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Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis.

Rosenthal, Ian M; Tasneen, Rokeya; Peloquin, Charles A; Zhang, Ming; Almeida, Deepak; Mdluli, Khisimuzi E; Karakousis, Petros C; Grosset, Jacques H; Nuermberger, Eric L.
Antimicrob Agents Chemother; 56(8): 4331-40, 2012 Aug.
Artigo em Inglês | MEDLINE | Jun 2012 | ID: mdl-22664964
Resumo: In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.