Publication:
D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Issued Date

2018-11-28

Resource Type

Article

ISSN

15376591
10584838

DOI

10.1093/cid/ciy624

Other identifier(s)

2-s2.0-85055117226

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Mahidol University

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SCOPUS

Bibliographic Citation

Clinical Infectious Diseases. Vol.67, (2018), S308-S316

Suggested Citation

Devyani Deshpande, Jan Willem C. Alffenaar, Claudio U. Köser, Keertan Dheda, Moti L. Chapagain, Noviana Simbar, Thomas Schön, Marieke G.G. Sturkenboom, Helen McIlleron, Pooi S. Lee, Thearith Koeuth, Stellah G. Mpagama, Sayera Banu, Suporn Foongladda, Oleg Ogarkov, Suporn Pholwat, Eric R. Houpt, Scott K. Heysell, Tawanda Gumbo D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal. Clinical Infectious Diseases. Vol.67, (2018), S308-S316. doi:10.1093/cid/ciy624 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46178

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Title

D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal

Author(s)

Devyani Deshpande
 Jan Willem C. Alffenaar
 Claudio U. Köser
 Keertan Dheda
 Moti L. Chapagain
 Noviana Simbar
 Thomas Schön
 Marieke G.G. Sturkenboom
 Helen McIlleron
 Pooi S. Lee
 Thearith Koeuth
 Stellah G. Mpagama
 Sayera Banu
 Suporn Foongladda
 Oleg Ogarkov
 Suporn Pholwat
 Eric R. Houpt
 Scott K. Heysell
 Tawanda Gumbo

Other Contributor(s)

Scientific Сentre for Family Health and Human Reproduction Problems SB RAMS
 University of Cambridge
 University of Virginia
 Baylor Research Institute
 Kalmar County Hospital
 Faculty of Medicine, Siriraj Hospital, Mahidol University
 International Centre for Diarrhoeal Disease Research Bangladesh
 Linköpings universitet
 University of Groningen, University Medical Center Groningen
 University of Cape Town
 Kibong'oto Infectious Diseases Hospital

Abstract

© 2019 The Author(s). Background. D-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods. We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10 000 patients using Monte Carlo experiments (MCEs). Results. There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%TMIC), with 1.0 log10 CFU/mL kill achieved by %TMIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions. Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

Keyword(s)

Medicine

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URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/46178

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Scopus 2018