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

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.

• Authors: Ian M Rosenthal, Rokeya Tasneen, Charles A Peloquin, Ming Zhang, Deepak Almeida, Khisimuzi E Mdluli, Petros C Karakousis, Jacques H Grosset, Eric L Nuermberger
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 8 Pg. 4331-40 (Aug 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22664964 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antitubercular
• Antitubercular Agents
• Pyrazinamide
• Ethambutol
• Isoniazid
• Rifampin
• rifapentine

Topics

• Animals
• Antibiotics, Antitubercular (administration & dosage, therapeutic use)
• Antitubercular Agents (administration & dosage, therapeutic use)
• Disease Models, Animal
• Drug Administration Schedule
• Drug Therapy, Combination
• Ethambutol (pharmacology, therapeutic use)
• Isoniazid (pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects)
• Pyrazinamide (pharmacology, therapeutic use)
• Random Allocation
• Rifampin (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Treatment Outcome
• Tuberculosis, Pulmonary (drug therapy, microbiology)