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

Despite the development of several agents, new classes of antimicrobials wi th 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 mu g/ml by the BACTEC system and 16 mu g/ml by broth microdilution fo r five MAC strains tested, An expansion of the screening with broth microdi lution to 24 macrolide-susceptible strains and 6 macrolide-resistant strain s determined that the MIC for all strains was 16 mu g/ml. To determine the intracellular activity of mefloquine, U937 macrophage monolayers infected w ith MAC strain 101, 100, or 109 (serovars 1, 8, and 4) were treated with me floquine daily, and the number of intracellular bacteria was quantitated af ter 4 days. Significant growth inhibition against the three MAC strains at concentrations greater than or equal to 10 mu g/ml (P < 0.05) was obtained. Due to the encouraging anti-MAC activity, in vivo efficacy in beige mice i nfected 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 splee n, No toxicity was observed with any of the treatment regimens. Mefloquine had borderline bactericidal activity at a dosage of 40 mg/kg daily (100% in hibition compared with a 1-week control), and significant inhibition was ob tained 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 mefl oquiue and ethambutol showed significantly more activity than did either dr ug alone in liver, spleen, and blood; the combination was also bactericidal against M, avium. Although safety is a potential concern, mefloquine and r elated compounds deserve further investigation as anti-MAC therapies.