Sterilizing Activities of Novel Combinations Lacking First- and Second-Line Drugs in a Murine Model of Tuberculosis

Author:

Williams Kathy1,Minkowski Austin1,Amoabeng Opokua1,Peloquin Charles A.2,Taylor Dinesh1,Andries Koen3,Wallis Robert S.4,Mdluli Khisimuzi E.5,Nuermberger Eric L.16

Affiliation:

1. Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

2. College of Pharmacy, University of Florida, Gainesville, Florida, USA

3. Tibotec BVBA, Johnson & Johnson, Beerse, Belgium

4. Pfizer Inc., Groton, Connecticut, USA

5. Global Alliance for TB Drug Development, New York, New York, USA

6. Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Abstract

ABSTRACT Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

Publisher

American Society for Microbiology

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