哌拉西林-他唑巴坦在开放性腹部和负压伤口封闭的重症患者中的药代动力学：使用蒙特卡洛模拟的给药考量

Pharmacokinetics of Piperacillin-Tazobactam in Critically Ill Patients with Open Abdomen and Vacuum-Assisted Wound Closure: Dosing Considerations Using Monte Carlo Simulation.

作者信息

Carrié Cédric, Butruille Jesse, Maingault Sophie, Lannou Alexandre, Dubuisson Vincent, Petit Laurent, Biais Matthieu, Breilh Dominique

机构信息

Surgical and Trauma Intensive Care Unit, Anesthesiology and Critical Care Department, Hôpital Pellegrin, CHU Bordeaux, 33076 Bordeaux, France.

Pharmacokinetics and Clinical Pharmacy Laboratory, University of Bordeaux, 33000 Bordeaux, France.

出版信息

Pharmaceutics. 2024 Sep 9;16(9):1191. doi: 10.3390/pharmaceutics16091191.

DOI:10.3390/pharmaceutics16091191

PMID:39339227

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11434833/

Abstract

BACKGROUND

Open abdomen with vacuum-assisted wound closure therapy (OA/VAC) is frequently used in critically ill patients although the impact of OA/VAC on antibiotics pharmacokinetics (PK) remains unknown. We thus aimed to characterize the PK of piperacillin-tazobactam (PTZ) in critically ill patients with OA/VAC and assess the optimal dosing regimens based on pharmacodynamics (PD) target attainment.

METHODS

Over a 15-month study period, 45 patients with OA/VAC treated with PTZ administered continuously and adapted to 24 h creatinine clearance (CL) underwent measurements of free concentrations in their plasma, urine, VAC exudate, and peritoneal fluid. Population PK modeling was performed considering the effect of covariates, and Monte Carlo simulations were employed to determine the probability of target attainment (PTA) for the PK/PD targets (100% fT > 16 mg/L) in the plasma and at the peritoneal site at steady state.

RESULTS

Piperacillin concentrations were described using a two-compartment model, with age and total body weight as significant covariates for central volume of distribution (V1) and estimated renal function for clearance (CL). Tazobactam concentrations were described using a two-compartment model with estimated renal function as a significant covariate. The central volume of distributions V1 of piperacillin and tazobactam were 21.2 and 23.2 L, respectively. The VAC-induced peritoneal clearance was negligible compared to renal clearance. Most patients achieved the desirable PK/PD target when using a CL-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day.

CONCLUSIONS

Despite a wide inter-individual variability, the influence of OA/VAC on piperacillin and tazobactam PK parameters is not straightforward. The use of a CL-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day is needed to reach a PTA > 85%.

摘要

背景

尽管开放性腹腔联合负压封闭引流治疗（OA/VAC）对重症患者常用，但OA/VAC对抗生素药代动力学（PK）的影响仍不清楚。因此，我们旨在描述OA/VAC重症患者哌拉西林-他唑巴坦（PTZ）的PK特征，并根据药效学（PD）目标达成情况评估最佳给药方案。

方法

在15个月的研究期间，45例接受PTZ持续给药并根据24小时肌酐清除率（CL）调整剂量的OA/VAC患者，对其血浆、尿液、VAC渗出液和腹腔液中的游离浓度进行了测量。考虑协变量的影响进行群体PK建模，并采用蒙特卡洛模拟确定稳态时血浆和腹腔部位PK/PD目标（100% fT > 16 mg/L）的目标达成概率（PTA）。

结果

哌拉西林浓度采用二室模型描述，年龄和总体重是中央分布容积（V1）的显著协变量，估计肾功能是清除率（CL）的显著协变量。他唑巴坦浓度采用二室模型描述，估计肾功能是显著协变量。哌拉西林和他唑巴坦的中央分布容积V1分别为21.2 L和23.2 L。与肾脏清除率相比，VAC诱导的腹腔清除率可忽略不计。大多数患者在使用12 g/1.5 g/天至20 g/2.5 g/天的CL校正PTZ给药方案时达到了理想的PK/PD目标。