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

TY - JOUR

T1 - Impact of Clofazimine Dosing on Treatment Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis

AU - Ammerman, Nicole C

AU - Swanson, Rosemary V

AU - Bautista, Elaine M

AU - Almeida, Deepak V

AU - Saini, Vikram

AU - Omansen, Till F

AU - Guo, Haidan

AU - Chang, Yong Seok

AU - Li, Si-Yang

AU - Tapley, Asa

AU - Tasneen, Rokeya

AU - Tyagi, Sandeep

AU - Betoudji, Fabrice

AU - Moodley, Chivonne

AU - Ngcobo, Bongani

AU - Pillay, Logan

AU - Bester, Linda A

AU - Singh, Sanil D

AU - Chaisson, Richard E

AU - Nuermberger, Eric

AU - Grosset, Jacques H

N1 - Copyright © 2018 American Society for Microbiology.

PY - 2018/7

Y1 - 2018/7

N2 - 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 dose- and 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 coadministered 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.

AB - 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 dose- and 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 coadministered 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.

KW - Animals

KW - Antitubercular Agents/therapeutic use

KW - Clofazimine/therapeutic use

KW - Disease Models, Animal

KW - Female

KW - Mice

KW - Mice, Inbred BALB C

KW - Random Allocation

KW - Tuberculosis/drug therapy

KW - Tuberculosis, Multidrug-Resistant/drug therapy

U2 - 10.1128/AAC.00636-18

DO - 10.1128/AAC.00636-18

M3 - SCORING: Journal article

C2 - 29735562

VL - 62

SP - e00636-18

JO - ANTIMICROB AGENTS CH

JF - ANTIMICROB AGENTS CH

SN - 0066-4804

IS - 7

ER -