ATP synthase inhibition of Mycobacterium avium is not bactericidal. Antimicrob Agents Chemother

The efficacy of ATP synthase inhibitor TMC207 was assessed in early and late Mycobacterium avium infections in mice. In contrast to what was earlier observed for M. tuberculosis, a bacteriostatic effect was obtained. In vitro, the minimal bactericidal concentration (MBC)/MIC ratio was very high. The MBC was more relevant for assessment of pharmacokinetic/pharmacodynamic relationships than the MIC. Mycobacterium avium is a pathogen that causes disseminated disease in immunocompromised individuals and pulmonary disease in immunocompetent adults (15) and is far less sus-ceptible than Mycobacterium tuberculosis to most antimicrobial agents; treatment options are very limited (7, 10). The most efficacious drugs are clarithromycin (CLA), the azalide antibi-otic azithromycin, and amikacin (AMK). They are generally part of a multidrug regimen including rifamycins and etham-butol (10) and need to be administered daily for up to 24 months (10). These regimens are expensive and poorly toler-ated (2, 6). TMC207 (also known as R207910) is a diarylquino-line ATP synthase inhibitor with potent activity against M. tuberculosis (1, 3, 13). It has broad antimycobacterial activity, with MICs against several clinical isolates of M. avium ranging from 0.007 to 0.25 g/ml (1, 8). Female C57BL/6J mice aged 6 to 7 weeks (Janvier Breeding, France) were infected intraperitoneally with 0.5 ml of a bac-terial suspension containing 2.3 107 CFU of M. avium 101. In a first group of 20 animals (Table 1), treatment started the day after infection (early infection model) and included a negative control, a positive control (CLA), and two test groups (TMC207 or CLA plus TMC207). Mice were sacrificed after 1 month of treatment. A second group of 165 mice was kept untreated for 1 month (late infection model) and then was treated with CLA alone, AMK alone, TMC207 alone, CL