模型指导下的接受缓慢延长每日透析（SLEDD）的重症患者美罗培南优化给药策略的识别：一项观察性研究。
Model-informed identification of optimised dosing strategies for meropenem in critically ill patients receiving SLEDD: an observational study.
作者信息
Weber Franz, Scharf Christina, Aulin Linda B S, Weinelt Ferdinand, Paal Michael, Mikus Gerd, Vogeser Michael, Habler Katharina, Huisinga Wilhelm, Zoller Michael, Michelet Robin, Kloft Charlotte, Liebchen Uwe
机构信息
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstraße 31, 12169, Berlin, Germany.
Graduate Research Training Program PharMetrX, Berlin/Potsdam, Germany.
出版信息
Infection. 2025 Apr 25. doi: 10.1007/s15010-025-02504-0.
PURPOSE
An increasing number of critically ill patients receive slow extended daily dialysis (SLEDD) due to their pathophysiology while suffering from sepsis, necessitating effective and safe antibiotic therapy. Although SLEDD reduces meropenem exposure and increases treatment failure risk, effective and safe dosing regimens are unclear. We aimed to identify optimised meropenem dosing strategies for critically ill SLEDD patients through population pharmacokinetic (PK) modelling and PK/pharmacodynamic (PD)-based probability of target attainment (PTA) analysis.
METHODS
Clinical data from a prospective study involving critically ill SLEDD patients receiving meropenem were monitored through routine therapeutic drug monitoring. A total of 178 blood samples from 13 patients (median 14 samples per patient) were analysed. A PK model was developed and utilised to evaluate 24 clinically relevant dosing regimens during SLEDD therapy (7-h on-SLEDD periods q24h) in PTA analyses. The PK/PD target window of minimum meropenem concentration between 8 mg/L (P. aeruginosa; R-breakpoint) and 44.45 mg/L (toxicity threshold) was used.
RESULTS
A one-compartment PK model with linear elimination and total clearance (CL) split into renal (CL; 45%) and SLEDD-associated (55%) CL well characterised the SLEDD data. Creatinine clearance (urine-collected; CLCR) was identified as significant factor on CL. Continuous infusions, specifically 2 g q24h for CLCR 0-25 mL/min and 3 g q24h for CLCR 25-40 mL/min, showed the highest PTA being effective and safe during SLEDD therapy. A comprehensive dosing nomogram was developed.
CONCLUSION
Our easy-to-use dosing nomogram presents a promising tool in optimising meropenem dosing regimens for critically ill SLEDD patients considering their kidney function in clinical practice.
TRIAL REGISTRATION
Clinicaltrials.gov NCT03985605. Registered 14 June 2019. https://classic.
CLINICALTRIALS
gov/ct2/show/study/NCT03985605.
目的
越来越多的重症患者因脓毒症的病理生理状况而接受缓慢持续低效透析（SLEDD），这就需要有效且安全的抗生素治疗。尽管SLEDD会减少美罗培南的药物暴露并增加治疗失败风险，但有效且安全的给药方案尚不清楚。我们旨在通过群体药代动力学（PK）建模以及基于PK/药效学（PD）的达标概率（PTA）分析，为重症SLEDD患者确定优化的美罗培南给药策略。
方法
通过常规治疗药物监测，对一项涉及接受美罗培南治疗的重症SLEDD患者的前瞻性研究的临床数据进行监测。共分析了13例患者的178份血样（每位患者中位数为14份血样）。建立了一个PK模型，并用于在PTA分析中评估SLEDD治疗期间（每24小时7小时的SLEDD时段）24种临床相关给药方案。使用了美罗培南最低浓度在8mg/L（铜绿假单胞菌；R断点）至44.45mg/L（毒性阈值）之间的PK/PD目标窗。
结果
一个具有线性消除且总清除率（CL）分为肾清除率（CL；45%）和SLEDD相关清除率（55%）的单室PK模型很好地描述了SLEDD数据。肌酐清除率（收集尿液；CLCR）被确定为影响CL的重要因素。持续输注，特别是对于CLCR为0至25mL/min的患者每24小时2g以及对于CLCR为25至40mL/min的患者每24小时3g，在SLEDD治疗期间显示出最高的有效且安全的PTA。制定了一个综合给药剂量图。
结论
我们易于使用的给药剂量图为在临床实践中考虑重症SLEDD患者肾功能优化美罗培南给药方案提供了一个有前景的工具。
试验注册
Clinicaltrials.gov NCT03985605。于2019年6月14日注册。https://classic.
CLINICALTRIALS
gov/ct2/show/study/NCT03985605。
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