Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters

Joseph S. Cavanaugh, Ruwen Jou, Mei Hua Wu, Tracy Dalton, Ekaterina Kurbatova, Julia Ershova, J. Peter Cegielski, Joey Lancaster, Ronel Odendaal, Lois Diem, Kathrine Tan, Allison Taylor Walker, Erika Sigman, Beverly Metchock, M. Therese C. Perez, M. Tarcela Gler, Cesar Bonilla, Oswaldo Jave, Inga Norvaisha, Girts SkendersIngrida Sture, Vija Riekstina, Andra Cirule, Sang Nae Cho, Seokyong Eum, Jongseok Lee, Ying Cai, Isdore C. Shamputa, Tatiana Kuznetsova, Rattanawadee Akksilp, Wanlaya Sitti, Jirapan Inyapong, Elena V. Kiryanova, Irina Degtyareva, Evgenia S. Nemtsova, Klavdia Levina, Manfred Danilovits, Tiina Kummik, Yung Chao Lei, Wei Lun Huang, Vladislav V. Erokhin, Larisa N. Chernousova, Sofia N. Andreevskaya, Elena E. Larionova, Tatyana G. Smirnova

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Abstract

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Background: 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 antimycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse. Methods: 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 resazurinmicrodilution assaywas 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 theMIC50 andMIC90 as theMICs atwhich growth of 50% and 90% of isolates was inhibited, respectively. Results: TheMIC50s, in mg/L, for initial isolateswere 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 MIC90s, in mg/L, for initial isolateswere 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 MIC90 of isoniazid was > 4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug. Conclusions: 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.
Original languageAmerican English
Pages (from-to)1678-1687
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
DOIs
StatePublished - 1 Jan 2017
Externally publishedYes

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    Cavanaugh, J. S., Jou, R., Wu, M. H., Dalton, T., Kurbatova, E., Ershova, J., Cegielski, J. P., Lancaster, J., Odendaal, R., Diem, L., Tan, K., Walker, A. T., Sigman, E., Metchock, B., Perez, M. T. C., Gler, M. T., Bonilla, C., Jave, O., Norvaisha, I., ... Smirnova, T. G. (2017). Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters. Journal of Antimicrobial Chemotherapy, 1678-1687. https://doi.org/10.1093/jac/dkx022