Contribution of Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and Pretomanid in a Mouse Model of Tuberculosis.
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.
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Rokeya
R
Tasneen
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Fabrice
F
Betoudji
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sandeep
S
Tyagi
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Si-Yang
SY
Li
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Kathy
K
Williams
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Paul J
PJ
Converse
Public Health Research Institute and New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Véronique
V
Dartois
Global Alliance for TB Drug Development, New York, New York, USA.
Tian
T
Yang
Global Alliance for TB Drug Development, New York, New York, USA.
Carl M
CM
Mendel
Global Alliance for TB Drug Development, New York, New York, USA.
Khisimuzi E
KE
Mdluli
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA enuermb@jhmi.edu.
Eric L
EL
Nuermberger
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D058491:Bacterial Load; D064687:Diarylquinolines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D000069349:Linezolid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D009593:Nitroimidazoles / Q000494:pharmacology*; D010755:Organophosphates / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D023303:Oxazolidinones / Q000494:pharmacology*; D011718:Pyrazinamide / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
D000995:Antitubercular Agents; D064687:Diarylquinolines; D004338:Drug Combinations; D009593:Nitroimidazoles; D010755:Organophosphates; D010080:Oxazoles; D023303:Oxazolidinones; C543015:PNU-100480; C518323:RWJ-416457; C410767:pretomanid; D011718:Pyrazinamide; C493870:bedaquiline; C453362:posizolid; D000069349:Linezolid; C515040:tedizolid phosphate