Identification of (+)-erythro-mefloquine as an active enantiomer with greater efficacy than mefloquine against Mycobacterium avium infection in mice.

Infection caused by Mycobacterium avium is common in AIDS patients who do not receive treatment with highly active antiretroviral therapy (HAART) or who develop resistance to anti-HIV therapy. Mefloquine, a racemic mixture used for malaria prophylaxis and treatment, is bactericidal against M. avium in mice. MICs of (+)-erythro-, (-)-erythro-, (+)-threo-, and (-)-threo-mefloquine were 32 µg/ml, 32 µg/ml, 64 µg/ml, and 64 µg/ml, respectively. The postantibiotic effect for (+)-erythro-mefloquine was 36 h (MIC) and 41 h for a concentration of 4× MIC. The mefloquine postantibiotic effect was 25 h (MIC and 4× MIC). After baseline infection was established (7 days), the (+)- and (-)-isomers of the diastereomeric threo- and erythro-α-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol were individually used to orally treat C57BL/6 bg(+)/bg(+) beige mice that were infected intravenously with M. avium. Mice were also treated with commercial mefloquine and diluent as controls. After 4 weeks of treatment, the mice were harvested, and the number of bacteria in spleen and liver was determined. Mice receiving (+)- or (-)-threo-mefloquine or (-)-erythro-mefloquine had numbers of bacterial load in tissues similar to those of untreated control mice at 4 weeks. Commercial mefloquine had a bactericidal effect. However, mice given the (+)-erythro-enantiomer for 4 weeks had a significantly greater reduction of bacterial load than those given mefloquine. Thus, (+)-erythro-mefloquine is the active enantiomer of mefloquine against M. avium and perhaps other mycobacteria.

SRI-286, a thiosemicarbazole, in combination with mefloquine and moxifloxacin for treatment of murine Mycobacterium avium complex disease.

Treatment of Mycobacterium avium disease remains challenging when macrolide resistance develops. We infected C57 beige mice and treated them with mefloquine, SRI-286, and moxifloxacin. SRI-286 (80 mg/kg) was bactericidal in the liver. Mefloquine plus moxifloxacin or mefloquine plus SRI-286 were better than mefloquine alone.

Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice.

In vitro screening of thiacetazone derivatives indicated that two derivatives, SRI-286 and SRI-224, inhibited a panel of 25 Mycobacterium avium complex (MAC) isolates at concentrations of 2 micro g/ml or lower. In mice, SRI-224 and thiacetazone had no significant activity against the MAC in livers and spleens, but treatment with SRI-286 resulted in significant reduction of bacterial loads in livers and spleens. A combination of SRI-286 and moxifloxacin was significantly more active than single drug regimens in liver and spleen.

Mefloquine, moxifloxacin, and ethambutol are a triple-drug alternative to macrolide-containing regimens for treatment of Mycobacterium avium disease.

Macrolides are the core of effective drug regimens for the treatment of Mycobacterium avium complex (MAC) disease. Mefloquine (MFQ), moxifloxacin (MXF), and ethambutol (EMB), in combination, were evaluated against both clarithromycin-resistant (CLR-R) and CLR-susceptible (CLR-S) MAC; MFQ (40 mg/kg), MXF (100 mg/kg), or EMB (100 mg/kg/day) was given to mice for 4 weeks. MFQ was bactericidal, whereas MXF and EMB were bacteriostatic against both MAC 101 CLR-S and CLR-R. The combination of MFQ and EMB reduced (P<.05, for comparison with controls), and the combination of MFQ and MXF significantly reduced, the load of CLR-R in both the liver and the spleen. Treatment with all 3 drugs was associated with approximately 1-log reduction of CLR-R after 1 week, 2.1-log reduction of CLR-R after 4 weeks, and 2.17-log reduction in MAC/mL blood. Treatment of MAC 101 CLR-S strain had comparable results.