Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 60, Issue 1, Pages 270-277Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01691-15
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Funding
- Global Alliance for TB Drug Development [90036107]
- National Institutes of Health [R01-AI090820]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI090820] Funding Source: NIH RePORTER
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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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