Contribution of oxazolidinones to the efficacy of novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)270-277
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume60
Issue number1
DOIs
StatePublished - Jan 1 2016

    Fingerprint

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Tasneen, R., Betoudji, F., Tyagi, S., Li, S. Y., Williams, K., Converse, P. J., Dartois, V., Yang, T., Mendel, C. M., Mdluli, K. E., & Nuermberger, E. L. (2016). Contribution of oxazolidinones to the efficacy of novel regimens containing bedaquiline and pretomanid in a mouse model of tuberculosis. Antimicrobial agents and chemotherapy, 60(1), 270-277. https://doi.org/10.1128/AAC.01691-15