Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice

Jacques H. Grosset, Sandeep Tyagi, Deepak V. Almeida, Paul J. Converse, Si Yang Li, Nicole C. Ammerman, William R. Bishai, Donald Enarson, Arnaud Trébucq

Research output: Contribution to journalArticle

Abstract

Rationale: Although observational studies suggest that clofaziminecontaining regimens are highly active against drug-resistant tuberculosis, the contribution of clofazimine for the treatment of this disease has never been systematically evaluated. Objectives: Our goal wasto directlycomparethe activity of a standard second-line drug regimen with or without the addition of clofaziminein a mousemodelof multidrug-resistant tuberculosis.Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation. Methods: Mice were aerosol-infected with an isoniazid-resistant (as a surrogate ofmultidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce clofazimine carryover. Relapse was assessed 6months after treatment cessation. Measurements and Main Results: After 2 months, the bacillary load in lungs was reduced from 9.74 log10 at baseline to 3.61 and 4.68 in mice treated with or without clofazimine, respectively (P , 0.001). Mice treated with clofazimine were culture-negative after 5 months, whereas all mice treatedwithout clofazimine remainedheavily culturepositive for the entire 9 months of the study. The relapse rate was 7% amongmice treated with clofazimine for 8 to 9 months. Conclusions: The clofazimine contribution was substantial in these experimental conditions.

Original languageEnglish (US)
Pages (from-to)608-612
Number of pages5
JournalAmerican journal of respiratory and critical care medicine
Volume188
Issue number5
DOIs
StatePublished - Sep 1 2013

Keywords

  • Clofazimine
  • Inbred BALB/c mice
  • Multidrug-resistant tuberculosis
  • Tuberculosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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