Serum concentrations of cycloserine and outcome of multidrug-resistant tuberculosis in Northern Taiwan

Hung, Wei-Lun; Yu, Ming Chih; Chiang, Yi Chun; Chang, Jer‐Hwa; Chiang, Chifa; Chang, Cheng-Erh; Chuang, Hsiao-Chi; Bai, Kuan Jen

doi:10.5588/ijtld.13.0268

Cited by 18 publications

(16 citation statements)

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“…A possible explanation for this finding is that treatment of MDR-TB includes multiple drugs, and an observational study without strict placebo controls hardly assesses the efficacy of a single agent. Furthermore, a recent study has shown that more than half of patients with the recommended dosage of 10 mg/kg of cycloserine prescription had peak serum concentrations lower than the minimum inhibitory concentrations of the strains isolated from the corresponding patients, suggesting the need for adjusting each patient’s dosages depending on the clinical pharmacokinetic and pharmacodynamic assessments 24,25…”

Section: Discussionmentioning

confidence: 99%

<p>Cycloserine for treatment of multidrug-resistant tuberculosis: a retrospective cohort study in China</p>

Yang

Wang

et al. 2019

IDR

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Purpose Cycloserine has been used in multidrug-resistant tuberculosis (MDR-TB) treatment since the 1950s. We evaluated the efficacy and safety of cycloserine and sought to clarify the role of cycloserine for treatment of simple MDR-TB, pre-extensively drug-resistant tuberculosis (pre-XDR-TB), and extensively drug-resistant tuberculosis (XDR-TB). Materials and methods A retrospective observational study was performed in Zhejiang Province, China. We enrolled 144 cycloserine-treated and 181 cycloserine-nontreated patients consecutively and determined the treatment outcome as the primary outcome. The proportion of patients with sputum culture conversion and the frequency of adverse drug reactions were also assessed. Results One-hundred (69.4%) out of 144 patients in the cycloserine group successfully completed treatment. The HR of any unfavorable treatment outcome after the introduction of cycloserine was 0.58 (95% CI: 0.38–0.86, P =0.008). Subgroup analysis showed that cycloser-ine could benefit simple MDR-TB cases reducing the risk of unfavorable treatment outcomes (HR: 0.43, 95% CI: 0.24–0.76, P =0.004), but not pre-XDR-TB (HR: 0.65, 95% CI: 0.30–1.38, P =0.263) or XDR-TB (HR: 0.73, 95% CI: 0.22–2.37, P =0.589). The culture conversion rate at the intensive phase was similar whether cycloserine was administered or not ( P =0.703). Of the 144 patients treated with cycloserine, a total of 16 (11.1%) patients experienced side effects attributed to cycloserine. Conclusion Cycloserine is an attractive agent for the treatment of MDR-TB, and its safety profile warrants its use in most MDR-TB cases. Cycloserine significantly improved the chance of a favorable outcome for patients with simple MDR-TB but not pre-XDR-TB and XDR-TB. Thus, more aggressive regimens might be required for pre-XDR-TB or XDR-TB patients.

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Section: Discussionmentioning

confidence: 99%

<p>Cycloserine for treatment of multidrug-resistant tuberculosis: a retrospective cohort study in China</p>

Yang

Wang

et al. 2019

IDR

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“…Figure 1 shows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram summarizing literature search findings for d-cycloserine, which shows that hitherto there have been no PK/PD studies performed in preclinical models. There were 9 pharmacokinetic studies; 2 were duplicates, leading to 7 studies shown in Supplementary Table 1 [26,28,38,[43][44][45][46]. Doses of cycloserine used in the pharmacokinetic studies ranged from 250 mg twice a day to 500 mg twice a day.…”

Section: Monte Carlo Experiments For Dose Selectionmentioning

confidence: 99%

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

Deshpande

Alffenaar

Köser

et al. 2018

Clinical Infectious Diseases

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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.

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“…Cycloserine was predominately employed at a low dose (250 mg daily) and TDM used to mitigate toxicity. This approach contrasts to a more commonly reported twice daily dosing with targets of 15 mg/kg or 750 mg total daily dose, such as recent report from Taiwan which confirmed a total daily dose correlation with peak concentration, as well as an event of psychosis in a patient with concentrations >35 µg/mL 21 . The low-dose approach did not appear to compromise treatment efficacy in our setting and minimized toxicity.…”

Section: Discussionmentioning

confidence: 74%

Outcomes and Use of Therapeutic Drug Monitoring in Multidrug-Resistant Tuberculosis Patients Treated in Virginia, 2009-2014

et al. 2015

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BackgroundReports of therapeutic drug monitoring (TDM) for second-line medications to treat multidrug-resistant tuberculosis (MDR-TB) remain limited.MethodsA retrospective cohort from the Virginia state tuberculosis (TB) registry, 2009-2014, was analyzed for TDM usage in MDR-TB. Drug concentrations, measured at time of estimated peak (Cmax), were compared to expected ranges.ResultsOf 10 patients with MDR-TB, 8 (80%) had TDM for at least one drug (maximum 6 drugs). Second-line drugs tested were cycloserine in seven patients (mean C2hr, 16.6±10.2 µg/mL; 4 [57%] below expected range); moxifloxacin in five (mean C2hr, 3.2±1.5 µg/mL; 1 [20%] below); capreomycin in five (mean C2hr, 21.5±14.0 µg/mL; 3 [60%] below); para-aminosalicylic acid in five (mean C6hr, 65.0±29.1 µg/mL; all within or above); linezolid in three (mean C2hr, 11.4±4.1 µg/mL, 1 [33%] below); amikacin in two (mean C2hr, 35.3±3.7 µg/mL; 1 [50%] below); ethionamide in one (C2hr, 1.49 µg/mL, within expected). Two patients died: a 38-year-old woman with human immunodeficiency virus/acquired immune deficiency syndrome and TB meningitis without TDM, and a 76-year-old man with fluoroquinolone-resistant (pre-extensively drug-resistant) pulmonary TB and low linezolid and capreomycin concentrations.ConclusionIndividual pharmacokinetic variability was common. A more standardized approach to TDM for MDR-TB may limit over-testing and maximize therapeutic gain.

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Serum concentrations of cycloserine and outcome of multidrug-resistant tuberculosis in Northern Taiwan

Abstract: Lower than recommended serum CS concentrations and delayed absorption were common. It is essential to develop practical TDM to maintain proper serum drug concentrations.

Cited by 18 publications

References 0 publications

<p>Cycloserine for treatment of multidrug-resistant tuberculosis: a retrospective cohort study in China</p>

<p>Cycloserine for treatment of multidrug-resistant tuberculosis: a retrospective cohort study in China</p>

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

Outcomes and Use of Therapeutic Drug Monitoring in Multidrug-Resistant Tuberculosis Patients Treated in Virginia, 2009-2014

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