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

for the Global PETTS Investigators

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 languageEnglish
Article numberdkx022
Pages (from-to)1678-1687
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number6
DOIs
Publication statusPublished - 2017 Jan 1

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Multidrug-Resistant Tuberculosis
Linezolid
nitazoxanide
meropenem
Clavulanic Acid
Mycobacterium tuberculosis
Pharmacokinetics
Clofazimine
Oxyphenbutazone
Sulfamethoxazole Drug Combination Trimethoprim
Thioridazine
Mefloquine
Pharmaceutical Preparations
Amoxicillin
Isoniazid
Poisons
Mycobacterium
Therapeutics
Growth

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

@article{0a57dd4f72fd463d80ef71375ba68d18,
title = "Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters",
abstract = "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.",
author = "{for the Global PETTS Investigators} and Cavanaugh, {Joseph S.} and Ruwen Jou and Wu, {Mei Hua} and Tracy Dalton and Ekaterina Kurbatova and Julia Ershova and Cegielski, {J. Peter} and Joey Lancaster and Ronel Odendaal and Lois Diem and Kathrine Tan and Walker, {Allison Taylor} and Erika Sigman and Beverly Metchock and Perez, {M. Therese C.} and Gler, {M. Tarcela} and Cesar Bonilla and Oswaldo Jave and Inga Norvaisha and Girts Skenders and Ingrida Sture and Vija Riekstina and Andra Cirule and Sangnae Cho and Seokyong Eum and Jongseok Lee and Ying Cai and Shamputa, {Isdore C.} and Tatiana Kuznetsova and Rattanawadee Akksilp and Wanlaya Sitti and Jirapan Inyapong and Kiryanova, {Elena V.} and Irina Degtyareva and Nemtsova, {Evgenia S.} and Klavdia Levina and Manfred Danilovits and Tiina Kummik and Lei, {Yung Chao} and Huang, {Wei Lun} and Erokhin, {Vladislav V.} and Chernousova, {Larisa N.} and Andreevskaya, {Sofia N.} and Larionova, {Elena E.} and Smirnova, {Tatyana G.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/jac/dkx022",
language = "English",
volume = "72",
pages = "1678--1687",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "6",

}

Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters. / for the Global PETTS Investigators.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 6, dkx022, 01.01.2017, p. 1678-1687.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters

AU - for the Global PETTS Investigators

AU - Cavanaugh, Joseph S.

AU - Jou, Ruwen

AU - Wu, Mei Hua

AU - Dalton, Tracy

AU - Kurbatova, Ekaterina

AU - Ershova, Julia

AU - Cegielski, J. Peter

AU - Lancaster, Joey

AU - Odendaal, Ronel

AU - Diem, Lois

AU - Tan, Kathrine

AU - Walker, Allison Taylor

AU - Sigman, Erika

AU - Metchock, Beverly

AU - Perez, M. Therese C.

AU - Gler, M. Tarcela

AU - Bonilla, Cesar

AU - Jave, Oswaldo

AU - Norvaisha, Inga

AU - Skenders, Girts

AU - Sture, Ingrida

AU - Riekstina, Vija

AU - Cirule, Andra

AU - Cho, Sangnae

AU - Eum, Seokyong

AU - Lee, Jongseok

AU - Cai, Ying

AU - Shamputa, Isdore C.

AU - Kuznetsova, Tatiana

AU - Akksilp, Rattanawadee

AU - Sitti, Wanlaya

AU - Inyapong, Jirapan

AU - Kiryanova, Elena V.

AU - Degtyareva, Irina

AU - Nemtsova, Evgenia S.

AU - Levina, Klavdia

AU - Danilovits, Manfred

AU - Kummik, Tiina

AU - Lei, Yung Chao

AU - Huang, Wei Lun

AU - Erokhin, Vladislav V.

AU - Chernousova, Larisa N.

AU - Andreevskaya, Sofia N.

AU - Larionova, Elena E.

AU - Smirnova, Tatyana G.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

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DO - 10.1093/jac/dkx022

M3 - Article

VL - 72

SP - 1678

EP - 1687

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

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