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D-Cycloserine Pharm...
D-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal
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- Deshpande, Devyani (author)
- Baylor Univ, TX USA
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- Alffenaar, Jan-Willem C. (author)
- Univ Groningen, Netherlands
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- Koser, Claudio U. (author)
- Univ Cambridge, England
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- Dheda, Keertan (author)
- Univ Cape Town, South Africa
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- Chapagain, Moti L. (author)
- Baylor Univ, TX USA
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- Simbar, Noviana (author)
- Univ Groningen, Netherlands
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- Schön, Thomas (author)
- Linköpings universitet,Avdelningen för mikrobiologi och molekylär medicin,Medicinska fakulteten
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- Sturkenboom, Marieke G. G. (author)
- Univ Groningen, Netherlands
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- McIlleron, Helen (author)
- Univ Cape Town, South Africa
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- Lee, Pooi S. (author)
- Baylor Univ, TX USA
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- Koeuth, Thearith (author)
- Baylor Univ, TX USA
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- Mpagama, Stellah G. (author)
- Kibongoto Infect Dis Hosp, Tanzania
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- Banu, Sayera (author)
- Int Ctr Diarrhoeal Dis Res, Bangladesh
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- Foongladda, Suporn (author)
- Mahidol Univ, Thailand
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- Ogarkov, Oleg (author)
- Sci Ctr Family Hlth and Human Reprod Problem, Russia
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- Pholwat, Suporn (author)
- Univ Virginia, VA USA
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- Houpt, Eric R. (author)
- Univ Virginia, VA USA
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- Heysell, Scott K. (author)
- Univ Virginia, VA USA
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- Gumbo, Tawanda (author)
- Baylor Univ, TX USA
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(creator_code:org_t)
- 2018-11-28
- 2018
- English.
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In: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 67, s. S308-S316
- Related links:
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
Keyword
- minimum inhibitory concentrations; cidal activity; tuberculous meningitis; neurotoxicity; Monte Carlo simulations
Publication and Content Type
- ref (subject category)
- art (subject category)
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Deshpande, Devya ...
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Alffenaar, Jan-W ...
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Koser, Claudio U ...
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Dheda, Keertan
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Chapagain, Moti ...
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Simbar, Noviana
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show more...
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Schön, Thomas
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Sturkenboom, Mar ...
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McIlleron, Helen
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Lee, Pooi S.
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Koeuth, Thearith
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Mpagama, Stellah ...
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Banu, Sayera
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Foongladda, Supo ...
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Ogarkov, Oleg
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Pholwat, Suporn
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Houpt, Eric R.
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Heysell, Scott K ...
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Gumbo, Tawanda
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show less...
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- MEDICAL AND HEALTH SCIENCES
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Clinical Infecti ...
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Linköping University