34 - Infectious Diseases: Spirochetal

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 37 - Anti-Infective Chemotherapeutic & Antibiotic Agents

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37

Anti-Infective Chemotherapeutic & Antibiotic Agents

Richard A. Jacobs MD, PhD

B. Joseph Guglielmo PharmD

Selected Principles of Antimicrobial Therapy

Specific steps (outlined below) are required when considering antibiotic therapy for patients. Drugs of first choice and alternative drugs are presented in Table 37-1.

A. Etiologic Diagnosis

Based on the organ system involved, the organism causing infection can often be predicted. See Tables 37-2 and 37-3.

B. “Best Guess”

Select an empiric regimen that is likely to be effective against the suspected pathogens.

C. Laboratory Control

Specimens for laboratory examination should be obtained before institution of therapy to determine susceptibility.

D. Clinical Response

Based on clinical response and other data, the laboratory reports are evaluated and then the desirability of changing the regimen is considered. If the specimen was obtained from a normally sterile site (eg, blood, cerebrospinal fluid, pleural fluid, joint fluid), the recovery of a microorganism in significant amounts is meaningful even if the organism recovered is different from the clinically suspected agent, and this may force a change in treatment. Isolation of unexpected microorganisms from the respiratory tract, gastrointestinal tract, or surface lesions (sites that have a complex flora) may represent colonization or contamination, and cultures must be critically evaluated before drugs are abandoned that were judiciously selected on a “best guess” basis.

E. Drug Susceptibility Tests

Some microorganisms are predictably inhibited by certain drugs; if such organisms are isolated, they need not be tested for drug susceptibility. For example, most group A hemolytic streptococci are inhibited by penicillin. Other organisms (eg, enteric gram-negative rods) are variably susceptible and often require susceptibility testing whenever they are isolated. Organisms that once had predictable susceptibility patterns have now become resistant and require testing. Examples include the pneumococci, which may be resistant to multiple drugs (including penicillin, macrolides, and trimethoprim-sulfamethoxazole) and the enterococci, which may be resistant to penicillin, aminoglycosides, and vancomycin.

Over the past 10 years, pharmaceutical companies have shifted away from developing and producing antibacterial medications. Consequently, few new agents, particularly those active against gram-negative pathogens, are expected. The lack of new drugs and increasing bacterial resistance reinforce the need to use these drugs judiciously.

Antimicrobial drug susceptibility tests may be performed on solid media as “disk tests,” in broth in tubes, in wells of microdilution plates, or as E-tests (strips with increasing concentration of antibiotic). The latter three methods yield results expressed as MIC (minimal inhibitory concentration), and the broth and microdilution techniques can be modified to give MBC (minimal bactericidal concentration) results. In most infections, the MIC is the appropriate in vitro test to guide selection of an antibacterial agent. When there appear to be marked discrepancies between susceptibility testing and clinical response, the following possibilities must be considered:

  • Selection of an inappropriate drug, drug dosage, or route of administration.

  • Failure to drain a collection of pus or to remove a foreign body.

  • Failure of a poorly diffusing drug to reach the site of infection (eg, central nervous system) or to reach intracellular phagocytosed bacteria.

  • Superinfection in the course of prolonged chemotherapy.

  • Emergence of drug-resistant organisms.

  • Participation of two or more microorganisms in the infectious process, of which only one was originally detected and used for drug selection.

  • Inadequate host defenses, including immunodeficiencies and diabetes.

  • P.1583


    P.1584


    P.1585


    P.1586


    P.1587


    P.1588


  • Noninfectious causes, including drug fever, malignancy, and autoimmune disease.

Table 37-1. Drugs of choice for suspected or proved microbial pathogens, 2004.1

Suspected or Proved Etiologic Agent Drug(s) of First Choice Alternative Drug(s)
Gram-negative cocci    
  Moraxella catarrhalis TMP-SMZ,2 a fluoroquinolone3 Cefuroxime, cefotaxime, ceftriaxone, cefuroxime axetil, an erythromycin,4 a tetracycline,5 azithromycin, amoxicillin-clavulanic acid, clarithromycin
  Neisseria gonorrhoeae (gonococcus) Ciprofloxacin or ofloxacin Ceftriaxone, spectinomycin, cefpodoxime proxetil
  Neisseria meningitidis (meningococcus) Penicillin6 Cefotaxime, ceftriaxone, ampicillin
Gram-positive cocci    
  Streptococcus pneumoniae8 (pneumococcus) Penicillin6 An erythromycin,4 a cephalosporin,7 vancomycin, TMP-SMZ,2 clindamycin, azithromycin, clarithromycin, a tetracycline,5 certain fluoroquinolones3
  Streptococcus, hemolytic, groups A, B, C, G Penicillin6 An erythromycin,4 a cephalosporin,7 vancomycin, clindamycin, azithromycin, clarithromycin
  Viridans streptococci Penicillin6 ± gentamicin Cephalosporin,7 vancomycin
  Staphylococcus, methicillin-resistant Vancomycin ± gentamicin TMP-SMZ,2 doxycycline, minocycline, a fluoroquinolone,3 linezolid, daptomycin, quinupristin-dalfopristin
  Staphylococcus, non-penicillinase-producing Penicillin6 A cephalosporin,8 clindamycin
  Staphylococcus, penicillinase-producing Penicillinase-resistant penicillin9 Vancomycin, a cephalosporin,7 clindamycin, amoxicillin-clavulanic acid, ticarcillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam, TMP-SMZ2
  Enterococcus faecalis Ampicillin ± gentamicin10 Vancomycin ± gentamicin
  Enterococcus faecium Vancomycin ± gentamicin10 Linezolid, quinupristin-dalfopristin, daptomycin
Gram-negative rods    
  Acinetobacter Imipenem or meropenem Tigecycline, minocycline, doxycycline, aminoglycosides,11 colistin
  Prevotella, oropharyngeal strains Clindamycin Penicillin,6 metronidazole
  Bacteroides, gastrointestinal strains Metronidazole Clindamycin, ticarcillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam
  Brucella Tetracycline + rifampin5 TMP-SMZ2 ± gentamicin; chloramphenicol ± gentamicin; doxycycline + gentamicin
  Campylobacter jejuni Erythromycin4 or azithromycin Tetracycline,5 a fluoroquinolone3
  Enterobacter TMP-SMZ,2 imipenem, meropenem Aminoglycoside, a fluoroquinolone,3 cefepime
  Escherichia coli (sepsis) Cefotaxime, ceftriaxone, Imipenem or meropenem, aminoglycosides,11 a fluoroquinolone3
  Escherichia coli (uncomplicated urinary infection) Fluoroquinolones,3 nitrofurantoin TMP-SMZ,2 oral cephalosporin, fosfomycin
  Haemophilus (meningitis and other serious infections) Cefotaxime, ceftriaxone Aztreonam
  Haemophilus (respiratory infections, otitis) TMP-SMZ2 Ampicillin, amoxicillin, doxycycline, azithromycin, clarithromycin, cefotaxime, ceftriaxone, cefuroxime, cefuroxime axetil, ampicillin-clavulanate
  Helicobacter pylori Amoxicillin + clarithromycin + proton pump inhibitor (PPI) Bismuth subsalicylate + tetracycline + metronidazole + PPI
  Klebsiella A cephalosporin TMP-SMZ,2 aminoglycoside,11 imipenem or meropenem, a fluoroquinolone,3 aztreonam
  Legionella species (pneumonia) Erythromycin4 or clarithromycin or azithromycin, or fluoroquinolones3 ± rifampin Doxycycline ± rifampin
  Proteus mirabilis Ampicillin An aminoglycoside,11 TMP-SMZ,2 a fluoroquinolone,3 a cephalosporin7
  Proteus vulgaris and other species (Morganella, Providencia) Cefotaxime, ceftriaxone, Aminoglycoside,11 imipenem, TMP-SMZ,2 a fluoroquinolone3
  Pseudomonas aeruginosa Aminoglycoside11 + antipseudomonal penicillin12 Ceftazidime ± aminoglycoside; imipenem or meropenem ± aminoglycoside; aztreonam ± aminoglycoside; ciprofloxacin (or levofloxacin) ± piperacillin; ciprofloxacin (or levofloxacin) ± ceftazidime; ciprofloxacin (or levofloxacin) ± cefepime
  Burkholderia pseudomallei (melioidosis) Ceftazidime Tetracycline,5 TMP-SMZ,2 amoxicillin-clavulanic acid, imipenem or meropenem
  Burkholderia mallei (glanders) Streptomycin + tetracycline5 Chloramphenicol + streptomycin
  Salmonella (bacteremia) Ceftriaxone, a fluoroquinolone3  
  Serratia Cefotaxime, ceftriaxone TMP-SMZ,2 aminoglycosides,11 imipenem or meropenem, a fluoroquinolone3
  Shigella A fluoroquinolone3 Ampicillin, TMP-SMZ,2 ceftriaxone
  Vibrio (cholera, sepsis) Tetracycline5 TMP-SMZ,2 a fluoroquinolone3
Yersinia pestis (plague, tularemia) Streptomycin ± a tetracycline5 Chloramphenicol, TMP-SMZ2
Gram-positive rods    
  Actinomyces Penicillin6 Tetracycline,5 clindamycin
  Bacillus (including anthrax) Penicillin6 (ciprofloxacin or doxycycline for anthrax; see Table 33-2) Erythromycin,4 tetracycline,5 a fluoroquinolone3
  Clostridium (eg, gas gangrene, tetanus) Penicillin6 Metronidazole, clindamycin, imipenem or meropenem
  Corynebacterium diphtheriae Erythromycin4 Penicillin6
  Corynebacterium jeikeium Vancomycin Ciprofloxacin, penicillin + gentamicin
  Listeria Ampicillin ± aminoglycoside11 TMP-SMZ2
Acid-fast rods    
  Mycobacterium tuberculosis13 Isoniazid (INH) + rifampin + pyrazinamide ± ethambutol (or streptomycin) Other antituberculous drugs (see Tables 9-13 and 9-14)
  Mycobacterium leprae Dapsone + rifampin ± clofazimine Minocycline, ofloxacin, clarithromycin
  Mycobacterium kansasii INH + rifampin ± ethambutol Ethionamide, cycloserine
  Mycobacterium avium complex Clarithromycin or azithromycin + one or more of the following: ethambutol, rifampin or rifabutin, ciprofloxacin Amikacin
  Mycobacterium fortuitum-cheilonei Amikacin + clarithromycin Cefoxitin, sulfonamide, doxycycline, linezolid
  Nocardia TMP-SMZ2 Minocycline, imipenem or meropenem, sulfisoxazole, linezolid
Spirochetes    
Borrelia burgdorferi (Lyme disease) Doxycycline, amoxicillin, cefuroxime axetil Ceftriaxone, cefotaxime, penicillin, azithromycin, clarithromycin
  Borrelia recurrentis (relapsing fever) Doxycycline5 Penicillin6
  Leptospira Penicillin,6 ceftriaxone Doxycycline5
  Treponema pallidum (syphilis) Penicillin6 Doxycycline, ceftriaxone
  Treponema pertenue (yaws) Penicillin6 Doxycycline
Mycoplasmas Erythromycin4 or doxycycline Clarithromycin, azithromycin, a fluoroquinolone3
Chlamydiae    
  C psittaci Doxycycline Chloramphenicol
  C trachomatis (urethritis or pelvic inflammatory disease) Doxycycline or azithromycin Ofloxacin
  C pneumoniae Doxycycline5 Erythromycin,4 clarithromycin, azithromycin, a fluoroquinolone3,14
Rickettsiae Doxycycline5 Chloramphenicol, a fluoroquinolone3
1Adapted from Med Lett Drugs Ther 2004;2:13.
2TMP-SMZ is a mixture of 1 part trimethoprim and 5 parts sulfamethoxazole.
3Fluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, and others (see text). Gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have the best activity against gram-positive organisms, including penicillin-resistant S pneumoniae and methicillin-sensitive S aureus. Activity against enterococci and S epidermidis is variable.
4Erythromycin estolate is best absorbed orally but carries the highest risk of hepatitis; erythromycin stearate and erythromycin ethylsuccinate are also available.
5All tetracyclines have similar activity against most microorganisms. Minocycline and doxycycline have increased activity against S aureus.
6Penicillin G is preferred for parenteral injection; penicillin V for oral administration–to be used only in treating infections due to highly sensitive organisms.
7Most intravenous cephalosporins (with the exception of ceftazidime) have good activity against gram-positive cocci.
8Infections caused by isolates with intermediate resistance may respond to high doses of penicillin, cefotaxime, or ceftriaxone. Infections caused by highly resistant strains should be treated with vancomycin. Many strains of penicillin-resistant pneumococci are resistant to macrolides, cephalosporins, tetracyclines, and TMP-SMZ.
9Parenteral nafcillin or oxacillin; oral dicloxacillin, cloxacillin, or oxacillin.
10Addition of gentamicin indicated only for severe enterococcal infections (eg, endocarditis, meningitis).
11Aminoglycosides–gentamicin, tobramycin, amikacin, netilmicin–should be chosen on the basis of local patterns of susceptibility.
12Antipseudomonal penicillins: ticarcillin, piperacillin.
13Resistance is common and susceptibility testing should be done.
14Ciprofloxacin has inferior antichlamydial activity compared with newer fluoroquinolones.
Key: ± = alone or combined with.

Table 37-2. Examples of initial antimicrobial therapy for acutely ill, hospitalized adults pending identification of causative organism.

Suspected Clinical Diagnosis Likely Etiologic Diagnosis Drugs of Choice
(A) Meningitis, bacterial, community-acquired Pneumococcus,1 meningococcus Cefotaxime,2 2–3 g IV every 6 hours; or ceftriaxone, 2 g IV every 12 hours plus vancomycin, 10 mg/kg IV every 8 hours
(B) Meningitis, bacterial, age > 50, community-acquired Pneumococcus, meningococcus, Listeria monocytogenes,3 gram-negative bacilli Ampicillin, 2 g IV every 4 hours, plus cefotaxime or ceftriaxone and vancomycin as in (A)
(C) Meningitis, postoperative (or posttraumatic) S aureus, gram-negative bacilli (pneumococcus, in posttraumatic) Vancomycin, 10 mg/kg IV every 8 hours, plus ceftazidime, 3 g IV every 8 hours
(D) Brain abscess Mixed anaerobes, pneumococci, streptococci Penicillin G, 4 million units IV every 4 hours, plus metronidazole, 500 mg orally every 8 hours; or cefotaxime or ceftriaxone as in (A) plus metronidazole, 500 mg orally every 8 hours
(E) Pneumonia, acute, community-acquired, severe Pneumococci, M pneumoniae, Legionella, C pneumoniae Doxycycline, 100 mg IV or orally every 12 hours (or azithromycin), plus cefotaxime, 2 g IV every 8 hours (or ceftriaxone, 1 g IV every 24 hours); or a fluoroquinolone5 alone
(F) Pneumonia, postoperative or nosocomial S aureus, mixed anaerobes, gram-negative bacilli Cefepime, 2 g IV every 8 hours; or ceftazidime, 2 g IV every 8 hours; or piperacillin-tazobactam, 45 g IV every 6 hours; or imipenem, 500 mg IV every 6 hours; or meropenem, 1 g IV every 8 hours plus tobramycin, 5 mg/kg IV every 24 hours; or ciprofloxacin, 400 mg IV every 12 hours; or levofloxacin, 500 mg IV every 24 hours plus vancomycin, 15 mg/kg IV every 12 hours
(G) Endocarditis, acute (including injection drug user) S aureus, E faecalis, gram-negative aerobic bacteria, viridans streptococci Vancomycin, 15 mg/kg IV every 12 hours, plus gentamicin, 1 mg/kg every 8 hours
(H) Septic thrombophlebitis (eg, IV tubing, IV shunts) S aureus, gram-negative aerobic bacteria Vancomycin, 15 mg/kg IV every 12 hours plus ciprofloxacin, 400 mg IV every 12 hours; or levofloxacin, 500 mg IV every 24 hours; or ceftriaxone, 1 g IV every 24 hours
(I) Osteomyelitis S aureus Nafcillin, 2 g IV every 4 hours; or cefazolin, 2 g IV every 8 hours
(J) Septic arthritis S aureus, N gonorrhoeae Ceftriaxone, 1-2 g IV every 24 hours
(K) Pyelonephritis with flank pain and fever (recurrent urinary tract infection) E coli, Klebsiella, Enterobacter, Pseudomonas Ceftriaxone, 1g IV every 24 hours; or ciprofloxacin, 400 mg IV every 12 hours (500 mg orally); or levofloxacin, 500 mg once daily (IV/PO)
(L) Fever in neutropenic patient receiving cancer chemotherapy S aureus, Pseudomonas, Klebsiella, E coli Ceftazidime, 2 g IV every 8 hours; or cefepime, 2 g IV every 8 hours
(M) Intra-abdominal sepsis (eg, postoperative, peritonitis, cholecystitis) Gram-negative bacteria, Bacteroides, anaerobic bacteria, streptococci, clostridia Piperacillin-tazobactam as in (F) or ticarcillin-clavulanate, 3.1 g IV every 6 hours; or ertapenem, 1 g every 24 hours; or moxifloxacin, 400 mg IV every 24 hours
1Some strains may be resistant to penicillin. Vancomycin can be used with or without rifampin.
2Cefotaxime, ceftriaxone, ceftazidime, or ceftizoxime can be used. Most studies on meningitis have been with cefotaxime or ceftriaxone (see text).
3TMP-SMZ can be used to treat Listeria monocytogenes in patients allergic to penicillin in a dosage of 15-20 mg/kg of TMP in three or four divided doses.
4Depending on local drug susceptibility pattern, use tobramycin, 5 mg/kg/d, or amikacin, 15 mg/kg/d, in place of gentamicin.
5Gatifloxacin, levofloxacin, moxifloxacin.

Table 37-3. Examples of empiric choices of antimicrobials for adult outpatient infections.

Suspected Clinical Diagnosis Likely Etiologic Agents Drugs of Choice Alternative Drugs
Erysipelas, impetigo, cellulitis, ascending lymphangitis Group A streptococcus Phenoxymethyl penicillin, 0.5 g orally four times daily for 7–10 days Cephalexin, 0.5 g orally four times daily for 7–10 days; or azithromycin, 500 mg on day 1 and 250 mg on days 2–5; or erythromycin, 0.5 g orally four times daily for 7–10 days
Furuncle with surrounding cellulitis Staphylococcus aureus Dicloxacillin, 0.5 g orally four times daily for 7–10 days Cephalexin, 0.5 g orally four times daily for 7–10 days
Pharyngitis Group A streptococcus Phenoxymethyl penicillin, 0.5 g orally four times daily for 10 days Clindamycin, 300 mg orally four times daily for 10 days; or erythromycin, 0.5 g orally four times daily for 10 days; or azithromycin, 500 mg on day 1 and 250 mg on days 2–5; or clarithromycin, 500 mg twice daily for 10 days
Otitis media Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis Amoxicillin, 0.5 g orally three times daily for 10 days Augmentin,2 0.875 g orally twice daily; or cefuroxime, 0.5 g orally twice daily; or cefpodoxime, 0.2–0.4 g daily; or doxycycline, 100 mg twice daily; or TMP-SMZ1, one double-strength tablet twice daily (all regimens for 10 days).
Acute sinusitis S pneumoniae, H influenzae, M catarrhalis Amoxicillin, 0.5 g orally three times daily; or TMP-SMZ, one double-strength tablet twice daily for 10 days Augmentin,2 0.875 g orally twice daily; or cefuroxime, 0.5 g orally twice daily; or cefpodoxime, 0.2–0.4 g daily; or doxycycline, 100 mg twice daily (all regimens for 10 days)
Aspiration pneumonia Mixed oropharyngeal flora, including anaerobes Clindamycin, 0.3 g orally four times daily for 10–14 days Phenoxymethyl penicillin, 0.5 g orally four times daily for 10–14 days
Pneumonia S pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae Doxycycline, 100 mg orally twice daily; or clarithromycin, 0.5 g orally twice daily, for 10–14 days; or azithromycin, 0.5 g orally on day 1 and 0.25 g on days 2–5 Amoxicillin, 0.5 g orally four times daily; or a fluoroquinolone5 for 10–14 days
Cystitis Escherichia coli, Klebsiella pneumoniae, Proteus species, Staphylococcus saprophyticus Fluoroquinolones,4 3 days for uncomplicated cystitis, nitrofurantoin macrocrystals, 100 mg orally QID × 7 days; nitrofurantoin monohydrate macrocrystals, 100 mg BID × 7 days TMP-SMZ,1 one double-strength tablet twice daily for 3 days; or cephalexin, 0.5 g orally four times daily for 7 days
Pyelonephritis E coli, K pneumoniae, Proteus species, S saprophyticus Fluoroquinolones4 for 7–14 days TMP-SMZ,1 one double-strength tablet twice daily for 7–14 days
Gastroenteritis Salmonella, Shigella, Campylobacter, Entamoeba histolytica See Note 3.  
Urethritis, epididymitis Neisseria gonorrhoeae, Chlamydia trachomatis Ciprofloxacin, 500 mg orally once, for N gonorrhoeae; plus doxycycline, 100 mg orally twice daily for 10 days, or ofloxacin, 300 mg orally twice daily for 10 days Ceftriaxone, 250 mg IM once or cefpodoxime 200–400 mg orally once, for N gonorrhoeae; plus doxycycline, 100 mg orally twice daily for 10 days, for C trachomatis
Pelvic inflammatory disease N gonorrhoeae, C trachomatis, anaerobes, gram-negative rods Ofloxacin, 400 mg orally twice daily, for 14 days, plus metronidazole, 500 mg orally twice daily, for 14 days Cefoxitin, 2 g IM, with probenecid, 1 g orally, followed by doxycycline, 100 mg orally twice daily for 14 days; or ceftriaxone, 250 mg IM once, followed by doxycycline, 100 mg orally twice daily for 14 days
Syphilis      
  Early syphilis (primary, secondary, or latent of < 1 year's duration) Treponema pallidum Benzathine penicillin G, 2.4 million units IM once Doxycycline, 100 mg orally twice daily for 2 weeks
  Latent syphilis of > 1 year's duration or cardiovascular syphilis T pallidum Benzathine penicillin G, 2.4 million units IM once a week for 3 weeks (total: 7.2 million units) Doxycycline, 100 mg orally twice daily, for 4 weeks
  Neurosyphilis T pallidum Aqueous penicillin G, 12–24 million units/d IV for 10–14 days Procaine penicillin G, 2–4 million units/d IM, plus probenecid, 500 mg orally four times daily, both for 10–14 days
1TMP-SMZ is a fixed combination of 1 part trimethoprim and 5 parts sulfamethoxazole. Single-strength tablets: 80 mg TMP, 400 mg SMZ; double-strength tablets: 160 mg TMP, 800 mg SMZ.
2Augmentin is a combination of amoxicillin, 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid. Augmentin XR is a combination of amoxicillin 1 g and clavulanic acid 62.5 mg.
3The diagnosis should be confirmed by culture before therapy. Salmonella gastroenteritis does not require therapy. For susceptible Shigella isolates, give TMP-SMZ double-strength tablets twice daily for 5 days; or ampicillin, 0.5 g orally four times daily for 5 days; or ciprofloxacin, 0.5 g orally twice daily for 5 days. For Campylobacter infection, give erythromycin, 0.5 g orally four times daily for 5 days, or ciprofloxacin, 0.5 g orally twice daily for 5 days. For E histolytica infection, give metronidazole, 750 mg orally three times daily for 5–10 days, followed by diiodohydroxyquin, 600 mg orally three times daily for 3 weeks.
4Fluoroquinolones and dosages include ciprofloxacin, 500 mg orally twice daily; ofloxacin, 400 mg orally twice daily; levofloxacin, 500 mg orally daily. For others see text.
5Fluoroquinolones with activity against S pneumoniae, including penicillin-resistant isolates, include levofloxacin (500 mg orally once daily), gatifloxacin (400 mg orally once daily), gemifloxacin (320 mg orally once daily), and moxifloxacin (400 mg orally once daily).

F. Promptness of Response

Response depends on a number of factors, including the patient (immunocompromised patients respond slower than immunocompetent patients), the site of infection (deep-seated infections such as osteomyelitis and endocarditis respond more slowly than superficial infections such as cystitis or cellulitis), the pathogen (virulent organisms such as Staphylococcus aureus respond more slowly than viridans streptococci; mycobacterial and fungal infections respond slower than bacterial infections), and the duration of illness (in general, the longer the symptoms are present, the longer it takes to respond). Thus, depending on the clinical situation, persistent fever and leukocytosis several days after initiation of therapy may not indicate improper choice of antibiotics but may be due to the natural history of the disease being treated. In most infections, either a bacteriostatic or a bactericidal agent can be used. In some infections (eg, infective endocarditis and meningitis), a bactericidal agent should be used. When potentially toxic drugs (eg, aminoglycosides, flucytosine) are used, serum levels of the drug are measured to minimize toxicity and ensure appropriate dosage. In patients with altered clearance of drugs, the dosage or frequency of administration must be adjusted. Especially in elderly, morbidly obese patients or those with altered renal function, it is best to measure levels directly and adjust therapy accordingly.

In renal or hepatic failure, the dosage should be adjusted as shown in Table 37-4.

Table 37-4. Use of antimicrobials in patients with renal failure1 and hepatic failure.

Drug Principal Mode of Excretion or Detoxification Approximate Half-Life in Serum Proposed Dosage Regimen in End-Stage Renal Failure (all doses IV unless stated otherwise) Removal of Drug by Hemodialysis Dose after Hemodialysis Dosage in Hepatic Failure
Normal Renal Failure2 Initial Dose3 Maintenance Dose
Acyclovir Renal 2.5–3.5 hours 20 hours 2.5 mg/kg 2.5 mg/kg q24h Yes 2.5 mg/kg No change
Amphotericin B Unknown 360 hours 360 hours No change No change No None No change
Ampicillin Tubular secretion 0.5–1 hour 8–12 hours 1 g 1 g q8–12h Yes 1 g No change
Ampicillin-sulbactam Renal 0.5–1 hour 8–12 hours 3 g 1.5 g q8–12h Yes 1.5 g No change
Azithromycin Renal 20%; hepatic 35% 3–4 hours Not known 500 mg 250 mg q24h No None Not known4
Aztreonam Renal 1.7 hours 6 hours 1–2 g 0.5–1 g q6–8h Yes 0.5–1 g No change
Caspofungin Liver 9–10 hours 9–10 hours 70 mg 50 mg q24h No None 35 mg q24h
Chloramphenicol Mainly liver 3 hours 4 hours 0.5 g 0.5 g q6h Yes 0.5 g 0.25–0.5 g q12h
Clarithromycin Renal 30%; hepatic > 50% 3–4 hours 15 hours 500 mg PO 250 mg q12h PO No None Not known4
Clindamycin Liver 2–4 hours 2–4 hours 0.6 g IV 0.6 g q8h No None 0.3–0.6 g q8h
Daptomycin Renal 8–12 hours >24 hours 4 mg/kg 4 mg/kg q48h No None No change
Doxycycline Renal 15–24 hours 15–24 hours 100 mg 100 mg q12h No None Not known4
Ertapenem Renal 4 hours 20 hours 1 g 0.5 g q24h Yes 0.15 g No change
Erythromycin Mainly liver 1.5 hours 1.5 hours 0.5–1 g 0.5–1 g q6h No None 0.25–0.5 g q6h
Famciclovir5 Renal 2.5 hours 13–20 hours 500 mg PO 500 mg q24h PO Yes 500 mg No change
Fluconazole Renal 30 hours 98 hours 0.2 g 0.1 g q24h Yes Give q24h dose No change
Flucytosine Renal 3–6 hours 30–250 hours 37.5 mg/kg PO 25 mg/kg q24h PO Yes 25 mg/kg No change
Foscarnet Renal 3–8 hours Not known 90–120 mg Not known6 No None No change
Fosfomycin Renal 6 hours 11–50 hours NA NA NA NA No change
Ganciclovir7 Renal 3 hours 11–28 hours 1.25 mg/kg 1.25 mg/kg q24h Yes Give q24h dose No change
Gemifloxacin Renal and liver 7 hours Not known 320 mg PO 160 mg q24h PO Not known Not known Not known
Imipenem Glomerular filtration 1 hour 3 hours 0.5 g 0.25–0.5 g q12h Yes 0.25–0.5 g No change
Isoniazid Renal 1–5 hours 2.5 hours 300 mg PO 300 mg q24h PO Yes None Not known4
Itraconazole Hepatic 21 hours 25 hours 50–200 mg PO 50–200 mg q24h PO No None Not known4
Ketoconazole Hepatic 8 hours 8 hours 200 mg PO 200–400 mg q24h PO No None Not known4
Meropenem Renal 1 hour 5–10 hours 1 g 0.5–1 g q24h Yes 0.5 g No change
Metronidazole Liver 6–10 hours 6–10 hours 0.5 g IV 0.5 g q8h Yes 0.25 g 0.25 g q12h
Micafungin Bilary/hepatic 15 hours 15 hours 150 mg 150 mg q24h No None No change
Nafcillin Liver 80%; kidney 20% 0.75 hour 1.5 hours 1.5 g 1.5 g q4h No None 2–3 g q12h
Penicillin G Tubular secretion 0.5 hour 7–10 hours 1–2 million units 1 million units q8h Yes 500,000 units No change
Pentamidine Not known 6–9 hours 6–9 hours 4 mg/kg 4 mg/kg q24h No None needed No change
Piperacillin and piperacillin + tazobactam Renal 50–70%; biliary 20–30% 1 hour 3–6 hours 3 g 2 g q6–8h Yes 1 g 1–2 g q8h
Rifampin Hepatic 2–3 hours 3–5 hours 600 mg PO 600 mg q24h PO No None Not known4
Telithromycin Hepatic 7–10 hours 7–10 hours 800 mg PO 800 mg q24h PO Not known Not known Not known
Ticarcillin Tubular secretion 1.1 hours 15–20 hours 3 g 2 g q6–8h Yes 1 g No change
Tigecycline Hepatic 25–40 hours 25–40 hours 100 mg 50 mg q12h No None No change
Trimethoprim-sulfamethoxazole Some liver TMP 10–12 hours; SMZ 8–10 hours TMP 24–48 hours; SMZ 18–24 hours 320 mg TMP + 1600 mg SMZ 80 mg TMP + 400 mg SMZ q12h Yes 80 mg TMP + 400 mg SMZ No change
Trimetrexate Hepatic 15 hours Not known 45 mg/m2 40 mg/m2 q24h No None Not known
Vancomycin Glomerular filtration 6 hours 6–10 days 1 g 1 g q6–10d based on serum levels8 No None No change
Voriconazole Hepatic 6–24 hours; dose-dependent 6–24 hours 200 mg orally; avoid IV in renal failure 200 mg orally twice daily; avoid IV in renal failure No None 100 mg twice daily
1For cephalosporins, see text and Table 37-7; for aminoglycosides, see Table 37-8.
2Considered here to be marked by creatinine clearance of 10 mL/min or less.
3For a 70-kg adult with a serious systemic infection.
4Dose adjustment in hepatic failure has not been studied, but because clearance of the drug is principally hepatic, dose reduction may be required.
5Pharmacokinetics and dosing are in reference to the active agent, penciclovir.
6When creatinine clearance is 30 mL/min, a dose of 60 mg/kg is given once daily. For clearances less than 30 mL/min, the dose has not been established.
7Oral valganciclovir is same as IV ganciclovir except that the initial dose is 900 mg, maintenance dose is 450 mg twice weekly in patients with creatinine clearance 10–40 mL/min. Post doses not known.
8When serum levels reach 10–15 mcg/mL, another dose should be given.

G. Duration of Antimicrobial Therapy

Generally, effective antimicrobial treatment results in reversal of the clinical and laboratory parameters of active infection and marked clinical improvement. However, varying periods of treatment may be required for cure. Key factors include (1) the type of infecting organism (bacterial infections generally can be cured more rapidly than fungal or mycobacterial

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ones), (2) the location of the process (eg, endocarditis and osteomyelitis require prolonged therapy), and (3) the immunocompetence of the patient. Recommendations about duration of therapy are often given based on clinical experience, not prospective controlled studies of large numbers of patients.

H. Adverse Reactions and Toxicity

These include hypersensitivity reactions, direct toxicity, superinfection by drug-resistant microorganisms, and drug interactions. If the infection is life-threatening and treatment cannot be stopped, the reactions are managed symptomatically or another drug is chosen that does not cross-react with the offending one (Table 37-1). If the infection is less serious, it may be possible to stop all antimicrobials and monitor the patient closely.

I. Route of Administration

Parenteral therapy is preferred for acutely ill patients with serious infections (eg, endocarditis, meningitis, sepsis, severe pneumonia) when dependable levels of antibiotics are required for successful therapy. Certain drugs (eg, fluconazole, voriconazole, rifampin, metronidazole, trimethoprim-sulfamethoxazole, and fluoroquinolones) are so well absorbed that they generally can be administered orally in seriously ill patients.

Food does not significantly influence the bioavailability of most oral antimicrobial agents. However, the tetracyclines and the quinolones chelate heavy metals resulting in decreased antibacterial absorption. Azithromycin capsules are associated with decreased bioavailability when taken with food and should be given 1 hour before or 2 hours after meals.

A major complication of intravenous antibiotic therapy is catheter infections. Peripheral catheters are changed every 48–72 hours to prevent phlebitis, and antimicrobial-coated central venous catheters (minocycline and rifampin, chlorhexidine and sulfadiazine) have been associated with a decreased incidence of catheter-related infections. Most of these infections present with local signs of infection (erythema, tenderness) at the insertion site. In a patient with fever who is receiving intravenous therapy, the catheter must always be considered a potential source. Small-gauge (20–23F) peripherally inserted silicone or polyurethane catheters (Per Q Cath, A-Cath, Ven-A-Cath, and others) are associated with a low infection rate and can be maintained for 3–6 months without replacement. Such catheters are ideal for long-term outpatient antibiotic therapy.

J. Cost of Antibiotics

The cost of these agents can be substantial. In addition to acquisition cost, monitoring costs, (drug levels, liver function tests, electrolytes, etc), the cost of treating adverse reactions, the cost of treatment failure, and the costs associated with drug administration must be considered. Table 37-5 lists the costs of commonly used antibiotics.

Drusano GL: Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev 2004;2:289.

Lampiris HW, Maddix DS: Clinical use of antimicrobial agents. In: Basic & Clinical Pharmacology, 9th ed. Katzung BG (editor). McGraw-Hill, 2004.

Spellberg B et al: Trends in antimicrobial drug development: implications for the future. Clin Infec Dis 2004;38:1279.

Penicillins

The penicillins share a common chemical nucleus (6-aminopenicillanic acid) that contains a β-lactam ring essential to their biologic activity.

Antimicrobial Action & Resistance

The initial step in penicillin action is the binding of the drug to receptors—penicillin-binding proteins. The proteins of different organisms vary in number and in affinity for a given drug. After penicillins have attached to receptors, peptidoglycan synthesis is inhibited because the activity of transpeptidation enzymes is blocked. The final bactericidal action is the removal of an inhibitor of the autolytic enzymes in the cell wall, which activates the enzymes and results in cell lysis. Organisms that produce β-lactamases (penicillinases) are resistant to some penicillins because the β-lactam ring is broken and the drug is inactivated. Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are susceptible to β-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are not susceptible.

Microbial resistance to penicillins is caused by four factors: (1) Production of β-lactamases, eg, by staphylococci, gonococci, Haemophilus species, and coliform organisms; (2) lack of penicillin-binding proteins or decreased affinity of penicillin-binding protein for β-lactam antibiotic receptors (eg, resistant pneumococci, methicillin-resistant staphylococci, enterococci) or impermeability of cell envelope; (3) failure of activation of autolytic enzymes in the cell wall—“tolerance,” eg, in staphylococci, group B streptococci; and (4) cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans.

Table 37-5. Approximate costs of antimicrobials.

Drug Dose per Day1 Cost per Unit2 Daily Cost of Therapy3
INTRAVENOUS PREPARATIONS
Acyclovir 15 mg/kg (mucocutaneous herpes) $19.20/1 g $19.20
Acyclovir 30 mg/kg (CNS herpes) $19.20/1 g $38.40
Amikacin (Amikin, others) 15 mg/kg $7.80/0.5 g $15.60
Ampicillin 100 mg/kg $16.75/2 g $67.00
Ampicillin plus sulbactam (Unasyn) 3 g q8h $15.50/3 g (IV) $46.50
Aztreonam (Azactam) 50 mg/kg $26.70/1 g $106.80
Caspofungin (Cancidas) 50 mg $395.00 $395.00
Cefazolin (Ancef, others) 50 mg/kg $4.30/1 g (IV) $12.90
Cefepime (Maxipime) 500 mg/kg $19.40/1 g $58.20
Cefoxitin (Mefoxin) 80 mg/kg $11.25/1 g $33.75
Ceftazidime (Fortaz, others) 50 mg/kg $14.25/1 g $42.75
Ceftizoxime (Cefizox) 50 mg/kg $11.40/1 g $34.20
Ceftriaxone (Rocephin) 30 mg/kg $49.00/1 g $49.00
Cefuroxime (Zinacef, others) 60 mg/kg $23.90/1.5 g $71.70
Ciprofloxacin (Cipro IV) 0.8 mg $28.80/0.4 g $57.60
Clindamycin (Cleocin, others) 2400 mg $4.30/0.6 g $17.20
Daptomycin (Cubicin) 4 mg/kg $171.10/500 mg $171.10
Fluconazole (Diflucan IV) 0.2–0.4 g $116.50/0.2 g
$170.30/0.4 g
$116.50–170.30
Foscarnet (Foscavir) 180 mg/kg (induction)
90–120 mg/kg (maintenance)
$83.25 (24 mg/mL × 250 mL = 6000 mg) $166.50
$83.25–111.00
Ganciclovir (Cytovene IV) 10 mg/kg $44.80/0.5 g $89.60
Gatifloxacin (Tequin) 400 mg $38.20/400 mg $38.20
Gentamicin 5 mg/kg $0.80/80 mg $2.40
Imipenem (Primaxin IV) 50 mg/kg $34.40/0.5 g $137.60
Meropenem (Merrem IV) 500 mg/kg $30.00/0.5 g $90.00–120.00
Metronidazole (Flagyl, others) 1500 mg $2.80/0.5 g $8.40
Micafungin (Mycamine) 150 mg $112.20/50 mg $336.60
Nafcillin 100 mg/kg $15.20/2 g $60.80
Penicillin 12 million units $8.00/1 million units $96.00
Piperacillin (Pipracil) 250 mg/kg $12.50/3 g $60.00
Piperacillin plus tazobactam (Zosyn) 3.75 g q6–8h $17.20/3.375 g $68.80
Ticarcillin (Ticar) 250 mg/kg $12.40/3 g $49.60
Ticarcillin-potassium clavulanic acid (Timentin) 3.1 g q6h $15.10/3.1 g $60.40
Tigecycline (Tygacil) 50 mg q12h $54.30/50 mg $108.60
Tobramycin 5 mg/kg $6.00/80 mg $30.00
Trimethoprim-sulfamethoxazole (Bactrim, Septra) 15 mg/kg TMP $19.50 (0.48 g TMP in 30 mL) $39.00
Vancomycin 20–30 mg/kg $6.00/1 g $12.00
Voriconazole (VFend) 200 mg q12h $110.30/200 mg $220.60
ORAL PREPARATIONS
Acyclovir 1000 mg (therapy of herpes) $1.10/0.2 g $5.50
Acyclovir 800 mg three times daily (herpes suppression for immunocompromised patient) $4.20/0.8 g $12.60
Amoxicillin 20–30 mg/kg $0.40/0.5 g $1.20
Ampicillin 20–30 mg/kg $0.40/0.5 g $1.60
Augmentin (0.5 g amoxicillin plus 0.125 g clavulanic acid) 30 mg/kg $3.80/0.5 g $7.60
Azithromycin (Zithromax) 500 mg as loading dose, then 250 mg/d for 4 days $8.80/0.25 g $17.60 load, then $8.80
Azithromycin (Zithromax) 1 g as single dose for C trachomatis infection $25.80/1 g packet $25.80/1 g packet
Cefaclor (Ceclor) 20–30 mg/kg $3.90/0.5 g $11.70
Cefditoren (Spectracef) 400 mg twice daily $2.10/200 mg $8.40
Cefpodoxime proxetil (Vantin) 400 mg $6.60/0.2 g $13.20
Cefprozil (0.5 g) (Cefzil) 15 mg/kg $8.90/0.5 g $17.80
Cefuroxime (0.5 g) (Ceftin) 0.5 g twice daily $8.00/0.5 g $16.00
Cephalexin (0.5 g) (Keflex, others) 30 mg/kg $1.40/0.5 g $5.60
Ciprofloxacin (0.5 g) (Cipro) 0.5–0.75 g twice daily $5.20/0.5 g $10.40
Ciprofloxacin (0.75 g) (Cipro)   $5.40/0.75 g $10.80
Clarithromycin (0.25 or 0.5 g) (Biaxin) 250–500 mg twice daily $4.80/0.5 g $9.60
Clindamycin (0.3 g) (Cleocin, others) 15 mg/kg $1.20/150 mg $9.60
Doxycycline (0.1 g) 3 mg/kg $1.35/0.1 g $2.70
Erythromycin (0.5 g) 30 mg/kg $0.30/0.5 g $0.90
Famciclovir (0.5 g) (Famvir) 500 mg three times daily $9.40/0.5 g $28.20
Fluconazole (0.1 g) 0.1–0.2 g daily $8.30/0.1 g $8.30
Fluconazole (0.2 g) (Diflucan)   $13.60/0.2 g $13.60
Flucytosine (0.5 g) (Ancobon) 150 mg/kg $9.70/0.5 g $194.00
Gatifloxacin (0.4 g) (Tequin) 400 mg $10.20/0.4 g $10.20
Gemifloxacin (.32 g) (Factiv) 320 mg $18.65/320 mg $18.65
Itraconazole (0.1 g) (Sporanox) 200–400 mg $9.90/0.1 g $19.80–39.60
Ketoconazole (0.2 g) (Nizoral) 0.2–0.4 g $3.20/0.2 g $3.20–6.40
Levofloxacin (0.5 g) (Levaquin) 0.5 g daily $11.80/0.5 g $11.80
Loracarbef (0.4 mg) (Lorabid) 800 mg $6.40/0.4 g $12.80
Metronidazole (0.5 g) (Flagyl) 20 mg/kg $0.70/0.5 g $2.10
Moxifloxacin (0.4 g) (Avelox) 400 mg $11.20/0.4 g $11.20
Ofloxacin (0.4 g) (Floxin) 400 mg twice daily $6.80/0.4 g $13.60
Penicillin VK (0.5 g) 30 mg/kg $0.40/0.5 g $1.60
Telithromycin (Ketec) 800 mg $5.80/400 mg $11.60
Tetracycline (0.5 g) 30 mg/kg $0.10/0.5 g $0.40
Trimethoprim-sulfamethoxazole (Bactrim, Septra) 5 mg/kg TMP $1.20/160 mg TMP and 800 mg SMZ $2.40
Valacyclovir (0.5 g) (Valtrex) 0.5–1 g three times daily $5.50/0.5 g $15.50–29.70
Valganciclovir 450 mg (Valcyte) 0.9 g twice daily $31.70/450 mg $126.80
Vancomycin (Vancocin) 125 mg three times daily $9.20/125 mg $27.60
Voriconazole (VFend) 200 mg twice daily $35.40/200 mg $70.80
1Doses based on a 70-kg individual with normal renal function.
2Approximate average wholesale price to pharmacist (for AB-rated generic when available) for quantity listed.
Source: Red Book Update, Vol. 25, No. 5, May 2006. Average wholesale price may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
3Daily cost for intravenous antibiotics includes acquisition cost only and not preparation and administration costs.

1. Natural Penicillins

The natural penicillins include penicillin G for parenteral administration (aqueous crystalline, procaine, and benzathine penicillin G) or for oral administration (penicillin G and phenoxymethyl penicillin [penicillin V]). They are most active against gram-positive organisms and are susceptible to hydrolysis by β-lactamases. They are used (1) for infections caused by susceptible and moderately susceptible pneumococci, depending on the site of infection (however, up to 30–35% of strains now demonstrate intermediate- or high-level resistance to penicillin); (2) streptococci (including anaerobic streptococci); (3) meningococci; (4) non-β-lactamase-producing

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staphylococci; (5) Treponema pallidum and other spirochetes; (6) Propionibacterium acnes and other gram-positive rods; (7) non-difficile clostridia; (8) actinomyces; and (9) most gram-positive anaerobes. See Table 37-1.

Pharmacokinetics & Administration

After parenteral administration, penicillin has wide extracellular distribution. Lower levels are present in the eye, prostate, and central nervous system. However, with inflammation of the meninges and with appropriate dosing, adequate penetration into the cerebrospinal fluid takes place.

Special dosage forms of penicillin permit delayed absorption to yield low blood and tissue levels for long periods, eg, benzathine penicillin G and procaine penicillin G.

Phenoxymethyl penicillin (penicillin V) is the oral penicillin of choice because of its superior bioavailability. Primarily renally eliminated, 90% is cleared by tubular secretion.

Clinical Uses

Most infections due to susceptible organisms respond to aqueous penicillin G in daily doses of 1–2 million units administered intravenously every 4–6 hours. For life-threatening infections (meningitis, endocarditis), larger daily doses (18–24 million units intravenously) are required.

Penicillin V is indicated in minor infections such as streptococcal pharyngitis and cellulitis. Syphilis is usually treated with weekly injections of benzathine penicillin, 2.4 million units intramuscularly for 1–3 weeks, depending on the stage of the disease (see Table 37-3).

Procaine penicillin is rarely used except as an alternative regimen for neurosyphilis.

2. Extended-Spectrum Penicillins

The extended-spectrum group of penicillins includes the aminopenicillins: ampicillin and amoxicillin, the carboxypenicillin ticarcillin, and the ureidopenicillin piperacillin. These drugs are all susceptible to destruction by staphylococcal (and other) β-lactamases. While this group of penicillins is more active against certain gram-negative rods, they have approximately the same activity as natural penicillins against gram-positive bacteria.

Antimicrobial Activity

Ampicillin and amoxicillin are active against most strains of Proteus mirabilis, Listeria organisms, and non-β-lactamase-producing strains of Haemophilus influenzae but are inactive against most gram-negative pathogens. Both drugs are effective against penicillin-susceptible pneumococcus and Enterococcus faecalis.

Ticarcillin extends the activity of ampicillin to include many strains of Pseudomonas, but it has poor activity against most strains of Klebsiella and enterococci and is less active than ampicillin against pneumococci.

Piperacillin is more active than ticarcillin against Pseudomonas aeruginosa and Klebsiella. Similar to ampicillin, piperacillin is active against E faecalis and is superior

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to ticarcillin against pneumococci. The extended-spectrum penicillins inhibit many but not all anaerobes. Ampicillin and amoxicillin are not active against β-lactamase-producing strains of Bacteroides fragilis—in contrast to piperacillin, which is active against most (not all) isolates.

Pharmacokinetics & Administration

Ampicillin can be given orally or parenterally. Amoxicillin is preferable to ampicillin in the oral treatment of infection because of its improved oral bioavailability and less frequent dosage frequency.

Ticarcillin and piperacillin are given intravenously and increased doses (200–300 mg/kg/d) are required for treatment of infections due to P aeruginosa.

Dosage adjustments are required in renal failure and are summarized in Table 37-4.

Clinical Uses

Amoxicillin is given orally for minor infections, such as exacerbations of chronic bronchitis, sinusitis, or otitis. Ampicillin is administered intravenously for pneumonia, meningitis, bacteremia, or endocarditis.

Amoxicillin is also used as prophylaxis for endocarditis. Because of the increased serum and respiratory secretion levels, this agent is valuable in the treatment of susceptible and moderately penicillin-susceptible pneumococcus. In general, if amoxicillin levels remain above the MIC of the pneumococcus for more than 40% of the dosing interval (which can be achieved with a dose of 40 mg/kg/d in adults), bacteriologic cure rates are optimal. Although ticarcillin and piperacillin can be used as monotherapy, they are more commonly administered in combination with other agents.

3. Penicillins Combined with β-Lactamase Inhibitors

The addition of β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) prevents inactivation of the parent penicillin by bacterial β-lactamases. Products available are Augmentin (amoxicillin, 250 mg, 500 mg, or 875 mg, plus 125 mg of clavulanic acid); Augmentin XR (amoxicillin 1 g plus 62.5 mg of clavulanic acid); Timentin (ticarcillin 3 g plus 100 mg of clavulanic acid); Unasyn (ampicillin 1 g plus sulbactam 0.5 g, and ampicillin 3 g plus sulbactam 1 g); and Zosyn (piperacillin 3 g plus tazobactam 0.375 g, and piperacillin 4 g plus tazobactam 0.5 g). Augmentin is given orally and the others intravenously. In general, the β-lactamase inhibitors effectively inactivate β-lactamases produced by S aureus, H influenzae, Moraxella catarrhalis, and B fragilis. In contrast, the β-lactamase inhibitors are variably and unpredictably effective against β-lactamases produced by certain aerobic gram-negative bacilli, such as Enterobacter. Of the available parenteral drugs, Zosyn has the broadest spectrum of activity. Like Unasyn (in contrast to Timentin), Zosyn is active against ampicillin-susceptible enterococci. It has greater in vitro activity against P aeruginosa than Timentin and is more active than either Timentin or Unasyn against Serratia and Klebsiella species. While these agents are sometimes active in vitro, they generally should not be used in the treatment of extended-spectrum β-lactamase (ESBL)-producing organisms.

Augmentin, because of its high cost and gastrointestinal intolerance, is limited to the treatment of refractory cases of sinusitis and otitis and prophylaxis of infections resulting from animal and human bites. The roles of Timentin, Unasyn, and Zosyn include the treatment of polymicrobial infections such as peritonitis from a ruptured viscus, osteomyelitis in a diabetic patient, or traumatic osteomyelitis.

The dosage regimens of these drugs are the same as those of the parent drugs. When Timentin or Zosyn is used to treat Pseudomonas infections, dosages of 200–300 mg/kg/d of the penicillin component are used. Nonpseudomonal infection can be treated with lower doses (100–200 mg/kg/d).

4. Penicillinase-Resistant Penicillins

Oxacillin, cloxacillin, dicloxacillin, and nafcillin are relatively resistant to destruction by β-lactamases produced by staphylococci. They are less active than natural penicillins against nonstaphylococcal gram-positives; however, they are still adequate in certain streptococcal infections, including those due to group A streptococci in skin and soft tissue infections.

The primary route of clearance of the above agents is nonrenal—thus, no dosage adjustment is needed in renal insufficiency.

5. Adverse Effects of Penicillins

Allergy

All penicillins are cross-sensitizing and cross-reacting. The responsible antigenic determinants appear to be degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis (minor antigenic determinants) bound to host protein. Skin tests with penicilloyl-polylysine, with minor antigenic determinants, and with undegraded penicillin can identify most individuals with IgE-mediated reactions (hives, bronchospasm). Among positive reactors to skin tests, the incidence of subsequent immediate severe penicillin reactions is high. Although many persons develop IgG antibodies to antigenic determinants of penicillin, the presence of such antibodies is not correlated with allergic reactivity (except for rare instances of hemolytic anemia), and serologic tests have little predictive value. A history of a penicillin reaction in the past is not reliable. Only 15–20% of patients with a history of penicillin allergy have an adverse reaction when challenged with the drug. The decision to administer penicillin or related drugs (other β-lactams)

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to patients with an allergic history depends on the severity of the reported reaction, the severity of the infection being treated, and the availability of alternative drugs. For patients with a history of severe reaction (anaphylaxis), alternative drugs should be used. In the rare situations when there is a strong indication for using penicillin (eg, syphilis in pregnancy) in allergic patients, desensitization can be performed. If the reaction is mild (nonurticarial rash), the patient may be rechallenged with penicillin or may be given another β-lactam antibiotic. (See Chapter 30 for discussion of penicillin allergy and methods of desensitization.)

Allergic reactions include anaphylaxis, serum sickness (urticaria, fever, joint swelling, angioneurotic edema 7–12 days after exposure), skin rashes, fever, interstitial nephritis, eosinophilia, hemolytic anemia, other hematologic disturbances, and vasculitis. The incidence of hypersensitivity to penicillin is estimated to be 1–5% among adults in the United States. Life-threatening anaphylactic reactions are very rare (0.05%). Ampicillin produces maculopapular skin rashes more frequently than other penicillins, but many ampicillin (and other β-lactam) rashes are not allergic in origin. The nonallergic ampicillin rash usually occurs after 3–4 days of therapy, is maculopapular, is more common in patients with coexisting viral illness (especially Epstein-Barr infection), and resolves with continued therapy. The maculopapular rash may or may not reappear with rechallenge. Rarely, penicillins can induce nephritis with primary tubular lesions associated with anti-basement membrane antibodies.

Toxicity

All penicillins in excessive doses, particularly in renal insufficiency, have been associated with seizures.

Of the oral penicillins, Augmentin is most commonly associated with diarrhea. Nafcillin administered at high doses is associated with a modest leukopenia. Oxacillin may cause a higher incidence of liver and skin toxicity than other agents in this class. High doses of penicillins, particularly ticarcillin or piperacillin, inhibit platelet aggregation and produce hypokalemia due to binding of potassium in the kidney.

Peterson LR: Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter? Clin Infect Dis 2006;42:224.

Robinson JL et al: Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic. Clin Infect Dis 2002;35:26.

Samaha-Kfoury JN et al: Recent developments in beta lactamases and extended spectrum beta lactamases. BMJ 2003;327:1209.

Cephalosporins (Tables 37-6 and 37-7)

The cephalosporins, structurally related to the penicillins, consist of a β-lactam ring attached to a dihydrothiazoline ring. Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial activities.

Table 37-6. Major groups of cephalosporins.

First Generation Second Generation Third Generation Fourth Generation
Cephalothin Cefamandole Cefotaxime Cefepime
Cephapirin Cefuroxime Ceftizoxime
Cefazolin Cefonicid Ceftriaxone
Cephalexin1 Ceforanide Ceftazidime
Cephradine1 Cefaclor1 Cefoperazone
Cefadroxil Cefoxitin Cefpodoxime proxetil1
Cefotetan
Cefprozil1 Ceftibuten1
Cefuroxime axetil1 Cefdinir1
Cefditoren pivoxil1
1Oral agents.

The mechanism of action of cephalosporins is analogous to that of the penicillins: (1) binding to specific penicillin-binding proteins, (2) inhibition of cell wall synthesis, and (3) activation of autolytic enzymes in the cell wall. Resistance to cephalosporins may be due to poor permeability of the drug into bacteria, lack of penicillin-binding proteins, or degradation by β-lactamases.

Cephalosporins have been divided into four major groups or “generations” (Table 37-6) based mainly on their antibacterial activity: First-generation cephalosporins have good activity against aerobic gram-positive organisms and some community-acquired gram-negative organisms (P mirabilis, Escherichia coli, Klebsiella species); second-generation drugs have a slightly extended spectrum against gram-negative bacteria, and some are active against gram-negative anaerobes; and third-generation cephalosporins are active against many gram-negative bacteria. Not all cephalosporins fit neatly into this grouping, and there are exceptions to the general characterization of the drugs in the individual classes; however, the generational classification of cephalosporins is useful for discussion purposes. Cefepime is considered a fourth-generation agent because it is more stable against plasmid-mediated β-lactamase and has little or no β-lactamase-inducing capacity. Cefepime compares favorably with ceftazidime with respect to its gram-negative activity; however, its stability versus plasmid-mediated β-lactamase results in improved coverage against Enterobacter and Citrobacter species. The gram-positive coverage of cefepime approaches that of cefotaxime or ceftriaxone. None of the currently available agents are active against the enterococcus.

Table 37-7. Pharmacology of the cephalosporins.

Drug Peak Serum Level (mcg/mL) after 1 g IV Serum Half-Life (min) Total Daily Dose (mg/kg) Dosage Interval (hrs) Dosage Adjustments in Renal Failure
Moderate (Clcr 10–50 mL/min) Severe (Clcr < 10 mL/min) Post-Hemodialysis Dose
Cephapirin 40–60 40 50–200 4–6 1–2 g q6–12h 1 g q12h 1 g
Cefazolin 90–120 90 25–100 8 0.5–1 g q6–12h 0.5 g daily 0.5 g
Cephalexin, cephradine1 15–20 50–60 15–30 6 0.25–0.5 g q8–12h 0.25–0.5 g daily 0.5 g
Cefadroxil1 15 75 15–30 12–24 1 g daily 0.5 g daily 0.5 g
Cefamandole 60–80 45 75–200 6–8 1 g q12h 1–2 g daily 0.5 g
Cefditoren pivoxil 2–3 90 6 12 0.2 g q12h 0.2 g q12h None
Cefepime 60–70 120 50–75 8–12 1 g q12h 1 g q24h 1 g
Ceftibuten1 20 120 9 12–24 0.4 g daily 0.1–0.2 g daily 0.7 g
Cefuroxime 80–100 80 50 6–12 1 g q12h 1–2 g daily 0.5 g
Cefuroxime axetil1 6–8 75 5–15 12 0.5 g q24h 0.25 g daily 0.25 g
Cefonicid 200–250 240 15–30 24 0.5 g daily 1 g q72h 0.25 g
Ceforanide 125 180 15–30 12 1 g daily 1 g q48h 0.25 g
Cefaclor1 15–20 50 10–15 6–8 0.5 g q8–12h 0.25–0.5 g q12–24h 0.25–0.5 g
Cefpodoxime proxetil1 2 150 5 12 0.2 g q24h 0.2 g 3 times/wk after dialysis 0.2 g
Cefprozil1 10 90 10–15 12 0.5 g q12–24h 0.25–0.5 g q12–24h 0.5 g
Cefotetan 60–80 150 50–100 8–12 1 g q8–12h 0.5–1 g daily 0.5 g
Cefotaxime 40–60 60 50–75 6–8 1–2 g q6–8h 1–2 g q24h 1–2 g
Cefoxitin 60–80 60 50–100 6–8 1 g q12h 1–2 g daily 0.5 g
Ceftizoxime 80–100 100 50–75 8–12 0.5–1 g q8–12h 0.25–0.5 g q12–24h 0.5 g
Ceftriaxone 150 480 30–50 12–24 1–2 g daily 1–2 g daily None
Ceftazidime 100–120 120 50–75 8–12 1 g q12h 0.5–1 g daily 0.5 g
Cefoperazone 150 120 30–200 8–12 1–2 g q12h 1–2 g q12h None
Loracarbef1 10 60 10–15 12 0.2 g q24h 0.2 g 3 times/wk after dialysis 0.2 g
1Oral agents. Serum levels based on 0.5 g oral dose.

1. First-Generation Cephalosporins

Antimicrobial Activity

These drugs are very active against gram-positive cocci, including penicillin-susceptible pneumococci,

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viridans streptococci, group A hemolytic streptococci, and S aureus. As with all cephalosporins, they are inactive against enterococci and methicillin-resistant staphylococci. Activity against H influenzae is poor, and penicillin-resistant streptococci (both intermediately and highly resistant) are resistant to first-generation cephalosporins. Among gram-negative bacteria, E coli, Klebsiella pneumoniae, and P mirabilis are usually susceptible except for some hospital-acquired strains. Anaerobic gram-positive cocci are usually susceptible, but B fragilis is not.

Pharmacokinetics & Administration

A. Oral

Cephalexin, cephradine, and cefadroxil are variably absorbed. Cefadroxil, because of its longer half-life, can be given twice daily instead of four times daily.

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B. Intravenous

Cefazolin is preferred because its longer half-life allows for less frequent dosing. In renal insufficiency, it requires dosage adjustment.

C. Intramuscular

Cefazolin can be given intramuscularly; however, the intravenous route is preferred because of the every 8-hour dosing schedule.

Clinical Uses

Oral drugs are sometimes used for treatment of urinary tract infections, and they can be used for minor staphylococcal infections (eg, cellulitis, soft tissue abscess).

Intravenous first-generation cephalosporins are the drugs of choice for surgical prophylaxis, particularly for clean procedures. Second- and third-generation cephalosporins offer no advantage over first-generation agents except where anaerobes play an important role, such as for colorectal surgery or for hysterectomy.

First-generation cephalosporins do not adequately penetrate into cerebrospinal fluid and cannot be used to treat meningitis.

2. Second-Generation Cephalosporins

Second-generation cephalosporins are a heterogeneous group with marked individual differences in activity, pharmacokinetics, and toxicity. In general, they are active against gram-negative organisms inhibited by first-generation drugs, but they have an extended gram-negative coverage. Indole-positive Proteus and Klebsiella (including first-generation cephalosporin-resistant strains) as well as M catarrhalis and Neisseria species are usually sensitive. Cefuroxime is active against H influenzae, including β-lactamase-producing strains, but has little activity against Serratia and B fragilis. In contrast, cefoxitin and cefotetan are active against many strains of B fragilis and some strains of Serratia. Against gram-positive organisms, these drugs are generally less active than the first-generation cephalosporins (cefuroxime is an exception). Second-generation agents have no activity against P aeruginosa. Of note, the manufacturer has abandoned the marketing of cefotetan; thus, this agent is unlikely to be available.

Pharmacokinetics & Administration

A. Oral

Only cefaclor, cefuroxime axetil, and cefprozil can be given orally. Cefuroxime axetil is deesterified to cefuroxime after absorption. Its longer half-life permits twice-daily dosing, and absorption is enhanced when it is taken with food (as is not the case with many other oral antibiotics).

B. Intravenous and Intramuscular

Because of differences in drug half-life and protein binding, peak serum levels achieved and dosing intervals vary greatly for this group of drugs (Table 37-7). Drugs with shorter half-lives (cefoxitin) require higher doses and more frequent dosing than drugs with longer half-lives (eg, cefuroxime). Dosage adjustment is required with renal impairment.

Clinical Uses

Because of their activity against β-lactamase-producing H influenzae and M catarrhalis, cefprozil and cefuroxime axetil can occasionally be used to treat sinusitis and otitis media in patients unresponsive to more established agents.

Because of their activity against B fragilis, cefoxitin and cefotetan can be used to treat mixed anaerobic infections, eg, peritonitis and diverticulitis. However, since many B fragilis and enteric gram-negative organisms are resistant to these drugs, alternative agents are preferred for life-threatening intra-abdominal infections. Cefoxitin and cefotetan (if and when available) are useful as prophylaxis in colorectal surgery, vaginal or abdominal hysterectomy, and appendectomy because of their activity against B fragilis.

3. Third- & Fourth-Generation Cephalosporins

Antimicrobial Activity

Most of these drugs are active against staphylococci (not methicillin-resistant strains) but less so than first-generation cephalosporins. Ceftazidime, however, has notably weak activity against S aureus and pneumococci. While inactive against enterococci, third- and fourth-generation cephalosporins inhibit most streptococci. Ceftriaxone and cefotaxime offer the most reliable antipneumococcal coverage. A major advantage of these cephalosporins is their expanded gram-negative coverage. In addition to organisms inhibited by other cephalosporins, they are consistently active against Serratia marcescens, Providencia, Haemophilus, and Neisseria, including β-lactamase-producing strains. Ceftazidime is unique among all third-generation agents because it is active against P aeruginosa. Acinetobacter, Citrobacter, Enterobacter. Nonaeruginosa strains of Pseudomonas are variably sensitive to third-generation cephalosporins, and Listeria is uniformly resistant. Activity against B fragilis is variable. In contrast to the third-generation agents, cefepime—the only currently available fourth-generation cephalosporin—is active against Enterobacter and Citrobacter, has activity comparable to that of ceftazidime against P aeruginosa, and has gram-positive activity similar to that of ceftriaxone.

Cefpodoxime proxetil, cefdinir, cefditoren pivoxil, cefixime and ceftibuten, the only oral agents in this group, are more active than cefuroxime axetil but are not as active as parenteral third-generation cephalosporins against gram-negative organisms such as Pseudomonas, Enterobacter, Morganella, and S marcescens. While temporarily discontinued, cefixime is once again available

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as a suspension. All third- and fourth-generation cephalosporins are active against Streptococcus pyogenes (group A streptococcus). Cefpodoxime proxetil, cefditoren pivoxil, and cefdinir are active against methicillin-sensitive S aureus, whereas ceftibuten has little activity (none are active against methicillin-resistant strains). Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are active against penicillin-sensitive strains of Streptococcus pneumoniae (the pneumococcus), but ceftibuten has marginal activity. None of the oral cephalosporins are reliable against intermediately susceptible or penicillin-resistant S pneumoniae. Like other members of this class, these drugs are ineffective against enterococci and Listeria monocytogenes.

Pharmacokinetics & Administration

The intravenous agents distribute into extracellular fluid and reach levels in the cerebrospinal fluid that exceed those needed to inhibit susceptible pathogens. The half-lives of these drugs are variable, which accounts for the differences in dosing intervals (Table 37-7). Ceftriaxone is eliminated primarily by biliary excretion, and no dosage adjustment is required in renal insufficiency. The other drugs are eliminated primarily by the kidney and thus require dosage adjustment in renal insufficiency.

Clinical Uses

Because of their penetration into the cerebrospinal fluid and potent in vitro activity, intravenous third-generation cephalosporins can be used to treat meningitis due to susceptible pneumococci, meningococci, H influenzae, and susceptible enteric gram-negative rods. In meningitis in older patients, third-generation cephalosporins should be combined with ampicillin or trimethoprim-sulfamethoxazole until L monocytogenes has been excluded as the etiologic pathogen. Ceftazidime has been used to treat meningitis due to Pseudomonas. The dosage for meningitis should be at the upper limits of the recommended range, because cerebrospinal fluid levels of these drugs are only 10–20% of serum levels. Ceftazidime or cefepime is frequently administered empirically in the febrile neutropenic patient. Ceftriaxone is indicated for gonorrhea, chancroid, and more serious forms of Lyme disease (see Chapter 34). Because of its long half-life and once-daily dosing requirement, ceftriaxone is an attractive option for the outpatient parenteral therapy of infections due to susceptible organisms.

Cefepime is useful for third-generation cephalosporin-resistant isolates such as Enterobacter and Citrobacter.

Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are the best third-generation oral agents against pneumococci and S aureus. Single-dose cefixime or cefpodoxime proxetil is probably as effective as ceftriaxone for the therapy of genital, rectal, and pharyngeal gonorrhea.

4. Adverse Effects of Cephalosporins

Allergy

Cephalosporins are sensitizing, and a variety of hypersensitivity reactions occur, including anaphylaxis, fever, skin rashes, nephritis, and hemolytic anemia. The frequency of IgE cross-allergy between cephalosporins and penicillins approximates 5–10%. Persons with a history of anaphylaxis to penicillins should not receive cephalosporins. Allergies to a given agent may or may not extend to the entire cephalosporin class.

Toxicity

Ceftriaxone has been associated with a dose-dependent biliary sludging syndrome and cholelithiasis due to precipitation of drug when its solubility in bile is exceeded. Long-term administration of 2 g/d or more is a risk factor for this complication.

Casey JR et al: Meta-analysis of cephalosporins versus penicillin treatment of group A streptococcal tonsillopharyngitis in adults. Clin Infect Dis 2004;38:1526.

Chapman TM et al: Cefepime: a review of its use in the management of hospitalized patients with pneumonia. Am J Respir Med 2003;2:75.

Romano A et al: Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann Intern Med 2004;141:16.

Other β-Lactam Drugs

Monobactams

These are drugs with a monocyclic β-lactam ring that are resistant to many β-lactamases and active against gram-negative organisms (including Pseudomonas) but have no activity against gram-positive organisms or anaerobes. Aztreonam resembles ceftazidime in its gram-negative activity. Clinical uses of aztreonam are limited because of the availability of third-generation cephalosporins with a broader spectrum of activity and minimal toxicity. Despite the structural similarity of aztreonam to penicillin, cross-reactivity is limited, and it can therefore be used in most patients with IgE-mediated penicillin allergy.

Carbapenems

This class of drugs is structurally related to β-lactam antibiotics. Imipenem, the first drug of this type, has a wide spectrum of activity that includes most gram-negative rods (including P aeruginosa) and gram-positive organisms and anaerobes, with the exception of Burkholderia cepacia, Stenotrophomonas maltophilia, Enterococcus faecium, and methicillin-resistant S aureus and Staphylococcus epidermidis. The half-life of imipenem is 1 hour. Dosage adjustment is required in renal insufficiency.

Meropenem is similar to imipenem in spectrum of activity and pharmacology. It is less likely to cause seizures

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than imipenem, although the risk of seizures is low with imipenem if dosage is appropriately adjusted for renal insufficiency. Meropenem is associated with less nausea and vomiting than imipenem, a feature of importance when high doses must be used, as in the treatment of Pseudomonas infection in patients with cystic fibrosis. The usual dose is 1–2 g intravenously every 8 hours. Dosage adjustment in renal insufficiency is required.

Ertapenem is similar to imipenem and meropenem in its activity against aerobic gram-positive and anaerobic organisms but is less active against Pseudomonas and Acinetobacter. Because of its long half-life (4 hours), it can be administered once daily. The usual dose is 1 g intravenously every 24 hours and adjustments are needed for renal insufficiency.

The carbapenems should not be routinely used as first-line therapy unless the pathogen is multidrug-resistant and is known to be susceptible to these agents. In patients hospitalized for a prolonged period with presumed infection with a multidrug-resistant organism, empiric use of carbapenems is reasonable. (Ertapenem should not be used if Pseudomonas and Enterobacter are common nosocomial pathogens.) Pseudomonas may rapidly develop resistance to carbapenems. The use of imipenem or meropenem alone appears to be as effective as combination therapy in the febrile neutropenic patient, and the carbapenems are as effective as combination therapy in certain polymicrobial infections such as peritonitis and pelvic infections.

The most common adverse effects of imipenem and meropenem are nausea, vomiting, diarrhea, reactions at the infusion site, and skin rashes. Seizures are more commonly observed with imipenem. Patients allergic to penicillins may be allergic to imipenem and meropenem as well.

Edwards SJ et al: Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infection. Curr Med Res Opin 2005;21:785.

Lipsky BA et al: Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet 2005;366:1695.

Erythromycin Group (Macrolides)

The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring to which various sugars are attached.

Antimicrobial Activity

Erythromycins inhibit protein synthesis by binding to the 50S subunit of bacterial ribosomes. They generally are bacteriostatic and sometimes bactericidal for gram-positive organisms, including most streptococci and corynebacteria. Similar to penicillin, the rate of macrolide-resistant S pneumoniae has increased (15–50%), and recent reports demonstrate increased resistance in group A streptococci in some centers. Erythromycin-resistant pneumococci are azalide-resistant as well (azithromycin, clarithromycin). Chlamydia, Mycoplasma, Legionella, and Campylobacter organisms are susceptible.

Pharmacokinetics & Administration

Preparations for oral use include erythromycin base, erythromycin stearate, estolate, and ethyl succinate. Erythromycins are excreted primarily nonrenally; no adjustment is therefore required in renal failure.

Erythromycin and azithromycin are available for intravenous use, particularly in the treatment of Legionnaires' disease.

Clinical Uses

Macrolides are effective in the treatment of infection due to Legionella, Mycoplasma, Ureaplasma, Corynebacterium (including diphtheria), and Chlamydia (including ocular and respiratory infections) organisms. They are useful adjuncts in the treatment of streptococcal and pneumococcal disease in penicillin-allergic patients. Oral erythromycin base is used with neomycin as prophylaxis for colonic surgery. When administered early, erythromycin may shorten the course of Campylobacter enteritis. Erythromycins are effective against certain Bartonella species (bacillary angiomatosis) and Rhodococcus species. In vitro data suggest that macrolides have a direct effect on neutrophil function and the production of cytokines associated with inflammation. Thus, these agents are being evaluated for their anti-inflammatory effects in infectious diseases as well. The most well-documented anti-inflammatory benefit associated with the macrolides is in the prevention of cystic fibrosis exacerbation. Earlier studies suggested that macrolides reduced the incidence of cardiac events in patients with coronary artery disease. A potential link between chlamydia infection and coronary disease was identified, and it was hypothesized that the benefit of macrolides was due to the antichlamydial activity of these agents. However, more recent studies have not demonstrated this benefit.

Adverse Effects

Nausea, vomiting, and diarrhea may occur after oral or intravenous intake. Erythromycins—particularly the estolate—can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Hepatitis recurs if the drug is readministered. Reversible auditory impairment occurs with large erythromycin doses (4 g/d or more), particularly in patients with impaired renal or hepatic function. However, ototoxicity has been reported with high doses of all agents. Intravenous erythromycin has been associated with prolongation of the QT interval and torsades de pointes—more commonly in women. Erythromycins (and clarithromycin) can increase the effects of oral anticoagulants, digoxin, theophylline, and cyclosporine by inhibiting cytochrome P450. An increased risk of cardiac-associated

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death has been reported with erythromycin, particularly in patients receiving concomitant inhibitors of cytochrome P450 3A4.

Azalides (azithromycin, clarithromycin, and others) are closely related structurally to the macrolides. They are similar to erythromycin in activity against most organisms and are slightly more active in vitro than erythromycin against H influenzae (azithromycin > clarithromycin > erythromycin). They are also active against Chlamydia trachomatis, Ureaplasma urealyticum, and Haemophilus ducreyi. In addition, these drugs have in vitro activity against a number of unusual pathogens, including atypical mycobacteria (Mycobacterium avium-intracellulare, Mycobacterium chelonei, Mycobacterium fortuitum, Mycobacterium marinum), Toxoplasma gondii, Campylobacter jejuni, Helicobacter pylori, and Borrelia burgdorferi.

The azalides are more acid-stable than erythromycin, concentrate intracellularly and in tissues, and have a long terminal half-life, with high tissue concentrations that persist for days with azithromycin. The elevated tissue levels associated with azithromycin and clarithromycin has been proposed to overcome the high incidence of in vitro resistance seen with pneumococci (30%), but clinical observations suggest that the reported resistance can translate to clinical failure. Azithromycin and clarithromycin are approved for treatment of streptococcal pharyngitis, uncomplicated skin infections, and acute bacterial exacerbations of chronic bronchitis. Because of the long half-life, outpatient oral treatment with azithromycin is with once-daily dosing for a total of 5 days (500 mg on day 1 and then 250 mg on days 2–5). Clarithromycin is usually administered in a dosage of 250–500 mg orally twice daily, although an extended-release formulation that is given as a single daily 1000-mg dose is approved for acute sinusitis and acute exacerbation of chronic bronchitis. The azalides are more expensive than erythromycin. However, the less frequent dosing and better tolerability make them preferable choices in certain patients.

Azithromycin has also been approved as single-dose therapy (1 g) for chlamydial genital infections. While more expensive than 7 days of treatment with doxycycline (Table 37-5), the assurance of adequate supervised therapy makes azithromycin preferred therapy in many patients. Azithromycin can also be used as single-dose therapy (1 g) for chancroid, and a single dose of 1 g is as efficacious as 7 days of doxycycline for nongonococcal urethritis in men and incubating syphilis. While a 2-g dose of azithromycin is used for the treatment of gonorrhea, its efficacy is less than that observed with ceftriaxone. Furthermore, the incidence of upper gastrointestinal side effects is increased with this dose. A single dose of azithromycin (20 mg/kg, maximum dose of 1 g) is effective in treating trachoma and reducing disease burden in endemic areas. The spectrum of activity of the macrolides—particularly their atypical coverage—results in their usefulness in mild to moderate cases of community-acquired pneumonia; however, penicillin-resistant strains are often resistant to these agents as well. Weekly 1200-mg doses of azithromycin are effective in preventing Mycobacterium avium complex infections in HIV-positive patients, and doses of 500 mg daily may be effective in M avium complex pulmonary infections in non-HIV-positive patients. Azithromycin may be considered for therapy of dysentery caused by multidrug-resistant Shigella organisms. Used as prophylaxis, azithromycin (500 mg weekly) is as effective as benzathine penicillin in preventing upper respiratory tract infections in military recruits, and at a dose of 250 mg daily it is adequate as prophylaxis for malaria (although inferior to doxycycline for multidrug-resistant Plasmodium falciparum). Clarithromycin has been used for the therapy of M avium complex infections, usually in combination with other drugs (eg, rifabutin and ethambutol), and can be given daily (500 mg twice daily) or three times weekly (1000 mg) as intermittent therapy. Oral clarithromycin (500 mg twice daily for 6 months), in combination with other agents, is effective therapy for disseminated M chelonei infections. Clarithromycin has also been used in combination regimens for the therapy of H pylori infections. When clarithromycin is given with omeprazole and amoxicillin, cure rates in excess of 80–90% have been achieved.

Adverse effects of these agents are similar to those of erythromycin, but upper gastrointestinal upset, the major side effect, occurs less often with the azalides. Hepatic enzyme elevations and reversible cochlear toxicity have been reported. Clarithromycin is similar to erythromycin in its effect on the cytochrome P450 system. Azithromycin is associated with minimal to no drug interactions.

Grayston JT et al; ACES Investigators: Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637.

Nuermberger E et al: The clinical significance of macrolide-resistant Streptococcus pneumoniae: it's all relative. Clin Infect Dis 2004;38:99.

Vanderkooi OG et al; Toronto Invasive Bacterial Disease Network: Predicting macrolide resistance in invasive pneumococcal infections. Clin Infect Dis 2005;40:1288.

Ketolides

Ketolides (such as telithromycin) are similar in structure to macrolides, but they have a broader spectrum of activity and may offer additional benefit in the treatment of community-acquired respiratory infections. They are active against both penicillin-resistant and macrolide-resistant pneumococci and equal to azithromycin therapeutically against atypical pathogens and H influenzae. Upper gastrointestinal adverse events are the complications most commonly associated with these drugs. Visual disturbances are moderately common, occurring more frequently in women. The dose is 800 mg/d orally, and no adjustment is needed for renal or hepatic insufficiency. Cytochrome P450 inhibition with telithromycin approximates that

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of erythromycin, and increased serum levels of warfarin and other agents would be expected with concomitant administration of telithromycin.

Telithromycin (Ketek) for respiratory infections. Med Lett Drugs Ther 2004;46:66.

Tetracycline Group

The tetracyclines are a large group of drugs with common basic chemical structures, antimicrobial activity, and pharmacologic properties.

Antimicrobial Activity

Tetracyclines are inhibitors of protein synthesis and are bacteriostatic for many gram-positive and gram-negative bacteria. They are strongly inhibitory for the growth of mycoplasmas, rickettsiae, chlamydiae, spirochetes, and some protozoa (eg, amebas). Their antipneumococcal activity approaches that of the macrolides; almost all H influenzae are inhibited. Tetracyclines also have moderate activity against some vancomycin-resistant enterococci. Doxycycline and minocycline are potential options for therapy of staphylococcal infections, including infections with many methicillin-resistant strains. There are marked in vitro differences between tetracyclines with respect to staphylococci. Tetracyclines are not useful in the treatment of gram-negative aerobic infection.

Pharmacokinetics & Administration

Oral bioavailability varies depending on the drug. Absorption is impaired by dairy products, aluminum hydroxide gels (antacids), and chelation with divalent cations, eg, Ca2+ or Fe2+. Chelation is less problematic with doxycycline and minocycline when compared with tetracycline. Consequently, doses of tetracyclines should be staggered at least 2 hours before or after receipt of multivalent cations. Oral bioavailability is moderate with tetracycline and highest with doxycycline and minocycline (95% or more). Lipid solubility of minocycline and doxycycline accounts for their penetration into the cerebrospinal fluid, prostate, tears, and saliva.

Tetracyclines are primarily metabolized in the liver and excreted in bile. Doxycycline requires no dosage adjustment in renal failure; in contrast, other tetracyclines should be avoided or given in reduced dosage.

For patients unable to take oral medication, some tetracyclines (doxycycline, minocycline) are formulated for parenteral administration in doses similar to the oral ones.

Clinical Uses

Tetracyclines are drugs of choice for infections with Chlamydia, Mycoplasma, Rickettsia, Ehrlichia, and Vibrio organisms and for some spirochetal infections. Sexually transmitted diseases in which chlamydiae often play a role—endocervicitis, urethritis, proctitis, and epididymitis—should be treated with doxycycline for 7–14 days. Pelvic inflammatory disease is often treated with doxycycline plus cefoxitin or cefotetan. Other chlamydial infections (psittacosis, lymphogranuloma venereum, trachoma) and sexually transmitted diseases (granuloma inguinale) also respond to doxycycline. Other uses include treatment of acne, respiratory infections, Lyme disease and relapsing fever, brucellosis, glanders, tularemia (often in combination with streptomycin), cholera, mycoplasmal pneumonia, actinomycosis, nocardiosis, malaria, infections caused by M marinum and Pasteurella species (typically after an animal bite), and as malaria prophylaxis (including multidrug-resistant P falciparum). They also have been used in combination with other drugs for amebiasis, falciparum malaria, and recurrent ulcers due to H pylori. Because of generally good activity against pneumococci; H influenzae; and Chlamydia, Legionella, and Mycoplasma organisms, doxycycline should be considered as a potential empiric therapy for mild to moderate outpatient pneumonia.

Minocycline is equally as efficacious as doxycycline for the therapy of nongonococcal urethritis and cervicitis.

Adverse Effects

A. Allergy

Hypersensitivity reactions with fever or skin rashes are uncommon.

B. Gastrointestinal Side Effects

Diarrhea, nausea, and anorexia are common. Tetracycline administration, particularly doxycycline, should be avoided at bedtime due to the risk of esophageal erosion.

C. Bones and Teeth

Tetracyclines are bound to calcium deposited in growing bones and teeth, causing fluorescence, discoloration, enamel dysplasia, deformity, or growth inhibition. Therefore, tetracyclines should not be given to pregnant women or children under 6 years of age.

D. Liver Damage

Tetracyclines can impair hepatic function or even cause liver necrosis, particularly during pregnancy or in the presence of preexisting liver disease.

E. Kidney Effects

Demeclocycline can cause nephrogenic diabetes insipidus and has been used therapeutically to treat inappropriate antidiuretic hormone secretion. Tetracyclines, particularly tetracycline, may increase blood urea nitrogen (BUN) due to their antianabolic activity.

F. Other

Tetracyclines—principally demeclocycline—may induce photosensitization, especially in fair-skinned individuals. Minocycline induces vestibular reactions

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(dizziness, vertigo, nausea, vomiting), with a frequency of 35–70% after doses of 200 mg daily and has also been implicated as a cause of hypersensitivity pneumonitis.

Glycylcyclines

Tigecycline, a tetracycline derivative, is available as a parenteral antibacterial for the treatment of nosocomial infection. It is active against most gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. It is active against a number of multidrug resistant aerobic gram-negative bacilli, including Acinetobacter, Enterobacter, and Citrobacter. However, tigecycline has little to no activity against Pseudomonas and Proteus spp. In addition, tigecycline demonstrates excellent anaerobic activity against B fragilis and gram-positive anaerobes. A loading dose of 100 mg is administered intravenously with maintenance at 50 mg every 12 hours. The drug distributes into deep compartments with a large volume of distribution and low serum levels; tigecycline is primarily eliminated via biliary/fecal excretion with a half-life of 30–40 hours. Dose adjustment to 25 mg every 12 hours is recommended in Child-Turcotte-Pugh C liver disease. Tigecycline has similar adverse events as the tetracyclines; upper gastrointestinal side effects are common. While approved for complicated skin and soft-tissue infection and intra-abdominal infection, tigecycline likely will have a role in the treatment of certain resistant gram-negative pathogens.

Frampton JE et al: Tigecycline. Drugs 2005;65:2623.

Jones RN et al: Doxycycline use for community-acquired pneumonia: contemporary in vitro spectrum of activity against Streptococcus pneumoniae (1999–2002). Diagn Microbiol Infect Dis 2004;49:147.

Stein GE: Safety of newer parenteral antibiotics. Clin Infect Dis 2005;41(Suppl 5):S293.

Chloramphenicol

Antimicrobial Activity

Chloramphenicol is active against certain rickettsiae. It binds to the 50S subunit of ribosomes and inhibits protein synthesis. While active against S pneumoniae, H influenzae, and Neisseria meningitidis, it is used minimally because of its toxicity and the availability of alternative agents.

Pharmacokinetics & Administration

Chloramphenicol is widely distributed in tissues, including the eye and cerebrospinal fluid. Chloramphenicol is metabolized in the liver, and less than 10% is excreted unchanged in the urine. Thus, no dosage adjustment is needed in renal insufficiency. Patients with liver disease may accumulate the drug, and levels should be monitored.

Clinical Uses

Chloramphenicol is an occasional alternative to more standard therapy for (1) meningococcal, H influenzae, or pneumococcal infections of the central nervous system; (2) anaerobic or mixed infections in the central nervous system, eg, brain abscess; (3) as an alternative to tetracyclines in rickettsial infections, especially in pregnant women, in whom tetracycline is contraindicated.

Adverse Effects

Nausea, vomiting, and diarrhea are uncommon. The most serious adverse effects are hematologic. Chloramphenicol in excess of 50 mg/kg/d regularly causes reversible disturbances in red cell maturation within 1–2 weeks. In contrast, aplastic anemia is an irreversible consequence of chloramphenicol administration and represents a specific, probably genetically determined individual defect. It occurs in 1:40,000–1:25,000 courses of chloramphenicol treatment.

Aminoglycosides

Aminoglycosides are a group of bactericidal drugs sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. At present, the group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, paromomycin, and spectinomycin. All these agents inhibit protein synthesis in bacteria by inhibiting the function of the 30S subunit of the bacterial ribosome. Resistance is based on (1) a deficiency of the ribosomal receptor (chromosomal mutant); (2) the enzymatic destruction of the drug (plasmid-mediated transmissible resistance of clinical importance) by acetylation, phosphorylation, or adenylylation; or (3) a lack of permeability to the drug molecule or failure of active transport across cell membranes. Resistance can be chromosomal (eg, streptococci are relatively impermeable to aminoglycosides) or plasmid-mediated (eg, in gram-negative enteric bacteria.) Anaerobic bacteria are resistant to aminoglycosides because transport across the cell membrane is an oxygen-dependent energy-requiring process.

All aminoglycosides are more active at alkaline than at acid pH. All are potentially ototoxic (cochlear and vestibular) and nephrotoxic, although to different degrees. All can accumulate in renal insufficiency; therefore, dosage adjustments must be made in patients with renal dysfunction (see Table 37-8).

Table 37-8. Dosing of aminoglycosides.1

Drug (IV) Creatinine Clearance (mL/min)
> 80 60–80 40–60 20–40 < 20
Gentamicin, tobramycin, netilmicin 5 mg/kg q24h 1.5–2.5 mg/kg q12h 1.2–1.5 mg/kg q24h 1.2–1.5 mg/kg q12–24h 2 mg/kg as loading dose and then 1–1.5 mg/kg q24–48h
Amikacin 15 mg/kg q24h 4.5–7.5 mg/kg q12h 3.5–4.5 mg/kg q12h 3.5–4.5 mg/kg q12–24h 7.5 mg/kg as loading dose and then 3–4.5 mg/kg q24–48h
1Traditional dosing should be guided by serum level measurements (peaks 30 minutes after the end of intravenous infusion and troughs ≤ 30 minutes before the next dose). When a single large daily dose is given, peak levels are not required. Trough levels should be undetectable with high-dose (5 mg/kg) once-daily gentamicin or amikacin. For those patients with creatinine clearances less than 80 mL/min, the dosage ranges in the table are used to treat gram-negative infections and are intended to achieve, for gentamicin, tobramycin, and netilmicin, peak levels of 6–10 mg/L and trough levels of ≤ 2 mg/L; for amikacin, peak levels of 20–30 mg/L and trough levels of ≤ 5 mg/L. (See text.)

Because of their considerable toxicity and the availability of less toxic agents, (eg, cephalosporins, quinolones, carbapenems, β-lactamase inhibitor combinations), aminoglycosides have been used less often in recent years. They are most commonly used to treat resistant gram-negative organisms that are sensitive only to aminoglycosides, or in low doses in combination with β-lactam drugs or vancomycin for their synergistic effect (eg, enterococci, penicillin-resistant viridans streptococci, right-sided S aureus endocarditis,

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S aureus and S epidermidis prosthetic valve infection). Although aminoglycosides demonstrate in vitro activity against many gram-positive bacteria, they should never be used alone to treat infections caused by these organisms—both because there is minimal clinical experience with such infections and because less toxic alternatives are available. Aminoglycosides are inferior as monotherapy in the treatment of Pseudomonas infections.

General Properties of Aminoglycosides

Because of the similarities of the aminoglycosides, a summary of properties is presented briefly.

A. Absorption, Distribution, Metabolism, and Excretion

Aminoglycosides are not absorbed from the gastrointestinal tract. They diffuse poorly into the eye, prostate, bile, central nervous system, and spinal fluid after parenteral injection.

The serum half-life is 2–3 hours in patients with normal renal function. Excretion is almost entirely by glomerular filtration. Aminoglycosides are removed effectively by hemodialysis or continuous hemofiltration.

B. Dosage and Effect of Impaired Renal Function

In persons with normal renal function who have gram-negative infections, the dosage of amikacin is 15 mg/kg/d in a single daily dose; that for gentamicin, tobramycin, or netilmicin is 5 mg/kg injected once daily. A single large daily dose of gentamicin, tobramycin, netilmicin, or amikacin is as efficacious as—and no more nephrotoxic than—traditional dosing every 8–12 hours. When a single large daily dose is given, peak levels are not required. Trough aminoglycoside levels should be undetectable in patients with normal body composition and renal function receiving once-daily dosing. Some clinicians recommend serum level monitoring 12–18 hours after the dose and extending the interval to every 48–72 hours for patients with elevated aminoglycoside levels. Others have suggested maintaining the dosage interval but decreasing the dose. Patients with renal failure, volume overload, or obesity have altered antibiotic clearance or volume of distribution. In patients with abnormal renal function or body composition, once-daily dosing is not recommended and aminoglycoside levels are recommended to guide dosing. For more traditional dosing, peak levels greater than 6 mcg/mL are desirable in the treatment of serious gram-negative infection, including pneumonia. Trough levels of more than 2 mcg/mL have been associated with an increased incidence of nephrotoxicity. In patients with normal body composition, once-daily dosing regimens as set forth in Table 37-8 should be followed. Reduced gentamicin doses (1 mg/kg every 8 hours) are recommended when used synergistically with β-lactams or vancomycin in the treatment of serious gram-positive infection (eg, enterococcal endocarditis).

C. Adverse Effects

All aminoglycosides can cause ototoxicity and nephrotoxicity. Ototoxicity can be irreversible and is cumulative, presenting as hearing loss (cochlear damage), noted first with high-frequency tones, or as vestibular damage, manifested by vertigo and ataxia. Amikacin appears to be more cochlear-toxic than gentamicin, tobramycin, or netilmicin. Nephrotoxicity, which is more common than ototoxicity, is accompanied by rising serum creatinine levels or reduced creatinine clearance. Nephrotoxicity is usually reversible and occurs with similar frequency with gentamicin, tobramycin, amikacin, and netilmicin.

In very high doses, usually associated with irrigation of an inflamed peritoneum, aminoglycosides can be neurotoxic, producing a curare-like effect with reversible neuromuscular blockade that results in respiratory paralysis.

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1. Streptomycin

The usual dosage of streptomycin is 15–25 mg/kg/d (about 1 g/d) injected in one or two divided doses intramuscularly. If administered over 30–60 minutes, it can also be given intravenously. Streptomycin exhibits all the adverse effects typically associated with the aminoglycosides; however, it has greater vestibular toxicity and probably less nephrotoxicity when compared with gentamicin.

Resistance emerges so rapidly and has become so widespread that only a few specific indications for this drug remain: plague and tularemia; endocarditis caused by E faecalis or viridans streptococci (use in conjunction with penicillin or vancomycin) in strains that are susceptible to high levels of streptomycin (ie, ≤ 2000 mcg/mL)—gentamicin may be substituted for streptomycin in this setting; active tuberculosis when other less toxic drugs cannot be used; and acute brucellosis (in combination with tetracycline).

2. Neomycin, Kanamycin, & Paromomycin

These aminoglycosides are closely related, with similar activity and complete cross-resistance. Systemic use has been abandoned because of ototoxicity and nephrotoxicity.

Ointments containing neomycin, often combined with bacitracin and polymyxin, can be applied to infected superficial skin lesions. While the drug mixture covers most staphylococci, streptococci, and gram-negative bacteria likely to be present, the efficacy of topical application is questionable.

In preparation for elective bowel surgery, 1 g of neomycin is given orally every 6–8 hours for 1–2 days (combined with erythromycin, 1 g) to reduce aerobic bowel flora. Activity against gram-negative anaerobes is negligible. In hepatic encephalopathy, the coliform bacteria can be suppressed for prolonged periods by oral neomycin, 1 g every 6–8 hours, during reduced protein intake, resulting in diminished ammonia production. Lactulose is more widely used for this indication.

Neomycin or kanamycin can give rise to allergic reactions when applied topically to skin or eye.

Paromomycin, closely related to neomycin and kanamycin, is poorly absorbed after oral administration and has been used mainly to treat asymptomatic intestinal amebiasis and in doses of 25–30 mg/kg/d in three divided doses for 7 days to treat giardiasis in pregnancy. A dosage of 500 mg orally three or four times daily is marginally effective for cryptosporidiosis in AIDS.

3. Amikacin

Amikacin is a semisynthetic derivative of kanamycin. It is relatively resistant to several of the enzymes that inactivate gentamicin and tobramycin. Many gram-negative enteric bacteria—including many gentamicin-resistant strains of Proteus, Enterobacter, and Serratia organisms—are inhibited. After injection of 500 mg of amikacin every 12 hours (15 mg/kg/d), peak levels in serum are 10–30 mcg/mL. In addition to therapy for serious gram-negative infections, amikacin is sometimes included with other drugs for therapy of M avium complex and M fortuitum complex.

Like all aminoglycosides, amikacin is nephrotoxic and ototoxic (particularly for the auditory portion of the eighth nerve). Its levels should be monitored in patients with renal failure.

4. Gentamicin

With doses of 5 mg/kg/d of this aminoglycoside, serum levels are sufficient for bactericidal effect against most gram-negative organisms. Enterococci are resistant unless a penicillin or vancomycin is also given. Gentamicin may be synergistic with penicillins active against Pseudomonas, Proteus, Enterobacter, and Klebsiella organisms as well as other gram-negatives.

Indications, Dosages, & Routes of Administration

Gentamicin is used in serious infections caused by gram-negative bacteria. The usual dosage is 5 mg/kg/d intravenously administered once daily. In endocarditis due to viridans streptococci or E faecalis, gentamicin in lower synergistic doses (3 mg/kg/d) is combined with penicillin or ampicillin. A single daily dose of 3 mg/kg is just as effective as divided daily doses in the synergistic treatment of endocarditis due to viridans streptococci. In renal insufficiency, the dose should be adjusted as noted above.

5. Tobramycin

Tobramycin closely resembles gentamicin in antibacterial activity, toxicity, and pharmacologic properties and exhibits partial cross-resistance. It may be effective against some gentamicin-resistant pseudomonads but is not used synergistically with penicillin for enterococcal endocarditis. Dosing is the same as for gentamicin. Tobramycin is also given by aerosol (300 mg twice daily) to patients with cystic fibrosis and improves pulmonary function and decreases colonization with Pseudomonas without toxicity and without selecting for resistant strains.

Netilmicin shares many characteristics with gentamicin and tobramycin and can be given in a similar dosage. It may be less ototoxic and less nephrotoxic than the other aminoglycosides.

6. Spectinomycin

Spectinomycin is an aminocyclitol antibiotic (related to aminoglycosides) for intramuscular administration. Its sole application is in the treatment of uncomplicated urogenital and anorectal gonorrhea in persons who are hypersensitive to penicillin and who cannot

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tolerate fluoroquinolones. It is not effective for pharyngeal gonorrhea.

Bliziotis IA et al: Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials. Clin Infect Dis 2005;41:149.

Polymyxins

The polymyxins (colistin and polymixin B) are basic polypeptides that are bactericidal for certain gram-negative aerobic rods, including Pseudomonas. Because of poor distribution into tissues and substantial toxicity (primarily nephrotoxicity and neurotoxicity), systemic use of these agents is limited to infections caused by multidrug-resistant gram-negative organisms that are sensitive only to the polymyxins. Colistin has been used with increasing frequency in the treatment of pan-resistant Acinetobacter baumanii and P aeruginosa. The more recent experience suggests colistin to be associated with less nephrotoxicity and neurotoxicity than previously described. Dosage adjustments are required with renal insufficiency.

Murray CK et al: Treatment of multidrug resistant Acinetobacter. Curr Opin Infect Dis 2005;18:502.

Antituberculous Drugs

Singular problems exist in the treatment of tuberculosis and other mycobacterial infections. The organisms are intracellular, have long periods of metabolic inactivity, and tend to develop resistance to any one drug. Therefore, combined drug therapy is used to delay the emergence of this resistance. First-line drugs, increasingly used together in all tuberculosis, are isoniazid, ethambutol, rifampin, and pyrazinamide.

See Chapter 9 for a discussion of these medications.

Alternative Drugs in Tuberculosis Treatment

The drugs listed alphabetically below are usually considered only in cases of drug resistance (clinical or laboratory) to first-line drugs.

Capreomycin is an injectable agent given intramuscularly in doses of 15–30 mg/kg/d (maximal dose 1 g). Major toxicities include ototoxicity (both vestibular and cochlear) and nephrotoxicity. If the drug must be used in older patients, the dose should not exceed 750 mg.

Clofazimine is a phenazine dye used in the treatment of leprosy and is active in vitro against M avium complex and Mycobacterium tuberculosis. It is given orally as a single daily dose of 100 mg for treatment of M avium complex disease. Its clinical efficacy for the therapy of tuberculosis has not been established. Adverse effects include nausea, vomiting, abdominal pain, and skin discoloration.

Cycloserine, a bacteriostatic agent, is given in doses of 15–20 mg/kg (not to exceed 1 g) orally and has been used in re-treatment regimens and for primary therapy of highly resistant M tuberculosis. It can induce a variety of central nervous system dysfunctions and psychotic reactions.

Ethionamide, like cycloserine, is bacteriostatic and is given orally in a dose of 15–20 mg/kg (maximal dose 1 g). It has been used in combination therapy but is poorly tolerated with marked gastric irritation.

The fluoroquinolones ofloxacin, levofloxacin, ciprofloxacin, and moxifloxacin are active in vitro against M tuberculosis, with MICs of 0.25–2 mcg/mL. These drugs have been demonstrated to be efficacious in treating tuberculosis in patients unable to take isoniazid, rifampin, and pyrazinamide; however, rapid emergence of resistance recently has been described. Doses include ciprofloxacin, 750 mg orally twice daily; ofloxacin, 400 mg orally twice daily; levofloxacin, 750 mg orally once daily.

Jasmer RM et al: Clinical practice. Latent tuberculosis infection. N Engl J Med 2002;347:1860.

Rifamycins

Rifaximin, a derivative of rifamycin, is nonabsorbable, reaches very high levels in the stool, and has a broad spectrum of antibacterial activity, including aerobic and anaerobic gram-positive and gram-negative organisms. It is approved for use in nonpregnant women and for persons aged 12 years and older to treat noninvasive traveler's diarrhea (200 mg three times daily for 3 days) and should not be used if fever or bloody diarrhea is present. Other potential uses include prophylaxis of traveler's diarrhea (200 mg/d) and therapy of hepatic encephalopathy (400 mg twice daily). It is well tolerated and safe. Concerns for inducing cross-resistance to rifampin and rifabutin will require post-marketing surveillance.

Adachi JA et al: Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clinical Infect Dis 2006;42:541.

Sulfonamides & Antifolate Drugs

Antimicrobial Activity

Sulfonamides are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. Organisms that utilize PABA in the synthesis of folates and pyrimidines are inhibited. Animal cells and some resistant microorganisms (eg, enterococci) use exogenous folate and thus are not affected by sulfonamides.

Trimethoprim, pyrimethamine, and trimetrexate are compounds that inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid by blocking the enzyme dihydrofolate reductase. These agents are generally used in combination with other drugs (usually sulfonamides)

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to prevent or treat a number of bacterial and parasitic infections. At high doses, all can inhibit mammalian dihydrofolate reductase, but clinically this is a problem only with pyrimethamine and trimetrexate. Folinic acid (leucovorin) is given concurrently with pyrimethamine and trimetrexate to prevent bone marrow suppression.

Sulfonamides alone are rarely used in the treatment of bacterial infection. When used in combination with other drugs, sulfonamides are useful in the treatment of toxoplasmosis and pneumocystosis.

The combination of trimethoprim (one part) plus sulfamethoxazole (five parts) is bactericidal for such gram-negative organisms as E coli, Klebsiella, Enterobacter, Salmonella, and Shigella, though substantial resistance has emerged. It is also active against many strains of Serratia, Providencia, S maltophilia, B cepacia (formerly Pseudomonas cepacia), and Burkholderia pseudomallei, but not against P aeruginosa. It is inactive against anaerobes and enterococci but inhibits most Nocardia and S aureus and about 50% S epidermidis. M catarrhalis, H influenzae, H ducreyi, L monocytogenes, and some atypical mycobacteria are also inhibited by this combination.

Pharmacokinetics & Administration

Trimethoprim-sulfamethoxazole is well absorbed from the gastrointestinal tract and widely distributed in tissues and fluids, including cerebrospinal fluid. For patients who are unable to take oral drugs, intravenous trimethoprim-sulfamethoxazole is available. Dosage adjustment is required for significant renal impairment (creatine clearance ≤ 50 mL/min).

Clinical Uses

Present indications for sulfonamides are outlined below.

A. Urinary Tract Infections

Coliform bacteria, the most common cause of urinary tract infections, are moderately inhibited by sulfonamides, though widespread resistance of E coli has emerged. Short-course therapy (3 days) with oral double-strength trimethoprim-sulfamethoxazole (160 mg trimethoprim + 800 mg sulfamethoxazole) given twice daily is effective therapy for lower urinary tract infections in women who are symptomatic for less than 1 week. Since trimethoprim is concentrated in the prostate, trimethoprim-sulfamethoxazole, one double-strength tablet twice daily for 14–21 days, is effective in acute prostatitis. In chronic prostatitis, treatment for 6–12 weeks is indicated. Considering the above resistance trend, the routine use of trimethoprim-sulfamethoxazole for empiric therapy of urinary tract infections has been questioned. In those areas where resistance of E coli is greater than 10–20%, alternative agents should be used as empiric therapy.

B. Parasitic Infections

Trimethoprim-sulfamethoxazole is effective for prophylaxis and treatment of Pneumocystis pneumonia, Cyclospora infection, and Isospora belli infection. For therapy of Pneumocystis pneumonia, 15–20 mg/kg/d of trimethoprim and 75–100 mg/kg/d of sulfamethoxazole in three or four divided doses is administered intravenously or orally—depending on the severity of disease—for 3 weeks. The dose for prophylaxis is 160 mg trimethoprim + 800 mg sulfamethoxazole daily or three times per week. (When given daily, it is also effective prophylaxis against toxoplasmal encephalitis.) I belli infection in AIDS has been successfully treated with 160 mg trimethoprim + 800 mg sulfamethoxazole orally four times daily for 10 days followed by twice-daily administration for 3 weeks. Cyclosporiasis is successfully treated with 160 mg trimethoprim and 800 mg sulfamethoxazole twice daily for 7–10 days. Sulfadiazine with pyrimethamine is also used to treat and prevent recurrence of toxoplasmosis.

C. Other Bacterial Infections

Sulfonamides are the drugs of choice for Nocardia infections. Trimethoprim-sulfamethoxazole is widely distributed in tissues, penetrates into the cerebrospinal fluid, and has been used to treat meningitis caused by gram-negative rods, though third-generation cephalosporins are now preferred. While it is occasionally used for outpatient respiratory tract infections, the increasing pattern of resistance associated with S pneumoniae has decreased its utility.

Trimethoprim-sulfamethoxazole is effective also for infections with Enterobacter, B pseudomallei (melioidosis), S maltophilia, or B cepacia; in combination with rifampin, for eradication of nasopharyngeal carriage of staphylococci; for prophylaxis against meningococcal disease when susceptible strains predominate; for antibacterial prophylaxis in organ transplant recipients or patients with chronic granulomatous disease; for treatment of L monocytogenes meningitis; and perhaps also for management of pulmonary Wegener's granulomatosis.

D. Leprosy

Certain sulfones are widely used (see below).

Adverse Effects

Adverse reactions to sulfonamides occur in 10–15% of non-AIDS patients (usually a minor rash or gastrointestinal disturbance) and in up to 50% of patients with AIDS (predominantly rash, fever, neutropenia, and thrombocytopenia, often severe enough to require discontinuation of therapy). These drugs have many side effects—due partly to hypersensitivity, partly to direct toxicity—that must be considered whenever unexplained symptoms or signs occur in a patient who may have received these drugs.

A. Systemic Side Effects

Fever, skin rashes, urticaria; nausea, vomiting, or diarrhea; stomatitis, conjunctivitis, arthritis, aseptic meningitis, exfoliative dermatitis; bone marrow depression,

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thrombocytopenia, hemolytic (in G6PD deficiency) or aplastic anemia, granulocytopenia, leukemoid reactions; hepatitis, polyarteritis nodosa, vasculitis, Stevens-Johnson syndrome; reversible hyperkalemia; and many others have been reported. Because of the risk of Stevens-Johnson syndrome, patients with a previous rash after trimethoprim-sulfamethoxazole should not receive the drug again. Patients reporting an allergic reaction to sulfonamides have an increased risk of allergy to penicillin.

HIV-positive patients intolerant to trimethoprim-sulfamethoxazole can often be desensitized. A 70% success rate has been reported after giving 0.004 mg trimethoprim/0.02 mg sulfamethoxazole as oral suspension and increasing the dose tenfold each hour to achieve a final dose of 160 mg trimethoprim/500 mg sulfamethoxazole.

B. Urinary Tract Disturbances

Older sulfonamides were relatively insoluble and would precipitate in urine. The most commonly used sulfonamides presently (sulfamethoxazole) are quite soluble, and the old admonition to force fluids is no longer warranted. Sulfonamides have been implicated in interstitial nephritis. Patients with toxoplasmosis receiving high-dose sulfadiazine therapy are predisposed to crystalluria.

Sulfones used in the Treatment of Leprosy

A number of drugs closely related to the sulfonamides (eg, dapsone) have been used effectively in the long-term treatment of leprosy. The clinical manifestations of both lepromatous and tuberculoid leprosy can often be suppressed by treatment extending over several years. At least 5–30% of Mycobacterium leprae organisms are resistant to dapsone, so initial combined treatment with rifampin is advocated. Dapsone, 100 mg daily, is effective therapy for mild to moderate Pneumocystis pneumonia in AIDS when combined with trimethoprim, 15–20 mg/kg/d in four divided doses. At a dose of 50–100 mg daily or 100 mg two or three times a week, it is effective prophylaxis for Pneumocystis jiroveci (formerly Pneumocystis carinii) infection and, when combined with pyrimethamine, 50 mg per week, also prevents Toxoplasma encephalitis in HIV-infected patients.

Absorption, Metabolism, & Excretion

All sulfones are well absorbed from the intestinal tract, are distributed widely in all tissues, and tend to be retained in skin, muscle, liver, and kidney. Leprous skin contains ten times more drug than normal skin. Sulfones are excreted into the bile and reabsorbed by the intestine, prolonging therapeutic blood levels. Excretion into the urine is variable, and the drug occurs in urine mostly as a glucuronic acid conjugate. Some persons acetylate sulfones slowly and others rapidly, potentially requiring dosage adjustment.

Dosages & Routes of Administration

See the section on Leprosy in Chapter 33 for recommendations.

Adverse Effects

The sulfones may cause any of the side effects listed above for sulfonamides. Anorexia, nausea, and vomiting are common. Hemolysis, methemoglobinemia, or agranulocytosis may occur. G6PD levels should be determined prior to initiation of dapsone therapy. If sulfones are not tolerated, clofazimine can be substituted.

Specialized Drugs used Against Bacteria

1. Bacitracin

This polypeptide is selectively active against gram-positive bacteria. Because of severe nephrotoxicity upon systemic administration, its use has been limited to topical application on surface lesions, usually in combination with polymyxin or neomycin.

2. Mupirocin

Mupirocin (formerly pseudomonic acid) is a naturally occurring antibiotic produced by Pseudomonas fluorescens active against most gram-positive cocci, including methicillin-sensitive and methicillin-resistant S aureus and most streptococci (but not enterococci). Used topically, it is effective in eliminating staphylococcal nasal carriage in the majority of patients for up to 3 months after application to the anterior nares twice daily for 5 days. However, recurrent colonization occurs (50% at the end of 1 year), and when mupirocin is used long-term over months, resistant organisms can emerge. Monthly application for 5 days each month for up to a year decreases staphylococcal colonization, which in turn lowers the risk of recurrent staphylococcal skin infections. Recent studies demonstrate an associated reduction in postoperative staphylococcal lung infections in colonized patients treated with mupirocin. Whether it is more effective than trimethoprim-sulfamethoxazole or dicloxacillin plus rifampin for eradication of staphylococcal nasal carriage is unknown. The other major use of mupirocin is for therapy of impetigo; it is useful in mild disease.

3. Clindamycin

Clindamycin is active against gram-positive organisms including S pneumoniae, viridans streptococci, group A streptococci, and S aureus, though resistance has been described in all of these organisms. Pneumococci with an efflux-based mechanism of resistance can be effectively treated with clindamycin. However, isolates with ribosomal methylase resistance (about 10% of isolates) are also resistant to clindamycin. Enterococci, most methicillin-resistant S aureus, and

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most S epidermidis also are resistant. A dosage of 0.15–0.3 g orally every 6 hours generally is used. It is widely distributed in tissues but not in cerebrospinal fluid. Excretion is primarily nonrenal. Clindamycin is currently recommended as an alternative drug for prophylaxis against endocarditis following oral procedures in patients allergic to amoxicillin. Clindamycin, 300 mg orally twice daily for 7 days, can be used as an alternative to metronidazole for the therapy of bacterial vaginosis. Topical application of a 2% vaginal cream once or twice daily for 7 days is also effective. Clindamycin is active against most anaerobes, including Bacteroides, Prevotella, Clostridium, Peptococcus, Peptostreptococcus, and Fusobacterium organisms. However, up to 25% of Bacteroides isolates are resistant, and alternative agents should be considered for life-threatening anaerobic infections due to these organisms. It is frequently used to treat less severe infections in which anaerobes are significant pathogens (eg, aspiration pneumonia, pelvic and abdominal infections), often in combination with other drugs (aminoglycosides, cephalosporins, fluoroquinolones). Seriously ill patients are given clindamycin, 600–900 mg (20–30 mg/kg/d) intravenously every 8 hours. It has also been of use in staphylococcal osteomyelitis. Because tissue models document that clindamycin significantly decreases toxin production, the addition of clindamycin to penicillin for therapy of group A streptococcus toxic shock syndrome has been suggested. In the sulfonamide-allergic patient, high-dose clindamycin therapy (600–1200 mg intravenously every 6 hours or 600 mg orally every 6 hours) in conjunction with pyrimethamine has been used to treat toxoplasmosis of the central nervous system and appears to be as effective as pyrimethamine and sulfadiazine. Clindamycin in combination with primaquine is effective in Pneumocystis pneumonia, and clindamycin with quinine is of value for falciparum malaria. While useful in brain abscess, clindamycin is ineffective in meningitis.

Common side effects are diarrhea, nausea, and skin rashes. Antibiotic-associated colitis has been associated with the administration of clindamycin and other antibiotics and is due to a necrotizing toxin produced by Clostridium difficile. The organism is resistant to the antimicrobial, is selected out by its presence, and is favored in its growth and toxin production. C difficile is usually susceptible to—and can be treated with—metronidazole or vancomycin given orally, though metronidazole is the drug of choice (see below).

4. Metronidazole

Metronidazole is an antiprotozoal drug (see Chapter 35) that also has striking antibacterial effects against most anaerobic gram-negative bacilli (Bacteroides, Prevotella, Fusobacterium) and Clostridium species but has minimal activity against many anaerobic gram-positive and microaerophilic organisms. It is well absorbed after oral administration and is widely distributed in tissues. It penetrates well into the cerebrospinal fluid, yielding levels similar to those in serum. The drug is metabolized in the liver, and dosage reduction is required in severe hepatic insufficiency or biliary dysfunction.

Metronidazole is used to treat amebiasis and giardiasis (see Chapter 35) and in the following circumstances:

  • Vaginitis caused by Trichomonas vaginalis responds to either a single dose (2 g) or to 250 mg orally three times daily for 7–10 days. Bacterial vaginosis responds to a single 2-g dose or to 500 mg twice daily for 7 days. Metronidazole vaginal cream (0.75%) applied twice daily for 5 days is also effective.

  • In anaerobic infections, metronidazole can be given orally or intravenously, 500 mg three times daily (30 mg/kg/d). It is more predictable against B fragilis than clindamycin or second-generation cephalosporins.

  • Metronidazole is less expensive and equally as efficacious as oral vancomycin for the therapy of C difficile colitis and is the drug of choice for the disease. A dosage of 500 mg orally three times daily is recommended. If oral medication cannot be tolerated, intravenous metronidazole can be tried at the same dose; however, this route is unproved and usually less effective than the oral one. Because of the emergence of vancomycin-resistant enterococci as a major pathogen and the role of oral vancomycin in selecting for these resistant organisms, metronidazole should be used as first-line therapy for C difficile disease.

  • Preparation of the colon before bowel surgery.

  • Therapy of brain abscess, often in combination with penicillin or a third-generation cephalosporin.

  • In combination with clarithromycin and omeprazole for therapy of H pylori infections.

Adverse effects include stomatitis, nausea, and diarrhea. Ingestion of alcohol while taking metronidazole occasionally results in a disulfiram reaction. With prolonged use at high doses, reversible peripheral neuropathy can develop. Metronidazole can decrease the metabolism of warfarin, necessitating dosage adjustment of warfarin. Metronidazole is carcinogenic in certain animal models and mutagenic for certain bacteria, but to date an increased incidence of malignancy has not been confirmed in humans.

Fihn SD: Acute uncomplicated urinary tract infection in women. N Engl J Med 2003;349:259.

Masters PA et al: Trimethoprim-sulfamethoxazole revisited. Arch Intern Med 2003;163:402.

Raz R et al: Empiric use of trimethoprim-sulfamethoxazole (TMP-SMX) in the treatment of women with uncomplicated urinary tract infections, in a geographic area with a high prevalence of TMP-SMX-resistant uropathogens. Clin Infect Dis 2002;34:1165.

Strom BL et al: Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628.

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5. Vancomycin

This drug is bactericidal for most gram-positive organisms, particularly staphylococci and streptococci, and is bacteriostatic for most enterococci. While active against staphylococci, vancomycin kills more slowly when compared with nafcillin. Although vancomycin has retained activity against staphylococci and streptococci, vancomycin-resistant strains of enterococci (particularly E faecium) have emerged. S aureus both intermediately sensitive and highly vancomycin-resistant has been observed in patients receiving long-term vancomycin therapy. Vancomycin is not absorbed from the gastrointestinal tract. It is given orally only for the treatment of antibiotic-associated enterocolitis. For systemic effect, the drug must be administered intravenously (20–30 mg/kg/d in two or three divided doses). Vancomycin is excreted mainly via the kidneys. In renal insufficiency, the half-life may be up to 8 days. Vancomycin is cleared via high-flux hemodialysis and continuous arteriovenous hemofiltration (CAVH) generally resulting in the need for increased dosing. In patients with impaired renal function, the dosing interval is determined by measuring trough serum levels. When trough serum levels decline to 10–15 mcg/mL, repeat dosing is required.

Indications for parenteral vancomycin include the following: (1) Severe staphylococcal infections in penicillin-allergic patients; for methicillin-resistant S aureus and S epidermidis infections and for serious infections (pneumonia, meningitis) due to highly resistant S pneumoniae. (2) Severe enterococcal infections in the penicillin-allergic patient or if the enterococcus is penicillin-resistant. (3) Other gram-positive infections in penicillin-allergic patients, eg, viridans streptococcal endocarditis. (4) Surgical prophylaxis in penicillin-allergic patients. (5) For gram-positive infections due to organisms that are multidrug-resistant, ie, Corynebacterium jeikeium. (6) Endocarditis prophylaxis in the penicillin-allergic patient undergoing certain genitourinary and gastrointestinal procedures (in combination with an aminoglycoside). (See Table 33-3.)

In antibiotic-associated enterocolitis, vancomycin, 0.125 g, is given orally four times daily.

Vancomycin is irritating to tissues; thrombophlebitis sometimes follows intravenous injection. The drug is infrequently ototoxic when given concomitantly with aminoglycosides or high-dose intravenous erythromycins; it is potentially nephrotoxic when administered with aminoglycosides. Rapid infusion or high doses (1 g or more) may induce diffuse hyperemia (“red man syndrome”) and can be avoided by extending infusions over 1–2 hours, by reducing the dose, or by pretreating with a histamine antagonist such as hydroxyzine.

Bal AM et al: Antibiotic resistance in Staphylococcus aureus and its relevance in therapy. Expert Opin Pharmacother 2005;6:2257.

Streptogramins

Streptogramins are structurally similar to macrolides but do not share cross-resistance with that class. Pristinamycin is an oral streptogramin marketed in France for treatment of gram-positive infections. Synercid is a combination of two synthetic derivatives of pristinamycin—quinupristin and dalfopristin—in a 30:70 ratio that is administered intravenously. It is bactericidal and inhibits protein synthesis by binding to bacterial ribosomes. In vitro, it has activity against M catarrhalis, H influenzae, Clostridium, Peptostreptococcus, Mycoplasma, Legionella, and Chlamydia. It has no activity against enteric gram-negative bacilli. However, its major clinical use is in the therapy of gram-positive infections, including those due to streptococci (including penicillin-resistant pneumococci) staphylococci (including methicillin-sensitive and methicillin-resistant S aureus and S epidermidis) and enterococci, including vancomycin-resistant E faecium. The combination is not reliably active against E faecalis. The drug is generally bacteriostatic against the enterococci. The recommended dose is 7.5 mg/kg/dose intravenously every 8 hours. In addition to phlebitis with peripheral administration, the major adverse effect is arthralgias and myalgias that resolve with discontinuation of the drug. It is primarily cleared via the liver; streptogramins inhibit the cytochrome P450 system, resulting in increased levels of cyclosporine and other agents.

Oxazolidinones

Oxazolidinones represent a class of antibacterials of which linezolid is the one available agent. Linezolid is primarily active against aerobic gram-positive pathogens, including penicillin-resistant pneumococci, methicillin-resistant staphylococci and enterococci (both E faecalis and vancomycin-sensitive and vancomycin-resistant E faecium). Linezolid is bacteriostatic against all of these pathogens. Linezolid-resistant and vancomycin-resistant enterococci and linezolid-resistant S aureus may be encountered, however. The oral bioavailability of linezolid is complete, with serum levels approaching those observed with intravenous administration. The drug is eliminated primarily by nonrenal mechanisms. The primary toxicity is bone marrow suppression with long-term therapy, particularly the platelet line. Other adverse effects include tongue discoloration and mild MAO inhibition. Studies suggest a more rapid response to therapy and reduction in length of hospitalization associated with linezolid when compared with vancomycin; however, these findings require confirmation by prospective controlled studies. Of particular concern are the increasing reports of linezolid-resistant enterococcus, which reinforce that this agent should be used judiciously.

Daptomycin

Daptomycin is a bactericidal lipopeptide with a spectrum of activity similar to that of linezolid or quinupristin-dalfopristin.

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This spectrum includes methicillin-resistant staphylococci and vancomycin-resistant enterococci. Daptomycin has poor oral bioavailability, thus is only available as a parenteral product. Its long pharmacologic half-life allows for once-daily dosing (4 mg/kg every 24 hours); dosage adjustment is necessary in the presence of renal failure. The primary adverse event associated with daptomycin is a reversible, dose-dependent myopathy observed with > 7 days of therapy. At the present time, daptomycin is only approved in the treatment of skin and soft tissue infection; however, the drug is being investigated at higher doses in the treatment of staphylococcal bacteremia and endocarditis. Daptomycin cannot be used in the treatment of respiratory tract infection. Pulmonary surfactant binds daptomycin, resulting in minimal free drug concentrations in pulmonary secretions.

Carpenter CF et al: Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathgogens. Clinical Infect Dis 2004;38:994.

Eliopoulos GM: Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis 2003;36:473.

Steenbergen JN et al: Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 2005;55:283.

Tedesco KL et al: Daptomycin. Pharmacotherapy 2004;24:41.

Weigelt J et al: Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005;49:2260.

Quinolones

The quinolones are synthetic analogs of nalidixic acid that have an exceedingly broad spectrum of activity against many bacteria. The mode of action of all quinolones involves inhibition of bacterial DNA synthesis by blocking the enzyme DNA gyrase.

The earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) did not achieve systemic antibacterial levels after oral intake and thus were useful only as urinary antiseptics. The newer fluorinated derivatives (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin) have more potent antibacterial activity, achieve clinically useful levels in blood and tissues, and have low toxicity.

Antimicrobial Activity

A number of fluoroquinolones are in use. Most have quite similar spectrums of activity. In general, these drugs have moderate to excellent activity against enterobacteriaceae but are also active against other gram-negative bacteria such as Haemophilus, Neisseria, Moraxella, Brucella, Legionella, Salmonella, Shigella, Campylobacter, Yersinia, Vibrio, and Aeromonas organisms. Resistance to E coli has significantly increased over the past decade, with some centers reporting up to 20–30% resistance. Ciprofloxacin and levofloxacin have slightly better activity against P aeruginosa than the other fluoroquinolones, but the increasing resistance of P aeruginosa to fluoroquinolones limits their usefulness in the treatment of infections caused by that organism. None of these agents have reliable activity against S maltophilia or B cepacia—though the newer drugs are more active against S maltophilia—as they are for treating genital tract pathogens such as Mycoplasma hominis, U urealyticum, and Chlamydia pneumoniae. M tuberculosis is sensitive to the quinolones, as is M fortuitum and Mycobacterium kansasii. Although most M avium complex organisms are resistant to fluoroquinolones, when combined with other antibiotics (ethambutol, rifabutin, and amikacin), fluoroquinolones may have a role.

In general, the fluoroquinolones are less potent against gram-positive than against gram-negative organisms. Gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have the best gram-positive activity, including against pneumococci and strains of S aureus and S epidermidis, including some methicillin-resistant strains. However, the emergence of resistant strains of staphylococci has limited the use of these drugs as monotherapy of infections caused by these organisms. Enterococci, including E faecalis, S pneumoniae, group A, B, and D streptococci, and viridans streptococci, are only moderately inhibited by the older quinolones. Anaerobic bacteria, T pallidum, and Nocardia are resistant to the earlier fluoroquinolones.

Moxifloxacin demonstrates activity against many of the significant anaerobic pathogens, including B fragilis and mouth anaerobes, and is approved for the treatment of intra-abdominal infection. However, increased rates of anaerobic resistance over time have been reported.

Pharmacokinetics & Administration

After oral administration, the fluoroquinolones are well absorbed and widely distributed in body fluids and tissues and are concentrated intracellularly. Fluoroquinolones bind some heavy metals; thus, absorption is inhibited when given with iron, calcium, and other multivalent cations. Optimal oral bioavailability is achieved if fluoroquinolones are taken 1 hour before or 2 hours after meals. The serum half-life ranges from 4 hours (ciprofloxacin) to 12 hours (moxifloxacin). After ingestion of 500 mg, the peak serum level of ciprofloxacin is 2.5 mcg/mL, which is lower than that of the other quinolones (4–6 mcg/mL), but this is offset by ciprofloxacin's slightly greater in vitro potency against most gram-negative organisms. A number of the fluoroquinolones can be administered intravenously, resulting in peak serum levels ranging from 4 mcg/mL to 9 mcg/mL (Table 37-9). Most are eliminated via mixed renal and nonrenal pathways. As a result, only modest accumulation takes place in the presence of renal insufficiency. Exceptions are ofloxacin, levofloxacin, and gatifloxacin, which are primarily dependent upon the kidney for elimination.

Table 37-9. Pharmacology of the quinolones.

Drug Peak Serum Levels (mcg/mL) Serum Half-Life (h) Total Daily Dose Dosage Adjustments in Renal Failure
Dosage Interval (h) Moderate (Clcr10–50 mL/min) Severe (Clcr < 10 mL/min) Posthemodialysis Dose
Ciprofloxacin 3–4 (400 mg IV, 500–750 mg PO) 3–6 800–1200 mg (IV), 0.5–1.5 g (PO) 8–12 400 mg q12h 200 mg q12h None
Gatifloxacin 4–5 (400 mg PO or IV) 7 400 mg (PO/IV) 24 200 mg q24h 200 mg q24h 200 mg
Gemifloxacin 2–4 (320 mg PO) 7 320 mg PO Not known Not known Not known Not known
Levofloxacin 5–7 (500 mg PO or IV) 6–8 250–750 mg (PO/IV) 24 250–500 mg q24–48h 250–500 mg q48h None
Moxifloxacin 3–4 (400 mg PO) 12 400 mg (PO) 24 400 mg q24h 400 mg q24h Not known
Ofloxacin 5–7 (400 mg PO or IV) 6–8 400–800 mg (PO/IV) 12 200–400 mg q24h 200 mg q24h None

Clinical Uses

Urinary tract infections caused by trimethoprim-sulfamethoxazole-resistant gram-negative organisms have

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resulted in quinolones being recognized as one of the drugs of choice in areas with > 10–20% resistance of E coli to trimethoprim-sulfamethoxazole.

Because of good penetration into prostatic tissue, quinolones are effective in treating bacterial prostatitis and are alternatives to trimethoprim-sulfamethoxazole (doses for prostatitis are the same as for urinary tract infection, but the duration should be 6–12 weeks).

Quinolones are approved for treatment of certain sexually transmitted diseases. Ofloxacin, 300 mg orally twice daily for 7 days, is as effective as doxycycline, 100 mg orally twice daily for 7 days, for the therapy of C trachomatis cervicitis, urethritis, and proctitis. It is also effective for nongonococcal urethritis caused by U urealyticum. Ciprofloxacin is not effective for the therapy of chlamydial infections or nongonococcal urethritis. In general, the use of quinolones for the treatment of any sexually transmitted disease will be limited by their lack of efficacy with concomitant syphilis. Gonococcal urethritis, cervicitis, pharyngitis, and proctitis can be treated with a single oral dose of 500 mg of ciprofloxacin or 400 mg of oral ofloxacin. However, the increased prevalence of quinolone-resistant gonococci in California and Hawaii has resulted in the use of ceftriaxone and certain oral cephalosporins as the primary choices in those regions.

Pelvic inflammatory disease is usually caused by C trachomatis, N gonorrhoeae, enterobacteriaceae, or anaerobes. Oral outpatient treatment with ofloxacin, 400 mg twice daily for 14 days, in addition to clindamycin, 450 mg orally four times daily for 14 days, or metronidazole, 500 mg orally twice daily for 14 days, can be used. Epididymitis in young men (< 35 years of age) is caused most commonly by chlamydia and the gonococcus.Single-dose oral ciprofloxacin (500 mg) or oral ofloxacin (400 mg) followed by oral doxycycline, 100 mg twice daily for 10 days, is adequate therapy. Alternatively, ofloxacin, 300 mg orally twice daily for 10 days, can be used. H ducreyi, the pathogen that causes chancroid, is sensitive to quinolones, and ciprofloxacin, 500 mg orally twice daily, or enoxacin, 400 mg orally daily for 3 days, can be used as an alternative to erythromycin, azithromycin, or ceftriaxone as therapy for this disease.

Fluoroquinolones have been used successfully to treat complicated skin and soft tissue infections and osteomyelitis caused by gram-negative organisms. Ciprofloxacin, 500–750 mg orally twice daily for at least 6 weeks, has been effective therapy for malignant otitis externa.

Quinolones are among the few oral agents active against Campylobacter despite increasing resistance. In addition, they are active against the other major bacterial pathogens associated with diarrhea (Salmonella, Shigella, toxigenic E coli). Consequently, they have been used for the therapy of traveler's diarrhea as well as domestically acquired acute diarrhea. Norfloxacin, ciprofloxacin, and ofloxacin may be effective in eradicating the chronic carrier state of salmonella when therapy is continued for 4–6 weeks.

Ciprofloxacin has been used to eradicate meningococci from the nasopharynx of carriers.

Fluoroquinolones are effective for prophylaxis against gram-negative infections in the neutropenic patient, and intravenous ciprofloxacin in combination with β-lactam antibiotics has been used successfully to treat the febrile neutropenic patient.

Gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin are sometimes referred to as “respiratory fluoroquinolones” due to their activity against the pneumococci, including penicillin-resistant strains as well as atypical bacteria. However, their broad aerobic gram-negative spectrum suggests that they should be reserved

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for the treatment of refractory infections or high-risk patients, including those with comorbidities or recent receipt of β-lactam antibacterials. One setting in which ciprofloxacin is indicated for the therapy of lower respiratory tract infections is in cystic fibrosis, where P aeruginosa is the predominant pathogen. However, the increasing rate of resistance to ciprofloxacin has diminished the use of the drug for this indication.

Ciprofloxacin in combination with other agents has been used to treat M avium complex infections, and ciprofloxacin, levofloxacin, ofloxacin, and moxifloxacin may be efficacious in the therapy of multidrug-resistant tuberculosis.

Adverse Effects

The most prominent adverse effects of the quinolones are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, seizures, insomnia, impaired liver function, and skin rashes have been observed as well as more serious reactions such as acute renal failure, hypoglycemia (especially with gatifloxacin), and anaphylaxis. Fluoroquinolones as a class prolong the QT interval; it is debated whether any one agent is implicated more than another. Quinolones should be used cautiously in patients receiving antiarrhythmics such as amiodarone or in persons with a history of prolonged QT. Prolongation of the prothrombin time has been observed in some patients receiving stable doses of warfarin after ciprofloxacin has been given, but this interaction is unpredictable and modest. Tendinitis and tendon rupture have been reported with quinolone agents. Risk factors include concomitant corticosteroid use and age > 60 years. Patients experiencing musculoskeletal symptoms while receiving fluoroquinolones should discontinue therapy.

Lautenbach E et al: Association between fluoroquinolone resistance and mortality in Escherichia coli and Klebsiella pneumoniae infections: the role of inadequate empirical antimicrobial therapy. Clin Infect Dis 2005;41:923.

Mohr JF et al: A retrospective, comparative evaluation of dysglycemias in hospitalized patients receiving gatifloxacin, levofloxacin, ciprofloxacin, or ceftriaxone. Pharmacotherapy 2005;25:1303.

Saravolatz LD et al: Gatifloxacin, gemifloxacin, and moxifloxacin: the role of 3 newer fluoroquinolones. Clin Infect Dis 2003;37:1210.

Pentamidine & Atovaquone

Pentamidine and atovaquone are antiprotozoal agents that are primarily used to treat Pneumocystis pneumonia. Pentamidine is discussed in Chapters 31 and 35. Atovaquone inhibits mitochondrial electron transport and probably also folate metabolism. The solid dosage form is poorly absorbed and should be given with food to maximize bioavailability. The suspension is significantly better absorbed and preferred especially in high-risk patients (those with diarrhea, malabsorption). It has moderate activity against P jiroveci. In comparative trials with trimethoprim-sulfamethoxazole and pentamidine in the therapy of Pneumocystis pneumonia in AIDS, atovaquone, 750 mg orally three times daily for 3 weeks, is less effective than both agents but better tolerated. It has also been used as prophylaxis in AIDS patients at a dosage of 1500 mg daily. Major adverse effects include rash, nausea, vomiting, diarrhea, fever, and abnormal liver function tests. The use of atovaquone is limited to patients with mild to moderate Pneumocystis infections who have not responded to or cannot tolerate other therapies.

Urinary Antiseptics

These drugs exert antimicrobial activity in the urine but have little or no systemic antibacterial effect. Their usefulness is limited to therapy and prevention of urinary tract infections.

1. Nitrofurantoin

Nitrofurantoin is active against the common gram-positive urinary pathogens E faecalis and Staphylococcus saprophyticus, but the drug inhibits only about 50% of E faecium. It is also used against E coli and Citrobacter, but activity against Proteus, Serratia, and Pseudomonas is poor. Following oral administration, about 50% of the drug is absorbed, but serum concentrations are very low and tissue levels are undetectable. Levels in the urine reach concentrations of 200–400 mcg/mL, which are well above the MICs of susceptible organisms. However, in renal failure, subtherapeutic urine levels are present and drug accumulation takes place in serum. Given low serum levels, poor tissue penetration, and renal elimination, the use of nitrofurantoin is limited to therapy or prophylaxis of cystitis in patients with normal renal function. Nitrofurantoin should not be used to treat pyelonephritis or prostatitis.

The average daily dose in urinary tract infections is 100 mg orally four times daily, taken with food. The macrocrystal preparation can be given at a dosage of 100 mg twice daily. A single daily dose of 50–100 mg can prevent recurrent urinary tract infections in women.

Oral nitrofurantoin often causes nausea and vomiting. The crystalline formulation is better tolerated than previous preparations. Hemolytic anemia may occur in G6PD deficiency. Other side effects are skin rashes and, uncommonly, peripheral neuropathy. Acute and chronic pulmonary hypersensitivity reactions may occur, and pulmonary fibrosis has occurred with prolonged use.

2. Fosfomycin

Fosfomycin tromethamine is a phosphonic acid derivative useful in the treatment of uncomplicated urinary tract infection. The spectrum of activity includes E coli, E faecalis, and other gram-negative aerobic urinary pathogens, but not P aeruginosa. Available as a 3-g sachet, fosfomycin may be useful for the single-dose

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treatment of the above organisms. Like nitrofurantoin, fosfomycin should not be used for systemic infection. However, the increased concentrations in urine allow for its use in uncomplicated bacteriuria. The most frequently reported adverse effects include diarrhea, headache, and nausea.

Antifungal Drugs

Empiric antifungal therapy is rarely instituted except for febrile neutropenic and other high-risk patients. Therapy is reserved for situations in which yeast or mold is seen on KOH preparation or when isolated organisms are thought to be pathogenic. Antifungal standardized susceptibility testing is available for Candida spp, and predict clinical outcome. In contrast, susceptibility testing for most other fungi is not generally available; in vitro results for these pathogens is less predictive of patient outcomes.

1. Amphotericin B

Amphotericin B in vitro inhibits several organisms producing systemic mycotic disease in humans, including Aspergillus, Histoplasma, Cryptococcus, Coccidioides, Candida, Blastomyces, Sporothrix, and others. This drug can be used for treatment of these systemic fungal infections. Pseudallescheria boydii and Fusarium are often resistant to amphotericin B.

There is no consensus on how conventional amphotericin B should be administered or on the dosage and the duration of therapy. A test dose is unnecessary, since anaphylaxis is extremely rare. The daily dose of amphotericin B for most fungal infections varies from 0.3 mg/kg to 0.7 mg/kg, though infections caused by Aspergillus and Mucor are often treated with 1–1.5 mg/kg daily.

Combined treatment with flucytosine is beneficial in cryptococcal meningitis and possibly systemic candidiasis. Amphotericin B may have some benefit in Naegleria meningoencephalitis.

Amphotericin B has been used prophylactically to prevent invasive fungal infections in bone marrow transplant recipients; however, other agents are less toxic and may be more efficacious. Whether prophylactic antifungal use is better than early empiric therapy in febrile patients who have not responded to broad-spectrum antibiotics has not been determined.

In patients with Foley catheters in place who have candiduria, amphotericin B bladder irrigations decrease colony counts; however, the efficacy of irrigation is marginal, and long-term eradication of candiduria following amphotericin B bladder irrigation rarely occurs.

Neither renal nor hepatic failure alters the pharmacokinetic disposition of amphotericin. The drug concentrates in the lung, liver, spleen, and kidney with minimal penetration into skin or adipose tissue. The drug is not removed by hemodialysis.

The intravenous administration of amphotericin B often produces chills, fever, vomiting, and headache. As a rule, infusions given over 1–2 hours are as well tolerated as those given over 4–6 hours. However, patients who experience infusion-related adverse effects may benefit from slowing the rate of administration. Tolerability may be enhanced by temporary lowering of the dose or premedication with acetaminophen and diphenhydramine. Addition of 25 mg of hydrocortisone to the infusion decreases the incidence of rigors, and meperidine, 25–50 mg, is effective in arresting rigors once they start. Central intravenous administration eliminates the likelihood of thrombophlebitis. Electrolyte disturbances (hypokalemia, hypomagnesemia, distal renal tubular acidosis) also commonly occur. Renal insufficiency can be reduced with sodium supplementation. As a result, administration of 0.5–1 L of 0.9% saline prior to infusion of amphotericin B is recommended.

The nephrotoxicity of amphotericin has resulted in the development of lipid-based amphotericin B products. Three such products are available: amphotericin B lipid complex (ABLC; Abelcet), amphotericin B colloidal dispersion (ABCD; Amphotec), and liposomal amphotericin B (L-AmB; AmBisome). Complexing amphotericin B with lipid allows larger doses to be administered (3–6 mg/kg, depending on the preparation and the fungal species). All three preparations are associated with less nephrotoxicity than conventional amphotericin B. Liposomal amphotericin is somewhat less nephrotoxic than ABLC. Infusion-related adverse effects are variable, with liposomal amphotericin the best tolerated. Liposomal amphotericin is equal to or better than that of conventional amphotericin B in febrile neutropenia, particularly in prevention of emergent Candida infections.

Drug acquisition costs for all three products are much higher than for conventional amphotericin B. The availability of echinocandins and triazoles has resulted in additional choices in the prevention and treatment of fungal infection. The lipid formulations are particularly effective for therapy of visceral leishmaniasis. Short courses (5–10 days) with low doses (2–4 mg/kg/d depending on which preparation is used) are very effective in eradicating the parasite, probably because of distribution of the drug to the reticuloendothelial system, the major site of parasite invasion.

Drew RH et al: Is it time to abandon the use of amphotericin B bladder irrigation? Clin Infect Dis 2005;40:1465.

Gibbs WJ et al: Liposomal amphotericin B: clinical experience and perspectives. Expert Rev Anti Infect Ther Infect Dis 2005;3:167.

Wong-Beringer A et al: Systemic antifungal therapy: new options, new challenges. Pharmacotherapy 2003;23:1441.

2. Nystatin

Nystatin has a wide spectrum of antifungal activity but is used almost exclusively to treat superficial candidal infections. It is too toxic for systemic administration, and the drug is not absorbed from mucous membranes or

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the gastrointestinal tract. Several preparations are available, including oral suspension (100,000 units/mL) and ointments, gels, and creams (100,000 units/g). For oral candidiasis, 500,000 units of suspension is used to rinse the mouth and is retained in the mouth as long as possible before it is swallowed. This is repeated four times a day for at least 2 days after resolution of the infection. Infections of skin are treated with cream or ointment, 100,000 units applied to the affected area twice daily until resolution of the infection. Nystatin is less effective than azoles for therapy of vaginal candidiasis.

3. Flucytosine

Flucytosine inhibits some strains of Candida, Cryptococcus, Aspergillus, and other fungi. Dosages of 3–8 g daily (75–150 mg/kg/d) orally produce therapeutic levels in serum, urine, and cerebrospinal fluid. Clinical remissions of meningitis or sepsis due to yeasts have occurred. However, resistant organisms are selected out rapidly, and flucytosine is therefore not used as a single drug except in urinary tract infections.

In renal insufficiency, flucytosine may accumulate to toxic levels, and dosage adjustments are needed. Because patients with HIV infection and normal renal function do not tolerate the previously used doses of flucytosine (150 mg/kg/d in four divided doses), 75–100 mg/kg/d is recommended. The drug is effectively removed by hemodialysis. Toxic effects include bone marrow depression, abnormal liver function, and nausea. Bone marrow suppression is caused by conversion of flucytosine to fluorouracil. Combined use of flucytosine and amphotericin B in cryptococcal meningitis and possibly systemic candidiasis has been shown to be of value.

4. Natamycin

Natamycin is a polyene antifungal drug effective against many different fungi in vitro. When it is combined with appropriate surgical measures, topical application of 5% ophthalmic suspension may be beneficial in the treatment of keratitis caused by Fusarium, Acremonium (cephalosporium), or other fungi. The toxicity after topical application appears to be low.

5. Terbinafine

Terbinafine, an allylamine, inhibits fungal cell membrane function by blocking ergosterol synthesis. Terbinafine is available topically as well as in 250-mg tablets for oral administration. The recommended dosage is 250 mg daily for 12 weeks for toenail infections and 250 mg daily for 6 weeks for fingernail infections (success rate about 70%). Pulse therapy (1 week on and 3 weeks off) is as effective as continuous therapy for 6–12 weeks. The drug also is active against many strains of Candida and Aspergillus organisms and has been used in combination with other antifungals to treat severe infections with these pathogens. Most adverse effects are minor (diarrhea, dyspepsia) or transient (taste disturbance). Rare cases of severe hepatic injury have occurred.

6. Antifungal Imidazoles & Triazoles

These antifungal drugs inhibit synthesis of ergosterol, resulting in inhibition of membrane-associated enzyme activity, cell wall growth, and replication.

Clotrimazole, taken orally in the form of 10-mg troches five times daily, can prevent and treat oral candidiasis. Vaginal azole tablets inserted daily for 1–7 days are effective for vaginal candidiasis. Topical preparations for treatment of cutaneous dermatophytes are also available.

Fluconazole, a bis-triazole with activity similar to that of ketoconazole, is water-soluble and can be given both orally and intravenously. Absorption of the drug after oral administration is not pH-dependent. It penetrates well into the cerebrospinal fluid and eye. The drug has been shown to be effective primarily in the treatment of Candida, Cryptococcus, and Blastomyces infections. Candida albicans, Candida tropicalis, and Candida parapsilosus are usually sensitive to fluconazole, but many other species of candida (C krusei, C glabrata, etc) are often resistant. Fluconazole-resistant strains of C albicans primarily have been observed in HIV-positive patients receiving long-term fluconazole therapy. With the advent of highly active antiretroviral therapy, the rate of fluconazole resistance in C albicans has decreased in this patient population. The drug is inactive against Aspergillus, Mucor, and Pseudallescheria. Fluconazole is effective in oropharyngeal candidiasis and candidal esophagitis in immunosuppressed patients. It is also valuable in vaginal candidiasis, where a single oral dose of 150 mg is 80–90% effective. Fluconazole, 400 mg intravenously and orally daily, is as effective as amphotericin B, 0.5–0.6 mg/kg/d, for candidemia in both neutropenic and nonneutropenic patients. Most of these infections are intravenous line-related, and removal of the line is critical to successful therapy. Fluconazole (200 mg/d) is effective as long-term suppressive therapy of cryptococcal meningitis in patients with AIDS and is the drug of choice in this setting. In the treatment of cryptococcal meningitis, response rates and overall mortality rates are the same in patients treated with oral fluconazole and with amphotericin B. However, the mortality rate in the first 2 weeks is higher with fluconazole and it takes longer to sterilize the cerebrospinal fluid among patients treated with fluconazole than among patients treated with amphotericin. Most clinicians would initiate therapy with amphotericin B for 2 weeks and then switch to oral fluconazole. A dosage of 400 mg of fluconazole daily is effective therapy for coccidioidal meningitis (80% response), but improvement is slow, taking as long as 4–8 months; efficacy has been observed in both non-HIV-infected and HIV-infected individuals. Higher doses (800–1200 mg/d) have been used; however, they have not been found to be superior to usual doses. Fluconazole, 400 mg daily, is effective

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prophylaxis against superficial and invasive fungal infections in bone marrow and liver transplant recipients, but concern has been raised about superinfection with resistant organisms (C krusei, C glabrata, Aspergillus). Because the overall incidence of invasive fungal disease in HIV infection is low, universal prophylaxis to prevent disease is discouraged, especially with the advent of more potent antiretroviral therapy. Fluconazole is also effective for the therapy of cutaneous leishmaniasis due to Leishmania major in a dose of 200 mg/d for 6 weeks.

Fluconazole is well absorbed after oral administration (> 90% bioavailability), and serum levels approach those seen after administering the same dose intravenously. Thus, unless the patient cannot take medication by mouth or is hemodynamically unstable, the preferred route of administration is by mouth. While generally well tolerated, fluconazole is associated with dose-dependent nausea and vomiting. Altered liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and hepatitis have been reported. While less potent than other azoles (itraconazole, ketoconazole, voriconazole), fluconazole inhibits cytochrome P450 resulting in reduced elimination of certain agents. Rifampin and phenytoin increase metabolism of fluconazole necessitating increased fluconazole dosage.

Itraconazole is an oral triazole that has variable bioavailability. It is moderately well absorbed from the gastrointestinal tract (food increases absorption from 30% to 60%; antacids and H2-receptor antagonists decrease absorption) and widely distributed in tissues with the notable exception of the central nervous system, where levels in spinal fluid are undetectable. Itraconazole solution is more predictably absorbed than the tablets. While the tablet formulation should be administered with food, the solution is best absorbed on an empty stomach. A parenteral formulation is available, but it is not approved for patients with renal insufficiency (creatinine clearance < 30 mL/min) because of the theoretic risk of pancreatic adenocarcinoma associated with accumulation of the cyclodextran vehicle. The drug is metabolized by the liver, and no dosage adjustment is needed in renal insufficiency. Itraconazole is very active against most strains of Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Sporotrichum schenkii, and various dermatophytes. It is also active against Aspergillus species but inactive against Fusarium and Zygomycetes. Itraconazole in doses of 200–400 mg/d is effective and approved therapy for localized or disseminated histoplasmosis. It is also effective in sporotrichosis, dermatophytic infections (including those of the nails), and oral and esophageal candidiasis. Noncomparative clinical trials indicate efficacy in therapy of invasive aspergillosis (55–80%) and coccidioidomycosis (57–94%). Itraconazole is at least as effective as fluconazole in the treatment of nonmeningeal coccidioidomycosis and may be superior in the management of skeletal disease. At doses of 200 mg twice daily, itraconazole increases exercise tolerance and decreases corticosteroid requirements in patients with allergic bronchopulmonary aspergillosis. Itraconazole has been shown to decrease superficial and invasive fungal infections when used as prophylaxis in neutropenic patients. Itraconazole has been approved for onychomycosis. Pulse therapy with 200 mg twice daily for 1 week each month, repeated for 4 consecutive months, is effective in 70% of cases.

Adverse effects are similar to those of ketoconazole and fluconazole, with anorexia, nausea, vomiting, and abdominal pain occurring most commonly. Skin rash has been reported in up to 8% of patients. Hepatitis and hypokalemia occur uncommonly. Exacerbation of heart failure occasionally occurs with itraconazole. Drugs that increase hepatic drug-metabolizing enzymes (isoniazid, rifampin, phenytoin, phenobarbital) may increase itraconazole metabolism, and higher doses may be needed when these drugs are administered concurrently with itraconazole. Itraconazole also impairs the metabolism of cyclosporine and can result in increased levels of certain agents, including digoxin and warfarin.

The usual dosage is 200 mg once or twice daily with meals.

Voriconazole is a triazole antifungal with broad in vitro activity against a number of pathogens, including most species of Candida and molds, Aspergillus, Fusarium, Pseudallescheria, and others. It is as efficacious as liposomal amphotericin in the therapy of documented and suspected fungal infections in febrile neutropenic patients, and it is superior to liposomal amphotericin in preventing breakthrough fungemias. Voriconazole is superior to conventional amphotericin in the treatment of disseminated aspergillosis. Animal data also suggest voriconazole to be the most effective agent against Aspergillus, particularly in combination with caspofungin or another echinocandin. Voriconazole is the drug of choice in the treatment of Fusarium and Scedosporium infections. Voriconazole is widely used in the treatment of neutropenic patients with suspected or documented fungal infection. Voriconazole has limited activity against zygomycete pathogens, and some centers have reported increased rates of infection due to Rhizopus and Mucor in this patient population. Similar to fluconazole, oral administration leads to predictable absorption. The primary toxicity associated with voriconazole is infusion-related, transient visual disturbances, particularly during the first week of therapy. In addition, voriconazole is associated with photosensitivity reactions. Similar to itraconazole, voriconazole is associated with numerous drug interactions. Enzyme inducers can decrease voriconazole plasma levels with possible reduction in efficacy. Voriconazole inhibits cytochrome P450 activity reducing the clearance of numerous agents, including cyclosporine and tacrolimus.

Ketoconazole, the first orally bioavailable azole, previously was used in the treatment of a variety of fungal infections. However, the improved spectrum of activity, reduced toxicity, and superior pharmacokinetics

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of newer azoles have reduced ketoconazole to a secondary role.

Kontoyiannus DP et al: Zygomycoses in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis 2005;191:1350.

Marr KA et al: Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797.

7. Echinocandins

The echinocandins (caspofungin, anidulafungin, micafungin) act by inhibiting fungal cell wall synthesis. They are active against Candida, including nonalbicans species, as well as Aspergillus species. They are not active against Cryptococcus or Fusarium. Their long pharmacologic half-life confers the advantage of once-daily dosing. No change in dose is necessary in patients with renal failure; however, moderate to severe hepatic disease necessitates a reduction in dosage for caspofungin. Because rifampin and phenytoin significantly increase the metabolism of caspofungin, increased doses of the antifungal are necessary when rifampin and phenytoin are given concomitantly. Animal data suggest that caspofungin is inferior to voriconazole in the treatment of Aspergillus; however, the addition of caspofungin to voriconazole has been associated with in vitro and in vivo additive or synergistic effects. Caspofungin is superior to conventional amphotericin B in the treatment of candidemia, primarily on the basis of greater patient tolerability. The echinocandins should be considered the drugs of choice in the treatment of infections due to C glabrata and C krusei. These agents are associated with minimal toxicity or adverse effects. Histamine release is common with basic polypeptide compounds, such as the echinocandins; thus infusion-related reactions have been reported. While increased liver function tests have been observed with the combination of caspofungin and cyclosporine, more recent analyses suggest that these two agents can be safely administered together. Considering the similarities in spectrum efficacy and safety between products, the choice of echinocandin likely will be based on cost differences.

Betts R et al: Efficacy of caspofungin against invasive Candida or Aspergillus infections in neutropenic patients. Cancer 2006;106:466.

Denning DW: Echinocandin antifungal drugs. Lancet 2003;362:1142.

Antiviral Chemotherapy

Several compounds can influence viral replication and the development of viral disease.

Amantadine is active against influenza A (but not influenza B) and has efficacy both in prophylaxis and therapy of this infection. Yearly immunization against influenza is recommended (see Chapter 30) for disease prevention, but in certain select situations amantadine can be used for this purpose. Amantadine prophylaxis for 6–8 weeks is 70–90% effective in patients who cannot be immunized and who are at increased risk for developing complications of influenza; in medical personnel who cannot receive vaccine but are capable of transmitting influenza to high-risk patients; if vaccine is not available; and if vaccine strains differ from the strain causing an epidemic. Short-term prophylaxis (2 weeks) is indicated if an outbreak occurs before vaccination has been given. In this setting, amantadine will protect against disease while antibody production is induced and will not interfere with antibody production. Because of its modest therapeutic benefit, high-risk patients and others with influenza A may benefit from treatment with amantadine if it is instituted within 48 hours after the onset of symptoms and continued for 1 week. The usual adult dosage is 200 mg orally per day (in persons over 65 years of age, 100 mg). Emergence of influenza A resistance to amantadine and rimantadine has been observed in patients receiving therapy. Efficacy of amantidine/rimantidine for prophylaxis depends on the sensitivity of the predominant circulating strain. Worldwide rates of amantadine/rimantadine resistance have significantly increased over the years. Considering this predisposition for resistance, neuraminidase inhibitors such as zanamivir or oseltamivir would be preferable if the circulating strain is resistant to amantadine/rimantidine. In preparation for a possible avian influenza pandemic, the Centers for Disease Control and Prevention recommend the neuraminidase inhibitors due to current resistance trends and documented past record of development of amantadine resistance while on therapy. The most marked untoward effects are insomnia, nightmares, and ataxia, especially in the elderly. Amantadine may accumulate and be more toxic in patients with renal insufficiency, and the dosage should be reduced. Rimantadine, an analog of amantadine, is as effective as amantadine and is associated with fewer central nervous system adverse effects.

Neuraminidase inhibitors, including zanamivir inhalation and oseltamivir tablets, are available for prevention and treatment of influenza A and B and are also active against the avian influenza virus. While no vaccine for avian influenza is currently available, future prevention will depend on immunization rather than on antivirals. As with amantadine and rimantadine, they must be administered soon (within 48 hours) after the onset of symptoms to be effective. Zanamivir inhalers are difficult to use for some patients, especially those with asthma and chronic obstructive pulmonary disease, in whom bronchospasm has been reported. Oseltamivir is somewhat limited because of its gastrointestinal side effects. Both drugs are administered twice daily (oseltamavir, 75 mg orally; zanamivir 10 mg inhalation) for 5 days when used for therapy. Both agents are significantly more expensive than amantadine and reduce the duration of symptoms by only 1 day and viral shedding by 2 days. The major advantages of neuraminidase inhibitors over amantadine or rimantadine include activity

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against both influenza A and B and a low likelihood of development of resistance, resulting in their preferential use in outbreak settings. Both agents also effectively prevent disease in household contacts when administered prophylactically (oseltamavir 75 mg orally once daily, zanamavir 10 mg inhaled once daily) for 10 days.

Acyclovir is active against herpes simplex virus and varicella-zoster virus. In herpes-infected cells, it is selectively active against viral DNA polymerase and thus inhibits virus proliferation. Given intravenously (15 mg/kg/d in three divided doses), it can promote healing of mucocutaneous herpes simplex in immunocompromised patients. It can reduce pain, accelerate healing, and prevent dissemination of herpes zoster and varicella in immunocompromised patients. The usual dosage for varicella-zoster infections is 30 mg/kg/d intravenously in three equal doses. The drug has no effect on establishment of latency, frequency of recurrence, or incidence of postherpetic neuralgia. Acyclovir (30 mg/kg/d intravenously in three equal doses) is the drug of choice for herpes encephalitis. Intravenous or oral acyclovir is effective prophylaxis against recurrent mucocutaneous and visceral herpes infections in transplant and other severely immunosuppressed patients. Prophylactic intravenous or oral acyclovir is effective in preventing cytomegalovirus (CMV) disease in some transplant settings (renal and perhaps bone marrow) but not in others (liver).

Oral acyclovir, 400 mg three times daily for 7–10 days, is effective in primary genital herpes simplex infections. Oral acyclovir at a dose of 800 mg three times a day for 2 days for recurrent genital herpes reduces viral shedding and symptoms. Suppressive therapy (400 mg twice daily) for 4–6 months reduces the frequency and severity of recurrent genital herpetic lesions. Acyclovir minimally affects symptoms or viral shedding in recurrent herpes labialis and is not generally used for this disease. However, in a dose of 400 mg twice daily, it is effective in preventing recurrent herpes labialis in those with frequent relapses and in preventing sun-induced relapses.

Other uses of oral acyclovir include (1) therapy of acute herpetic keratitis and prevention of recurrences, (2) prevention and treatment of herpetic whitlow, (3) acceleration of healing of herpes zoster in immunocompetent patients if initiated within 48 hours after onset (800 mg five times daily for 7 days), (4) more rapid healing of rash and lessened clinical symptoms of primary varicella in adults and children if instituted within 24 hours after onset of rash and continued for 5–7 days, (5) therapy of herpes proctitis (400 mg five times daily for 10 days), (6) prevention of herpes simplex and CMV infections in transplant recipients (in doses of 800 mg four or five times daily), (7) prevention of erythema multiforme that is herpes simplex-related, and (8) prophylaxis against varicella in susceptible household contacts.

Topical 5% acyclovir ointment can shorten the period of pain and viral shedding in herpes simplex mucocutaneous oral lesions in immunosuppressed patients but not in patients with normal immunity. In contrast, acyclovir cream or penciclovir ointment (see famciclovir, below) appears to reduce the duration of pain and viral shedding by approximately 1 day in immunocompetent patients. Oral acyclovir is significantly more efficacious than topical therapy.

The absolute oral bioavailability of acyclovir is 10–30%. Famciclovir and valacyclovir (see below) are significantly better absorbed than oral acyclovir and are administered less frequently. Dosage reduction in renal insufficiency is required. Since hemodialysis reduces serum levels significantly, the daily dose should be given after hemodialysis.

Acyclovir is relatively nontoxic. Precipitation of drug in renal tubules has been described with intravenous acyclovir and can best be avoided by maintaining adequate hydration and urine flow. Central nervous system toxicity manifested by confusion, agitation, tremors, and hallucinations has been reported. Resistance has been described, usually in immunosuppressed patients who have received multiple courses of therapy.

Famciclovir is a prodrug of penciclovir. After oral administration, 75–80% is absorbed and deacetylated in the intestinal wall to the active drug, penciclovir. Penciclovir, like acyclovir, inhibits viral replication by interfering with viral DNA polymerase. Acyclovir-resistant strains of herpes simplex and varicella-zoster virus are also resistant to famciclovir. Famciclovir in a dose of 500 mg three times daily for 7 days accelerates healing of lesions in acute herpes zoster if started within 72 hours after the onset of rash. At a dose of 125 mg twice daily for 5 days, famciclovir is effective therapy of recurrent genital herpes; at a dose of 500 mg twice daily, it is effective as chronic suppressive therapy.

Valacyclovir is a prodrug of acyclovir that has significantly increased oral bioavailability when compared with acyclovir. After absorption, it is converted to acyclovir and serum levels are three to five times higher than those achieved with acyclovir. Valacyclovir at a dosage of 1 g three times daily for 7–10 days is effective therapy for herpes zoster when started within 72 hours after onset of rash and is slightly more effective than acyclovir in relieving zoster-associated pain. It shortens the course of initial episodes of genital herpes (1 g twice daily for 7–10 days), can be used to treat recurrent genital herpes (500 mg twice daily for three days), and is effective prophylaxis for recurrent genital herpes when given as a single 1-g daily dose. Valacyclovir prophylaxis (500 mg daily) reduces the rate of viral shedding and transmission of herpes in discordant monogamous couples. At doses of 2 g four times daily, valacyclovir is more effective than placebo in preventing CMV infections in seronegative recipients of a kidney from a seropositive donor. The adverse effect profile of valacyclovir is comparable to that of acyclovir.

Foscarnet (trisodium phosphonoformate) is a pyrophosphate analog that inhibits viral DNA polymerase of human herpesviruses (CMV, herpes simplex, varicella-zoster) and the reverse transcriptase of HIV. The drug is

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less well tolerated than acyclovir and ganciclovir and more difficult to administer. Therefore, its use is limited to patients who do not respond to ganciclovir or acyclovir or cannot tolerate these drugs. Isolates of CMV resistant to ganciclovir and herpes simplex and varicella-zoster isolates resistant to acyclovir usually are susceptible to foscarnet. Foscarnet has been used to treat acyclovir-resistant mucocutaneous herpes simplex in AIDS patients as well as varicella cutaneous lesions in AIDS patients who did not respond to acyclovir. Oral absorption is poor, and the drug must be given intravenously. The half-life is 3–5 hours, and this is prolonged with renal insufficiency. The usual induction dose is 60 mg/kg/dose every 8 hours, and the dose for maintenance therapy is 120 mg/kg once daily. Adjustments are required for even minimal impairment in renal function (see package insert).

Foscarnet can cause severe phlebitis and generally necessitates central intravenous access unless substantially diluted. Nephrotoxicity, which is dose-dependent and reversible, is its major toxicity. Prehydration with 2.5 L of 0.9% saline reduces nephrotoxicity. Foscarnet binds divalent cations, and hypocalcemia with peripheral neuropathy, seizures and arrhythmias, hypomagnesemia, and hypophosphatemia can occur. Monitoring of electrolytes and renal function is required during therapy. Anemia (20–50%) and nausea and vomiting (20–30%) are other common adverse effects.

Cidofovir is a nucleotide analog that is active against all human herpesviruses and poxviruses. The drug has a prolonged pharmacokinetic intracellular half-life, allowing for administration every 1–2 weeks. Strains of CMV, herpes simplex virus, and herpes zoster virus that are resistant to ganciclovir or acyclovir often are susceptible to cidofovir. Cidofovir delays progression of CMV retinitis in newly diagnosed disease (5 mg/kg weekly for 2 weeks, followed by maintenance of 3–5 mg/kg every other week) and is effective therapy in relapsed disease or in patients who are intolerant of traditional therapy (5 mg/kg every other day). The drug is ineffective or only marginally effective in the treatment of AIDS-associated progressive multifocal leukoencephalopathy. Cidofovir is associated with a high incidence of nephrotoxicity, sometimes severe. To avoid this complication, probenecid and intravenous saline are administered with each dose. Ocular toxicity, including uveitis and iritis, is another complication reported with cidofovir.

Ribavirin aerosol is used in the treatment of respiratory syncytial virus infections in bone marrow transplant patients. It is not known whether the addition of immune globulin provides additional benefit. Intravenous ribavirin can significantly lower the fatality rate of Lassa fever and has been used as a therapeutic agent for hantavirus pneumonia. However, the benefit in hantavirus infection is unclear. While used in some patients in the treatment of severe acute respiratory syndrome (SARS), its value and tolerability has been debated. The drug is teratogenic in animals, and pregnant women should not take care of patients receiving the aerosol. Oral ribavirin is used in combination with interferons to treat chronic hepatitis C infections (see Chapter 15). The combination has been found to be superior to monotherapy with interferon.

Ganciclovir is an analog of acyclovir that has broad antiviral activity, including activity against CMV. The drug is efficacious in the therapy of CMV retinitis in AIDS patients, but once therapy is stopped, the relapse rate is high, and long-term maintenance suppressive therapy is required in patients not receiving highly active antiretroviral therapy. It has been suggested that the addition of intravenous immunoglobulin or CMV immune globulin to ganciclovir may improve outcomes associated with CMV pneumonitis. Since CMV viremia often predicts the presence of invasive disease, it should be treated when it occurs. Ganciclovir is frequently used in solid organ and stem cell transplant patients in the treatment and prevention of infection. However, there is no uniformity of opinion about the duration of therapy or the route of administration. Before the availability of oral valganciclovir (see below), which results in serum levels equivalent to those achieved with intravenous drug, ganciclovir was frequently administered intravenously and in the immediate posttransplant period for 1–2 weeks. Depending on the type of transplant (bone marrow transplant patients are at greater risk for developing CMV disease than solid organ transplant patients) and the serologic status of the donor and recipient (seronegative recipients who receive transplants from seropositive donors are at greatest risk for developing disease), various antiviral agents were used to prevent infection. Acyclovir, valacyclovir, ganciclovir, and valganciclovir have been used in the prevention of CMVin stem cell transplant patients. With the availability of oral valganciclovir, many transplant patients—especially those with the greatest risk of developing CMV infection—are placed on this drug as prophylaxis. In addition, because tests to detect early infection with CMV are very sensitive, the strategy for prevention has shifted from one of universal prophylaxis to one of preemptive therapy. At many institutions, high-risk patients are routinely screened for CMV DNA in blood by antigen detection or polymerase chain reaction. If the test is positive, only then are patients treated with either intravenous ganciclovir or oral valganciclovir.

The major adverse effect is neutropenia, which is reversible but may require the concomitant use of colony stimulating factors. Thrombocytopenia, disorientation, nausea, rash, and phlebitis occur less commonly.

Oral ganciclovir is no longer used because of its poor bioavailability, and it has been replaced by valganciclovir, an esterification product of ganciclovir that is significantly better absorbed. Administration of 900 mg of valganciclovir orally results in serum ganciclovir levels equal to that achieved with an intravenous 5 mg/kg dose of ganciclovir. In CMV retinitis in AIDS patients, the drug is as efficacious as intravenous therapy. Valganciclovir is widely used as prophylaxis

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in transplant patients; however, it was found to be inferior to oral ganciclovir in the prevention of CMV infection after liver transplant. Consequently, it has not been approved for that indication.

Lamivudine (3TC), a well-tolerated oral antiviral nucleoside analog used in treatment of HIV infection, is effective against hepatitis B. Once-daily therapy (100 mg) results in clinical, serologic, and histologic improvement in approximately 50% of patients. While lamivudine is useful, development of resistance is common with long-term therapy. Therapy post-liver transplantation is associated with a reduced risk of reinfection with hepatitis B. Unlike the combination of ribavirin and interferon, lamivudine does not improve the outcome seen with interferon monotherapy.

Adefovir is an antiviral agent with activity against hepatitis B. It is as effective against lamivudine-susceptible and lamivudine-resistant isolates. While previously used higher doses have been associated with substantial nephrotoxicity, this complication is rare with the lower doses (10 mg/d) used to treat hepatitis B. Twenty-five to 35 percent of patients experience marked increases in liver function tests associated with discontinuation of adefovir, presumably secondary to rebound viral replication. The drug is primarily eliminated by the kidney.

Human interferons have been prepared from stimulated lymphocytes and by DNA recombinant technology. These agents have antiviral, antitumor, and immunoregulatory properties. The most common uses of these agents include therapy of chronic hepatitis due to hepatitis B, C, and D (see Chapter 15). A long-acting preparation of interferon, peginterferon, in combination with oral ribavirin is superior to conventional interferon for therapy of hepatitis C. Relapse of the underlying disease after cessation of therapy is common but usually responds to reinstitution of drug. Adverse effects are common and include an influenza-like illness with fever, chills, nausea, vomiting, headache, arthralgia, and myalgias. Bone marrow suppression, especially with high-dose therapy, also occurs. Considering the poor tolerability of interferon, only a minority of patients infected with hepatitis C are actually candidates for therapy.

Entecavir tablets and oral solution have been approved in the treatment of chronic hepatitis B. The results of three studies confirm significant improvement in liver function tests and viral markers when compared with lamivudine. The primary side effects associated with entecavir were similar to those seen with previous hepatitis B treatments, including headache, abdominal pain, diarrhea, fatigue, dizziness, and a severe, brief worsening of hepatitis B after discontinuation of therapy.

Peters MG: Managing hepatitis B coinfection in HIV-infected patients. Curr HIV/AIDS Rep 2005;2:122.

Singh N: Cytomegalovirus infection in solid organ transplant recipients: New challenges and their implications for preventive strategies. J Virol 2006;35:474.

Ward P et al: Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005;55(Suppl 1):i5.