Contribution of Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and Pretomanid in a Mouse Model of Tuberculosis |
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| Authors: | Rokeya Tasneen Fabrice Betoudji Sandeep Tyagi Si-Yang Li Kathy Williams Paul J. Converse Véronique Dartois Tian Yang Carl M. Mendel Khisimuzi E. Mdluli Eric L. Nuermberger |
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| Affiliation: | aCenter for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;bPublic Health Research Institute and New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA;cGlobal Alliance for TB Drug Development, New York, New York, USA;dDepartment of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA |
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| Abstract: | New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid (PMD) is a nitroimidazole in phase 3 trials that has significant bactericidal activity alone and in combination with bedaquiline (BDQ) and/or pyrazinamide (PZA). We previously showed that the novel combination of BDQ+PMD plus the oxazolidinone sutezolid (SZD) had sterilizing activity superior to that of the first-line regimen in a murine model of TB. The present experiments compared the activity of different oxazolidinones in combination with BDQ+PMD with or without PZA in the same model. The 3-drug regimen of BDQ+PMD plus linezolid (LZD) had sterilizing activity approaching that of BDQ+PMD+SZD and superior to that of the first-line regimen. The addition of PZA further enhanced activity. Reducing the duration of LZD to 1 month did not significantly affect the activity of the regimen. Halving the LZD dose or replacing LZD with RWJ-416457 modestly reduced activity over the first month but not after 2 months. AZD5847 and tedizolid also increased the bactericidal activity of BDQ+PMD, but they were less effective than the other oxazolidinones. These results provide optimism for safe, short-course oral regimens for drug-resistant TB that may also be superior to the current first-line regimen for drug-susceptible TB. |
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