Mefloquine is active in vitro and in vivo against Mycobacterium avium complex.

TitleMefloquine is active in vitro and in vivo against Mycobacterium avium complex.
Publication TypeJournal Article
Year of Publication1999
AuthorsBermudez LE, Kolonoski P, Wu M, Aralar PA, Inderlied CB, Young LS
JournalAntimicrobial agents and chemotherapy
Volume43
Issue8
Pagination1870-4
Date Published1999 Aug
ISSN0066-4804
KeywordsAnimals, Antimalarials, Antitubercular Agents, Dose-Response Relationship, Drug, Drug Synergism, Ethambutol, Female, Humans, Macrophages, Mefloquine, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Mycobacterium avium Complex, Mycobacterium avium-intracellulare Infection, Radiometry, U937 Cells
Abstract

Despite the development of several agents, new classes of antimicrobials with activity against the Mycobacterium avium complex (MAC) are needed. Based on a broad screening of compounds, we found that mefloquine has MICs of 8 to 16 microg/ml by the BACTEC system and 16 microg/ml by broth microdilution for five MAC strains tested. An expansion of the screening with broth microdilution to 24 macrolide-susceptible strains and 6 macrolide-resistant strains determined that the MIC for all strains was 16 microg/ml. To determine the intracellular activity of mefloquine, U937 macrophage monolayers infected with MAC strain 101, 100, or 109 (serovars 1, 8, and 4) were treated with mefloquine daily, and the number of intracellular bacteria was quantitated after 4 days. Significant growth inhibition against the three MAC strains at concentrations greater than or equal to 10 microg/ml (P < 0.05) was obtained. Due to the encouraging anti-MAC activity, in vivo efficacy in beige mice infected with MAC 101 was evaluated. Animals were treated with 5, 10, 20, or 40 mg/kg of body weight daily, three times a week, twice a week, or once a week for 4 weeks, and bacteria were quantitated in blood, liver, and spleen. No toxicity was observed with any of the treatment regimens. Mefloquine had borderline bactericidal activity at a dosage of 40 mg/kg daily (100% inhibition compared with a 1-week control), and significant inhibition was obtained at dosages of 40 mg/kg three times a week, as well as 20 mg/kg daily. Mefloquine had no significant effect on bacteremia. A combination of mefloquine and ethambutol showed significantly more activity than did either drug alone in liver, spleen, and blood; the combination was also bactericidal against M. avium. Although safety is a potential concern, mefloquine and related compounds deserve further investigation as anti-MAC therapies.

Alternate JournalAntimicrob. Agents Chemother.