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.