Devyani Deshpande1, Jan-Willem C Alffenaar2, Claudio U Köser3, Keertan Dheda4, Moti L Chapagain1, Noviana Simbar2, Thomas Schön5,6, Marieke G G Sturkenboom2, Helen McIlleron7, Pooi S Lee1, Thearith Koeuth1, Stellah G Mpagama8, Sayera Banu9, Suporn Foongladda10, Oleg Ogarkov11, Suporn Pholwat12, Eric R Houpt12, Scott K Heysell12, Tawanda Gumbo1. 1. Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas. 2. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, The Netherlands. 3. Department of Genetics, University of Cambridge, United Kingdom. 4. Lung Immunity Unit, Division of Pulmonology, Department of Medicine, University of Cape Town, Observatory, South Africa. 5. Department of Infectious Diseases and Clinical Microbiology, Kalmar County Hospital. 6. Department of Clinical and Experimental Medicine, Division of Medical Microbiology, Linköping University, Sweden. 7. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa. 8. Kibong'oto Infectious Diseases Hospital, Sanya Juu, Tanzania. 9. International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka. 10. Siriraj Hospital, Mahidol University, Bangkok, Thailand. 11. Scientific Centre of the Family Health and Human Reproduction Problems, Irkutsk, Russian Federation. 12. Division of Infectious Diseases and International Health, University of Virginia, Charlottesville.
Abstract
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 10000 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.
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 10000 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.
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