title: Clofazimine has delayed antimicrobial activity against Mycobacterium tuberculosis both in vitro and in vivo.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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: Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.|KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Nicole C
authors: NC
authors: Ammerman
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.|School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa.
authors: Rosemary V
authors: RV
authors: Swanson
authors: Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.|KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.|University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA.|Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors: Asa
authors: A
authors: Tapley
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Chivonne
authors: C
authors: Moodley
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Bongani
authors: B
authors: Ngcobo
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: John
authors: J
authors: Adamson
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Afton
authors: A
authors: Dorasamy
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Sashen
authors: S
authors: Moodley
authors: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Zinhle
authors: Z
authors: Mgaga
authors: Biomedical Resources Unit, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa.
authors: Linda A
authors: LA
authors: Bester
authors: Biomedical Resources Unit, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa.
authors: Sanil D
authors: SD
authors: Singh
authors: Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.|KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Deepak V
authors: DV
authors: Almeida
authors: Johns Hopkins Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA jgrosse4@jhmi.edu.|KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban 4001, South Africa.
authors: Jacques H
authors: JH
authors: Grosset
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058491:Bacterial Load / Q000187:drug effects*; D002991:Clofazimine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007538:Isoniazid / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D002991:Clofazimine; D007538:Isoniazid