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

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

Research output: Contribution to journalArticlepeer-review

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 2019

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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