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The clinical application of antibacterial therapy is guided by the spectrum of the agent and the suspected or known target pathogen. Infections for which specific antibacterial agents are among the drugs of choice are listed, along with associated pathogens and susceptibility data, in Table 41-5. Resistance rates of specific organisms are dynamic and should be taken into account in the approach to antibacterial therapy. While national resistance rates can serve as a reference, the most useful reference for the clinician is the most recent local laboratory antibiogram, which provides details on local resistance patterns, often on an annual or semiannual basis.
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The β-lactam class of antibiotics consists of penicillins, cephalosporins, carbapenems, and monobactams. The term β-lactam reflects the drugs’ four-membered lactam ring, which is their core structure. The differing side chains among the agents of this family determine the spectrum of activity. All β-lactams exert a bactericidal effect by inhibiting bacterial cell-wall synthesis. The β-lactams are classified as time-dependent killing agents; therefore, their clinical efficacy is best correlated with the proportion of the dosing interval during which the drug levels remain above the MIC for the pathogenic organism.
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Penicillins and β-lactamase inhibitors
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Penicillin, the first β-lactam, was discovered in 1928 by Alexander Fleming. Natural penicillins, such as penicillin G, are active against non-β-lactamase-producing gram-positive and gram-negative bacteria, anaerobes, and some gram-negative cocci. Penicillin G is used for penicillin-susceptible streptococcal infections, pneumococcal and meningococcal meningitis, enterococcal endocarditis, and syphilis. The antistaphyloccocal penicillins, which have potent activity against methicillin-susceptible S. aureus (MSSA), include nafcillin, oxacillin, dicloxacillin, and flucloxacillin. Aminopenicillins, such as ampicillin and amoxicillin, provide added coverage beyond penicillin against gram-negative cocci, such as Haemophilus influenzae, and some Enterobacteriaceae, including E. coli, Proteus mirabilis, Salmonella, and Shigella. The aminopenicillins are hydrolyzed by many common β-lactamases. These drugs are commonly used for otitis media, respiratory tract infections, intraabdominal infections, endocarditis, meningitis, and urinary tract infections. The antipseudomonal penicillins include ticarcillin and piperacillin. These penicillin groups generally offer adequate anaerobic coverage; the exceptions are Bacteroides species (such as Bacteroides fragilis), which produce β-lactamases and are generally resistant. The rising prevalence of β-lactamase-producing bacteria has led to the increased use of β-lactam/β-lactamase inhibitor combinations, such as ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin-clavulanate, and piperacillin-tazobactam. The β-lactamase inhibitors themselves do not have antibacterial activity (with the exception of sulbactam, which has activity against Acinetobacter baumannii) but typically inhibit the S. aureus class A β-lactamase, β-lactamases of H. influenzae and Bacteroides species, and a number of plasmid-encoded β-lactamases. These combination agents are typically used when broader-spectrum coverage is needed—e.g., in pneumonia and intraabdominal infections. Piperacillin-tazobactam is a useful agent for broad coverage in febrile neutropenic patients. The combination agents, however, are not effective against organisms that produce AmpC β-lactamases or carbapenemases.
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The cephalosporin drug class encompasses five generations determined by spectrum of antibacterial activity. The first generation (cefazolin, cefadroxil, cephalexin) largely has activity against gram-positive bacteria, with some additional activity against E. coli, P. mirabilis, and K. pneumoniae. First-generation cephalosporins are commonly used for infections caused by MSSA and streptococci (e.g., skin and soft tissue infections). Cefazolin is a popular choice for surgical prophylaxis against skin organisms. The second generation (cefamandole, cefuroxime, cefaclor, cefprozil, cefuroxime axetil, cefoxitin, cefotetan) has additional activity against H. influenzae and Moraxella catarrhalis. Cefoxitin and cefotetan have potent activity against anaerobes as well. Second-generation cephalosporins are used to treat community-acquired pneumonia because of their activity against S. pneumoniae, H. influenzae, and M. catarrhalis. They are also used for other mild or moderate infections, such as acute otitis media and sinusitis. The third-generation cephalosporins are characterized by greater potency against gram-negative bacilli and reduced potency against gram-positive cocci. These cephalosporins, which include cefoperazone, cefotaxime, ceftazidime, ceftriaxone, cefdinir, cefixime, and cefpodoxime, are used for infections caused by Enterobacteriaceae, although resistance is an increasing concern. It is noteworthy that ceftazidime is the only third-generation cephalosporin with activity against P. aeruginosa but lacks activity against gram-positive bacteria. This drug is frequently used for pulmonary infections in cystic fibrosis and febrile neutropenia. Ceftriaxone penetrates the CSF and can be used to treat meningitis caused by H. influenzae, N. meningitidis, and susceptible strains of S. pneumoniae. It is also used for the treatment of later-stage Lyme disease. The fourth generation includes cefepime and cefpirome, broad-coverage agents that provide potent activity against both gram-negative bacilli, including P. aeruginosa, and gram-positive cocci. The fourth generation has clinical applications similar to those of the third generation and can be used in bacteremia, pneumonia, skin and soft tissue infections, and urinary tract infections caused by susceptible bacteria. Cefepime is also commonly used in febrile neutropenia. Ceftaroline, a fifth-generation cephalosporin, differs from the other cephalosporins in its added activity against MRSA, which is resistant to all other β-lactams. Ceftaroline’s gram-negative activity is similar to that of the third-generation cephalosporins but does not include P. aeruginosa. Ceftaroline is efficacious in community-acquired pneumonia and skin infections, but few data are available on its use for more serious infections, such as bacteremia.
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With a few exceptions for cefepime, all penicillins and cephalosporins are ineffective in the presence of ESBLs. Carbapenems, including doripenem, imipenem, meropenem, and ertapenem, offer the most reliable coverage for strains containing ESBLs. All carbapenems have broad activity against gram-positive cocci, gram-negative bacilli, and anaerobes. None is active against MRSA, but all are active against MSSA, Streptococcus species, and Enterobacteriaceae. Ertapenem is the only carbapenem that has poor activity against P. aeruginosa and Acinetobacter. Imipenem is active against penicillin-susceptible Enterococcus faecalis but not Enterococcus faecium. Carbapenems are not active against Enterobacteriaceae containing carbapenemases. Stenotrophomonas maltophilia and some Bacillus species are intrinsically resistant to carbapenems because of a zinc-dependent carbapenemase.
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Aztreonam is the sole monobactam. Its activity is limited to gram-negative bacteria and includes P. aeruginosa and most other Enterobacteriaceae. This drug is inactivated by ESBLs and carbapenemases. The principal use for aztreonam is as an alternative to penicillins, cephalosporins, or carbapenems in patients with serious β-lactam allergy. Aztreonam is structurally related to ceftazidime and should be used cautiously in individuals with a serious ceftazidime allergy. It is commonly used in febrile neutropenia and intraabdominal infections. Aztreonam does not penetrate the CSF and should not be used for treatment of meningitis.
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Adverse reactions to β-lactam drugs
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Agents within the β-lactam class are known for several adverse effects. Gastrointestinal side effects, mainly diarrhea, are common, but hypersensitivity reactions constitute the most common adverse effect of β-lactams. The reactions’ severity can range from rash to anaphylaxis, but the rate of true anaphylactic reactions is only 0.05%. An individual with an accelerated IgE-mediated reaction to one β-lactam agent may still receive another agent within the class, but caution should be taken to choose a β-lactam that has a dissimilar side chain and a low level of cross-reactivity. For example, the second-, third-, and fourth-generation cephalosporins and the carbapenems display very low cross-reactivity in patients with penicillin allergy. Aztreonam is the only β-lactam that has no cross-reactivity with the penicillin group. In cases of severe allergy, desensitization (a graded challenge) to the indicated β-lactam, with close monitoring, may be warranted if other antibacterial options are not suitable.
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β-Lactams can rarely cause serum sickness, Stevens-Johnson syndrome, nephropathy, hematologic reactions, and neurotoxicity. Neutropenia appears to be related to high doses or prolonged use. Neutropenia and interstitial nephritis caused by β-lactams generally resolve upon discontinuation of the agent. Imipenem and cefepime are associated with an increased risk of seizure, but this risk is likely a class effect and related to high doses or doses that are not adjusted in renal impairment.
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The glycopeptide antibiotics include vancomycin and telavancin. Vancomycin has activity against staphylococci (including MRSA and coagulase-negative staphylococci), streptococci (including S. pneumoniae), and enterococci. It is not active against gram-negative organisms. Vancomycin also displays activity against Bacillus species, Corynebacterium jeikeium, Listeria monocytogenes, and gram-positive anaerobes such as Peptostreptococcus, Actinomyces, Clostridium, and Propionibacterium species. Vancomycin has several important clinical uses. It is used for serious infections caused by MRSA, including health care–associated pneumonia, bacteremia, osteomyelitis, and endocarditis. It is also commonly used for skin and soft tissue infections. Oral vancomycin is not absorbed systemically and is reserved for the treatment of Clostridium difficile infection. Vancomycin is also an alternative for the treatment of infections caused by MSSA in patients who cannot tolerate β-lactams. Resistance to vancomycin is a rising concern. Strains of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant enterococci (VRE) are not uncommon. Vancomycin appears to be a concentration-dependent killer, with AUC/MIC ratio being the best predictor of efficacy (Fig. 41-2). Guidelines recommend targeting a vancomycin trough level of 15–20 μg/mL in MRSA infections in order to maintain an AUC/MIC ratio >400. When using vancomycin, clinicians should monitor for nephrotoxicity. The risk increases when trough levels are >20 μg/mL. Concomitant therapy with other nephrotoxic agents, such as aminoglycosides, also increases the risk of nephrotoxicity. Ototoxicity was reported with early formulations of vancomycin but is currently uncommon because purer formulations are available. Both of these adverse effects are reversible upon discontinuation of vancomycin. Clinicians should be aware of the “red man syndrome,” a common reaction that presents as a rapid onset of erythematous rash or pruritus on the head, face, neck, and upper trunk. This reaction is caused by histamine release from basophils and mast cells and can be treated with diphenhydramine and slowing of the vancomycin infusion.
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Telavancin, dalbavancin, and oritavancin are structurally similar to vancomycin and are referred to as lipoglycopeptides. They have antibacterial activity against S. aureus (including MRSA and some strains of VISA and vancomycin-resistant S. aureus [VRSA]), streptococci, and enterococci. They also have good activity against anaerobic gram-positive organisms except for Lactobacillus and some Clostridium species. The clinical efficacy of telavancin has been demonstrated in both skin and soft tissue infections and nosocomial pneumonia, and the efficacy of dalbavancin and oritivancin has been shown in skin and soft tissue infections. The vancomycin resistance phenotype may reduce the potency of all three lipoglycopeptides, but the rate of resistance to these drugs among S. aureus and enterococci has been low. Adverse effects of telavancin include insomnia, a metallic taste, nephrotoxicity, and gastrointestinal side effects. Clinicians should be aware of the potential for electrocardiographic QTc prolongation that can increase the risk of cardiac arrhythmias when telavancin is used concomitantly with other QTc-prolonging agents. Telavancin may interfere with certain coagulation tests (e.g., causing false elevations in prothrombin time). Dalbavancin and oritavancin have safety profiles similar to that of vancomycin.
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Daptomycin is a lipopeptide antibiotic with activity against a broad range of gram-positive organisms. This drug is active against staphylococci (including MRSA and coagulase-negative staphylococci), streptococci, and enterococci. Daptomycin remains active against enterococci that are resistant to vancomycin. In addition, it exhibits activity against Bacillus, Corynebacterium, Peptostreptococcus, and Clostridium species. Daptomycin’s pharmacodynamic parameter for efficacy is concentration-dependent killing. Resistance to daptomycin is rare, but MICs may be higher for VISA strains. Daptomycin is efficacious in skin and soft tissue infections, bacteremia, endocarditis, and osteomyelitis. It is an important alternative for MRSA and other gram-positive infections when bactericidal therapy is needed and vancomycin cannot be used. Daptomycin is generally well tolerated, and its main toxicity consists of elevation of creatinine phosphokinase (CPK) levels and myopathy. CPK should be monitored during daptomycin treatment, and the drug should be discontinued if muscular toxicities occur. There have also been case reports of reversible eosinophilic pneumonia associated with daptomycin use.
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The aminoglycosides are a class of antibacterial agents with concentration-dependent activity against most gram-negative organisms. The most commonly used aminoglycosides are gentamicin, tobramycin, and amikacin, although others, such as streptomycin, kanamycin, neomycin, and paromomycin, may be used in special circumstances. Aminoglycosides have a significant dose-dependent postantibiotic effect, meaning that they have an antibacterial effect even after serum drug levels are undetectable. The postantibiotic effect and concentration-dependent killing form the rationale behind extended-interval aminoglycoside dosing, in which a larger dose is given once daily rather than smaller doses multiple times daily. Aminoglycosides are active against gram-negative bacilli, such as Enterobacteriaceae, P. aeruginosa, and Acinetobacter. They also enhance the activity of cell wall–active agents such as β-lactams or vancomycin in some gram-positive bacteria, including staphylococci and enterococci. This combination therapy is termed synergistic because the effect of both agents provides a killing effect greater than would be predicted from the effects of either agent alone. Amikacin and streptomycin have activity against Mycobacterium tuberculosis, and amikacin has activity against Mycobacterium avium-intracellulare. The aminoglycosides do not have activity against anaerobes, S. maltophilia, or Burkholderia cepacia. Aminoglycosides are used in clinical practice in a variety of infections caused by gram-negative organisms, including bacteremia and urinary tract infections. They are frequently used alone or in combination for the treatment of P. aeruginosa infection. When used in combination with a cell wall–active agent, gentamicin and streptomycin are also important for the treatment of gram-positive bacterial endocarditis. All aminoglycosides can cause nephrotoxicity and ototoxicity. The risk of nephrotoxicity is related to the dose and duration of therapy as well as the concomitant use of other nephrotoxic agents. Nephrotoxicity is usually reversible, but ototoxicity can be irreversible.
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MACROLIDES AND KETOLIDES
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The macrolides (azithromycin, clarithromycin, erythromycin) and ketolides (telithromycin) are classes of antibiotics that inhibit protein synthesis. Compared with erythromycin (the older antibiotic), azithromycin and clarithromycin have better oral absorption and tolerability. Azithromycin, clarithromycin, and telithromycin all have broader spectra of activity than erythromycin, which is less frequently used. These agents are commonly used in the treatment of upper and lower respiratory tract infections caused by S. pneumoniae, H. influenzae, M. catarrhalis, and atypical organisms (e.g., Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae); group A streptococcal pharyngitis in penicillin-allergic patients; and nontuberculous mycobacterial infections (e.g., caused by M. marinum and M. chelonae) as well as in the prophylaxis and treatment of M. avium-intracellulare infection in patients with HIV/AIDS and in combination therapy for H. pylori infection and bartonellosis. Enterobacteriaceae, Pseudomonas species, and Acinetobacter species are intrinsically resistant to macrolides as a result of decreased membrane permeability, although azithromycin is active against gram-negative diarrheal pathogens. The major adverse effects of this drug class include nausea, vomiting, diarrhea and abdominal pain, prolongation of QTc interval, exacerbation of myasthenia gravis, and tinnitus. Azithromycin specifically has been associated with an increased risk of death, especially among patients with underlying heart disease, because of the risk of QTc interval prolongation and torsades de pointes. Erythromycin, clarithromycin, and telithromycin inhibit the CYP3A4 hepatic drug-metabolizing enzyme and can result in increased levels of coadministered drugs, including benzodiazepines, statins, warfarin, cyclosporine, and tacrolimus. Azithromycin does not inhibit CYP3A4 and lacks these drug–drug interactions.
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Clindamycin is a lincosamide antibiotic and is bacteriostatic against some organisms and bactericidal against others. It is used most often to treat bacterial infections caused by anaerobes (e.g., B. fragilis, Clostridium perfringens, Fusobacterium species, Prevotella melaninogenicus, and Peptostreptococcus species) and susceptible staphylococci and streptococci. Clindamycin is used for treatment of dental infections, anaerobic lung abscess, and skin and soft tissue infections. It is used together with bactericidal agents (penicillins or vancomycin) to inhibit new toxin synthesis in the treatment of streptococcal or staphylococcal toxic shock syndrome. Other uses include treatment of infections caused by Capnocytophaga canimorsus, a component of combination therapy for malaria and babesiosis, and therapy for toxoplasmosis. Clindamycin has excellent oral bioavailability. Adverse effects include nausea, vomiting, diarrhea, C. difficile–associated diarrhea and pseudomembranous colitis, maculopapular rash, and (rarely) Stevens-Johnson syndrome.
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TETRACYCLINES AND GLYCYLCYCLINES
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The tetracyclines (doxycycline, minocycline, and tetracycline) and the glycylcyclines (tigecycline) inhibit protein synthesis and are bacteriostatic. These drugs have wide clinical uses. They are used in the treatment of skin and soft tissue infections caused by gram-positive cocci (including MRSA), spirochetal infections (e.g., Lyme disease, syphilis, leptospirosis, and relapsing fever), rickettsial infections (e.g., Rocky Mountain spotted fever), atypical pneumonia, sexually transmitted infections (e.g., Chlamydia trachomatis infection, lymphogranuloma venereum, and granuloma inguinale), infections with Nocardia and Actinomyces, brucellosis, tularemia, Whipple’s disease, and malaria. Tigecycline, the only approved agent in the glycylcycline class, is a derivative of minocycline and is indicated in the treatment of infections due to MRSA, vancomycin-sensitive enterococci, many Enterobacteriaceae, and Bacteroides species. Tigecycline has no activity against P. aeruginosa. It has been used in combination with colistin for the treatment of serious infections with multidrug-resistant gram-negative organisms. A pooled analysis of 13 clinical trials found an increased risk of death and treatment failure among patients treated with tigecycline alone. Tetracyclines have reduced absorption when coadministered with calcium- and iron-containing compounds, including milk, and doses should be spaced at least 2 h apart. The major adverse reactions to both of these classes are nausea, vomiting, diarrhea, and photosensitivity. Tetracyclines have been associated with fetal bone-growth abnormalities and should be avoided during pregnancy and in the treatment of children <8 years old.
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TRIMETHOPRIM-SULFAMETHOXAZOLE
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Trimethoprim-sulfamethoxazole (TMP-SMX) is an antibiotic whose two components both inhibit folate synthesis and produce antibacterial activity. TMP-SMX is active against gram-positive bacteria such as staphylococci and streptococci; however, its use against MRSA is usually limited to community-acquired infections, and its activity against Streptococcus pyogenes may not be reliable. TMP-SMX is also active against many gram-negative bacteria, including H. influenzae, E. coli, P. mirabilis, N. gonorrhoeae, and S. maltophilia. TMP-SMX does not have activity against anaerobes or P. aeruginosa. It has many uses because of its wide spectrum of activity and high oral bioavailability. Urinary tract infections, skin and soft tissue infections, and respiratory tract infections are among the common uses. Another important indication is for both prophylaxis and treatment of Pneumocysitis jirovecii infections in immunocompromised patients. Resistance to TMP-SMX has limited its use against many Enterobacteriaceae. Resistance rates among urinary isolates of E. coli are almost 25% in the United States. The most common adverse reactions associated with TMP-SMX are gastrointestinal effects such as nausea, vomiting, and diarrhea. In addition, rash is a common allergic reaction and may preclude the subsequent use of other sulfonamides. With prolonged use, leukopenia, thrombocytopenia, and granulocytopenia can develop. TMP-SMX can also cause nephrotoxicity, hyperkalemia, and hyponatremia, which are more common at high doses. TMP-SMX has several important interactions with other drugs (Table 41-4), including warfarin, phenytoin, and methotrexate.
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The fluoroquinolones include norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and gemifloxacin. Ciprofloxacin and levofloxacin have the broadest spectrum of activity against gram-negative bacteria, including P. aeruginosa (similar to that of third-generation cephalosporins). Because of the risk of selection of resistance during fluoroquinolone treatment of serious pseudomonal infections, these agents are usually used in combination with an antipseudomonal β-lactam. Levofloxacin, moxifloxacin, and gemifloxacin have additional gram-positive activity, including that against S. pneumoniae and some strains of MSSA, and are used for treatment of community-acquired pneumonia. Strains of MRSA are commonly resistant to all fluoroquinolones. Moxifloxacin is used as one component of second-line regimens for multidrug-resistant tuberculosis. Fluoroquinolones exhibit concentration-dependent killing, are well absorbed orally, and have elimination half-lives that usually support once- or twice-daily dosing. Oral coadministration with compounds containing high concentrations of aluminum, magnesium, or calcium can reduce fluoroquinolone absorption. Their penetration into prostate tissue supports their use for bacterial prostatitis. Fluoroquinolones are generally well tolerated but can cause CNS stimulatory effects, including seizures; glucose dysregulation; and tendinopathy associated with Achilles tendon rupture, particularly in older patients, organ transplant recipients, and patients taking glucocorticoids. Worsening of myasthenia gravis also has been associated with quinolone use. Moxifloxacin causes modest prolongation of the QTc interval and should be used with caution in patients receiving other QTc-prolonging drugs.
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The rifamycins include rifampin, rifabutin, and rifapentine. Rifampin is the most commonly used rifamycin. For almost all therapeutic indications, it is used in combination with other agents to reduce the likelihood of selection of high-level rifampin resistance. Rifampin is used foremost in the treatment of mycobacterial infections—specifically, as a mainstay of combination therapy for M. tuberculosis infection or as a single agent in the treatment of latent M. tuberculosis infection. In addition, it is often used in the treatment of nontuberculous mycobacterial infection. Rifampin is used in combination regimens for the treatment of staphylococcal infections, particularly prosthetic valve endocarditis and bone infections with retained hardware. It is a component of combination therapy for brucellosis (with doxycycline) and leprosy (with dapsone for tuberculoid leprosy and with dapsone and clofazimine for lepromatous disease). Rifampin can be used alone for prophylaxis in close contacts of patients with H. influenzae or N. meningitidis meningitis. The drug has high oral bioavailability, which is further enhanced when it is taken on an empty stomach. Rifampin has several adverse effects, including elevated aminotransferase levels (14%), rash (1–5%), and gastrointestinal events such as nausea, vomiting, and diarrhea (1–2%). Its many clinically relevant interactions with other drugs mandate the clinician’s careful review of the patient’s medications before rifampin initiation to assess safety and the need for additional monitoring.
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Metronidazole is used in the treatment of anaerobic bacterial infections as well as infections caused by protozoa (e.g., amebiasis, giardiasis, trichomoniasis). It is the agent of choice as a component of combination therapy for polymicrobial abscesses in the lung, brain, or abdomen, the etiology of which often includes anaerobic bacteria, and for bacterial vaginosis, pelvic inflammatory disease, mild to moderate C. difficile–associated diarrhea, and anaerobic infections, such as those due to Bacteroides, Fusobacterium, and Prevotella species. Metronidazole is bactericidal against anaerobic bacteria and exhibits concentration-dependent killing. It has high oral bioavailability and tissue penetration, including penetration of the blood–brain barrier. The majority of Actinomyces, Propionibacterium, and Lactobacillus species are intrinsically resistant to metronidazole. The major adverse effects include nausea, diarrhea, and a metallic taste. Concomitant ingestion of alcohol may result in a disulfiram-like reaction, and patients are usually instructed to avoid alcohol during treatment. Long-term treatment carries the risk of leukopenia, neutropenia, peripheral neuropathy, and central nervous system toxicity manifesting as confusion, dysarthria, ataxia, nystagmus, and ophthalmoparesis. Through metronidazole’s effect on the CYP2C9 drug-metabolizing enzyme, its coadministration with warfarin can result in decreased metabolism and enhanced anticoagulant effects that require close monitoring. Concomitant administration of metronidazole with lithium can result in increased serum levels of lithium and associated toxicity; coadministration with phenytoin can result in phenytoin toxicity and possibly decreased levels of metronidazole.
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Linezolid is a bacteriostatic agent and is indicated for serious infections due to resistant gram-positive bacteria, such as MRSA and VRE. The intrinsic resistance of gram-negative bacteria is mediated primarily by endogenous efflux pumps. Linezolid has excellent oral bioavailability. Adverse effects include myelosuppression and ocular and peripheral neuropathy with prolonged therapy. Peripheral neuropathy may be irreversible. Linezolid is a weak, reversible monoamine oxidase inhibitor, and coadministration with sympathomimetics and foods rich in tyramine should be avoided. Linezolid has been associated with serotonin syndrome when coadministered with selective serotonin-reuptake inhibitors. Tedizolid has properties similar to those of linezolid, but with lower dosing it may be less likely to cause adverse hematologic and neuropathic effects.
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Nitrofurantoin’s antibacterial activity results from the drug’s conversion to highly reactive intermediates that can damage DNA and other macromolecules. Nitrofurantoin is bactericidal, and its action is concentration dependent. It displays activity against a range of gram-positive bacteria, including S. aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, E. faecalis, Streptococcus agalactiae, group D streptococci, viridans streptococci, and corynebacteria, as well as gram-negative organisms, including E. coli and Enterobacter, Neisseria, Salmonella, and Shigella species. Nitrofurantoin is used primarily in the treatment of urinary tract infections and is preferred in the treatment of such infections in pregnancy. It may be used for the prevention of recurrent cystitis. Recently, there has been interest in the use of nitrofurantoin for treatment of urinary tract infections caused by ESBL-producing Enterobacteriaceae such as E. coli, although resistance has been growing in Latin America and parts of Europe. Coadministration with magnesium should be avoided because of decreased absorption, and patients should be encouraged to take the drug with food to increase its bioavailability and decrease the risk of adverse effects, which include nausea, vomiting, and diarrhea. Nitrofurantoin may also cause pulmonary fibrosis and drug-induced hepatitis. Because the risk of adverse reactions increases with age, the use of nitrofurantoin in elderly patients is not recommended. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at elevated risk for nitrofurantoin-associated hemolytic anemia.
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Colistin and polymyxin B act by disrupting cell membrane integrity and are active against the nonenteric pathogens P. aeruginosa and A. baumannii but not against Burkholderia. These drugs also exhibit activity against many Enterobacteriaceae, with the exceptions of Proteus, Providencia, and Serratia species. They lack activity against gram-positive bacteria. Polymyxins are bactericidal and are available in IV formulations. Colistimethate is converted to the active form (colistin) in plasma. Polymyxins are most often used for infections due to pathogens resistant to multiple other antibacterial agents, including urinary tract infections, hospital-acquired pneumonia, and bloodstream infections. Nebulized formulations have been used for adjunctive treatment of refractory ventilator-associated pneumonia. The most important adverse effect is dose-dependent reversible nephrotoxicity. Neurotoxicity, including paresthesias, muscle weakness, and confusion, is reversible and less common than nephrotoxicity.
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QUINUPRISTIN-DALFOPRISTIN
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Quinupristin-dalfopristin is a member of the streptogramin class of antibiotics and kills bacteria by inhibiting protein synthesis. The antibacterial spectrum of quinupristin-dalfopristin includes staphylococci (including MRSA), streptococci, and E. faecium (but not E. faecalis). This drug is also active against Corynebacterium species and L. monocytogenes. Quinupristin-dalfopristin is not reliably active against gram-negative organisms. It exhibits concentration-dependent killing, with an AUC/MIC ratio predicting efficacy. The clinical use of quinupristin-dalfopristin is largely for infections due to vancomycin-resistant E. faecium and other gram-positive bacterial infections. The drug has demonstrated efficacy in a variety of infections, including urinary tract infections, bone and joint infections, and bacteremia. Adverse effects associated with quinupristin-dalfopristin include infusion-related reactions, arthralgias, and myalgias. The arthralgias and myalgias may be severe enough to warrant drug discontinuation. Quinupristin-dalfopristin inhibits the CYP3A4 drug-metabolizing enzyme, with consequent drug interactions (Table 41-4).
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Fosfomycin is a phosphonic acid antibiotic that has greater activity in acidic environments and is excreted in its active form in the urine. Thus, its use is primarily for prophylaxis and treatment of uncomplicated cystitis. The drug is administered as a single 3-g dose that results in high urine concentrations for up to 48 h. Fosfomycin is active against S. aureus, vancomycin-susceptible and vancomycin-resistant enterococci, and a wide range of gram-negative organisms, including E. coli, Enterobacter species, S. marcescens, P. aeruginosa, and K. pneumoniae. Notably, the vast majority of ESBL-producing Enterobacteriaceae are susceptible to fosfomycin. A. baumannii and Burkholderia species are resistant. The emergence of resistance to fosfomycin has not been observed during treatment of cystitis but has been documented during treatment of respiratory tract infections and osteomyelitis. The few adverse effects that have been reported include nausea and diarrhea.
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The use of chloramphenicol is limited by its potentially serious toxicities. When other agents are contraindicated or ineffective, chloramphenicol represents an alternative treatment for infections, including meningitis caused by susceptible bacteria such as N. meningitidis, H. influenzae, and S. pneumoniae. It has also been used for the treatment of anthrax, brucellosis, Burkholderia infections, chlamydial infections, clostridial infections, erlichiosis, rickettsial infections, and typhoid fever. Adverse reactions include aplastic anemia, myelosuppression, and gray baby syndrome. Chloramphenicol inhibits the CYP2C19 and CYP3A4 drug-metabolizing enzymes and consequently increases levels of many classes of drugs.