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Potent Twice-Weekly Rifapentine-containing Regimens in Murine Tuberculosis

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Infectious Diseases Pharmacokinetics Laboratory, National Jewish Medical and Research Center; Departments of Pharmacy and Medicine, University of Colorado, Denver, Colorado; and Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Eric L. Nuermberger, M.D., 1503 E. Jefferson Street, Baltimore, MD 21231-1002. E-mail: enuermb{at}jhmi.edu

Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.

Methods: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.

Results: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).

Conclusions: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.

Key Words: moxifloxacin • rifampin • rifapentine • tuberculosis • treatment

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