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Title: D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal
Authors: 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
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
Keywords: Medicine
Issue Date: 28-Nov-2018
Citation: Clinical Infectious Diseases. Vol.67, (2018), S308-S316
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.
ISSN: 15376591
Appears in Collections:Scopus 2018

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