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Antimicrobial Agents and Chemotherapy, August 2006, p. 2621-2625, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00451-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis{dagger}

Eric Nuermberger,1,2* Ian Rosenthal,1,2 Sandeep Tyagi,1 Kathy N. Williams,1 Deepak Almeida,1 Charles A. Peloquin,3,4 William R. Bishai,1,2 and Jacques H. Grosset1

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,1 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,2 Infectious Diseases Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, Colorado,3 Departments of Pharmacy and Medicine, University of Colorado, Denver, Colorado4

Received 11 April 2006/ Returned for modification 16 May 2006/ Accepted 2 June 2006

The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

* Corresponding author. Mailing address: Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD 21231. Phone: (410) 502-0580. Fax: (410) 614-8173. E-mail: enuermb{at}jhmi.edu.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, August 2006, p. 2621-2625, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00451-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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