Treatment-shortening effect of a novel regimen combining clofazimine and high-dose rifapentine in pathologically distinct mouse models of tuberculosis

Vikram Saini, Nicole Ammerman, Yong Seok Chang, Rokeya Tasneen, Richard E Chaisson, Sanjay Jain, Eric Nuermberger, Jacques H. Grosset

Research output: Contribution to journalArticle

Abstract

Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.

Original languageEnglish (US)
Article numbere00388-19
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number6
DOIs
StatePublished - Jun 1 2019

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rifapentine
Clofazimine
Tuberculosis
Rifampin
Therapeutics
Pharmaceutical Preparations

Keywords

  • BALB/c mice
  • C3HeB/FeJ mice
  • Clofazimine
  • Mouse models
  • Rifapentine
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

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title = "Treatment-shortening effect of a novel regimen combining clofazimine and high-dose rifapentine in pathologically distinct mouse models of tuberculosis",
abstract = "Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.",
keywords = "BALB/c mice, C3HeB/FeJ mice, Clofazimine, Mouse models, Rifapentine, Tuberculosis",
author = "Vikram Saini and Nicole Ammerman and Chang, {Yong Seok} and Rokeya Tasneen and Chaisson, {Richard E} and Sanjay Jain and Eric Nuermberger and Grosset, {Jacques H.}",
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AU - Saini, Vikram

AU - Ammerman, Nicole

AU - Chang, Yong Seok

AU - Tasneen, Rokeya

AU - Chaisson, Richard E

AU - Jain, Sanjay

AU - Nuermberger, Eric

AU - Grosset, Jacques H.

PY - 2019/6/1

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