Mycobacterium avium-M. intracellulare, a common opportunistic pathogen in HIV-infected patients, is a leading cause of death in patients with AIDS (1, 2, 6, 7, 9, 10). Public Health Service (4) recommends treating M. avium-M. intracellulare-infected patients with a macrolide, either clarithromycin or azithromycin, in combination with rifabutin and/or ethambutol. Monotherapy prophylaxis with clarithromycin or azithromycin is recommended for HIV-infected patients with a CD4+ cell count of <50 cells/μl. Recent findings suggest a greater microbiological response with clarithromycin than that with azithromycin when these agents are used either as monotherapy or in combination (3, 4, 13). Ward and colleagues found that the combination of clarithromycin-ethambutol cleared M. avium-M. intracellulare bacteremia in a significantly higher percentage of HIV-infected patients compared to azithromycin-ethambutol (87.5 versus 37.5% [P = 0.007]), with clearance occurring significantly faster (4.4 versus >16 weeks, [P = 0.0018]) (13). Our study evaluated the in vitro MICs of clarithromycin and azithromycin against M. avium-M. intracellulare.
Twenty clinical isolates of M. avium-M. intracellulare, identified with a gene probe, were plated on Löwenstein-Jensen medium or on Middlbrook 7H10 agar (Becton Dickinson, Cockeysville, Md.) and tested by a modified agar proportion method (14) against clarithromycin (2, 8, 16, 32, and 64 μg/ml) and azithromycin (4, 8, 16, 32, 64, and 128 μg/ml). Two different strains of M. avium-M. intracellulare (strains 9141 and 8867), obtained from the National Jewish Medical and Research Center in Denver, Colo., were tested as a quality control measure.
Petri dishes containing a 7H10 agar base, prepared according to the manufacturer’s directions and supplemented with 10% oleic acid-albumin-dextrose complex enrichment (Becton Dickinson) were used. Each isolate was grown in 7H9 broth and adjusted to a McFarland no. 1 standard, with a 100-μl aliquot inoculated into each petri dish quadrant. Two dilutions were tested for each isolate. Serial 10-fold dilutions of each isolate suspension were made to produce 50 to 100 colonies in the control quadrant of each agar plate. Following inoculation, the agar plates were dried, sealed with shrink seals, and incubated at 36°C and 6% CO2 for 21 days.
The number of colonies in each quadrant was determined and compared to that in the control quadrant. MIC was defined as the lowest concentration that resulted in less than 1% M. avium-M. intracellulare growth relative to growth in the drug-free quadrant.
For each of the 20 M. avium-M. intracellulare isolates, clarithromycin was more active (median MIC ≤2 μg/ml; range ≤2 to 8 μg/ml) than azithromycin (medium MIC 8 μg/ml; range ≤4 to 64 μg/ml). Specifically, the MICs of clarithromycin were two- to eightfold lower than those of azithromycin for 90% (18 of 20) of isolates. For two isolates, clarithromycin was 16-fold more potent than azithromycin.
The results obtained with clarithromycin were similar to those from a previous agar evaluation study (MIC, 1 to 4 μg/ml) of 49 M. avium-M. intracellulare isolates obtained from HIV patients (8). Azithromycin results were similar to those of previous investigations (MIC, 16 to 32 μg/ml) (12, 14).
Results of this in vitro evaluation suggest that clarithromycin is more effective against M. avium-M. intracellulare than azithromycin. These findings may help to explain the clinical microbiological responses observed in previous investigations.
REFERENCES
- 1.Bacellar H, Munoz A, Hoover D R, Phair J P, Besley D R, Kingsley L A, Vermund S H. Incidence of clinical AIDS conditions in a cohort of homosexual men with CD4+ cell counts <100/mm3. J Infect Dis. 1994;170:1284–1287. doi: 10.1093/infdis/170.5.1284. [DOI] [PubMed] [Google Scholar]
- 2.Benson C A, Ellner J J. AIDS commentary: Mycobacterium avium complex infection and AIDS: advances in theory and practice. Clin Infect Dis. 1993;17:7–20. doi: 10.1093/clinids/17.1.7. [DOI] [PubMed] [Google Scholar]
- 3.Berry A J, Koletar S, Williams D. Proceedings of the 1st National Conference on Human Retroviruses and Related Infections. Washington, D.C: American Society for Microbiology; 1993. Azithromycin for disseminated Mycobacterium avium-intracellulare in AIDS patients, abstr. 292. [Google Scholar]
- 4.Centers for Disease Control and Prevention. 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Morbid Mortal Weekly Rep. 1997;46(RR-12):1–46. [PubMed] [Google Scholar]
- 5.Chaisson R E, Benson C A, Dube M P, Heifets L B, Korvick J A, Elkin S, Smith T, Craft J C, Sattler F R. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease: a randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med. 1994;121:905–911. doi: 10.7326/0003-4819-121-12-199412150-00001. [DOI] [PubMed] [Google Scholar]
- 6.Havlik J A, Jr, Horsburgh C R, Jr, Metchock B, Williams P P, Fann S A, Thompson S E. Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends. J Infect Dis. 1992;165:577–580. doi: 10.1093/infdis/165.3.577. [DOI] [PubMed] [Google Scholar]
- 7.Havlir D V, Ellner J J. Mycobacterium avium complex. In: Mandell G L, Douglas R G, Dolin R, editors. Principles and practice of infectious diseaes. 4th ed. New York, N.Y: Churchill Livingstone; 1994. pp. 2250–2264. [Google Scholar]
- 8.Heifets L B, Lindholm-Levy P J, Comstock R D. Clarithromycin minimal inhibitory and bactericidal concentrations against Mycobacterium avium. Am Rev Respir Dis. 1992;145:856–858. doi: 10.1164/ajrccm/145.4_Pt_1.856. [DOI] [PubMed] [Google Scholar]
- 9.Horsburgh C R., Jr Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324:1332–1338. doi: 10.1056/NEJM199105093241906. [DOI] [PubMed] [Google Scholar]
- 10.Inderlied C B, Kemper C A, Bermudez L E. The Mycobacterium avium complex. Clin Microbiol Rev. 1993;6:266–310. doi: 10.1128/cmr.6.3.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.National Committee for Clinical Laboratory Standards. Antimycobacterial susceptibility testing for M. tuberculosis. Tenative Standard. Villanova, Pa: National Committee for Clinical Laboratory Standards; 1995. [Google Scholar]
- 12.Perronne C, Gikas A, Truffot-Pernot C, Grosset J, Vilde J L, Pocidalo J J. Activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine compared with that of clarithromycin against multiplication of Mycobacterium avium complex within human macrophages. Antimicrob Agents Chemother. 1991;35:1356–1359. doi: 10.1128/aac.35.7.1356. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ward T T, Rimland D, Kauffman C, Huycke M, Evans T G, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Clin Infect Dis. 1998;27:1278–1285. doi: 10.1086/514999. [DOI] [PubMed] [Google Scholar]
- 14.Watt B, Rayner A, Harris G. Comparative activity of azithromycin against clinical isolates of mycobacteria. J Antimicrob Chemother. 1979;38:539–542. doi: 10.1093/jac/38.3.539. [DOI] [PubMed] [Google Scholar]