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

Ian M. Rosenthal, Rokeya Tasneen, Charles A. Peloquin, Ming Zhang, Deepak Almeida, Khisimuzi E. Mdluli, Petros C. Karakousis, Jacques H. Grosset, Eric L. Nuermberger

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4331-4340
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume56
Issue number8
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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