Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis

Sandeep Tyagi, Nicole Ammerman, Si Yang Li, John Adamson, Paul J. Converse, Rosemary V. Swanson, Deepak V. Almeida, Jacques H. Grosset

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)869-874
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number3
DOIs
StatePublished - Jan 20 2015

Fingerprint

Clofazimine
Tuberculosis
Drug Therapy
Isoniazid
Rifampin
Therapeutics
Pyrazinamide
Pharmaceutical Preparations
Recurrence
Ethambutol
Multidrug-Resistant Tuberculosis
Lung
Withholding Treatment
Leprosy
Mycobacterium tuberculosis
Spleen

Keywords

  • Clofazimine
  • Experimental chemotherapy
  • Mouse model
  • Tuberculosis
  • Tuberculosis treatment

ASJC Scopus subject areas

  • General

Cite this

Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis. / Tyagi, Sandeep; Ammerman, Nicole; Li, Si Yang; Adamson, John; Converse, Paul J.; Swanson, Rosemary V.; Almeida, Deepak V.; Grosset, Jacques H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 3, 20.01.2015, p. 869-874.

Research output: Contribution to journalArticle

Tyagi, Sandeep ; Ammerman, Nicole ; Li, Si Yang ; Adamson, John ; Converse, Paul J. ; Swanson, Rosemary V. ; Almeida, Deepak V. ; Grosset, Jacques H. / Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 3. pp. 869-874.
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AU - Tyagi, Sandeep

AU - Ammerman, Nicole

AU - Li, Si Yang

AU - Adamson, John

AU - Converse, Paul J.

AU - Swanson, Rosemary V.

AU - Almeida, Deepak V.

AU - Grosset, Jacques H.

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AB - 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.

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