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

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.

• Authors: Jacques H Grosset, Sandeep Tyagi, Deepak V Almeida, Paul J Converse, Si-Yang Li, Nicole C Ammerman, William R Bishai, Donald Enarson, Arnaud Trébucq
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 188 Issue 5 Pg. 608-12 (Sep 01 2013) ISSN: 1535-4970 [Electronic] United States
• PMID: 23822735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antitubercular Agents
• Clofazimine

Topics

• Animals
• Antitubercular Agents (therapeutic use)
• Clofazimine (therapeutic use)
• Drug Resistance, Multiple, Bacterial
• Female
• Lung (microbiology)
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects)
• Recurrence
• Tuberculosis, Pulmonary (drug therapy)