Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
J Antimicrob Chemother. 2019 Jul 1;74(7):1952-1961. doi: 10.1093/jac/dkz143.
Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose.
Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients.
The MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments.
Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.
本研究旨在确定米诺环素在肺部鸟分枝杆菌复合群（MAC）中空纤维系统（HFS）模型中的药代动力学/药效学参数，并确定最佳临床剂量。
测定了来自荷兰的 55 株 MAC 临床分离株的米诺环素 MIC。我们还将感染 MAC 的原代分离巨噬细胞与米诺环素共同孵育。接下来，我们进行了一项为期 28 天的 HFS-MAC 剂量反应研究，模拟了患者肺部的浓度-时间曲线。在该模型中，每隔一段时间对 HFS-MAC 模型进行采样，以确定米诺环素的药代动力学和 MAC 负荷。我们确定了 AUC0-24/MIC 比值与第 0 天（静止期）以下的 1.0 log10 cfu/mL 杀灭相关，这被定义为杀菌作用。然后，我们进行了 10000 次蒙特卡罗模拟实验，以确定患者获得杀菌作用的最佳剂量。
50%和 90%累积临床分离株的 MIC 分别为 8 和 64 mg/L。米诺环素可降低原代分离巨噬细胞中 MAC 的细菌负荷，使其低于静止期。在 HFS-MAC 模型中，米诺环素在静止期以下实现了 3.6 log10 cfu/mL 的微生物杀灭。与杀菌作用相关的 AUC0-24/MIC 暴露量为 59。蒙特卡罗模拟实验确定米诺环素药敏 MIC 折点为 16 mg/L。在这个建议的折点，200mg/天的临床剂量预计将使约 50%的患者达到杀菌作用的暴露目标，而 400mg/天的剂量预计将使 73.6%的患者达到这一目标。
400mg/天的米诺环素剂量预计具有杀菌作用。我们建议进行临床试验以验证这一结论。
