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- Title
Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters.
- Authors
Cavanaugh, Joseph S.; Jou, Ruwen; Mei-Hua Wu; Dalton, Tracy; Kurbatova, Ekaterina; Ershova, Julia; Cegielski, J. Peter; Wu, Mei-Hua; Global PETTS Investigators
- Abstract
<bold>Background: </bold>The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse.<bold>Methods: </bold>We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively.<bold>Results: </bold>The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug.<bold>Conclusions: </bold>Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.
- Subjects
MYCOBACTERIUM tuberculosis; PHARMACODYNAMICS; DRUG resistance; SULFAMETHOXAZOLE; THIORIDAZINE; OXYPHENBUTAZONE; ANTITUBERCULAR agents; CLAVULANIC acid; DRUG resistance in microorganisms; DRUG design; ENZYME inhibitors; HETEROCYCLIC compounds; LEPROSTATIC agents; MICROBIAL sensitivity tests; CARBAPENEMS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2017, Vol 72, Issue 6, p1678
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkx022