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

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

Deshpande, Devyani (author): Baylor Univ, TX USA

Alffenaar, Jan-Willem C. (author): Univ Groningen, Netherlands

Koser, Claudio U. (author): Univ Cambridge, England

Dheda, Keertan (author): Univ Cape Town, South Africa

Chapagain, Moti L. (author): Baylor Univ, TX USA

Simbar, Noviana (author): Univ Groningen, Netherlands

Schön, Thomas (author): Linköpings universitet,Avdelningen för mikrobiologi och molekylär medicin,Medicinska fakulteten

Sturkenboom, Marieke G. G. (author): Univ Groningen, Netherlands

McIlleron, Helen (author): Univ Cape Town, South Africa

Lee, Pooi S. (author): Baylor Univ, TX USA

Koeuth, Thearith (author): Baylor Univ, TX USA

Mpagama, Stellah G. (author): Kibongoto Infect Dis Hosp, Tanzania

Banu, Sayera (author): Int Ctr Diarrhoeal Dis Res, Bangladesh

Foongladda, Suporn (author): Mahidol Univ, Thailand

Ogarkov, Oleg (author): Sci Ctr Family Hlth and Human Reprod Problem, Russia

Pholwat, Suporn (author): Univ Virginia, VA USA

Houpt, Eric R. (author): Univ Virginia, VA USA

Heysell, Scott K. (author): Univ Virginia, VA USA

Gumbo, Tawanda (author): Baylor Univ, TX USA

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2018-11-28
2018
English.
In: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 67, s. S308-S316

Related links:: https://academic.oup...; show more...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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 log(10) colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (% T-MIC), with 1.0 log(10) CFU/mL kill achieved by % T-MIC = 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.

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Infectious Medic ...

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By the university: Linköping University

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

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