Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, and Metronidazole

JERRY D. SMILACK, M.D.,* WALTER R. WILSON, M.D., Division ofInfectious Diseases and Internal Medicine; FRANKLIN R. COCKERILL III, M.D., Division of Infectious Diseases and Internal Medicine and Section of Clinical Microbiology The tetracyclines are effective in the treatment of Chlamydia, Mycoplasma pneumoniae, and rickettsial infections and also can be used for gonococcal infections in patients unable to tolerate penicillin. These drugs may cause gastrointestinal irritation, diarrhea, phototoxic dermatitis, and vestibular damage, and fatal reactions due to hepatotoxicity have occurred in pregnant women. Chloramphenicol has a broad spectrum of bacteriostatic activity, but its association with suppression of the bone marrow and aplastic anemia has relegated it to a historical role. Erythromycin is the drug of choice for the treatment of infections caused by M. pneumoniae, Legionella species, group A ~-hemolytic streptococci, and Streptococcus pneumoniae. The frequency of serious adverse effects associated with the use of erythromycin is low; dose-related epigastric distress may occur. Clindamycin is bactericidal to most nonenterococcal gram-positive aerobic bacteria and many anaerobic microorganisms. Although historically it was a frequent cause of antibiotic-associated diarrhea and colitis, cIindamycin is considered an excellent alternative to ~-Iactam antibiotics for treatment of many staphylococcal infections, and it has therapeutic utility in anaerobic infections and in several protozoan infections in immunosuppressed patients. Metronidazole is efficacious for treating nonpulmonary anaerobic infections, various parasitic infections (trichomoniasis, amebiasis, and giardiasis), nonspecific vaginitis, and Clostridium difficile-mediated colitis. With use of metronidazole, mild side effects such as epigastric discomfort, diarrhea, reversible neutropenia, and allergic-type cutaneous reactions may occur.

TETRACYCLINES Mechanism of Action.-The tetracyclines are congeneric derivatives of the polycyclic substance naphthacenecarboxamide. These drugs exert their activity against microorganisms by inhibiting synthesis of proteins. The site of action of the tetracyclines is the bacterial ribosome.' At least two processes are necessary for the tetracyclines to gain access to the ribosomes of gram-negative microorganisms.' The first process is passive diffusion through hydrophilic pores in the outer cell membrane. Minocycline and doxycy*Mayo Clinic Scottsdale, Scottsdale, Arizona. Individual reprints of this article are not available. The entire Symposium on Antimicrobial Agents will be available for purchase as a bound booklet from the Proceedings Circulation Office at a later date. Mayo Clin Proc 66:1270-1280,1991

cline are more lipophilic than are other tetracyclines and pass directly through the lipid bilayer. The second process necessitates an energy-dependent active transport mechanism that pumps tetracyclines through the inner cytoplasmic membrane. Intercellularly, the tetracyclines inhibit synthesis of proteins by binding to the 30 S ribosomes. They prevent access of aminoacyl transfer RNA to the messenger RNAribosome complex. Resistance to the tetracyclines appears slowly, is incremental, and is mediated by plasmids. Plasmids impart resistance by coding for proteins that interfere with active transport of tetracyclines through the cytoplasmic membrane. Microorganisms that acquire resistance to one tetracycline are usually resistant to the other tetracyclines as well. Spectrum of Activity and Main Indications.- The in vitro spectrum of activity of the tetracyclines is shown in

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Table I. The tetracyclines are useful in the treatment of sexually transmitted diseases such as urethritis, endocervicitis, acute pelvic inflammatory disease, and rectal infections caused by Chlamydia? In patients with pelvic inflammatory infections, a combination of doxycycline and a cephalosporin is usually administered. Tetracyclines are also effective for treating other chlamydial infections such as lymphogranuloma venereum, psittacosis, trachoma, inclusion conjunctivitis, and pneumonitis caused by the TW AR strain. A tetracycline may also be used for gonococcal infections in patients unable to tolerate penicillin. Epididymitis in male patients younger than 40 years of age is usually caused by gonococci or C. trachomatis and is effectively treated with a tetracycline. Other sexually transmitted diseases that can be treated with tetracyclines include chancroid and granuloma inguinale. A tetracycline or erythromycin is considered the drug of choice for the treatment of Mycoplasma pneumoniae infection.' Combination therapy with a tetracycline and an aminoglycoside is the most effective treatment for brucellosis. Tetracyclines are also beneficial for rickettsial infections, tularemia, and cholera; in patients unable to tolerate penicillin, a tetracycline may be used for treating actinomycosis. Doxycycline is effective prophylactic therapy for traveler's diarrhea caused by toxicogenic strains of Escherichia coli.' Tetracyclines may be alternated with ampicillin or other broad-spectrum antimicrobial agents for long-term intermittent suppressive therapy in patients with chronic bronchopulmonary infections. In patients with acne, tetracyclines are efficacious; they presumably act by decreasing the content of fatty acid in sebum. Minocycline may be effective in the treatment of Nocardia infections. Although rifampin is the agent of choice for carriers of meningococcus, minocycline may be administered alternatively if the use of rifampin is contraindicated. Tetracyclines are effective therapy for Lyme disease in patients without involvement of the central nervous system. Tetracyclines have been used to treat infections caused by Mycobacterium marinum. Whipple's disease may also respond to tetracycline therapy. Although the tetracyclines are active in vitro against many aerobic gram-positive cocci, these agents should not be used to treat staphylococcal, group A ~-hemolytic streptococcal, or Streptococcus pneumoniae infections because of the occurrence of resistant strains. Moreover, the tetracyclines are bacteriostatic in vitro against Staphylococcus aureus, and patients with severe staphylococcal infections should be treated with bactericidal antistaphylococcal agents. Group A ~-hemolytic streptococcal pharyngitis should not be treated with a tetracycline because streptococci may persist in the pharynx and may thus increase the risk of acute rheumatic fever." Because of the emergence oftetracy-

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Table I.-Susceptibility of Organisms to the Tetracyclines, Expressed as Cumulative Percentage Inhibited Organism Acinetobacter calcoaceticus Var. anitratus Var. lwoffi Citrobacter diversus C.freundii Enterobacter aerogenes E. cloacae Escherichia coli Klebsiella oxytoca K. pneumoniae Morganella morganii Pseudomonas aeruginosa P. cepacia P. fluorescens Serratia marcescens Xanthomonas maltophilia

Concentration of tetracycline 54 ug/ml 84 95 100

75 97 95

78 96 85 22 3 93

68 2 6

cline-resistant strains of S. pneumoniae, the tetracyclines are contraindicated for the treatment of pneumonia and other infections caused by S. pneumoniae.' The tetracyclines should not be used as prophylaxis for subacute bacterial endocarditis or recurrent acute rheumatic fever. Although the tetracyclines were initially useful for treating urinary tract infections caused by susceptible gram-negative bacilli, their usefulness has been limited because of increased numbers of gram-negative bacilli resistant to the tetracyclines. Tetracyclines should not be used for the treatment of acute pyelonephritis. The acute urethral syndrome in women has been effectively treated with doxycycline," Because of the emergence of resistant strains of Shigella and Salmonella, tetracyclines are currently contraindicated for treatment of infections caused by these microorganisms. The widespread use of tetracyclines as additives in feed for livestock has resulted in increased bacterial resistance to the tetracyclines. Pharmacologic Properties and Dosage.-The tetracyclines are adequately but incompletely absorbed primarily from the stomach and small intestine in the fasting state. Absorption is somewhat impaired by consumption of dairy products and is drastically decreased by the concomitant administration of aluminum hydroxide gels, sodium bicarbonate, calcium and magnesium salts, and iron preparations.? Absorption is probably decreased by chelation and an increase in gastric pH. The presence of food does not interfere with the absorption of doxycycline or minocycline. The percentage of an oral dose that is absorbed after administration is lowest for chlortetracycline (30%); intermediate for oxytetracycline, demeclocycline, and tetracycline (60 to 80%); and highest for doxycycline and minocy-

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cline (95 to 100%).10 Peak serum concentrations 2 hours after oral administration (500 mg of tetracycline or 200 mg of doxycycline or minocycline) are approximately 3 to 5 flg/ ml. Peak serum concentrations 1 hour after intravenous administration of doxycycline or minocycline (in the aforementioned doses) are 10 to 20 ug/ml. The semisynthetic newer tetracyclines-doxycycline, methacycline, and minocycline-are characterized by considerable prolongation in the half-life in serum in comparison with the older tetracyclines. The amount of tetracyclines bound to plasma proteins varies. Those with the highest protein binding (80 to 95%) are doxycycline, demeclocycline, and methacycline. Protein binding is intermediate (65 to 75%) with minocycline and tetracycline. The least amount of protein binding (20 to 40%) occurs with oxytetracycline. I 1 Tetracyclines are metabolized by the liver and concentrated in the bile. Biliary concentrations average 5 to 10 times higher than concurrent plasma concentrations. Obstruction of the hepatobiliary tract or diminished hepatic function decreases the biliary concentration of the tetracyclines and prolongs the half-life in serum. Excretion occurs primarily in the urine and to a lesser extent in the feces. An exception is doxycycline, which is excreted primarily (90%) in the feces, largely as an inactive conjugate or as a chelate. Accordingly, doxycycline has less effect on intestinal microflora than do the other tetracyclines. In patients with impaired renal function, doxycycline does not accumulate substantially in the serum, and no adjustment of dosage is necessary. The dosage of the other tetracyclines should be decreased in patients with abnormal renal function; therefore, except for minocycline, these drugs should not be administered to patients with considerably decreased creatinine clearance. In patients with abnormal hepatic function, the dosage of tetracyclines should be reduced. Minocycline is excreted in the urine and feces in lower concentrations than other tetracyclines. The half-life of minocycline in serum is not prolonged in patients with reduced hepatic function. Thus, minocycline is probably the safest of the tetracyclines to administer to patients with hepatic failure, and doxycycline is the safest for patients with renal failure. The tetracyclines penetrate well into body tissues, including synovial fluid. Oral administration of a tetracycline results in a very low concentration in the cerebrospinal fluid. After intravenous administration, the drug gradually appears in the cerebrospinal fluid, where the concentration will be approximately a fourth of the serum concentration. Inflammation of the meninges is not a prerequisite for penetration of tetracycline into the cerebrospinal fluid. Tetracyclines cross the placental barrier, and relatively high concentrations are found in human milk. 11 Minocycline is unique among the

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tetracyclines because of the relatively high concentrations that may be found in tears and saliva, an important factor for elimination of the meningococcal carrier state. The recommended dosages and routes of administration for the various tetracyclines are summarized in Table 2. Toxicity and Adverse RC?actions.-Gastrointestinal irritation is a frequent side effect with the use of tetracyclines, especially oxytetracycline and doxycycline. Because of its lower pH, doxycycline may cause esophageal ulceration, especially in elderly patients. Gastrointestinal symptoms may be alleviated if the tetracyclines are administered with food (not milk or other dairy products) or antacids (those not containing aluminum, magnesium, or calcium). Tetracyclines have been reported to cause acute fatty necrosis of the liver, most often in patients who receive 2 g or more per day parenterally." Tetracyclines pose a special danger to pregnant women; fatal reactions due to hepatotoxicity have occurred in these patients. Therefore, these agents should not be administered to pregnant women unless use of all other antimicrobial agents is contraindicated, and then hepatic function must be carefully monitored. Except for doxycycline, which is excreted in the feces, the tetracyclines increase the occurrence of azotemia in patients with chronic renal failure by inhibiting the synthesis of proteins, which results in metabolism of amino acids; hence, they should be used with caution in these patients. Demeclocycline and doxycycline may cause mild to severe phototoxic dermatitis. In addition, tetracyclines cause brown discoloration of the teeth and may retard growth of bone in the human fetus and in children. Doxycycline is less likely than the other tetracyclines to cause discoloration of the teeth. The tetracyclines are not recommended for use in patients younger than 12 years of age. Superinfections, especially oral and anogenital candidiasis, are common in patients who are taking a tetracycline. Diarrhea due to a change in intestinal microflora may occur during tetracycline therapy; this cause of diarrhea must be distinguished from diarrhea related to pseudomembranous colitis, which occurs infrequently in association with tetracycline therapy. Patients who receive minocycline therapy may experience dose-related vestibular toxicity manifested by dizziness, ataxia, nausea, and vomiting." These symptoms may become evident after administration of the initial dose and usually subside within 48 hours after discontinuation of minocycline therapy. Drug-related interactions have been noted during tetracycline therapy. Severe renal failure has occurred in patients who received tetracycline therapy after general anesthesia with methoxyflurane." The renal failure was caused by formation of calcium oxalate crystals. The half-life of doxycycline may be reduced in patients who are receiving con-

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Table 2.-Recommended Dosages and Route of Administration for Various Tetracyclines Route of administrationAgent Tetracycline } Oxytetracycline Chlortetracycline Demeclocycline Doxycycline Methacycline Minocycline

Oral

Intravenous

250-500 mg every 6 h

Should not exceed 2 g/day

150-300 mg every 6 h 100 mg every 12 h on first day; 100 mg every 12-24 h thereafter 150 mg every 6 h 200-mg initial dose followed by 100 mg every 12 h

Same as oral Same as oral Same as oral Same as oral

*For all tetracyclines, intramuscular administration is not recommended because of local irritation and poor absorption.

comitant therapy with barbiturates or phenytoin, because of increased hepatic metabolism of doxycycline."

CHLORAMPHENICOL First introduced into the marketplace 42 years ago, chloramphenicol was widely prescribed until bone marrow toxicity associated with its use dampened enthusiasm. Nevertheless, over the years chloramphenicol remained a drug with a definite niche until other recently available agents consigned it to historical footnote status. Mechanism of Action.-The antibacterial activity of chloramphenicol is generally thought to result from inhibition of synthesis of proteins." The drug binds to the 50 S subunit of the 70 S ribosome to prevent formation of bonds between amino acids and peptides. Chloramphenicol inhibits, but does not kill (with some exceptions), a wide variety of aerobic and anaerobic bacteria, including Rickettsia and Chlamydia. Resistance to its activity is due to loss of permeability into the bacterial cell wall or is a result of bacterial production of acetyltransferase, an enzyme that acetylates chloramphenicol to an inactive compound. 15 Spectrum of Activity.-Chloramphenicol inhibits most strains of clinically important bacteria at concentrations usually achieved in humans; notable exceptions are shown in Table 3. 14 •16 Bactericidal activity can be demonstrated against the important group of meningitis-causing bacteria-Haemophilus influenzae, Neisseria meningitidis, and S. pneumoniae-although exceedingly rare strains of each of these have been resistant to chloramphenicol. Almost all obligately anaerobic bacteria are susceptible to chloramphenicol. 17 Main Indications.-Chloramphenicol has been officially approved by the Food and Drug Administration for use in acute S. typhi infections (such as typhoid fever); in serious infections caused by other Salmonella species, H. influenzae, rickettsiae, and lymphogranuloma-psittacosis; and in regi-

mens for cystic fibrosis." In patients with bacterial meningitis who are allergic to penicillin, chloramphenicol has been recommended. 15,16 Currently, however, the availability of numerous alternative agents and the concern about toxicity (see subsequent discussion) lead most specialists in infectious diseases to consider chloramphenicol in few situations. In patients with bacterial meningitis and a history of severe penicillin or ~­ lactam hypersensitivity, when a third-generation cephalosporin might otherwise be appropriate before the identity of the infecting organism is known, chloramphenicol is a reasonable choice. For treatment of rickettsial infections (such as Rocky Mountain spotted fever, scrub or murine typhus, and Q fever) in young children and pregnant women, in whom tetracycline is contraindicated, chloramphenicol is considered the drug of choice. The use of chloramphenicol for treatment of brain abscesses, anaerobic infections, and ampicillin-resistant H. influenzae infections is only of historical interest because other antimicrobial agents have replaced chloramphenicol as the drugs of choice. 19

Pharmacologic Properties and Dosage.-Chloramphenicol is available for oral administration in the form of capsules and a suspension (as chloramphenicol palmitate) and for intravenous administration (as the sodium succinate). The capsular preparation is well absorbed from the gastrointestinal tract. With a l-g dose, a mean peak serum level of 11.2 ug/ml is reached within 1 hour, exceeding the "breakpoint" minimal inhibitory concentration of 8 ug/ml recommended for considering an organism susceptible in vitro. 20 The palmitate preparation for children is hydrolyzed to release the active chloramphenicol compound; the resultant serum concentrations are comparable to those achieved with the crystalline drug. After intravenous administration of chloramphenicol succinate, the drug is rapidly hydrolyzed to the biologically active unesterified compound, but blood levels of the latter reach a peak concentration of approxi-

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Table 3.-Major Antimicrobial Activity of Chloramphenicol Exceptions

Group Most aerobic gram-positive bacteria

Enterococcus species (varies) Methicillin-resistant Staphylococcus aureus

Most aerobic gram-negative bacteria

Many Klebsiella and Enterobacter species Serratia marcescens Many Proteus species (non-mirabilis) Pseudomonas aeruginosa Acinetobacter species

Most anaerobic gram-positive and gram-negative bacteria Rickettsia

mately 70% of those achieved with equivalent oral dosing, probably because of incomplete hydrolysis in the liver, lungs, and kidneys.":" Intramuscular administration results in delayed absorption and suboptimal serum concentrations" and should be avoided. Systemic absorption can occur after ophthalmic use of the drug. Chloramphenicol distributes widely in human tissues, and measurable amounts can be detected in most body fluids, including the cerebrospinal fluid. 15 The drug is primarily metabolized by the liver to the microbiologically inactive glucuronide and then excreted renally. Small amounts of active, nonmetabolized chloramphenicol are excreted in the urine and are adequate to treat infections of the urinary tract. In patients with hepatic disease, active drug can accumulate and lead to dose-related toxicity. Therefore, serum concentrations should be monitored closely in patients with hepatic dysfunction. In patients with renal impairment, no appreciable accumulation is detected, although levels of the glucuronate metabolite may be high. No adverse effect has thus far been attributed to such an occurrence, however. The elimination half-life of chloramphenicol in adults ranges from 1.6 to 4.1 hours.lv" but it is prolonged to between 3 and 12 hours in patients with advanced disease of the liver." Because of impaired glucuronidation, slow hydrolysis, and delayed urinary excretion, chloramphenicol should be used with extreme caution in neonates, and only when serum concentrations can be closely monitored. The usual daily dosage in adults is 50 mg/kg divided into three or four doses; for serious or life-threatening infection, up to 100 mg/kg per day is recommended. Dosage guidelines for neonates and older children are available. 15 The dosing of chloramphenicol need not be adjusted for renal insufficiency, but reduced doses are imperative in patients with hepatic disease. Serum levels should be monitored in such patients, and drug concentrations of 10 to 30 Ilg/ml should be sought. 14

Hepatic microsomal metabolism of other drugs may be inhibited by chloramphenicol. Toxic levels of orally administered hypoglycemic agents, phenytoin, cyclophosphamide, and warfarin have occurred in chloramphenicol-treated patients. The metabolism of chloramphenicol is increased; consequently, suboptimal antimicrobial activity may be encountered in patients receiving phenobarbital, rifampin, and possibly phenytoin.">' Toxicity and Adverse Reactions.-Bone marrow aplasia is the most serious unpredictable toxic effect associated with the administration of chloramphenicol." Believed to be idiosyncratic (occurring in from 1:24,200 to 1:40,500 recipients of the drug), the reaction usually occurs weeks or months after completion of chloramphenicol treatment, but it has developed during therapy in almost a fourth of the cases of aplasia, Irreversible and typically fatal, pancytopenia is most often observed, but pure red cell aplasia, agranulocytosis, or thrombocytopenia has occurred in isolation. The reaction has been associated with intravenous, intramuscular, ophthalmic, and oral administration; the previous suggestion" that only the oral route could be incriminated probably reflects the most frequent use of this route of administration. A far more common toxic effect is dose-related, reversible bone marrow depression. Dosages of more than 4 g/day or serum concentrations in excess of 25 ug/ml predispose to the anemia, leukopenia, or thrombocytopenia that may occur. The hematologic changes resolve shortly after administration of chloramphenicol is discontinued. A very rare but potentially fatal reaction, termed "gray syndrome," consists of abdominal distention, cyanosis, and vasomotor collapse. It has been diagnosed almost exclusively in premature infants and newborns, and it results from exceedingly high serum concentrations of the drug. Other infrequent adverse effects of chloramphenicol include gastrointestinal intolerance, glossitis, optic neuritis, headache, and delirium."

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ERYTHROMYCIN Mechanism ofAction.-=Erythromycin is a macrolide compound that contains a many-membered lactone ring to which are attached one or more deoxy sugars. Erythromycin and other macrolide antibiotics inhibit the synthesis of proteins by reversible binding to the 50 S. ribosomal subunits of susceptible microorganisms. Binding occurs only when the 50 S subunit is free from transfer RNA molecules. Erythromycin may interfere with the binding of chloramphenicol, which also reacts at the same site. Spectrum of Activity and Main Indications.-The in vitro spectrum of activity of erythromycin is shown in Table 4. Erythromycin is the drug of choice for the treatment of M. pneumoniae and Legionella infections. Erythromycin is also effective therapy for infections caused by group A 13-hemolytic streptococci or S. pneumoniae. Accordingly, erythromycin is the preferred drug for treating community-acquired pneumonitis in nonimmunosuppressed patients who do not require hospitalization." The availability of semisynthetic penicillins, cephalosporins, and vancomycin has decreased the need for erythromycin in the treatment of serious staphylococcal infections. Nevertheless, erythromycin may be effective for treating minor staphylococcal infections, especially cutaneous infections. Erythromycin may be used as prophylaxis for subacute bacterial endocarditis and for recurrence of acute rheumatic fever in patients who are allergic to penicillin. It may also be used for treating gonorrhea and syphilis in patients who are unable to tolerate penicillin G or tetracycline. Chlamydia infections may be treated effectively with erythromycin as an alternative to tetracycline, especially in pregnant patients. Erythromycin hastens the eradication of Campylobacter jejuni from the feces in patients with gastroenteritis. When therapy is initiated 4 or more days after the onset of symptoms, however, erythromycin does not alter the clinical course." Erythromycin is effective in eradicating the acute or chronic carrier state of diphtheria. If administered early in the course of whooping cough, erythromycin may shorten the duration of illness. The drug has little influence on the disease once the paroxysmal stage of whooping cough has occurred. Several new macrolides such as clarithromycin, azithromycin, and roxithromycin are currently under investigation but are not yet available commercially. These new compounds, especially clarithromycin, may exhibit increased potency in vitro against S. aureus, H. influenzae, Moraxella catarrhalis, C. pneumoniae (TWAR strain), and some species of mycobacteria, especially M. avium-intracellulare. Approval of these new agents for commercial use could considerably expand the clinical utility of macrolide therapy. Pharmacologic Properties and Dosage.-Erythromycin is well absorbed from the gastrointestinal tract. Food in the

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Table 4.-Susceptibility of Organisms to Erythromycin, Expressed as Cumulative Percentage Inhibited Organism

Concentration of erythromycin $4 ug/ml

Staphylococcus aureus* S. epidermidis Group A ~-hemolytic streptococci Streptococcus pneumoniae

54 100 100

85

*Methicillin-susceptible.

stomach decreases absorption of the drug, except the estolate form." Four hours after oral administration of a dose of 500 mg of the base, stearate, or ethylsuccinate, peak serum concentrations are I to 2 llg/m1.11 Higher serum concentrations of erythromycin may be achieved by intravenous administration of erythromycin lactobionate or gluceptate. Serum concentrations I hour after intravenous administration of 0.5 to 1 g are approximately 10 to 15 ug/ml. Erythromycin is excreted primarily in the bile; only 2 to 5% is excreted in the urine. Concentrations in the bile may exceed 10 times those in plasma. Erythromycin diffuses readily into most tissues except the brain and cerebrospinal fluid. Erythromycin is one of the few antibiotics that penetrates readily into prostatic fluid. Erythromycin crosses the placental barrier and is present in maternal milk. The recommended oral dose of erythromycin is 250 mg to 1 g every 6 hours. For intravenous administration, I g every 6 hours is recommended, but use of this route is limited because of phlebitis. Intramuscular administration is not recommended because of pain and local irritation. Toxicity and Adverse Reactions.-Erythromycin is one of the safest antibiotics; the incidence of serious untoward effects is low. Dose-related gastrointestinal irritation is one of the most common adverse effects of erythromycin therapy. Cholestatic hepatitis occurs infrequently, most often in association with erythromycin estolate but occasionally after administration of other forms of the drug. I I This disorder mimics acute cholecystitis, viral hepatitis, or acute pancreatitis. Uncommonly, rash, fever, and eosinophilia may occur because of hypersensitivity to the drug. Transient auditory impairment has occurred in patients with abnormal renal function who received large dosages of erythromycin, usually administered intravenously in excess of 4 mg/day." The hearing becomes normal after erythromycin treatment is discontinued. Erythromycin therapy may increase the serum concentrations of theophylline or cyclosporine because of competition for protein binding sites in serum. I 1

CLINDAMYCIN A derivative of lincomycin, clindamycin was introduced in the mid-1960s and gained widespread acceptance until its

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association with colitis was recognized. It remains a valuable drug for treatment of selected infections. In particular, its role has expanded in recent years as a result of a search for alternative agents to treat certain opportunistic infections associated with acquired immunodeficiency syndrome (AIDS). Mechanism ofAction.-Clindamycin is thought to exert its antibacterial activity through inhibition of synthesis of proteins at the level of the 50 S ribosome, perhaps by acting on the early phase of formation of peptides.P-" In addition, it is thought to facilitate opsonization, phagocytosis, and intracellular killing of bacteria, perhaps at drug concentrations below in vitro minimal inhibitory concentrations.i? Resistance may be mediated by ribosomal mutation or other means. Spectrum of Activity.-Most strains of aerobic grampositive cocci, such as pneumococci, streptococci, and staphylococci, are inhibited and killed by clinically achievable concentrations of clindamycin (Table 5),28 Important exceptions are methicillin-resistant S. aureus and enterococci.P-" Although some strains of aerobic gram-negative bacteria are inhibited, they should generally be considered resistant to clindamycin. In contrast, most species of anaerobic gram-positive and gram-negative bacteria are susceptible. Included in the range of antimicrobial activity of clindamycin are most isolates of peptococci and peptostreptococci, propionibacteria, Clostridium perfringens, and fusobacteria.F:" Among the Bacteroides fragilis group, resistance seems to be slowly increasing; 5 to 19% resistance was recently encounrered.I'r'P? Non-perj'ringens clostridia, particularly C. difficile and C. ramosum, are also resistant. Some protozoa, especially Toxoplasma gondii, plasmodia, and Babesia, are inhibited by clindamycin.F'" Main Indications.-Several clinical situations lend themselves to possible therapy with clindamycin, either as a sole agent or as part of a combination regimen. Use of clindamycin is indicated in circumstances in which anaerobic bacteria may be pathogens, particularly intra-abdominal or pelvic infections. For mixed aerobic and anaerobic infections, additional antimicrobial agents (usually an aminoglycoside) are necessary. For treatment of anaerobic pulmonary abscesses, some investigators have suggested that clindamycin may be superior to penicillin.v-" Clindamycin can be used as an alternative to penicillin in penicillin-allergic patients. For treating streptococcal, penicillin-susceptible and penicillin-resistant staphylococcal (but not methicillin-resistant S. aureus), and pneumococcal infections, clindamycin is highly effective. Selected parasitic infections can be treated with clindamycin. The combination of clindamycin and pyrimethamine has been used to treat toxoplasmosis in sulfonamide-allergic patients infected with human immunodeficiency virus.v-"

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Some patients infected with the intraerythrocytic protozoan Babesia microti have responded to clindamycin and quinine therapy." The same treatment combination is an effective alternative regimen for chloroquine-resistant Plasmodium falciparum malaria." Clindamycin is also being investigated as therapy for Pneumocystis pneumonia. 39,40 Topically applied clindamycin is effective therapy for acne vulgaris. In addition, clindamycin can be used as an alternative agent to metronidazole in patients with bacterial vaginosis."

Pharmacologic Properties and Dosage.-Clindamy-

cin, in capsules and syrup formulations (as the hydrochloride and palmitate ester, respectively), is absorbed rapidly after oral administration." Approximately 90% bioavailability has been noted, and the resultant peak serum concentration is 3.6 flg/ml after a 300-mg dose, exceeding the minimal inhibitory concentration for susceptibility to clindamycin. The parenteral formulation, clindamycin phosphate, is available for both intramuscular and intravenous administration; serum levels of 11 to 14 ug/ml can be achieved with 900- to 1,200-mg doses. Topical application of clindamycin results in extremely high local concentrations of the drug but minimal systemic absorption (0 to 3 ng/ml in the serum). High concentrations of clindamycin can be detected in most body tissues and fluids after oral or parenteral administration; an important exception is the cerebrospinal fluid. Clindamycin is metabolized in the liver to products with variable antimicrobial activity, which are then slowly eliminated from the body through the urine and feces (the latter a result primarily of biliary secretion). The elimination halflife of 2.4 hours is substantially affected by only severe renal insufficiency and thus allows administration every 6 to 8 hours. Hemodialysis and peritoneal dialysis do not clear clindamycin." Most infections in adult patients can be treated with orally administered clindamycin in a dosage of 150 to 300 mg every 6 hours. Dosage recommendations for parenteral administration vary considerably, depending on the severity of the infection and patient factors, from 600 to 2,700 (or more) mg/day divided into three or four equal doses. The dosage should be halved in patients with severe renal insufficiency. In patients with severe hepatic disease, especially in association with renal failure, a reduction in dosage is recommended.Fr" Because clindamycin phosphate and the aminoglycoside antibiotics (for example, gentamicin) are compatible, the two agents can be mixed in a single diluent for simultaneous intravenous administration. Thus, the number and cost of infusions can be decreased for critically ill hospitalized patients. Toxicity and Adverse Reactions.-The most notorious adverse reaction associated with the use of clindamycin is C. difficile toxin-mediated pseudomembranous colitis. AI-

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Table 5.-Major Antimicrobial Activity of Clindamycin Aerobic gram-positive cocci Streptococcus pyogenes S. pneumoniae Staphylococcus aureus*

Anaerobic gram-negative bacteria Bacteroides fragilis Other Bacteroides species Fusobacteria

Anaerobic gram-positive bacteria

Protozoa Toxoplasma gondii Some Plasmodium species Babesia microti Pneumocystis carinii

Peptococci

Peptostreptococci Propionibacteria Clostridium perfringens Actinomyces *Except methicillin-resistant S. aureus.

though use of clindamycin was strongly linked to this disease initially, most cases are now clearly associated with /3lactam antibiotics (penicillins and cephalosporinsj.w-' This condition has a variable incidence, ranging widely among studied populations, and may be spread in hospitals through environmental or human sources.r-" The traditional infection-control practices of hand-washing and gloving have been suggested as a means of decreasing nosocomial acquisition. 42,44 The optimal method of establishing the diagnosis of C. dijficile diarrheal disease is still unsettled, inasmuch as stool cultures for the organism may result in high sensitivity at the cost of a variable rate of false-positive findings.r':" Cytotoxin assay is considered highly specific but may detect only two-thirds of the cases." The need for cell-culture capability severely limits application of this test procedure to large hospitals and reference laboratories. A commercially available and rapid method for detection of C. dijficile toxin can be used in most laboratories, but lack of sensitivity of the procedure relegates the test to that of a screening function. C. dijficile-associated colitis can be treated by discontinuing the course of clindamycin (or other precipitating agent) and instituting oral administration of vancomycin or metronidazole if diarrhea fails to resolve within a brief period or if the patient is seriously ill from C. dijficile disease. Other gastrointestinal side effects, such as nausea, anorexia, vomiting, and non-C. dijficile-mediated diarrhea, can follow administration of clindamycin. Increased hepatocellular enzymes, hematologic changes, allergic reactions, and neuromuscular blockade have also been notedy,28 METRONIDAZOLE Available in Europe since 1959 and approved by the Food and Drug Administration in the United States several years later, metronidazole has found use far beyond its original indication for Trichomonas infections. Since discovery of its activity against obligate anaerobic microorganisms, the drug has become one of the most useful agents available for seriously ill patients.

Mechanism of Action.-Microbial reduction of metronidazole by the enzyme nitroreductase liberates toxic intermediate compounds that disrupt bacterial DNA and cause cell death. These toxic intermediates are further metabolized to inactive compounds, acetamide and 2-hydroxyethyl oxamic acid. 4?48 The low oxidation-reduction potential necessary for. intracellular reduction of metronidazole is not present in aerobic bacteria, a factor that presumably explains the inability of the drug to inhibit this class of bacteria." Spectrum of Activity.-The in vitro activity of metronidazole is summarized in Table 6. T. vaginalis, Entamoeba histolytica, and Giardia lamblia, common anaerobic protozoa, are sensitive to metronidazole. Some spirochetes, including Treponema pallidum and oral nontreponemal spirochetes, are also susceptible. Against most obligate anaerobic bacteria, particularly gram-negative bacilli, metronidazole exerts potent bactericidal activity, with most strains inhibited at levels of 2llg/ml or less. 17,32 No increase in resistance among the B. fragilis group, other Bacteroides, or fusobacteria was detected at the Mayo Clinic during a 10year period, when resistance to clindamycin increased somewhat, particularly among Bacteroides isolates.'? Of importance, however, rare metronidazole-resistant strains of Bacteroides have been encountered." Among anaerobic gram-positive cocci and non-sporeforming bacilli (such as peptostreptococci, peptococci, Actinomyces, and bifidobacteria), activity is marginal, with as many as half of the tested isolates not being inhibited. 17,50 Likewise, Propionibacterium acnes, the common anaerobic bacterium endogenous to the skin, is totally resistant. Clostridia, including C. perfringens and C. dijficile, are susceptible to metronidazole, although at concentrations somewhat higher than those inhibitory toward gram-negative anaerobic bacilli. I? Facultative anaerobic bacteria (that is, "aerobic" gram-positive and gram-negative bacteria) are resistant. Main Indications.- The major utility of metronidazole is in the treatment of anaerobic and selected parasitic infections. Numerous anaerobic infections-with involvement of the intra-abdominal and pelvic area, central nervous system,

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Table 6.-Major Antimicrobial Activity of Metronidazole Anaerobic gram-positive bacteria Peptococci* Peptostreptococci * Clostridium perfringens C. difficile Anaerobic gram-negative bacteria Bacteroides fragilis Other Bacteroides species Fusobacteria Protozoa Entamoeba histolytica Giardia lamblia Trichomonas vagina lis *Limited activity.

bones and joints, skin and soft tissues, and bloodstreamhave been treated effectively with antimicrobial regimens that contain metronidazole. Because therapeutic failures have occurred, caution in the use of metronidazole for anaerobic pleuropulmonary infections has been emphasized.5 1,52 These infections are often mixed aerobic and anaerobic and may be partly due to anaerobic gram-positive cocci, which are seldom susceptible to metronidazole. In the case of endocarditis and meningitis, in which bactericidal agents are generally considered necessary for optimal treatment, metronidazole is particularly appealing in the rare instance of gram-negative anaerobic infections. Another important indication for metronidazole is the treatment of parasitic infections. The drug is the only approved agent available for Trichomonas vaginitis and is one of the major therapeutic options for giardiasis and intestinal and extraintestinal amebiasis (administered in combination with iodoquinol for the latter)." Investigational uses include treatment of balantidiasis, guinea worm infestation, and the questionably pathogenic Blastocystis hominis infestation." Nonspecific vaginitis (or bacterial vaginosis) can be treated effectively with metronidazole," presumably because of the activity of the drug against Gardnerella vaginalis. Controlled studies have shown metronidazole to be as effective as orally administered vancomycin in the treatment of C. difficile-associated pseudomembranous colitis, although some investigators still favor vancomycin for the critically ill patient." Recently, attention has been focused on the possible utility of metronidazole in patients with Helicobacter pylori-associated gastrointestinal disease, inflammatory bowel disease, and intestinal bacterial overgrowth syndromes. Finally, as a topical preparation, metronidazole is effective therapy for rosacea." Pharmacologic Propertiesand Dosage.-Metronidazole is absorbed well after oral administration; serum levels achieved are equivalent to those after intravenous dosing.

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After a standard dose of 7.s mg/kg, a peak serum concentration of 20 to 25 ug/ml can be expected." Hepatic metabolism of the drug produces several compounds, one of which-the 2-hydroxymethyl metabolite-possesses intrinsic antibacterial activity. These compounds, as well as unmetabolized metronidazole, are excreted in the urine (60 to 80% of the administered dose) or in the feces." The half-life of the drug in the serum is approximately 8 hours. The recommended dosages of metronidazole for various indications are shown in Table 7. No adjustment is necessary for renal failure; however, because of accumulation of metabolites, some authorities recommend a one-half dosage reduction in patients with creatinine clearance of less than 10 ml/min.>' The drug and its metabolites are removed by hemodialysis but not peritoneal dialysis." The manufacturer recommends an unspecified reduction in dosage in patients with severe hepatic disease. Antacids, barbiturates, and cholestyramine have been reported to decrease the serum concentration of metronidazole. 55 Toxicity and Adverse Reactions.-With use of metronidazole, mild side effects are common." Orallyadministered metronidazole can cause nausea in up to 12% of patients; epigastric discomfort, diarrhea, reversible neutropenia, and allergic-type cutaneous eruptions may occur. A metallic taste in the mouth has been described. Patients should be cautioned to avoid alcoholic beverages or alcoholcontaining medications because of the occurrence of a disulfiram-like effect. The prothrombin time may be prolonged because of potentiation of coumarin. Convulsive seizures and peripheral neuropathy are important, but rare, side effects of metronidazole. These may be dose-related phenomena. Although considerable concern has been expressed about carcinogenesis in laboratory rats and mice and mutagenesis in in vitro assay systems, little or no evidence of carcinogenesis has been found in humans." Nevertheless, metronidazole should be avoided during the first trimester of pregnancy and during periods of breast-feeding.

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Table 7.-Principal Indications for Metronidazole and Recommended Dosages Clinical condition

Dosage of metronidazole

Mixed aerobic-anaerobic infections; metronidazole is probably not an optimal agent for pleuropulmonary infection (see text) Trichomonas vaginitis Bacterial vaginosis (nonspecific vaginitis) Clostridium difficile-associated colitis Intestinal giardiasis Intestinal and extraintestinal amebiasis

Initial dose of 15 mg/kg, then 7.5 mg/kg every 6 h (intravenously)" 1-2 g/day in 2-4 divided doses (orally)* 2 g as a single dose or 250 mg 3 times/day for 7 days (orally) 500 mg twice daily for 7 days (ora.lly) 250-500 mg 3-4 times/day for 7-10 days (orally) 250 mg 3 times/day for 5 days (orally) 750 mg 3 times/day for 10 days (orally), followed by iodoquinol

*To be used in combination with an antimicrobial agent active against the aerobic component. Modified from Finegold and Mathisen." By permission of Churchill Livingstone Inc.

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Gudiol F, Manresa F, Pallares R, Dorea J, Rufi G, Boada J, Ariza X, Casanova A, \T.iladrich PF: Clindamycin vs penicillin for anaerobic lung infections: high rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus. Arch Intern Med 150:2525-2529, 1990 Pedrol E, Gonzalez-Clemente JM, Gatell JM, Mallolas J, Mir6 JM, Graus F, Alvarez R, Mercader JM, Berenguer J, Jimenez de Anta MT, et al: Central nervous system toxoplasmosis in AIDS patients: efficacy of an intermittent maintenance therapy. AIDS 4:511-517, 1990 Leport C, Bastuji-Garin S, Perronne C, Salmon D, Marche C, Bricaire F, Vilde JL: An open study of the pyrimethamineclindamycin combination in AIDS patients with brain toxoplasmosis (letter to the editor). J Infect Dis 160:557558, 1989 Drugs for parasitic infections. Med Lett Drugs Ther 32:2332, 1990 Toma E, Fournier S, Poisson M, Morisset R, Phaneuf D, Vega C: Clindamycin with primaquine for Pneumocystis carinii pneumonia. Lancet 1:1046-1048, 1989 Ruf B, Pohle HD: Clindamycin/primaquine for Pneumocystis carinii pneumonia (letter to the editor). Lancet 2:626-627, 1989 Centers for Disease Control: Bacterial vaginosis. MMWR 38 (SuppI8):36-37, 1989 McFarland LV, Surawicz CM, Stamm WE: Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in a cohort of hospitalized patients. J Infect Dis 162:678-684, 1990 Bartlett JG: Clostridium difficile: clinical considerations. Rev Infect Dis 12 (Supp12):S243-S251, 1990

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End of Symposium on Antimicrobial Agents, Part IV. Part V will appear in the January 1992 issue.