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Am J Respir Crit Care Med. 2013 Sep 1;188(5):608-12. doi: 10.1164/rccm.201304-0753OC.

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

Author information

1
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. jgrosse4@jhmi.edu

Abstract

RATIONALE:

Although observational studies suggest that clofazimine-containing 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 was to directly compare the activity of a standard second-line drug regimen with or without the addition of clofazimine in a mouse model of 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 of multidrug-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 6 months 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 treated without clofazimine remained heavily culture-positive for the entire 9 months of the study. The relapse rate was 7% among mice treated with clofazimine for 8 to 9 months.

CONCLUSIONS:

The clofazimine contribution was substantial in these experimental conditions.

PMID:
23822735
PMCID:
PMC3827279
DOI:
10.1164/rccm.201304-0753OC
[Indexed for MEDLINE]
Free PMC Article

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