Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy
| Autor: | Sanil D. Singh, Chivonne Moodley, Jacques H. Grosset, Nicole C. Ammerman, Linda A. Bester, Zinhle Mgaga, Afton Dorasamy, Deepak V. Almeida, Rosemary V. Swanson, Sashen Moodley, Bongani Ngcobo, John W. Adamson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Tuberculosis medicine.medical_treatment 030106 microbiology Antitubercular Agents Pharmacology Clofazimine Mycobacterium tuberculosis Mice 03 medical and health sciences Isoniazid Animals Medicine Experimental Therapeutics Pharmacology (medical) Ethambutol Mice Inbred BALB C Chemotherapy biology business.industry Pyrazinamide biology.organism_classification medicine.disease Disease Models Animal Drug Combinations Regimen 030104 developmental biology Infectious Diseases Withholding Treatment Drug Therapy Combination Female Rifampin business medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 60:2864-2869 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00177-16 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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