Department of Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Antimicrob Agents Chemother. 2013 Aug;57(8):3676-80. doi: 10.1128/AAC.00558-13. Epub 2013 May 20.
Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time- and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories.
利奈唑胺在治疗耐多药结核病（MDR-TB）方面发挥着越来越重要的作用。然而，由于其具有时间和剂量依赖性毒性，患者应接受密切监测。克拉霉素的作用较为有限。治疗药物监测可能有助于评估治疗方案，在降低毒性的同时保持足够的药物暴露。在无法或不希望进行常规血浆采样的情况下，口服液采样可能是一种受欢迎的替代方法。本研究旨在对耐多药结核病患者口服液中利奈唑胺及其代谢物羟氯唑胺和克拉霉素的分析进行临床验证。在两种基质之间进行了广泛的交叉验证后，同时采集了血清和口服液样本，并使用经过验证的方法进行了分析。Passing-Bablok 回归和 Bland-Altman 分析表明，口服液分析利奈唑胺和克拉霉素似乎适用于 MDR-TB 患者的治疗药物监测。无需校正因子即可解释口服液中利奈唑胺浓度，其血清/口服液浓度比值为 0.97（95%置信区间 [CI]，0.92 至 1.02）。然而，克拉霉素血清/克拉霉素口服液浓度比值为 3.07（95%CI，2.45 至 3.69）。由于血清和口服液之间的浓度存在非线性关系，本研究无法对羟氯唑胺进行分析。总之，无需校正因子即可分析口服液中的利奈唑胺（无校正因子）和克拉霉素（校正因子为 3），可作为替代常规血清采样的方法，用于耐多药结核病的治疗药物监测。使用非侵入性技术进行简便采样可能有助于特定患者类别的治疗药物监测。
