Antibacterial Agents

Penicillins (PCN)

PCNs drugs of choice for syphilis, group A Streptococcus, Listeria monocytogenes, Pasteurella multocida, Actinomyces, susceptible enterococcus species, and some anaerobic infections.

Aqueous penicillin G [2-4 million units (mu) IV q4h or 18-24 mu qd by continuous infusion]

IV preparation of PCN.

therapy of choice for neurosyphilis.

Although the potassium salt is more common, the sodium salt is available and should be given in the setting of hyperkalemia or azotemia.

Procaine penicillin G IM repository form of penicillin G, rarely used today.

Benzathine penicillin

long-acting repository form of penicillin G

commonly used for treating early syphilis [ < 1-year duration (one dose 2.4 mu IM)] and late latent syphilis [unknown duration or > 1 year (2.4 mu IM qwk for 3 doses)]. It is occasionally given for group A streptococcal pharyngitis and prophylaxis after acute rheumatic fever or poststreptococcal glomerular nephritis.

Penicillin V (250-500 mg PO qid)

an oral version of PCN

typically used to treat group A streptococcal pharyngitis.

Ampicillin (2-3 g IV q4-6h)

drug of choice for susceptible enterococcus species and L. monocytogenes.

Oral ampicillin (250-500 mg PO qid)

commonly used for uncomplicated sinusitis, pharyngitis, otitis media, and UTIs. Ampicillin/sulbactam (1.5-3.0 g IV q6h)

combines ampicillin with the beta-lactamase inhibitor sulbactam

extending its spectrum to include oxacillin-sensitive Staphylococcus aureus(OSSA), anaerobes, and gram-negative upper airway pathogens.

effective for upper and lower respiratory tract, genitourinary tract, and polymicrobial soft-tissue infections.

IV antibiotic of choice for serious cellulitis due to human or animal bites.

Amoxicillin (250-500 mg PO tid)

commonly used for uncomplicated sinusitis, pharyngitis, otitis media, and UTIs. Amoxicillin/clavulanic acid (875 mg PO bid or 500 mg PO tid)

combines amoxicillin with the beta-lactamase inhibitor clavulanate

an oral antibiotic similar to ampicillin/sulbactam.

useful for treating complicated sinusitis, otitis media, and skin infections

the antibiotic of choice for prophylaxis in human or animal bites after appropriate local treatment. It is often used as a step-down therapy from IV ampicillin/sulbactam. The 875-mg PO bid dosing regimen causes less diarrhea.

Nafcillin and oxacillin (2 g IV q4-6h)

penicillinase-resistant synthetic PCNs

the drugs of choice for treating OSSA infections.

little activity against enterococci or gram-negative bacteria.

Dose reduction by one-half should be considered in decompensated liver disease.

Dicloxacillin and cloxacillin (250-500 mg PO qid) are oral antibiotics with a spectrum of activity similar to that of nafcillin and oxacillin.

They are typically used to treat localized skin infections without systemic signs or symptoms.

Mezlocillin, ticarcillin, and piperacillin (3 g IV q4h or 4 g IV q6h) are penicillin derivatives with improved gram-negative activity.

Ticarcillin and piperacillin have reasonable antipseudomonal activity but require coadministration of an aminoglycoside for serious infections.

Mezlocillin and piperacillin have good enterococcal activity and accumulate to high levels in bile, making them useful drugs for ascending cholangitis and prophylaxis before manipulations of the biliary tree.

Ticarcillin/clavulanic acid (3.1 g IV q4-6h) combines ticarcillin with the beta-lactamase inhibitor clavulanate. This combination extends the spectrum to include most Enterobacteriaceae and anaerobes, making it a useful antibiotic for intra-abdominal infections. It is second-line therapy for complicated soft-tissue infections. Ticarcillin/clavulanic acid may have a unique role in treating Stenotrophomonas. Alternative therapy with imipenem, cefepime, or a quinolone should be used when bacteria with AmpC-inducible beta-lactamases (i.e., Enterobacter, Citrobacter, Serratia, Providencia, Acinetobacter, and Morganella species) are identified as principal pathogens. Ticarcillin/clavulanic acid has a high sodium load for salt-sensitive patients.

Piperacillin/tazobactam (3.375 g IV q4-6h) combines piperacillin with the beta-lactamase inhibitor tazobactam. It has a similar spectrum and indications as ticarcillin/clavulanate plus activity against ampicillin-sensitive enterococci. Ticarcillin/clavulanate and piperacillin/tazobactam are not reasonable monotherapy for serious infections caused by Pseudomonas aeruginosaor nosocomial pneumonias; an aminoglycoside should be coadministered.

Adverse effects. All penicillin derivatives have been associated with anaphylaxis, interstitial nephritis, anemia, and leukopenia. Oxacillin and nafcillin can cause hepatitis. Ticarcillin can aggravate bleeding by interfering with platelet adenosine diphosphate receptors. Prolonged high-dose therapy ( > 2 weeks) is typically monitored with weekly serum creatinine and blood counts [liver function tests (LFTs) are included with oxacillin/nafcillin]. All patients should be asked about PCN or cephalosporin allergy. These agents should not be used in a patient with a reported allergy without prior skin testing or desensitization, or both.

Cephalosporins kill bacteria by interfering with cell wall synthesis by the same mechanism as PCNs. These agents are popular because of their low toxicity and broad spectrum of activity.

First-generation cephalosporins have

activity against staphylococci, streptococci, and community-acquired Escherichia coli, Klebsiella, and Proteus species.

limited efficacy against the other enteric gram-negative rods and anaerobes.

These agents are commonly used for treating OSSA osteomyelitis, pharyngitis, UTIs, and skin/soft-tissue infections.

IV Cefazolin(1-2 g IV/IM q8h), and cephalothin, cephapirin, and cephradine (1-2 g IV/IM q4-6h), have similar spectrums of activity and indications.

PO Cefadroxil (500 mg-1 g PO bid), cephalexin, and cephadrine (500 mg-1 g PO qid) are oral preparations of the parenteral first-generation cephalosporins.

Second-generation cephalosporins have expanded coverage against enteric gram-negative rods. They are divided into above-the-diaphragm and below-the-diaphragm agents.

Cefuroxime (1.5 g IV/IM q8h), cefonicid (1-2 g IV/IM qd), and cefamandole (1-2 g IV/IM q4-6h) are useful antibiotics above the diaphragm. They have reasonable staphylococcal and streptococcal activity in addition to an extended spectrum against gram-negative aerobes and are typically used for skin/soft-tissue infections, complicated UTIs, and community-acquired pneumonia (cefuroxime). They do not cover Bacteroides fragilis.

Cefoxitin (1-2 g IV q4-8h), cefotetan (1-3 g IV/IM q12h), and cefmetazole (2 g IV q6-12h) are below-the-diaphragm antibiotics. They do not have dependable staphylococcal or streptococcal activity. They have an extended spectrum against gram-negative aerobes and anaerobes including B. fragilis. These antibiotics are typically used for intra-abdominal or gynecologic surgical prophylaxis and infections, including diverticulitis and pelvic inflammatory disease. Cefoxitin has a unique role in the treatment of atypical mycobacterial infections.

Cefuroxime axetil (250-500 mg PO bid), cefprozil (250-500 mg PO bid), cefdinir (300 mg PO bid), and cefaclor(250-500 mg PO bid) are oral second-generation cephalosporins that are typically used for bronchitis, sinusitis, otitis media, UTIs, local soft-tissue infections, and step-down therapy for pneumonia or cellulitis that is responsive to parenteral second-generation cephalosporins. Cefdinir is approved for treating uncomplicated community-acquired pneumonia (when an atypical agent is not suspected). Loracarbef (200-400 mg PO q12-24h), technically a carbacephem rather than a cephalosporin, is used for the same indications as the oral second-generation cephalosporins, with the additional indication for uncomplicated pyelonephritis.

Third-generation cephalosporins have the broadest coverage for enteric, aerobic gram-negative rods and retain good activity against streptococci other than enterococci. They have moderate anaerobic activity but do not cover B. fragilis. Ceftazidime is the only third-generation cephalosporin that is useful for treating serious P. aeruginosa infections. Several of these agents have good CNS penetration and are useful in treating meningitis (see Chap. 14 ). Third-generation cephalosporins are not reliable for treatment of organisms with the AmpC-inducible beta-lactamases regardless of the results of susceptibility testing. These microbes should be treated with cefepime, carbapenems, or quinolones.

Ceftriaxone (1-2 g IV/IM q12-24h), cefotaxime (1-2 g IV/IM q4-12h), ceftizoxime (1-4 g IV/IM q8-12h), and cefoperazone (2-4 g IV q12h) are very similar to one another in spectrum and efficacy. They are used as empiric therapy for pyelonephritis, urosepsis, pneumonia, intra-abdominal infections (combined with metronidazole), gonorrhea, and meningitis (ceftriaxone and cefotaxime). They are also used for osteomyelitis, septic arthritis, endocarditis, and soft-tissue infections once an organism has been identified. OSSA should be treated with oxacillin or a first-generation cephalosporin rather than these agents. Ceftizoxime is the most convenient agent in dialysis patients, as it is eliminated exclusively by the kidneys. Dialysis patients with infections other than meningitis should receive a 2-g initial dose followed by 1-2 g at the end of each dialysis session. This feature can be exploited to avoid placement of additional venous access.

Cefixime (400 mg PO qd), cefpodoxime proxetil (100-400 mg PO bid), and ceftibuten (400 mg PO qd) are oral third-generation cephalosporins. They are useful drugs for bronchitis and complicated sinusitis, otitis media, and UTIs. These agents are reasonable step-down therapy for pneumonia that is responsive to the parenteral third-generation cephalosporins. Cefpodoxime proxetil is approved for uncomplicated community-acquired pneumonia. Cefixime and cefpodoxime have roles in the management of gonorrhea.

Ceftazidime (1-2 g IV/IM q8h) is a drug of choice for infections caused by susceptible P. aeruginosa. Pseudomonas UTIs can be treated with lower doses (500 mg IV/IM q12h).

Cefepime (500 mg-2 g IV/IM q8-12h) is a fourth-generation cephalosporin that has excellent aerobic gram-negative rod coverage, including P. aeruginosa and bacteria with AmpC-inducible beta-lactamases. Its gram-positive spectrum and anaerobe coverage are similar to those of the third-generation cephalosporins. Cefepime is routinely used for empiric therapy in febrile neutropenic patients. It has a role in treating antibiotic-resistant gram-negative bacteria and polymicrobial infections in any site except the CNS, where clinical experience is lacking.

Metronidazole should be given with cefepime for intra-abdominal infections.

Adverse effects. All cephalosporins have been associated with anaphylaxis, interstitial nephritis, anemia, and leukopenia. All patients should be asked about PCN or cephalosporin allergies. Patients who are allergic to PCNs have a 10% incidence of a cross-hypersensitivity reaction to cephalosporins. These agents should not be used in a patient with a reported allergy without prior skin testing or desensitization, or both. Prolonged therapy ( > 2 weeks) is typically monitored with a weekly serum creatinine and CBC. Ceftriaxone (and possibly cefoperazone) can cause biliary sludging and symptomatic gallbladder disease, requiring discontinuation of the medication. Cefamandole, cefmetazole, cefoperazone, and cefotetan have an N-methylthiotetrazole side chain that interferes with vitamin K-dependent clotting factor metabolism and is associated with disulfiram-like reactions with ethanol intake. N-methylthiotetrazole-containing cephalosporins should be avoided when a prolonged course of therapy is likely, as a significant coagulopathy may develop.

Aztreonam (1-2 g IV/IM q6-12h) is a monobactam that is active only against aerobic gram-negative rods including P. aeruginosa. It has no gram-positive or anaerobic activity. Aztreonam is useful in patients with known PCN or cephalosporin allergies, as no apparent cross reactivity is present.

Carbapenems kill bacteria by interfering with cell wall synthesis, similar to PCNs and cephalosporins. They are among the antibiotics of choice for infections caused by organisms with the AmpC-inducible beta-lactamases and have good activity against P. aeruginosa. They are important agents for treatment of antibiotic-resistant bacterial infections at any site except the CNS, where drug penetration is borderline and seizures likely. They are commonly used for severe polymicrobial infections including Fournier's gangrene, intra-abdominal catastrophes, and sepsis in compromised hosts. Carbapenems are active against most gram-positive and gram-negative bacteria including anaerobes. Notably resistant bacteria include ampicillin-resistant enterococci, oxacillin-resistantS. aureus (ORSA), Stenotrophomonas, and Burkholderia species.

Imipenem (500 mg-1 g IV/IM q6-8h) and meropenem (1 g IV q8h) are the two currently available parenteral carbapenems and have a similar spectrum of activity, toxicity, and indications.

Adverse effects. Carbapenems can precipitate seizure activity or confusion, or both, in older patients, patients on dialysis, and patients with pre-existing seizure disorders or CNS pathology. Carbapenems should be avoided in these patients unless no reasonable alternative therapy is available. Like cephalosporins, carbapenems have been associated with anaphylaxis, interstitial nephritis, anemia, and leukopenia. All patients should be asked about PCN or cephalosporin allergy. Patients who are allergic to PCNs/cephalosporins infrequently have a cross-hypersensitivity reaction to carbapenems; however, these agents should not be used in a patient with a reported severe allergy without prior skin testing, desensitization, or both. Prolonged therapy ( > 2 weeks) is typically monitored with a weekly serum creatinine, LFTs, and CBC.

Aminoglycosides kill bacteria by binding to the bacterial ribosome, causing misreading during translation of bacterial messenger RNA into proteins. These drugs are commonly used in severe infections caused by gram-positive and gram-negative aerobes as a second agent until the patient's condition stabilizes. Prolonged therapy is indicated for patients with endovascular infections caused by enterococcus species or PCN/cephalosporin-resistant streptococci. Aminoglycosides tend to be synergistic with cell wall-active antibiotics such as penicillins, cephalosporins, and vancomycin. They are ineffective in the low pH/low oxygen environment of abscesses and do not have activity against anaerobes. Use of these antibiotics is limited by significant nephro- and ototoxicities. Resistance to one aminoglycoside is not routinely associated with resistance to all members of this class, and in cases of serious infections, susceptibility testing with each aminoglycoside is appropriate.

Traditional dosing of aminoglycosides is q8h, with the upper end of the dose range reserved for life-threatening infections. Peak and trough levels should be obtained with the third or fourth dose and then every 3-4 days, along with a serum creatinine. Increasing serum creatinine or peak/troughs out of the acceptable range requires immediate attention. Traditional dosing should be used for pregnant patients and for those with endocarditis, burns that cover more than 20% of the body, cystic fibrosis (CF), anasarca, and creatinine clearance (ClCr ) of less than 20 ml/minute. For all other indications extended-interval dosing is more convenient for the patient and the physician.

Extended-interval dosing of aminoglycosides is an alternative method of administration. Extended-interval doses are given in the following sections with each drug. A drug level is obtained 6-14 hours after the first dose, and the nomogram ( Fig. 13-1 ) is consulted to determine the dosing interval. Monitoring includes obtaining a drug level at 6-14 hours after the dosage every week and a serum creatinine three times a week. In patients who are not responding to therapy, a 12-hour level should be checked, and if that level is undetectable, extended-interval dosing should be abandoned in favor of traditional dosing. For obese patients [actual weight > 20% above ideal body weight (IBW)] (see Chap. 2 for calculation of IBW) an obese dosing weight must be used for determining doses in either traditional or extended-interval dosing.

Specific agents

Gentamicin is the least expensive antibiotic in this class. Traditional dosing is an initial loading dose of 2 mg/kg IV (3 mg/kg in the critically ill) followed by 1.0-1.7 mg/kg IV q8h (peak, 4-10 mu g/ml; trough, < 2 mu g/ml). Extended-interval dosing is 5 mg/kg, with interval determined by nomogram.

Tobramycin tends to be favored by physicians who treat CF patients. Traditional dosing is an initial loading dose of 2 mg/kg IV (3 mg/kg in the critically ill) followed by 1.0-1.7 mg/kg IV q8h (peak, 4-10 mu g/ml; trough, < 2 mu g/ml). Extended-interval dosing is 5 mg/kg, with interval determined by nomogram. Tobramycin is also available as an inhalational agent for adjunctive therapy for patients with CF or bronchiectasis complicated by P. aeruginosa infection (300-mg inhalation bid).

Amikacin has an additional unique role in mycobacterial and Nocardia infections. Traditional dosing is an initial loading dose of 5.0-7.5 mg/kg IV (9 mg/kg in the critically ill) followed by 5 mg/kg IV q8h or 7.5 mg/kg IV q12h (peak, 20-35 mu g/ml; trough, < 10 mu g/ml). Extended-interval dosing is 15 mg/kg, with the interval determined by nomogram.

Streptomycin is most commonly used for treating drug-resistant tuberculosis (TB; 15 mg/kg/day IM; maximum dose per day is 1 g for daily dosing and 1.5 g for twice- or thrice-weekly dosing) and enterococcal endocarditis (7.5 mg/kg IM/IV q12h; maximum, 500 mg q12h). It generally has less gram-negative activity than the other aminoglycosides and no activity against P. aeruginosa. Other indications for streptomycin (tularemia, brucellosis, plague) have largely been supplanted by gentamicin or nonaminoglycoside antibiotic therapy.

Adverse effects. Nephrotoxicity is the major adverse effect of aminoglycosides. If possible, prolonged therapy with aminoglycosides should be monitored by physicians who routinely administer home IV therapy with systematic monitoring of patients' laboratory studies. Nephrotoxicity is reversible when detected early but can be permanent, especially in patients with tenuous renal function due to other medical conditions. Aminoglycosides should be avoided in patients with decompensated liver disease except for life-threatening infections (Gastroenterology 82:97, 1982 ). Ototoxicity (vestibular or cochlear) is less of a problem but requires weekly hearing tests with extended therapy ( > 7-14 days). Streptomycin is unique in that it causes more ototoxicity with a lower risk of nephrotoxicity. One should avoid giving aminoglycosides with other known nephrotoxic agents (i.e., amphotericin, foscarnet, nonsteroidal anti-inflammatory drugs, pentamidine, polymyxins, cidofovir, and cisplatin).

Vancomycin (15 mg/kg IV q12h; 30 mg/kg IV q12h for meningitis) is a glycopolypeptide antibiotic that kills gram-positive bacteria by interfering with cell wall synthesis. The goal trough should be 5 mu g/ml or greater. Peak levels should only be measured in critically ill patients, with a goal of 20-40 mu g/ml. Dialysis patients should receive a single dose and then be redosed when the level drops below 10-15 mu g/ml. It binds a D-alanyl-D-alanine precursor that is critical for peptidoglycan cross linking in most gram-positive (not gram-negative) bacterial cell walls. Vancomycin is bacteriostatic for enterococci. Vancomycin was the only antibiotic with efficacy against many enterococci and ORSA until the approval of quinupristin/dalfopristin and linezolid. Several factors, including the emergence of resistant nosocomial pathogens, the low toxicity of vancomycin, and its ease of administration, led to an overuse of vancomycin and the evolution of vancomycin-resistant bacteria.

Indications for usage. Today, most hospitals have serious problems with vancomycin-resistant Enterococcus faecium (VRE), and reports of vancomycin intermediate-sensitivity S. aureus (VISA) are increasing. With the continued use of vancomycin, it is possible that S. aureus will acquire vancomycin resistance, generating a difficult-to-treat, virulent nosocomial pathogen. Therefore, vancomycin should be restricted to use in the following circumstances: (1) treatment of serious infections caused by ORSA, (2) treatment of serious infections caused by ampicillin-resistant enterococci, (3) treatment of serious infections caused by gram-positive bacteria in patients who are allergic to all other appropriate therapies, (4) oral treatment of Clostridium difficile colitis that has not responded to two courses (10 days each) of metronidazole or failing metronidazole with a potentially life-threatening colitis, (5) surgical prophylaxis for placement of prosthetic devices at institutions with known high rates of ORSA or in patients who are known to be colonized with ORSA, (6) empiric use in meningitis until an organism has been identified and sensitivities done if the pathogen is pneumococcus, and (7) life-threatening sepsis syndrome in a patient with known ORSA colonization or extended hospitalization until pathogen(s) are identified. Vancomycin should not be used routinely in the following circumstances: (1) routine surgical prophylaxis, (2) empiric therapy for nonseptic neutropenic fever, (3) treatment of single blood culture isolates of coagulase-negative staphylococcus or treatment of coagulase-negative staphylococcus blood cultures in cases in which the site of infection is inconsistent with the organism (e.g., community-acquired pneumonia and intra-abdominal infection), (4) routine treatment of C. difficile colitis, (5) to complete a course of therapy in the absence of ORSA or ampicillin-resistant enterococci, (6) to prophylax against catheter infection, and (7) use in topical application or irrigation. In dialysis patients, vancomycin use should be avoided in clinical situations in which ORSA is unlikely. Vancomycin should also be avoided in small localized infections (e.g., cellulitis, carbuncles) well away from graft sites or catheters. Ceftizoxime (2 g IV/IM, then 1-2 g after hemodialysis) is convenient therapy for community-acquired pneumonia, intra-abdominal infections (with metronidazole), and many soft-tissue infections. For more serious infections ceftizoxime can be given with a single dose of aminoglycoside (gentamicin or tobramycin, 1.5-2.0 mg/kg). For uncomplicated soft-tissue infections, cefprozil (500 mg PO q12h for 2 doses, then 500 mg PO qd), cefdinir (300 mg PO q12h for 2 doses, then 300 mg PO qd), dicloxacillin (500 mg PO qid), or clindamycin (450 mg PO tid) are reasonable therapies for dialysis patients with good insight and follow-up.

Adverse effects. Vancomycin is typically given by slow infusion over at least 1 hour. Infusion rates of greater than 10 mg/minute can cause the red man syndrome (flushing of the upper body).

Fluoroquinolones kill bacteria by inhibiting bacterial DNA gyrase and topoisomerase, which are critical for DNA replication. In general these antibiotics are well absorbed orally, with serum levels that approach those of parenteral therapy. With the addition of new fluoroquinolones, the spectrum of activity in this class of antibiotics rivals that of the cephalosporins. These agents typically have poor activity against enterococci, although they may have some efficacy for UTIs when other agents are inactive or contraindicated. Newer fluoroquinolones have activity against OSSA but should be considered only when oxacillin, nafcillin, and first-generation cephalosporins are contraindicated or inactive. Enoxacin (400 mg), ciprofloxacin (500 mg), or ofloxacin (400 mg) can be used as single-dose therapy to treat gonorrhea. Aluminum- and magnesium-containing antacids, sucralfate, bismuth, oral iron, oral calcium, and oral zinc preparations can markedly impair absorption of oral quinolones.

Norfloxacin (400 mg PO q12h), enoxacin (200-400 mg PO q12h), and lomefloxacin (400 mg PO qd) are useful for the treatment of UTIs caused by gram-negative rods. These agents are not used to treat systemic infections.

Ciprofloxacin (250-750 mg PO q12h or 200-400 mg IV q12h) and ofloxacin (200-400 mg IV or PO q12h) are active against gram-negative aerobes including AmpC pathogens. Ciprofloxacin is the most active quinolone against P. aeruginosa and is the quinolone of choice for serious infections with that pathogen. It has relatively poor activity against gram-positive cocci and anaerobes and should not be used for empiric therapy for community-acquired pneumonia or for treating OSSA. These agents are commonly used for UTIs, pyelonephritis, infectious diarrhea, prostatitis, and intra-abdominal infections (with metronidazole). They are second-line agents for TB therapy. Oral and IV therapy give similar maximum serum levels.

Levofloxacin (250-500 mg PO or IV q24h), sparfloxacin (400 mg PO once, then 200 mg PO qd), gatifloxacin (400 mg PO/IV qd), and moxifloxacin (400 mg PO qd) are newer fluoroquinolones with improved coverage of aerobic gram-positive bacteria (streptococci, staphylococci, and enterococci), with less gram-negative activity (especially against P. aeruginosa) than ciprofloxacin. Sparfloxacin, gatifloxacin, and moxifloxacin also have reasonable anaerobic activity, possibly expanding their role in mixed aerobic/anaerobic infections. Overall, these agents can be thought of as above-the-diaphragm quinolones that are useful for sinusitis, bronchitis, or chronic obstructive pulmonary disease exacerbations; community-acquired pneumonia; UTIs; and pyelonephritis. They are reasonable therapy for soft-tissue infections if penicillins or cephalosporins are inactive or contraindicated. The newer quinolones should not be used routinely to treat diabetic foot infections/osteomyelitis until clinical trials support their use for this indication. Some of these agents have reasonable activity against mycobacteria and have a potential role in treating drug-resistant TB and atypical mycobacterial infections.

Trovafloxacin/alatrofloxacin (200-400 mg PO/IV; PO and IV dosing are equivalent) has the broadest spectrum of the quinolones including gram-positive aerobes/anaerobes and gram-negative aerobes/anaerobes including B. fragilis. Its spectrum of activity is comparable to that of the carbapenems and can be used for polymicrobial infections at any site except the CNS and osteomyelitis, where clinical experience is lacking. This antibiotic should be reserved for severe pulmonary, intra-abdominal, and soft-tissue infections. This agent is one of the drugs of choice for severely ill patients with PCN or cephalosporin allergies. Unfortunately, since its original approval trovafloxacin has been associated with rare cases of hepatotoxicity, resulting in liver transplant or death. For this reason its use has been restricted to "treatment of serious infections in hospitalized patients where alternative therapies are not available." LFTs should be performed every 3-4 days and therapy limited to 14 days.

Adverse effects. The principal adverse reactions with fluoroquinolones include nausea, CNS disturbances (drowsiness, headache, restlessness, and dizziness, especially in the elderly), rashes, and phototoxicity. The use of sparfloxacin and lomefloxacin requires an explicit warning to patients about photosensitivity reactions. Sparfloxacin and moxifloxacin can cause prolongation of the QT interval and should not be used in patients with known conduction abnormalities on ECG or in those who are taking medications that prolong the QT interval or induce bradycardia. Sparfloxacin and moxifloxacin should be used cautiously in the elderly, in whom asymptomatic conduction disturbances are more common. Trovafloxacin/alatrofloxacin requires careful monitoring of the liver function profile because of rare, fatal drug-associated hepatitis. Fluoroquinolones should not be used in patients younger than 18 years or in pregnant or lactating women. They cause an age-related arthropathy and should be discontinued in patients in whom joint pain or tendonitis (Achilles tendon) develops. This class of antibiotics has major drug interactions (see Appendix C ).

Macrolide antibiotics are bacteriostatic agents that block protein synthesis in bacteria by binding the 50S subunit of the bacterial ribosome. These antibiotics are commonly used to treat pharyngitis, otitis media, sinusitis, and bronchitis, especially in PCN-allergic patients. They are also among the drugs of choice for treating Legionella, Chlamydia, and Mycoplasma infections. The newer macrolides are reasonable therapy for community-acquired pneumonia and have a unique role in the treatment of Mycobacterium avium complex (MAC) infections in HIV patients. This class of antibiotics has good activity against gram-positive cocci and upper respiratory gram-negative bacteria, with no meaningful activity against enteric gram-negative rods.

Erythromycin (250-500 mg PO qid or 0.5-1.0 g IV q6h; poorly tolerated through peripheral veins) is commonly used to treat bronchitis, pharyngitis, sinusitis, otitis media, and soft-tissue infections in PCN-allergic patients. It has good activity against gram-positive cocci except enterococci. Erythromycin is effective for treatment of atypical respiratory tract infections due to Legionella pneumophila (1 g IV q6h), Chlamydia pneumoniae, and Mycoplasma pneumoniae. It is also used in treatment of Chlamydia trachomatis (500 mg PO qid × 7 days) and as an alternate therapy for syphilis in PCN-allergic patients. Usefulness of this antibiotic for upper and lower respiratory tract infections is hampered by significant resistance among Haemophilus influenzae and Moraxella catarrhalis isolates.

Dirithromycin (500 mg PO qd) has a similar spectrum of activity and clinical application as erythromycin with the convenience of once-a-day dosing. It is not used in treatment of sexually transmitted diseases. It does not have the numerous drug interactions seen with erythromycin and clarithromycin and can be used instead of erythromycin to avoid drug interactions.

Clarithromycin (250-500 mg PO bid) has a spectrum of activity similar to that of erythromycin but with enhanced activity against upper respiratory pathogens (Moraxellaand Haemophilus). It is commonly used to treat bronchitis, sinusitis, otitis media, pharyngitis, soft-tissue infections, and community-acquired pneumonia. It has a prominent role in treating MAC infections in HIV patients and is an important component of regimens used to eradicate Helicobacter pylori (see Chap. 17 ).

Azithromycin [500 mg PO × 1 day, then 250 mg PO qd × 4 days (Zpack); 250-500 mg PO qd; 500 mg IV qd] is very similar to clarithromycin in spectrum and indications. It has a prominent role in MAC prophylaxis (1200 mg PO qwk) and treatment (250-500 mg PO qd) in HIV patients. It is commonly used to treat C. trachomatis infections (1 g PO × 1 day). It does not have the numerous drug interactions seen with erythromycin and clarithromycin.

Clindamycin (150-450 mg PO tid-qid or 600-900 mg IV q8h) is a lincosamide with a predominantly gram-positive spectrum similar to that of erythromycin plus activity against most anaerobes including B. fragilis. It has excellent oral bioavailability, 90%, and penetrates into bone and abscess cavities. Clindamycin is commonly used in children to treat osteomyelitis. In adults it is used as monotherapy for lung abscesses. A significant number of ORSA isolates remain susceptible to clindamycin. It is typically used as the second agent in combination therapy when anaerobic infections (peritonsillar/retropharyngeal abscesses, necrotizing fasciitis, recurrent group A streptococcal pharyngitis) are suspected. Metronidazole is more commonly used for intra-abdominal infections. Clindamycin has additional uses, including treatment of babesiosis (in combination with quinine), treatment of toxoplasmosis (in combination with pyrimethamine), and treatment of Pneumocystis carinii pneumonia (PCP; in combination with primaquine).

Adverse effects. Macrolides are associated with nausea, abdominal cramping (less common with clarithromycin, azithromycin, and clindamycin), and LFT abnormalities. Liver function profiles should be checked intermittently during extended therapy. Hypersensitivity reactions with prominent skin rash are more commonly seen with clindamycin, as is pseudomembranous colitis. Erythromycin and clarithromycin have multiple drug interactions, including potentially fatal arrhythmias, when used with certain medications (i.e., cisapride, digoxin). This class of antibiotics has major drug interactions (see Appendix C ).

Sulfamethoxazole, sulfadiazine, sulfisoxazole, trimetrexate, and trimethoprim slowly kill bacteria by inhibiting folic acid metabolism. This class of antibiotics is most commonly used for uncomplicated UTIs, sinusitis, and otitis media. They have unique roles in treatment of PCP, Nocardia, Toxoplasma, and Stenotrophomonas infections.

Sulfamethoxazole (2 g PO, then 1 g PO q12h), sulfisoxazole (1 g PO q6h), and trimethoprim (100 mg PO bid) are occasionally used to treat UTIs as monotherapy. These drugs are more logically used in combination preparations outlined in the following sections. Trimethoprim in combination with dapsone is an alternate therapy for mild PCP pneumonia (see Chap. 15 ).

Trimethoprim-sulfamethoxazole is a combination antibiotic (IV or PO) with a 1:5 ratio of trimethoprim to sulfamethoxazole. The IV preparation is dosed at 5 mg/kg IV q8h (based on the trimethoprim content) for serious infections. The oral preparations [160 mg trimethoprim/800 mg sulfamethoxazole per double-strength (DS) tablet] are almost completely bioavailable, and similar drug levels can be obtained by taking 5 mg/kg q8h PO. Both components have excellent tissue penetration, including bone, prostate, and CNS. The combination has a broad spectrum of activity but typically does not inhibit P. aeruginosa or anaerobes. It is the therapy of choice for PCP pneumonia (see Chap. 15 ), Stenotrophomonas maltophilia, Trophermyma whippleii, and Nocardia infections. It is commonly used for treating sinusitis, otitis media, bronchitis, prostatitis, and UTIs (1 DS PO bid). Some strains of ORSA remain susceptible to trimethoprim-sulfamethoxazole. It is used as PCP prophylaxis (1 DS PO twice a week, 3 times a week, or daily) in transplant patients, bone marrow transplant patients, patients receiving fludarabine, and HIV patients. IV therapy is routinely converted to the PO equivalent for patients who require prolonged therapy (PCP, Actinomyces,Nocardia). For serious infections such as Nocardiabrain abscesses, it is useful to monitor sulfamethoxazole peaks (100-150 mu g/ml) and troughs (50-100 mu g/ml) occasionally during the course of therapy and to adjust dosing accordingly. In patients with renal insufficiency, doses can be adjusted by following trimethoprim peaks (5-10 mu g/ml). Prolonged therapy can cause bone marrow suppression, requiring treatment with leucovorin, 5-10 mg PO qd until cell counts normalize.

Sulfadiazine (1.0-1.5 g PO q6h) in combination with pyrimethamine (200 mg PO followed by 50-75 mg PO qd) and leucovorin (10-20 mg PO qd) is the therapy of choice for toxoplasmosis. Sulfadiazine is occasionally used in Nocardia infections.

Trimetrexate (45 mg/m2 IV qd) combined with leucovorin (20 mg/m2 PO or IV q6h continued for 3 days after the last dose of trimetrexate) is an alternate therapy for PCP pneumonia. Bone marrow suppression, renal insufficiency, and hepatotoxicity may occur.

Adverse effects. These drugs are associated with cholestatic jaundice, bone marrow suppression, interstitial nephritis, and severe hypersensitivity reactions (Stevens-Johnson/erythema multiforme). Nausea is common with higher doses. All patients should be asked whether they are allergic to "sulfa drugs," and specific commercial names should be mentioned (i.e., Bactrim or Septra).

Chloramphenicol (12.5-25.0 mg/kg IV q6h; maximum, 1 g IV q6h) is a bacteriostatic antibiotic that binds to the 50S ribosomal subunit, blocking protein synthesis in susceptible bacteria. It has broad activity against aerobic and anaerobic gram-positive and gram-negative bacteria, including S. aureus, enterococci, and enteric gram-negative rods. It also is active against Spirochetes, Rickettsia, Mycoplasma, and Chlamydia. Today it is used almost exclusively for serious VRE infections. Adverse effects include idiosyncratic aplastic anemia (¬1/30,000) and dose-related bone marrow suppression as the principal toxicities. Peak drug levels (1 hour postinfusion) should be checked every 3-4 days (goal peak < 25) and doses adjusted accordingly. Dosage adjustment is necessary in the presence of significant liver disease. This class of antibiotics has major drug interactions (see Appendix C ).

Metronidazole (250-750 mg PO/IV q8h) kills anaerobic bacteria and some protozoa by accumulation of toxic metabolites that interfere with multiple biological processes. It has excellent tissue penetration, including abscess cavities, bone, and CNS. Metronidazole has greater activity against gram-negative than gram-positive anaerobes but is active against Clostridium perfringens and difficile. It is used as monotherapy to treat C. difficile colitis and bacterial vaginosis and in combination with other antibiotics to treat intra-abdominal infections and brain abscesses (see Chap. 14 ). Protozoan infections that are routinely treated with metronidazole include Giardia, Entamoeba histolytica, and Trichomonas vaginalis. A dose reduction may be warranted for patients with decompensated liver disease. Adverse effects include nausea, dysgeusia, disulfiram-like reactions to alcohol, and mild CNS disturbances (headache, restlessness). Rarely, this medication is associated with seizures and peripheral neuropathy.

Tetracyclines are bacteriostatic antibiotics that bind the 30S ribosomal subunit blocking protein synthesis. These agents have unique roles in the treatment of Rickettsia, Chlamydia, Nocardia, and Mycoplasma infections. They are used as therapy for Lyme-related arthritis and as alternate therapy for syphilis and P. multocida in PCN-allergic patients. Their general use is limited because of widespread resistance among more common bacterial pathogens.

Tetracycline (250-500 mg PO q6h) is commonly used for severe acne and some Helicobacter pylori eradication regimens (see Chap. 17 ). Aluminum- and magnesium-containing antacids and preparations containing oral calcium, oral iron, or other cations can significantly impair oral absorption. Milk and antacids should be avoided within 2 hours of the dose. It can be used for treatment of acute Lyme borreliosis, Rocky Mountain spotted fever, psittacosis, Mycoplasma pneumonia, Chlamydia pneumonia (TWAR), and chlamydial infections of the eye or genitourinary tract, but these infections are generally treated with doxycycline or other antibiotics.

Doxycycline (100 PO/IV q12h) is the most commonly used tetracycline. It is standard therapy for C. trachomatis, Rocky Mountain spotted fever, ehrlichiosis, and psittacosis.

Minocycline (200 mg IV/PO, then 100 mg IV/PO q12h) is similar to doxycycline in its spectrum of activity and clinical indications. It is second-line therapy for pulmonary nocardiosis and cervicofacial actinomycosis.

Adverse effects. Nausea and photosensitivity are common side effects. Patients should be warned about sun exposure. Rarely, these medications are associated with pseudotumor cerebri. They cannot be given to children because they can cause tooth enamel discoloration.

Streptogramins are a new class of marginally bactericidal antimicrobial agents that complex with bacterial ribosomes to inhibit protein synthesis.

Quinupristin/dalfopristin (7.5 mg/kg IV q8h) is the only U.S. Food and Drug Administration (FDA)-approved drug in this class. This antibiotic combination gained FDA approval largely because of its activity against antibiotic-resistant gram-positive organisms, especially VRE, ORSA, VISA, and antibiotic-resistant strains of Streptococcus pneumoniae. It has some activity against gram-negative upper respiratory pathogens (Haemophilusand Moraxella) and anaerobes, but more appropriate antibiotics are available to treat these infections. Quinupristin/dalfopristin should be reserved for serious infections with ORSA and S. pneumoniae when vancomycin cannot be tolerated. Quinupristin/dalfopristin is bacteriostatic for enterococci. It may be first-line therapy for serious infections with VISA and VRE (it has little activity against Enterococcus faecalis), although chloramphenicol remains reasonable therapy for VRE in settings in which it remains susceptible. For VRE peritonitis in continuous ambulatory peritoneal dialysis patients, IV therapy is combined with 25 mg/L quinupristin/dalfopristin in alternate dialysis bags (Lancet 344:1025, 1994 ).

In polymicrobial infections (in which a resistant organism has been identified or strongly suspected), consideration should be given to an additional agent such as a quinolone or cephalosporin to improve the gram-negative coverage. This antibiotic (or linezolid) may be the drug of choice if the much-feared debut of vancomycin-resistantS. aureus comes to pass.

Adverse effects include arthralgias and myalgias, which occur frequently and can force discontinuation of therapy. IV site pain and thrombophlebitis are common when the drug is administered through a peripheral vein. Quinupristin/dalfopristin has been associated with increased bilirubin levels. It is primarily cleared by hepatic metabolism and likely requires dose adjustment with significant hepatic impairment, but data are currently lacking. This drug should be avoided if possible in the setting of decompensated liver disease. Quinupristin/dalfopristin is similar to erythromycin in regard to drug interactions (see Appendix C ).

Oxazolidinones are a new class of marginally bactericidal antibiotics that block assembly of bacterial ribosomes to inhibit protein synthesis.

Linezolid(600 mg IV/PO bid; IV/PO drug levels are equivalent) is the only FDA-approved drug in this class. It has good activity against aerobic and anaerobic gram-positive bacteria, including drug-resistant enterococci, staphylococci, and streptococci. It has no meaningful activity against the Enterobacteriaceae and borderline activity against Moraxella and H. influenzae. A second agent such as a cephalosporin or quinolone should be considered for mixed infections. Clinical experience with this antibiotic has not been extensive. In early use it has shown excellent activity in VRE infections. Its activity against ORSA is comparable to that of vancomycin. Its use should be restricted to serious infections with VRE, patients with an indication for vancomycin therapy who are intolerant of that medication, and possibly for ORSA cellulitis (400 mg PO bid) when IV access is an issue. Use of this medication for other applications such as osteomyelitis and endocarditis cannot be recommended without supporting data. Resistance does develop to this antibiotic, and it is imperative that abscesses be adequately drained to minimize this risk. Linezolid is well tolerated. Its principal adverse effects are diarrhea, nausea, headaches, and thrombocytopenia that rarely limit therapy. A CBC, serum creatinine, and LFTs should probably be checked every 1-2 weeks during prolonged therapy with this new agent. Linezolid is a mild monoamine oxidase inhibitor. Patients should be advised to avoid over-the-counter cold remedies that contain pseudoephedrine or phenylpropanolamine, as coadministration with linezolid can elevate blood pressure. Linezolid does not require dose adjustments for renal or hepatic dysfunction.

Fosfomycin (3-g sachet dissolved in cold water PO once) is a bactericidal oral antibiotic approved for treatment of uncomplicated UTIs. It kills bacteria by inhibiting an early step in cell wall synthesis and has an impressive spectrum of activity that includes all the major urinary pathogens and difficult-to-treat organisms, including P. aeruginosa, Enterobacter species, and enterococci (including VRE). It has formal FDA approval for treating uncomplicated UTIs in women with susceptible strains of E. coli and E. faecalis. It should not be used to treat pyelonephritis or systemic infections. It should only be administered once, as therapeutic drug levels are maintained in the urine for approximately 48 hours and repeat dosing does not improve clinical outcomes. No guidelines have been formulated for its use in significant renal impairment. Diarrhea is the most common adverse effect. Fosfomycin should not be taken with metoclopramide or cisapride, as they interfere with fosfomycin absorption.

Nitrofurantoin macrocrystals (50-100 mg PO qid for 5-7 days) are a bactericidal oral antibiotic useful for uncomplicated UTIs except those caused by Proteusspecies. The drug is metabolized by bacteria into toxic intermediates that inhibit multiple bacterial processes. This drug has had a modest resurgence, as it is frequently effective against uncomplicated VRE UTIs. It has no activity against P. aeruginosa or Serratia species. Although the drug was commonly used in the past for "UTI suppression" therapy, this should be avoided, as prolonged therapy is associated with chronic pulmonary syndromes that can be fatal. This drug should not be used for pyelonephritis or any other systemic infections. Adverse effects include nausea as the most common side effect. The drug should be taken with food to minimize this problem. Patients should be warned that their urine may become brown secondary to the medication. It should not be used with elevated serum creatinine, as the risk for development of treatment-associated neuropathy may be increased. Pulmonary toxicities are associated with prolonged therapy. Nitrofurantoin should not be given with probenecid, as this combination decreases the concentration of nitrofurantoin in the urine.

Methenamine[methenamine hippurate or methenamine mandelate; 1 or 2 tablets (depending on the specific preparation) PO qid] is a urine/bladder antiseptic that is converted into formaldehyde in the urine when the pH is less than 6.0. The pharmacy or package insert for the specific preparation should be consulted for dosing. Because the active drug is formaldehyde, nearly all bacteria and fungi are potentially susceptible to therapy. The formaldehyde is generated while the urine is retained in the bladder; therefore, methenamine is effective only in the lower urinary tract, and its efficacy is impaired in the setting of a draining Foley catheter. These drugs are rarely used because of the large number of alternative antibiotics that are available today. They do have a limited role in treating uncomplicated UTI caused by multiple drug-resistant bacteria or yeast. Urine pH should be obtained once early in therapy. Adverse effects include bladder irritation, dysuria, and hematuria with prolonged use. Therapy should be limited to a maximum of 3 weeks at a time. This drug is contraindicated in the setting of glaucoma, significant renal insufficiency, and acidosis. It should not be given concomitantly with sulfonamides, as these drugs form an insoluble precipitate in the urine.

Colistimethate (polymyxin E; IV therapy is 2.5-5.0 mg/kg/day divided into 2-4 doses; maximum dose, 5 mg/kg/day) and polymyxin B [12,000-15,000 units/kg/day by continuous infusion (500,000 units in 500 ml 5% dextrose in water, adjust rate to achieve desired daily dosing)] are bactericidal polypeptide antibiotics that kill by disrupting the cell membrane of gram-negative bacteria. These drugs have roles in the treatment of multiple drug-resistant gram-negative rods, predominantly P. aeruginosa, in patients with CF or bronchiectasis. These medications should only be given under the guidance of an experienced clinician, as parenteral therapy has significant CNS side effects and potential nephrotoxicity. Inhaled colistimethate (75 mg given by standard nebulizer tid) is better tolerated, with only mild upper airway irritation, and has some efficacy as adjunctive therapy for P. aeruginosa (J Antimicrob Chemother 19:831, 1987 ). Adverse effects with parenteral therapy include paresthesias, slurred speech, peripheral numbness, tingling, and significant dose-dependent nephrotoxicity. The package insert or appropriate text should be consulted for dosing for patients with renal insufficiency, as overdosage in this setting can result in neuromuscular blockade and apnea. If CNS side effects are significant with bid dosing of colistimethate, qid dosing or continuous infusion (total daily dose in 500 ml 5% dextrose in water infused over 24 hours) should be arranged. Serum creatinine should be monitored daily early in therapy and then at a regular interval for the duration of therapy. These antibiotics should not be coadministered with aminoglycosides, other known nephrotoxins, or neuromuscular blockers.