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Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models.

Publication ,  Journal Article
Tasneen, R; Garcia, A; Converse, PJ; Zimmerman, MD; Dartois, V; Kurbatova, E; Vernon, AA; Carr, W; Stout, JE; Dooley, KE; Nuermberger, EL
Published in: Antimicrob Agents Chemother
April 19, 2022

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

Duke Scholars

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 19, 2022

Volume

66

Issue

4

Start / End Page

e0239821

Location

United States

Related Subject Headings

  • Tuberculosis
  • Rifabutin
  • Pyrazinamide
  • Oxazoles
  • Nitroimidazoles
  • Mycobacterium tuberculosis
  • Moxifloxacin
  • Microbiology
  • Mice, Inbred BALB C
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Tasneen, R., Garcia, A., Converse, P. J., Zimmerman, M. D., Dartois, V., Kurbatova, E., … Nuermberger, E. L. (2022). Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models. Antimicrob Agents Chemother, 66(4), e0239821. https://doi.org/10.1128/aac.02398-21
Tasneen, Rokeya, Andrew Garcia, Paul J. Converse, Matthew D. Zimmerman, Veronique Dartois, Ekaterina Kurbatova, Andrew A. Vernon, et al. “Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models.Antimicrob Agents Chemother 66, no. 4 (April 19, 2022): e0239821. https://doi.org/10.1128/aac.02398-21.
Tasneen R, Garcia A, Converse PJ, Zimmerman MD, Dartois V, Kurbatova E, et al. Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models. Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0239821.
Tasneen, Rokeya, et al. “Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models.Antimicrob Agents Chemother, vol. 66, no. 4, Apr. 2022, p. e0239821. Pubmed, doi:10.1128/aac.02398-21.
Tasneen R, Garcia A, Converse PJ, Zimmerman MD, Dartois V, Kurbatova E, Vernon AA, Carr W, Stout JE, Dooley KE, Nuermberger EL. Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models. Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0239821.

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 19, 2022

Volume

66

Issue

4

Start / End Page

e0239821

Location

United States

Related Subject Headings

  • Tuberculosis
  • Rifabutin
  • Pyrazinamide
  • Oxazoles
  • Nitroimidazoles
  • Mycobacterium tuberculosis
  • Moxifloxacin
  • Microbiology
  • Mice, Inbred BALB C
  • Mice