Nicole C Ammerman1,2, Rosemary V Swanson2,3, Asa Tapley1,2,4,5, Chivonne Moodley2, Bongani Ngcobo2, John Adamson2, Afton Dorasamy2, Sashen Moodley2, Zinhle Mgaga2, Linda A Bester6, Sanil D Singh6, Deepak V Almeida1,2, Jacques H Grosset7,2. 1. Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. 2. KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa. 3. School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa. 4. University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA. 5. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. 6. Biomedical Resources Unit, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa. 7. Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA jgrosse4@jhmi.edu.
Abstract
OBJECTIVES: The anti-leprosy drug clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and has been associated with treatment-shortening activity in both clinical and preclinical studies of TB chemotherapy. However, a reported lack of early bactericidal activity (EBA) in TB patients has raised questions regarding the usefulness of clofazimine as an anti-TB drug. Our objective was to systematically evaluate the EBA of clofazimine in vitro and in vivo to provide insight into how and when this drug exerts its antimicrobial activity against M. tuberculosis. METHODS: We evaluated the 14 day EBA of clofazimine (i) in vitro at concentrations ranging from 4 times below to 4 times above the MIC for M. tuberculosis and (ii) in vivo in infected BALB/c mice at doses ranging from 1.5 to 100 mg/kg/day, and serum clofazimine levels were measured. In both experiments, isoniazid was used as the positive control. RESULTS: In vitro, clofazimine, at any concentration tested, did not exhibit bactericidal activity during the first week of exposure; however, in the second week, it exhibited concentration-dependent antimicrobial activity. In vivo, clofazimine, at any dose administered, did not exhibit bactericidal activity during the first week, and limited antimicrobial activity was observed during the second week of administration. While serum clofazimine levels were clearly dose dependent, the antimicrobial activity was not significantly related to the dose administered. CONCLUSIONS: Our data suggest that clofazimine's delayed antimicrobial activity may be due more to its mechanism of action rather than to host-related factors.
OBJECTIVES: The anti-leprosy drug clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and has been associated with treatment-shortening activity in both clinical and preclinical studies of TB chemotherapy. However, a reported lack of early bactericidal activity (EBA) in TBpatients has raised questions regarding the usefulness of clofazimine as an anti-TB drug. Our objective was to systematically evaluate the EBA of clofazimine in vitro and in vivo to provide insight into how and when this drug exerts its antimicrobial activity against M. tuberculosis. METHODS: We evaluated the 14 day EBA of clofazimine (i) in vitro at concentrations ranging from 4 times below to 4 times above the MIC for M. tuberculosis and (ii) in vivo in infected BALB/c mice at doses ranging from 1.5 to 100 mg/kg/day, and serum clofazimine levels were measured. In both experiments, isoniazid was used as the positive control. RESULTS: In vitro, clofazimine, at any concentration tested, did not exhibit bactericidal activity during the first week of exposure; however, in the second week, it exhibited concentration-dependent antimicrobial activity. In vivo, clofazimine, at any dose administered, did not exhibit bactericidal activity during the first week, and limited antimicrobial activity was observed during the second week of administration. While serum clofazimine levels were clearly dose dependent, the antimicrobial activity was not significantly related to the dose administered. CONCLUSIONS: Our data suggest that clofazimine's delayed antimicrobial activity may be due more to its mechanism of action rather than to host-related factors.
Authors: Vikram Saini; Nicole C Ammerman; Yong Seok Chang; Rokeya Tasneen; Richard E Chaisson; Sanjay Jain; Eric Nuermberger; Jacques H Grosset Journal: Antimicrob Agents Chemother Date: 2019-05-24 Impact factor: 5.191
Authors: Nicole C Ammerman; Rosemary V Swanson; Elaine M Bautista; Deepak V 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 Journal: Antimicrob Agents Chemother Date: 2018-06-26 Impact factor: 5.191
Authors: Mahmoud Tareq Abdelwahab; Sean Wasserman; James C M Brust; Neel R Gandhi; Graeme Meintjes; Daniel Everitt; Andreas Diacon; Rodney Dawson; Lubbe Wiesner; Elin M Svensson; Gary Maartens; Paolo Denti Journal: J Antimicrob Chemother Date: 2020-11-01 Impact factor: 5.790