Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Meropenem in Neurocritical Care Patients: a Prospective Two-Center Study
Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Meropenem in Neurocritical Care Patients: a Prospective Two-Center Study
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DOI：
10.1128/aac.00142-22
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发表时间：
2022-07-06
影响因子：
4.9
通讯作者：
Roberts, Jason A.
中科院分区：
文献类型：
--
作者：
Kumta, Nilesh;Heffernan, Aaron J.;Roberts, Jason A.
神经重症监护患者中与脑室炎相关的发病率和死亡率仍然很高。抗生素剂量优化可改善治疗结果。本研究建立了美罗培南在感染危重患者中的群体药代动力学模型。我们应用最终模型来确定实现目标脑脊液暴露所需的最佳美罗培南给药方案。本研究从两个中心招募了接受美罗培南治疗并诊断为脑室炎或颅外感染的神经重症监护患者。收集并分析系列血浆和脑脊液样本。使用Pmetrics进行群体药代动力学建模和Monte Carlo给药模拟。我们试图确定优化的给药方案，使美罗培南脑脊液浓度在40%的给药间隔内高于病原体MIC，或美罗培南脑脊液谷浓度与病原体MIC的更高目标比值>= 1。总共从8名患者中获得了53份血浆和34份脑脊液样本。美罗培南的药代动力学使用三室模型进行适当描述，线性血浆清除率按肌酐清除率缩放，脑脊液渗透率按患者年龄缩放。相当大的个体间药代动力学变异性是明显的，特别是在脑脊液中。血浆和脑脊液中美罗培南清除率的变异系数分别为41.7%和89.6%;血浆和脑脊液中美罗培南分布容积值分别为63.4%和58.3%。高剂量（高达8 - 10 g/天）改善了美罗培南脑脊液目标暴露的实现，特别是对于敏感性较低的微生物（MIC，>= 0.25 mg/L）。每8小时2 g的标准美罗培南剂量可能无法在所有危重患者的脑脊液中达到有效浓度。更高剂量或替代给药方法（例如，负荷剂量，然后连续输注）可能需要优化脑脊液暴露。剂量高达8 - 10 g/天（间歇推注或连续输注）适用于肾清除率增加的患者;经验建议，肾功能受损患者可考虑使用较低剂量。持续给药应根据个体患者的情况进行调整。值得注意的是，研究人群较小，给药建议可能无法推广到所有重症患者。
Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of >= 1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, >= 0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.