Clofazimine has delayed antimicrobial activity against Mycobacterium tuberculosis both in vitro and in vivo
| Autor: | Deepak V. Almeida, Asa Tapley, Linda A. Bester, Chivonne Moodley, Sanil D. Singh, Bongani Ngcobo, Zinhle Mgaga, Sashen Moodley, Nicole C. Ammerman, Rosemary V. Swanson, Afton Dorasamy, John W. Adamson, Jacques H. Grosset |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Drug Tuberculosis media_common.quotation_subject 030106 microbiology Antitubercular Agents Microbial Sensitivity Tests Pharmacology Clofazimine Mycobacterium tuberculosis 03 medical and health sciences Mice In vivo Isoniazid Medicine Animals Pharmacology (medical) Lung Tuberculosis Pulmonary media_common Mice Inbred BALB C biology business.industry Antimicrobial medicine.disease biology.organism_classification In vitro Bacterial Load 030104 developmental biology Infectious Diseases business medicine.drug |
| Zdroj: | The Journal of antimicrobial chemotherapy. 72(2) |
| ISSN: | 1460-2091 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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