期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：869-874
DOI：10.1073/pnas.1416951112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe infectious disease tuberculosis (TB) is a major public health problem that affects millions of people worldwide. TB treatment consists of a multidrug regimen that needs to be taken for a minimum of 6 mo, and lack of adherence to this regimen is associated with treatment failure and emergence of drug resistance. In a mouse model of TB chemotherapy, we have found that inclusion of the antileprosy drug clofazimine in the first-line regimen for TB reduces the duration of treatment necessary to achieve relapse-free cure from 6 mo to 3 mo. Our data suggest that clofazimine, a drug already known to be safe for long-term administration to patients with leprosy, has the potential to significantly shorten the duration of TB treatment. A key drug for the treatment of leprosy, clofazimine has recently been associated with highly effective and significantly shortened regimens for the treatment of multidrug-resistant tuberculosis (TB). Consequently, we hypothesized that clofazimine may also shorten the duration of treatment for drug-susceptible TB. We conducted a controlled trial in the mouse model of TB chemotherapy comparing the activity of the 6-mo standard regimen for TB treatment, i.e., 2 mo of daily rifampin, isoniazid, pyrazinamide, and ethambutol followed by 4 mo of rifampin and isoniazid, with a 4-mo clofazimine-containing regimen: 2 mo of daily rifampin, isoniazid, pyrazinamide, and clofazimine followed by 2 mo of rifampin, isoniazid, and clofazimine. Treatment efficacy was assessed on the basis of Mycobacterium tuberculosis colony counts in the lungs and spleens during treatment and on the proportion of mice with culture-positive relapse 6 mo after treatment cessation. No additive effect of clofazimine was observed after the first week of treatment, but, by the second week of treatment, the colony counts were significantly lower in the clofazimine-treated mice than in the mice receiving the standard regimen. Lung culture conversion was obtained after 3 and 5 mo in mice treated with the clofazimine-containing and standard regimens, respectively, and relapse-free cure was obtained after 3 and 6 mo of treatment with the clofazimine-containing and standard regimens, respectively. Thus, clofazimine is a promising anti-TB drug with the potential to shorten the duration of TB chemotherapy by at least half (3 mo vs. 6 mo) in the mouse model of TB.
