Experimental and clinical studies have indicated that the antileprosy
drug clofazimine may contribute treatment-shortening activity when included in
tuberculosis treatment regimens.
Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in
tuberculosis treatment, accumulated
clofazimine may contribute sustained antimicrobial activity
after treatment cessation, and we used the BALB/c mouse model of chronic
tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either
isoniazid alone,
clofazimine alone, the first-line regimen
rifampin-
isoniazid-
pyrazinamide-
ethambutol, or a first-line regimen where
clofazimine was administered in place of
ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of
treatment cessation and 2, 4, 6, and 8 weeks
after treatment was stopped. Bacterial regrowth was delayed in all mice receiving
clofazimine, either alone or in combination, compared to the mice that did not receive
clofazimine. This effect was especially evident in mice receiving multidrug
therapy. In mice not receiving
clofazimine, bacterial regrowth began almost immediately
after treatment was stopped, while in mice receiving
clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum
clofazimine levels remained at or above the 0.25-μg/ml MIC for M.
tuberculosis Thus, sustained activity of
clofazimine may be important in the treatment-shortening effect associated with this
drug.