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Published ahead of print on September 1, 2005, doi:10.1164/rccm.200507-1072OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 11, December 2005, 1457-1462

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Submitted on July 12, 2005
Accepted on August 31, 2005

Weekly Moxifloxacin and Rifapentine is More Active than the Denver Regimen in Murine Tuberculosis

Ian M Rosenthal1, Kathy Williams2, Sandeep Tyagi2, Andrew A Vernon3, Charles A Peloquin4, William R Bishai1, Jacques H Grosset2, and Eric L Nuermberger1*

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

* To whom correspondence should be addressed. 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: In order 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 tuberculosis patients. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed in order to evaluate the effect of intermittent drug administration during the initial phase of therapy. Results: After 2 months of treatment, lung CFU 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 increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.
Key words: moxifloxacin, rifapentine, mouse, tuberculosis, intermittent




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