title: Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy.
abstract: Experimental and clinical studies have indicated that the antileprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in tuberculosis treatment, accumulated clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the BALB/c mouse model of chronic tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either isoniazid alone, clofazimine alone, the first-line regimen rifampin-isoniazid-pyrazinamide-ethambutol, or a first-line regimen where clofazimine was administered in place of ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation and 2, 4, 6, and 8 weeks after treatment was stopped. Bacterial regrowth was delayed in all mice receiving clofazimine, either alone or in combination, compared to the mice that did not receive clofazimine. This effect was especially evident in mice receiving multidrug therapy. In mice not receiving clofazimine, bacterial regrowth began almost immediately after treatment was stopped, while in mice receiving clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum clofazimine levels remained at or above the 0.25-μg/ml MIC for M. tuberculosis Thus, sustained activity of clofazimine may be important in the treatment-shortening effect associated with this drug.
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Rosemary V
authors.initials: RV
authors.lastname: Swanson
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa Center for Tuberculosis Research, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
authors.forename: Bongani
authors.initials: B
authors.lastname: Ngcobo
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
authors.forename: Chivonne
authors.initials: C
authors.lastname: Moodley
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
authors.forename: Afton
authors.initials: A
authors.lastname: Dorasamy
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
authors.forename: Sashen
authors.initials: S
authors.lastname: Moodley
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
authors.forename: Zinhle
authors.initials: Z
authors.lastname: Mgaga
authors.affiliation: Biomedical Resources Unit, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville, South Africa.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Bester
authors.affiliation: Biomedical Resources Unit, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville, South Africa.
authors.forename: Sanil D
authors.initials: SD
authors.lastname: Singh
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa Center for Tuberculosis Research, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
authors.affiliation: KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa Center for Tuberculosis Research, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA jgrosse4@jhmi.edu.
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002991:Clofazimine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000627:therapeutic use; D005260:Female; D007538:Isoniazid / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*; D028761:Withholding Treatment
chemical_list: D000995:Antitubercular Agents; D004338:Drug Combinations; C087181:isoniazid, pyrazinamide, rifampin drug combination; D011718:Pyrazinamide; D004977:Ethambutol; D002991:Clofazimine; D007538:Isoniazid; D012293:Rifampin