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Published ahead of print on March 30, 2006, doi:10.1164/rccm.200602-280OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 1, July 2006, 94-101

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Submitted on February 25, 2006
Accepted on March 30, 2006

Potent Twice-weekly Rifapentine-containing Regimens in Murine Tuberculosis

Ian M Rosenthal1, Kathy Williams2, Sandeep Tyagi2, Charles A Peloquin3, Andrew A Vernon4, William R Bishai1, Jacques H Grosset2, and Eric L Nuermberger1*

1 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 2 Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3 Infectious Diseases Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, CO, USA; Department of Pharmacy and Medicine, University of Colorado, Denver, CO, USA, 4 Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA, USA

* To whom correspondence should be addressed. E-mail: enuermb{at}jhmi.edu.

Rationale: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid and pyrazinamide may be improved by increasing M. 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 months of treatment to assess stable cure. Single and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined. Results: After 2 months 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 months of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 months 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 months. Such regimens warrant clinical investigation.
Key words: tuberculosis, rifapentine, intermittent therapy, mouse model,




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