or 1 g every 12 hours. To avoid hypotension and histaminelike reactions, the drug should always be infused slowly over a period of 1 hour. Pretreatment with antihistamines can help avert the so-called red-man syndrome; in rare cases, desensitization may be necessary. Other adverse effects may include thrombophlebitis at the infusion site, chills and fever, ototoxicity, and possibly nephrotoxicity. Particular attention to ototoxicity and nephrotoxicity is required when vancomycin is administered with an aminoglycoside.
Vancomycin is the drug of choice in the treatment of infections caused by MRSA. Concomitant administration of an aminoglycoside is often necessary when vancomycin is used in the treatment of enterococcal endocarditis. Vancomycin can be very useful in therapy for prosthetic valve endocarditis caused by coagulase-negative staphylococci; it is frequently administered in combination with rifampin and gentamicin in this setting.
Vancomycin does not penetrate normal meninges but does enter the CSF when the meninges are inflamed. Most of the drug is eliminated through the kidneys; in the presence of renal failure, the dose must be reduced. Although serum vancomycin levels are often monitored, there is little evidence to support a relationship between specific serum concentrations and either efficacy or toxicity; consequently, drug measurements are not necessary in routine cases.59 However, determination of serum trough levels is an important guide to dosage when the drug must be administered in the presence of impaired renal function; in these cases, trough concentrations of about 10 µg/ml are typically recommended. In difficult-to-treat infections such as endocarditis, osteomyelitis, and ventilator-associated pneumonia,60 some authorities have recommended trough concentrations of 15 to 20 µg/ml on the basis of pharmacokinetic and pharmacodynamic properties; however, supporting clinical data are limited. Because vancomycin is an antimicrobial that is not concentration dependent and because it exhibits predictable pharmacokinetics (i.e., the peak concentration being 15 to 30 µg/ml above the trough level), it is not necessary to measure peak concentrations of this drug.
The epidemiology of vancomycin use provides a cautionary tale for this drug and for other antimicrobials.61 Although vancomycin is a valuable and effective drug, it is often used inappropriately. This has resulted in substantial financial costs and the emergence of vancomycin-resistant organisms, including enterococci and staphylococci; infections with these organisms are very difficult to treat [see 7:I Infections Due to Gram-Positive Cocci].
Quinupristin and dalfopristin are two structurally distinct streptogramins that bind to separate sites on the bacterial 50S ribosomal subunit and act synergistically to inhibit protein synthesis.62 The drugs are marketed together in a 30-to-70 ratio as Synercid. Although quinupristin-dalfopristin is active against a variety of gram-positive bacteria, including S. pneumoniae and group A streptococci, its major use is in the treatment of serious infections caused by vancomycin-resistant E. faecium. E. faecalis, however, is intrinsically resistant to quinupristin-dalfopristin as a result of drug efflux. Quinupristin-dalfopristin may also be useful in occasional vancomycin-intolerant patients with severe infections caused by MRSA or coagulase-negative staphylococci. The combination has activity against S. aureus that is intermediately resistant to vancomycin and against vancomycin-resistant S. aureus. Although quinupristin-dalfopristin was first marketed in 1999, resistance is already emerging.
The usual dosage of quinupristin-dalfopristin is 7.5 mg/kg given intravenously over 1 hour every 8 hours. Because quinupristin-dalfopristin is associated with a high incidence of phlebitis, a central line should be used for intravenous delivery. Other adverse effects include arthralgias and myalgias, which may be severe, and elevated bilirubin levels. The drug is metabolized by the liver, so no dose reduction is required in azotemic patients. Careful attention to drug interactions is important because quinupristin-dalfopristin inhibits the metabolism of drugs such as cyclosporine through the hepatic cytochrome P-450 CYP3A4 enzyme.
In 2000, linezolid became the first member of the oxazolidinone class to be approved for clinical use in the United States. Linezolid is a synthetic antibiotic that inhibits protein synthesis by binding to a site on the bacterial 23S ribosomal RNA of the 50S subunit, thus preventing the formation of the 70S initiation complex that is required for ribosomal function.62,63 It has a unique mechanism of action, and no cross-resistance with other antimicrobials has been reported.
Linezolid is active against nearly all aerobic gram-positive cocci at concentrations of 4 mg/ml or less, including penicillin-resistant pneumococci, MRSA, and VRE; however, resistant strains have been isolated.64 The drug is bacteriostatic against staphylococci and enterococci, but it is bactericidal against most streptococci. Linezolid is also active against Corynebacterium species, L. monocytogenes, Bacillus species, and some Nocardia and mycobacteria species. Although active against many gram-positive anaerobes, linezolid has borderline activity against Bacteroides fragilis; enteric gram-negative bacilli and Pseudomonas species are resistant to linezolid.
Intravenous and oral preparations of linezolid are available; the usual dosage is 600 mg every 12 hours regardless of the choice of route. The oral form is absorbed rapidly and completely and has 100% bioavailability that is not affected by meals. Linezolid is widely distributed in well-perfused tissues. Nonrenal mechanisms account for 65% of the drug's clearance. Patients with mild to moderate renal or hepatic insufficiency do not require dose reduction. Linezolid is removed by hemodialysis.
Linezolid is fairly well tolerated. Nausea, vomiting, and headaches are the most common side effects, but reversible bone marrow suppression, including thrombocytopenia, leukopenia, and anemia, can occur in patients receiving therapy for more than 2 weeks. Rare cases of lactic acidosis and optic neuritis have been reported in patients receiving long-term linezolid therapy. Patients require careful monitoring during prolonged treatment courses as a precaution against these complications. Because linezolid is a reversible inhibitor of monoamine oxidase, patients taking linezolid may experience an exaggerated hypertensive response to sympathomimetic agents such as pseudoephedrine. In addition to avoiding decongestants, patients taking linezolid should avoid foods or beverages with high tyramine content; these include aged cheeses, air-dried meats, tap beer, red wine, soy sauce, and sauerkraut. Concomitant use of adrenergic or serotoninergic antidepressants should be avoided.65
Linezolid has been used successfully in the treatment of multidrug-resistant gram-positive bacterial infections, including VRE and MRSA,62,66but clinical experience with deep-seated infections such as endocarditis and osteomyelitis is limited. Although resistance is uncommon, it can develop during therapy. As a result, it may be wise to reserve this unique antibiotic for serious infections caused by MRSA, VRE, or coagulase-negative staphylococci that do not respond to vancomycin. It also has a role in decreasing hospital stay for some patients with resistant gram-positive infections,67 although these patients require close outpatient monitoring.
Daptomycin is a cyclic lipopeptide naturally produced by Streptomyces roseosporus. It has a unique mechanism of action: it binds to bacterial membranes and causes a rapid depolarization of membrane potential, which leads to the inhibition of protein, DNA, and RNA synthesis, resulting in bacterial death.68 It is active against most gram-positive aerobic bacteria, including VRE, MRSA, glycopeptide intermediately susceptible S. aureus, coagulase-negative staphylococci, and penicillin-resistant S. pneumoniae. It also has activity againstS. pyogenes, S. agalactiae, S. dysgalactiae, and C. jeikeium. It is currently approved only for complicated skin and soft tissue infections.69Daptomycin achieves suboptimal levels in the lungs and should not be used for pulmonary infections.
Daptomycin is bactericidal, and synergy with gentamicin has been demonstrated against staphylococci and enterococci. Although there is limited experience with this new drug, no mechanism of resistance has been identified. In addition, there appears to be no cross-resistance with other antibiotic classes.
Daptomycin is available only in intravenous formulation. The main adverse event seen in early studies of daptomycin administered every 12 hours was a reversible myopathy that affected skeletal muscles. The current once-daily intravenous dose of 4 mg/kg appears to improve the efficacy-toxicity ratio by decreasing the incidence of myopathy. Because daptomycin is primarily excreted by the kidney, the dose should be 4 mg/kg every 48 hours in patients who have a creatinine clearance rate of less than 30 ml/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis. The role of daptomycin in therapeutics is currently limited, given its narrow indications and the availability of alternative agents, including vancomycin and linezolid.
Sulfonamides and Trimethoprim
Sulfonamides were the first class of antimicrobial agents to be discovered. They inhibit dihydropteroate synthetase in the bacterial folic acid pathway. Although their clinical role has diminished, they are still useful in certain situations. Because of their efficacy and low cost, sulfonamides can be useful in treating uncomplicated urinary tract infections caused by E. coli, although resistance is high. Sulfonamides are also useful for Nocardia and Toxoplasma infections. Topical sulfonamides are still used in a few situations. Sulfacetamide eyedrops are sometimes employed to treat superficial ocular infections. Topical silver-sulfadiazine cream is administered to burn surfaces to suppress bacterial growth and to prevent subsequent invasive infection. Both the silver ion and the sulfadiazine components of the compound probably contribute to the antibacterial activity.
Trimethoprim inhibits dihydrofolate reductase in the bacterial folic acid pathway. Trimethoprim is well absorbed from the GI tract and is widely distributed in most tissues, including the prostate. Most of the drug is excreted unchanged in the urine. Its antibacterial spectrum encompasses many aerobic gram-negative bacilli, but it is not active against P. aeruginosa. Trimethoprim is generally well tolerated. Side effects include skin rash (less common than with sulfonamides) and megaloblastic marrow changes. Trimethoprim inhibits renal potassium excretion, and reversible hyperkalemia has been observed in AIDS patients receiving high-dose trimethoprim-sulfamethoxazole.
Trimethoprim is approved only for the treatment of uncomplicated urinary tract infections, for which it has been shown to be as effective as trimethoprim-sulfamethoxazole in 3- and 7-day regimens. The oral dosage is 100 mg twice daily. As a result of the widespread use of trimethoprim in many parts of the world, resistance in uropathogenic E. coli has emerged; this has impaired its usefulness in the treatment of urinary tract infections.
Use of the trimethoprim-sulfamethoxazole combination extended the list of clinical situations in which sulfonamides appear to be of value46: urinary tract infections, prostatitis, acute otitis media, sinusitis or bronchitis caused by susceptible strains of H. influenzae and S. pneumoniae, and certain infections caused by MRSA. Trimethoprim-sulfamethoxazole can be used to prevent or treat traveler's diarrhea. It is the drug of choice for the prevention70 and treatment of P. jirovecii pneumonia and nocardiosis. With widespread use, trimethoprim-sulfamethoxazole-resistant strains of E. coli are appearing. In areas where the prevalence of E. coli resistance is at least 20%, an alternative agent such as a fluoroquinolone should be considered for urinary tract infections.71,72
The trimethoprim-sulfamethoxazole synergistic combination is available in oral or intravenous preparations in a 1-to-5 ratio (80 or 160 mg of trimethoprim and 400 or 800 mg of sulfamethoxazole). Both drugs are excreted primarily by the kidneys. The oral dosage of trimethoprim-sulfamethoxazole for the treatment of most infections, including urinary tract infection, in an adult is two single-strength tablets (or one double-strength tablet) every 12 hours. For serious systemic infections, the intravenous dosage is 8 to 10 mg/kg (based on the trimethoprim component) in two to four equal doses every 6 to 12 hours. For Pneumocystis pneumonia, the dosage is 15 to 20 mg/kg (based on the trimethoprim component) in equally divided doses every 6 hours. Reduction in dosage is necessary if renal function is impaired.
Adverse reactions to trimethoprim-sulfamethoxazole are similar to those caused by sulfonamides alone and include hypersensitivity reactions, photosensitivity, and nausea and vomiting. Hepatitis, pancreatitis, aseptic meningitis, and megaloblastic anemia occur infrequently. Although hypersensitivity reactions are more common in HIV-infected patients, desensitization protocols have enabled many of these patients with prior reactions to tolerate this medication.73
Since the introduction of ciprofloxacin more than a decade ago, this class of antimicrobial agents has continued to evolve and now includes agents that differ from each other significantly with regard to activity as well as pharmacokinetic and pharmacodynamic properties [seeTable 5]. The first-generation fluoroquinolones (e.g., ciprofloxacin and ofloxacin) are primarily active against gram-negative and a few gram-positive organisms. The second-generation fluoroquinolone levofloxacin has improved activity against gram-positive bacteria and atypical bacteria but is less potent against certain gram-negative bacteria, such as P. aeruginosa. The newer fluoroquinolones (i.e., gemifloxacin and moxifloxacin) have enhanced coverage of gram-positive, atypical, and anaerobic organisms, compared with that of the first-generation and second-generation fluoroquinolones.74 In particular, these new agents appear to be more active against S. pneumoniaeand may have decreased potential for the development of resistance.75
Table 5 Selected Properties of Fluoroquinolone Antibiotics
The fluoroquinolones are bactericidal compounds that inhibit DNA synthesis and introduce double-strand DNA breaks by targeting DNA gyrase and topoisomerase IV.76 In gram-negative bacteria such as E. coli, Pseudomonas, and N. gonorrhoeae, the primary target is DNA gyrase and the secondary target is topoisomerase IV. In gram-positive bacteria such as S. aureus and S. pneumoniae, the primary and secondary targets are reversed. These differences in primary and secondary targets are particularly evident in the earlier fluoroquinolones (e.g., ciprofloxacin and levofloxacin). The newer fluoroquinolones (e.g., gemifloxacin and moxifloxacin) bind equivalently to the two targets. This may imply that concurrent mutations in the two target enzymes would be required for resistance to develop, although this is controversial.
Fluoroquinolones demonstrate concentration-dependent killing. The ratios of the peak concentration to MIC and of the area under the curve to MIC appear to best correlate with clinical efficacy. On the basis of these ratios, ciprofloxacin is the most active fluoroquinolone againstPseudomonas, and moxifloxacin demonstrates the most favorable parameters for S. pneumoniae. Because the newer fluoroquinolones bind equally to DNA gyrase and topoisomerase IV and because they have enhanced pharmacokinetic and pharmacodynamic parameters for S. pneumoniae, it has been argued that they are the preferred fluoroquinolones for community-acquired pneumonia; it is argued that because of their specific properties, the newer fluoroquinolones would prevent the emergence of resistance and maintain the antimicrobial activity of the class.75,77 When antimicrobial resistance does develop, there tends to be cross-resistance to other fluoroquinolones. Such resistance is usually mediated chromosomally, but plasmid-mediated resistance raises the possibility of transferable resistance.
The fluoroquinolones are broad-spectrum antimicrobials.78 Most enteric gram-negative bacilli, including E. coli, Proteus, Klebsiella, andEnterobacter, are highly susceptible. Pseudomonas susceptibility has decreased in recent years as fluoroquinolone use has increased. Common GI pathogens such as Salmonella, Shigella, and Campylobacter species have typically been susceptible, although Campylobacterresistance is increasing. Other gram-negative organisms that are killed by low concentrations of the fluoroquinolones are H. influenzae, P. multocida, M. catarrhalis, and Y. enterocolitica. Acinetobacter and Serratia are somewhat less susceptible. B. cepacia and S. maltophilia are fluoroquinolone resistant. Fluoroquinolone-resistant strains of N. gonorrhoeae have emerged in the Far East, Hawaii, and mainland United States.79 Ciprofloxacin is the drug of choice for B. anthracis, though other fluoroquinolones are also active in vitro.56 Among gram-positive cocci, methicillin-susceptible strains of S. aureus and coagulase-negative staphylococci are usually susceptible to fluoroquinolones, but resistance has developed, particularly in MRSA, when fluoroquinolones have been used as monotherapy. Activity against enterococci is marginal. Ciprofloxacin and ofloxacin are only moderately active against S. pneumoniae. Subsequent generations of fluoroquinolones have increased pneumococcal activity, even against non-penicillin-susceptible pneumococci. Intracellular pathogens such as Chlamydia, Mycoplasma, Legionella, and M. tuberculosis are susceptible to fluoroquinolones. Gemifloxacin and moxifloxacin are active against anaerobes, though C. difficile is resistant.
The fluoroquinolones are rapidly absorbed from the GI tract and have a nearly 100% bioavailability. Penetration into body fluids and tissues is generally excellent, and therapeutic concentrations are readily achieved in bile, stool, urine, prostate, respiratory tract, bone, and muscle. The fluoroquinolones appear to penetrate the CSF in the presence of meningeal inflammation,80 but experience in treating meningitis is scant. Although serum protein binding is modest, the fluoroquinolones have long serum half-lives, which range from 3 to 4 hours for ciprofloxacin to 12 hours for moxifloxacin. Most fluoroquinolones are eliminated by glomerular filtration and tubular secretion, and their dosages should be reduced in the presence of moderately severe renal failure. Moxifloxacin, however, is excreted chiefly by the liver and achieves low urine levels. As a result, moxifloxacin should not be used in the treatment of urinary tract infections.
The fluoroquinolones appear to be very well tolerated, with mild GI side effects (nausea, vomiting, or anorexia), CNS side effects (light-headedness, dizziness, somnolence, or insomnia), or rash occurring in fewer than 10% of treated patients.81 Gemifloxacin use for more than 7 days may be associated with an increased risk of rash, particularly in women younger than 40 years. Sparfloxacin contains a halide at position 8 and is associated with significantly more photosensitivity reactions than the other fluoroquinolones. Sparfloxacin and grepafloxacin were withdrawn because they were shown to prolong the QTc interval, but this adverse event has also been reported with levofloxacin and moxifloxacin. Risk factors include underlying cardiac disease, advanced age, hypokalemia, hypomagnesemia, and the concomitant use of other agents that may prolong the QTc interval, such as antiarrhythmics, macrolides, and certain antihistamines. Hyperglycemia or hypoglycemia has been described in less than 2% of patients treated with fluoroquinolones, particularly gatifloxacin, which has been withdrawn from the market.81,82 Given the risk of blood-sugar complications associated with fluoroquinolone use, dose adjustment should be considered in elderly patients with type 2 diabetes. Tendinitis and tendon rupture occur very rarely. Less common side effects include allergic interstitial nephritis, pseudomembranous colitis, and neutropenia. Hepatic toxicity, including fulminant liver failure, has led to the withdrawal of trovafloxacin. Because fluoroquinolones have caused arthropathy in young animals, these drugs should be avoided in children and in women who are pregnant or nursing.
The fluoroquinolones have been useful clinically in a variety of infections, including urinary tract, genital, prostatic, GI, respiratory tract, soft tissue, and bone infections.78 The fluoroquinolones are effective in preventing gram-negative bacteremia when administered prophylactically to neutropenic patients, but they do not reduce gram-positive bacteremias, febrile episodes, or infection-related mortality. Oral ciprofloxacin in combination with amoxicillin-clavulanate has been used successfully in patients at low risk of complications who have fever and neutropenia after chemotherapy.83 Use of fluoroquinolones in uncomplicated urinary tract infections has increased in response to the concern about rising resistance to trimethoprim-sulfamethoxazole among uropathogens.71 Fluoroquinolones should be considered as first-line therapy for pyelonephritis and complicated urinary tract infections. The fluoroquinolones, administered in various regimens ranging from a single dose to 5 days of therapy, are effective in preventing and treating traveler's diarrhea and shigellosis. They have been highly effective in the treatment of typhoid fever. However, prolongation of the carrier state limits their role in nontyphoidal Salmonella enteritis, and the development of resistance limits their role in Campylobacter enteritis. The fluoroquinolones may be useful in the empirical treatment of severe community-acquired gastroenteritis, particularly if treatment is started early. The role of fluoroquinolones in the intensive care unit, particularly as monotherapy, is limited by the widespread resistance to these agents that has developed among many gram-negative bacteria responsible for nosocomial infections (e.g., Acinetobacter and Pseudomonas).
Because of their extraordinarily broad antimicrobial activity, their favorable pharmacokinetics, and their low toxicity, the fluoroquinolones are extremely valuable drugs. Like all antimicrobial agents, however, fluoroquinolones should be used judiciously, especially in view of the emerging resistance that accompanies the increased use of these drugs.84
Nitrofurantoin has been commercially available for over 50 years and continues to have an important therapeutic role. It is readily absorbed from the GI tract and rapidly excreted by the kidneys. Therapeutic utility results from the high urinary concentrations achieved. Because antimicrobial levels are not attained in the blood, this drug should be employed only in the treatment of uncomplicated mild to moderate cystitis or for the prevention of cystitis.85 The spectrum of antibacterial activity includes E. coli, enterococci (including VRE), and some strains of Klebsiella and Enterobacter. Proteus and Pseudomonas species are usually resistant. Nitrofurantoin is administered orally at a dosage of 50 mg four times daily or 100 mg twice daily. It should not be administered when there is significant impairment of renal function. Nausea and vomiting are common side effects, but their incidence is decreased by use of the macrocrystalline formulation and by taking the drug with food. Less frequent adverse reactions include rash, hypersensitivity pneumonitis, peripheral neuropathy, hepatitis, and hemolytic anemia in association with G6PD deficiency.
Fosfomycin is a broad-spectrum antibiotic that inhibits cell wall synthesis and is active against E. coli and many other common urinary tract pathogens.86 However, it has poor in vitro activity against S. saprophyticus. Although fosfomycin has been used parenterally in Europe for many years, the drug is approved in the United States only for the single-dose oral treatment of uncomplicated urinary tract infections in women. A 3 g sachet dose is generally effective and well tolerated, with diarrhea being the most common side effect.
Since its development in the 1960s, rifampin has emerged as a major antituberculosis drug. Rifampin is also active against a variety of bacteria, including coagulase-negative staphylococci and S. aureus, but resistance develops rapidly as a result of a single point mutation in bacterial DNA-dependent RNA polymerase when used as monotherapy.87 When rifampin is combined with a second drug, however, resistance is less likely. It may be combined with vancomycin to treat serious infections with coagulase-negative staphylococci, such as prosthetic valve endocarditis. The combination of rifampin and a fluoroquinolone has been effective in the oral treatment of Staphylococcus-infected orthopedic prostheses,88 S. aureus right-sided endocarditis in injection drug users,89 and osteomyelitis in the diabetic foot.90 It is also effective in eradicating nasopharyngeal carriage of N. meningitidis. More study is needed to determine the optimal role for rifampin in antimicrobial therapy.
Rifaximin, a poorly absorbed (< 0.4%) rifamycin, was approved by the FDA in 2004 for the treatment of traveler's diarrhea caused by noninvasive E. coli91; in this setting, rifaximin has been demonstrated to have an efficacy similar to that of ciprofloxacin. Because of its poor bioavailability, rifaximin should not be used when there is concern about invasive disease, as evidenced by fever or bloody stools. Rifaximin is well tolerated at oral dosages of either 200 mg three times daily or 400 mg twice daily for 3 days; both dosings achieve very high stool concentrations. Rifaximin is currently being evaluated for its efficacy in the management of small bowel overgrowth syndromes and hepatic encephalopathy.
Topical Antimicrobial Agents
Topical antimicrobial agents have been used for prophylaxis against cutaneous infections, for the treatment of minor wounds and infections, and for the eradication of S. aureus nasal carriage. These agents provide high drug concentrations to the desired site with minimal toxicity.92
Mupirocin inhibits protein synthesis by preventing the incorporation of isoleucine into the growing protein by binding to isoleucyl transfer-RNA synthetase. It is predominantly active against aerobic gram-positive cocci, including S. aureus, S. epidermidis, and β-hemolytic streptococci. Intranasal mupirocin is highly effective for the short-term elimination of S. aureus93; it has been shown to decrease S. aureusinfections in dialysis patients,94 as well as S. aureus infections in postsurgery wounds in colonized patients.95 Although targeted populations may benefit from mupirocin, frequent recolonization and the development of resistance warrant caution against widespread use.
Bacitracin is active against a variety of gram-positive and gram-negative organisms; neomycin and polymyxin target gram-negative organisms, and polymyxin is bactericidal for P. aeruginosa.92 Silver sulfadiazine is most commonly used for the prevention of wound infections in burn patients because of its broad gram-positive and gram-negative activity, including activity against S. aureus and P. aeruginosa.
The term antimicrobial prophylaxis refers to the use of antimicrobial agents in the prevention of infection either before or very shortly after the introduction of pathogenic organisms—for example, after the occurrence of a compound fracture but before the appearance of clinical infection. Prophylaxis is most effective when a specific drug is selected for its activity against a particular organism, such as postexposure anthrax prophylaxis with ciprofloxacin, doxycycline, or amoxicillin.56 When prophylaxis is aimed at preventing infection by all possible organisms through the use of broad-spectrum antimicrobials, it merely increases the selection pressure for the emergence of resistant organisms in any infection that may follow. Thus, prophylaxis is ineffective in the prevention of complicating bacterial or mycotic infections in patients with viral respiratory tract infections. Most uses of prophylaxis fall into three general categories: prevention of infection after exposure to a specific pathogen, prevention of specific types of infection in highly susceptible individuals, and prevention of postoperative infectious complications. In many instances, prophylactic use of antimicrobial agents is widely practiced, but convincing data validating the efficacy of this approach are not available.96
Antimicrobial Prophylaxis for Surgical Procedures
The use of antimicrobial prophylaxis in surgical patients involves a risk-to-benefit appraisal that varies depending on the nature of the operative procedure. To help prevent wound infections in patients undergoing elective surgery, antibiotics should be administered within 60 minutes before the incision is made.97,98 If prophylactic antibiotics are to be effective, administration should be timed so that therapeutic levels are attained at surgery; in addition, a limited-spectrum antimicrobial should be used to prevent the emergence of resistant organisms. Antibiotics should usually be discontinued within 24 hours after the procedure. The indications for prophylaxis with different operations have been reviewed, but in many instances, the available data are insufficient to make recommendations.99 For clean elective surgical procedures (e.g., breast surgery and herniorrhaphy without mesh) in which no tissue (other than the skin) carrying indigenous flora is penetrated, the risks of routine antibiotic prophylaxis outweigh the possible benefits.
When cardiovascular prostheses are employed, vancomycin or a first-generation cephalosporin (e.g., cefazolin) should be administered within 60 minutes before incision and continued for 3 to 5 days. Similar regimens may be employed for major vascular surgery. Because of the grave consequences of infection in a prosthetic joint, vancomycin or a first-generation cephalosporin is used prophylactically when a total hip replacement is performed. In the repair of open fractures, which are commonly contaminated, prophylactic treatment with a cephalosporin for 5 to 7 days is warranted. Controlled clinical studies have indicated that the administration of oral antibiotics (e.g., enteric-coated erythromycin plus neomycin, or tetracycline plus neomycin) just before colon surgery significantly reduces the incidence of infectious complications. The erythromycin-neomycin combination, 1 g of each administered orally at 1:00 P.M., 2:00 P.M., and 11:00 P.M. on the day before an 8:00 A.M. surgery, has been found to reduce the number of aerobic and anaerobic organisms remaining in the colon at the time of surgery. Although the additive benefit of parenteral antimicrobial drugs in colorectal surgery has not been clearly established, a survey showed that most surgeons do combine parenteral cefoxitin or cefotetan with the previously established oral regimens.100
Editors: Dale, David C.; Federman, Daniel D.