Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
Department of Anaesthesiology, LMU University Hospital, LMU Munich, Munich, Germany.
Antimicrob Agents Chemother. 2024 Sep 4;68(9):e0045124. doi: 10.1128/aac.00451-24. Epub 2024 Jul 31.
Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: n = 243, n = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), c/c) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP ( < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II.
This study is registered with ClinicalTrials.gov as NCT04426383.
本研究旨在比较间歇性输注(II)和连续输注(CI)时脑脊液(CSF)中美罗培南的浓度和药代动力学。
这是一项前瞻性观察性研究(NCT04426383),纳入了接受美罗培南 II 或 CI 的有外部脑室引流的危重症患者。采用群体药代动力学建模(NONMEM 7.5)描述美罗培南在血浆和 CSF 中的药代动力学。采用该模型比较 II 和 CI 之间的浓度-时间曲线和目标达标概率(PTA)。
共纳入 16 名患者(8 名 CI,8 名 II;样本:n=243,n=263),其中 9 名患者患有脑内感染,7 名患者患有脑外感染。一个一室模型能很好地描述血浆浓度。美罗培南进入 CSF 的能力(分配系数(KP),c/c)通常较低(6.0%),具有较大的个体间变异性(变异系数:84.0%)。输注方式与 KP 之间无相关性,但 CSF 中白细胞介素(IL)-6 与 KP 呈强正相关(<0.001)。给药模拟显示,CI 与 II 相比,CSF 中的 CSF 浓度和 PTA 无明显差异。
与 II 相比,CI 并未显示美罗培南在 CSF 中的穿透率增加或浓度升高。
本研究在 ClinicalTrials.gov 注册为 NCT04426383。