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Weekly Moxifloxacin and Rifapentine Is More Active Than the Denver Regimen in Murine Tuberculosis

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

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

Rationale: Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non–high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens.

Methods: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of high-risk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy.

Results: After 2 mo of treatment, lung colony-forming unit counts were 1 log₁₀ lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between once-weekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen.

Conclusions: These results suggest that the efficacy of the once-weekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.

Key Words: antibiotics • intermittent therapy • mouse • treatment

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