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Impact of Clofazimine Dosing on Treatment Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis

Ammerman, N. C., Swanson, R., Bautista, E. M., Almeida, D., Saini, V., Omansen, T. F., Guo, H., Chang, Y. S., Li, S-Y., Tapley, A., Tasneen, R., Tyagi, S., Betoudji, F., Moodley, C., Ngcobo, B., Pillay, L., Bester, L. A., Singh, S. D., Chaisson, R. E., Nuermberger, E. & Grosset, J. H., Jul-2018, In : Antimicrobial Agents and Chemotherapy. 62, 7, 18 p., ARTN e00636-18.

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  • Impact of Clofazimine Dosing on Treatment Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis

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DOI

  • Nicole C. Ammerman
  • Rosemary Swanson
  • Elaine M. Bautista
  • Deepak Almeida
  • Vikram Saini
  • Till F. Omansen
  • Haidan Guo
  • Yong Seok Chang
  • Si-Yang Li
  • Asa Tapley
  • Rokeya Tasneen
  • Sandeep Tyagi
  • Fabrice Betoudji
  • Chivonne Moodley
  • Bongani Ngcobo
  • Logan Pillay
  • Linda A. Bester
  • Sanil D. Singh
  • Richard E. Chaisson
  • Eric Nuermberger
  • Jacques H. Grosset

The antileprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes doseand duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when coad-ministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.

Original languageEnglish
Article numberARTN e00636-18
Number of pages18
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number7
Publication statusPublished - Jul-2018

    Keywords

  • BALB/c, clofazimine, mouse model, tuberculosis, MULTIDRUG-RESISTANT TUBERCULOSIS, PROTON MOTIVE FORCE, MYCOBACTERIUM-TUBERCULOSIS, STERILIZING ACTIVITY, IN-VITRO, MURINE MODEL, ANTIMICROBIAL ACTIVITY, BACTERICIDAL ACTIVITY, C3HEB/FEJ MICE, PYRAZINAMIDE

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