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Home , Azithromycin, Clarithromycin

CURRENT DRUG THERAPY

DONALD G. VIDT, MD, AND ALAN BAKST, PHARMD, EDITORS

The role of and in clinical practice

MORTON P. GOLDMAN, PHARMD, AND DAVID L. LONGWORTH, MD

INCE ITS DISCOVERY IN the BACKGROUND Azithromycin and clarithromycin are the 1950s, has newest approved . been a very important an- Stimicrobial agent for the OBJECTIVE To review the pharmacology, microbiology, and treatment of a variety of infections. clinical utility of these agents. But it has its limitations: its an- timicrobial spectrum is relatively SUMMARY These agents have distinct advantages over eryth- narrow, it is bacteriostatic rather romycin, including an improved pharmacokinetic profile, less tox- than bacteriocidal, its dosing is in- icity, and a wider spectrum of activity. They are approved for the convenient (it must be given four treatment of respiratory tract infections and uncomplicated skin times a day), and many patients and skin-structure infections associated with specific organisms. experience gastrointestinal intol- Azithromycin is also indicated for the treatment of nongonococ- erance to it. cal . In addition, these agents may be useful in the treat- Of the many new de- ment of , mycobacterial disease, , and veloped in the past decade, az- legionellosis. Clarithromycin and azithromycin have lower rates ithromycin and clarithromycin of gastrointestinal side effects than erythromycin. were the first to be marketed in the United States. Their broader an- CONCLUSIONS Although clarithromycin and azithromycin timicrobial spectrum and improved show promise in the treatment of some less common infections, pharmacokinetic and side effect they should be considered alternatives to conventional agents in profiles compared with erythromy- the treatment of respiratory tract, skin, and skin-structure infec- cin make them promising agents tions caused by the usual pathogens. The expense of these agents for a variety of infections. We will may be prohibitive for routine use. review the pharmacology, microbi-

• INDEX TERMS: CLARITHROMYCIN; AZITHROMYCIN; ERYTHROMYCIN; ology, and clinical use of these RESPIRATORY TRACT INFECTIONS; SKIN DISEASES, INFECTIOUS agents with emphasis on innova- • CLEVE CLIN J MED 1993; 60:359-364 tive, nonapproved uses.

From the Departments of Hospital Pharmacy (M.P.G.) and In- CHEMISTRY AND ACTIVITY fectious Disease (D.L.L.), The Cleveland Clinic Foundation. Address reprint requests to M.P.G., Department of Hospital Pharmacy, S10, The Cleveland Clinic Foundation, 9500 Euclid Azithromycin and clarithromy- Avenue, Cleveland, OH 44195. cin are macrolide antibiotics simi- lar in structure to erythromycin.1 They act by inhibiting bacterial RNA-dependent protein synthesis

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TABLE 1 is only 0.8 |Xg/mL; how- OF MACROLIDE ANTIBIOTICS ever, it also achieves high Azithromycin Clarithromycin (14 hydroxy- Erythromycin tissue concentrations. (500 mg)18 (250 mg)19 clarithromycin) (500 mg)17 Clarithromycin is absorbed Half-life (hours)* 11-14 2.6-2.7 1.5-3 3.9-4.2 somewhat better than its (%) 37 52-55 Variable Not available macrolide counterparts, with a bioavailability of ap- Maximum serum 0.4 0.72-0.8 1.9-3.8 0.64-0.65 concentration (jig/mL) proximately 55%. All of Time to maximum serum 2.3 1.72-1.92 1.5 2.17-2.32 these agents are metabo- concentration (hours) lized in the to some degree, with azithromycin Half-life increases somewhat after multiple-dose administration. eliminated in the bile and ^Maximum serum concentrations increase after multiple doses. possibly the intestine as well. Clarithromycin un- by binding to the 50S-subunit of the 70S- dergoes both hydroxylation and N-demethylation, in the organism.2 Comparative microbiologic activ- and its 14'hydroxy metabolite is relatively active— ity of the new macrolides has been well studied.3"7 perhaps more active against H influenzae than the Like erythromycin, azithromycin and clarithromy- parent compound.20,21 These metabolites are primar- cin possess excellent activity against aerobic gram- ily eliminated via the . positive , pneumoniae, , and species of Legionella, , APPROVED USES FOR AZITHROMYCIN and . All three macrolides also have sig- AND CLARITHROMYCIN nificant activity against anaerobic flora and some mycobacterial species. The newer macrolides have Azithromycin and clarithromycin have been ap- improved activity against , proved by the Food and Drug Administration (FDA) , and Chlamydia species. Both of for the treatment of pharyngitis, , lower res- these agents have excellent activity against piratory tract infections, and uncomplicated skin and Toxoplasma gondii8'11; clarithromycin also has in- soft-tissue infections associated with various organ- creased activity against mycobacterial species com- isms (Table 2). Azithromycin is also indicated for the pared with the other macrolides.12"16 The macrolides treatment of nongonococcal urethritis. The effec- are not active against methicillin-resistant staphylo- tiveness of these compounds for these indications coccal species nor against most Enterobacteriaceae. has been extensively reviewed.1,22-25 However, each of the published trials examined relatively few pa- PHARMACOKINETICS tients, and many of these studies did not have suffi- cient power to detect potentially significant differ- The comparative pharmacokinetics of erythro- ences between treatment groups. mycin, azithromycin, and clarithromycin are sum- marized in Table 1.17-19 Azithromycin has the longest Azithromycin half-life of the three, which allows for once-daily Respiratory tract infections. The standard dosage of administration. Although the maximum serum con- azithromycin (500 mg, then 250 mg daily for the centration obtained with azithromycin after oral ad- next 4 days) has been compared with a 10-day ministration of 500 mg is only 0.4 |Xg/mL, tissue course of (250 mg every 6 hours) in the levels well exceed the serum concentration. The treatment of streptococcal pharyngitis. Clinical cure drug is concentrated inside cells, particularly in po- rates and streptococcal eradication rates were simi- lymorphonuclear leukocytes and macrophages. Az- lar between the two regimens.26 The same regimen ithromycin has variable protein binding, which is of azithromycin was compared with a 10-day course concentration-dependent. The drug is relatively of (500 mg three times daily) in the poorly absorbed, with a bioavailability of only 37%. treatment of bacterial sinusitis.27 The outcomes in Clarithromycin has a half-life of approximately 3 to both treatment groups were similar. With the small 5 hours, which allows for twice-daily dosing. Its number of patients studied, however, these data are maximum serum concentration after a 250-mg dose difficult to interpret.

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The standard dose of az- TABLE 2 FOOD AND DRUG ADMINISTRATION-APPROVED INDICATIONS ithromycin has also been FOR USE OF AZITHROMYCIN OR CLARITHROMYCIN compared with 10-day courses of erythromycin Disease Organism Drug (500 mg four times daily)28 Pharyngitis or pyogenes Clarithromycin, azithromycin and cefaclor (500 mg three Acute maxillary sinusitis Clarithromycin times daily)29 for the treat- Exacerbation of chronic Hemophilus influenzae Clarithromycin, azithromycin ment of community-ac- bronchitis Moraxella catarrhalis Clarithromycin, azithromycin quired and S pneumoniae Clarithromycin, azithromycin bronchitis. The cure rates Pneumonia (mild) S pneumoniae Clarithromycin, azithromycin were comparable with each Clarithromycin H influenzae Azithromycin treatment regimen. Al- Uncomplicated skin and skin- S pyogenes Clarithromycin, azithromycin though azithromycin per- structure infections Azithromycin formed well against H influ- Nongonococcal urethritis Azithromycin enzae in the cefaclor trial, and cervicitis an open-label trial of az- ^^^^ ithromycin in patients with chronic bronchitis showed frequent persistence and chronic bronchitis, respectively. A number of dos- clinical relapse.30 age regimens were studied, and eradication and cure Sexually transmitted diseases. Clinical trials have rates were similar between groups. also shown azithromycin to be as effective as stand- ard therapy in the treatment of sexually transmitted NONAPPROVED USES FOR AZITHROMYCIN diseases caused by , Chlamydia AND CLARITHROMYCIN trachomatis, and .31'33 The dosage regimens ranged from a single 500-mg or 1-g Azithromycin and clarithromycin may be useful dose to 3 days of therapy. Azithromycin is approved in the treatment of a variety of other infections, for the treatment of nongonococcal urethritis though use for these indications is not approved by caused by C trachomatis only. the FDA (Table 3). Both drugs have been investi- Skin and skin-structure infections. Azithromycin gated for activity against and treatment of nontu- has also been shown to be effective in the treatment berculous mycobacteria.12"16 of skin and skin-structure infections in two tri- als.28,32'34 The results of standard 5-day courses of Mycobacteriosis azithromycin were not clinically or bacteriologically Azithromycin's activity against different from 7-day courses of erythromycin or 10- avium-intracellulare complex has been studied in vitro day courses of cephalexin. and in a mouse model.14 Although its activity in vitro was unimpressive, its cure rate in the mouse model Clarithromycin was high. More data are needed to establish az- Clarithromycin (250 mg every 12 hours) has ithromycin's place in the treatment of mycobacterial been compared with erythromycin (500 mg every 6 disease, as no clinical data in humans are available. hours)35 and penicillin (500 mg every 6 hours)36,37 in In vitro studies of clarithromycin's activity the treatment of streptococcal pharyngitis; similar against mycobacterial species have been promising. cure and bacteriological eradication rates were Clarithromycin is a more active agent against My- achieved. To our knowledge, prevention of sub- cobacterium chelonei and Mycobacterium fortuitum sequent rheumatic fever has not been examined for than most other macrolides.16 Clarithromycin's ac- clarithromycin or azithromycin. The same dosage of tivity has also been studied in 49 strains of M clarithromycin has also been compared with avium-intracellulare.15 This study concluded that, al- amoxicillin (500 mg every 8 hours) in the treatment though active against these organisms, clarithromy- of bacterial sinusitis, with similar results.38 cin may be bacteriostatic rather than bactericidal. Clinical trials have shown clarithromycin to be as A examining the combination of effective as erythromycin39,40 or ampicillin41,42 in the clarithromycin, ciprofloxacin, and in the treatment of community-acquired pneumonia and treatment of M avium-intracellulare complex in pa-

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TABLE 3 patients were similar to results in patients who re- POTENTIAL USES OF CLARITHROMYCIN AND AZITHROMYCIN THAT HAVE NOT BEEN APPROVED ceive standard therapy. BY THE FOOD AND DRUG ADMINISTRATION Lyme disease Drug Organism References Azithromycin in vitro is active against Borrelia Clarithromycin Legionella pneumoniae 44 burgdorferi, the agent of Lyme disease.43 Azithromy- Toxoplasma gondii* 8,11 cin was active in vitro (minimal bactericidal con-

Mycobacterium t 12-15 centration 0.04 mg/L) and was effective in eradicat- aviumAntraceRulare ing the organism from experimentally infected Other mycobacterial species^ 16 hamsters. Data in humans are not yet available. Azithromycin Borrelia burgdorferi 43 (Lyme disease) Legionellosis 4. Toxoplasma gondii 9,10 Clarithromycin has been studied for the treat- ment of pneumonia caused by Legionella species.44 Limited human data available Forty-six Pakistani patients were enrolled in an ^No human data available open trial of clarithromycin at a dosage of 1 g twice daily (for all but one patient). The diagnosis was tients with acquired immunodeficiency syndrome made by culture, direct fluorescent antibody stain- (AIDS) has shown this regimen to be effective in ing of respiratory secretions, and serologic study. treating patients with bacteremia.13 Although the Clinical and radiographic changes were docu- sample size was small (12 patients), the results were mented at various times during the trial. Almost all encouraging. patients had clinical cure or improvement as well as radiographic improvement. The adverse reactions Toxoplasmosis reported (13 events in 10 patients) included taste The activity of azithromycin and clarithromycin disturbance, gastrointestinal symptoms, headache, against T gondii has also been studied.8"11 Derouin et dizziness, and mildly elevated serum transaminase al10 studied azithromycin's activity in experimental concentrations. Clarithromycin was safe and effec- toxoplasmosis in a murine model. These authors tive in this population. A trial comparing found that azithromycin significantly potentiates clarithromycin with erythromycin has not yet been the therapeutic effects of both sulfadiazine and performed. pyrimethamine. Deaths and relapses were less com- mon when azithromycin was added to sulfadiazine ADVERSE EFFECTS or pyrimethamine compared with treatment with any of the three agents alone. Clarithromycin has Adverse effects with these agents have been rela- also been shown to have significant activity against tively infrequent compared with erythromycin; mild T gondii in vitro and in a mouse model.8,9 gastrointestinal side effects have been the most In the only fully published trial in humans, 13 common. Abnormal liver function test results have patients with AIDS who had encephalitis caused by been noted with both clarithromycin and az- Toxoplasma were treated with a combination of ithromycin. Eosinophilia and headache have both pyrimethamine and clarithromycin.11 The patients been reported with the. use of clarithromycin. Pa- were 18 to 60 years old and had not received therapy tients infected with human immunodeficiency virus for Toxoplasma during the 48 hours before enroll- (HIV) seem to have a higher incidence of adverse ment. The regimen consisted of clarithromycin (1 g effects with clarithromycin than patients who do twice daily), pyrimethamine (a 200-mg load, fol- not have HIV, especially abdominal pain, , lowed by 75 mg daily), and folinic acid. All patients , and skin rash. In the trial of clarithromy- were to be assessed at 6 weeks. Eight patients com- cin in patients with AIDS and toxoplasma infec- pleted at least 6 weeks of therapy, and six had a tions,11 31% of patients experienced severe hema- complete response. The five patients who did not tologic abnormalities; however, this may have been complete therapy either voluntarily withdrew or ex- due in part to the patients' underlying disease. No perienced an adverse event possibly related to ther- hematologic abnormalities have been reported in apy. It was concluded that outcomes in these 13 clarithromycin recipients who are not HIV-positive.

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DRUG INTERACTIONS proximately $10.00.

The pharmacokinetic drug interactions of the SUMMARY macrolides have been extensively reviewed by Periti et al.45 Although few drug interactions have been Clarithromycin and azithromycin are excellent reported with either of the two new macrolide alternatives to conventional agents in the treatment agents, these drugs should be used with caution of infections of the respiratory tract, skin, and skin when combined with agents that have been re- structures caused by susceptible organisms. They are ported to interact with erythromycin, such as mor- better tolerated and possess a broader spectrum than phine, , , and cyclosporine. erythromycin; however, treatment failures have oc- Clearance of theophylline and may curred, especially in patients with bronchitis caused be decreased with the addition of clarithromycin. by H influenzae- Azithromycin is also effective in the treatment of nongonococcal urethritis. These new DOSAGE AND COST macrolides are promising additions to the armamen- tarium for the treatment of various mycobacterial The dosage of azithromycin for all approved indi- diseases and toxoplasmosis in HIV-infected patients. cations is 500 mg on the first day, followed by 250 Carefully performed clinical trials may help to de- mg daily for 4 days.46 For nongonococcal urethritis, a lineate the utility of the macrolides for treating single 1-g dose is recommended.46 The dosage of these infections. The expense of these agents may clarithromycin for all approved indications is 250 to be prohibitive for routine use. 500 mg twice daily for 7 to 14 days.46 A 7-day course of clarithromycin (250 mg twice a ACKNOWLEDGMENT day) costs the patient approximately $42.00, as does a 5-day course of azithromycin (500 mg for 1 day The authors thank Kathy Spearman for her assistance with then 250 mg daily). A 10-day course of erythromy- preparing the manuscript. cin (500 mg four times daily) costs the patient ap-

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