Drug monitoring of antiinfectives in critically ill patients receiving extracorporeal life support - a prospective observational pilot study

约70%的危重患者需要抗感染治疗。优化抗生素剂量是提高患者存活率、减少毒性影响和最大限度地减少细菌耐药性出现的关键。然而，越来越多的证据表明重症监护患者的药代动力学(PK)存在显著变化，特别是那些接受体外治疗(体外膜氧合(ECMO)、连续性肾脏替代治疗(CRRT))的患者。现有的抗感染给药方案假定PK为“正常”；目前还没有针对危重患者的循证抗感染给药指南。因此，Paul-Ehrlich学会和存活脓毒症运动的当前建议明确建议对重症监护患者应用治疗性药物监测(TDM)，以个别调整剂量，避免潜在的过量或不足剂量。为了表征危重患者体外治疗的效果，我们设计了一项使用药物监测的前瞻性先导性观察研究。6种抗感染药物(美罗培南、替考拉宁、利奈唑胺、哌拉西林/他唑巴坦、左氧氟沙星和阿昔洛韦)将作为不同抗感染组的指示物质进行研究。将100例患者分为5组，每组20例：1.静脉-静脉(Vv)-ECMO，2.静脉-动脉(Va)-ECMO，3.vv-ECMO+CRRT，4.va-ECMO+CRRT，5.对照组。将在不同的剂量间隔内进行采样，以确定研究物质的谷值和峰值水平。患者将在使用至少一种指标物质开始抗感染治疗后24-48小时内开始ECMO治疗；观察期总共为5天。收集的数据将被分析，以确定与接受体外治疗的危重患者6种不同抗感染药物的PK变化相关的协变量。利用收集的综合数据集，将构建6种抗感染药物的药代动力学曲线以及其他影响因素，以评估这些患者是否需要调整抗感染药物的剂量。这项前瞻性观察试验旨在解决目前知识不足的问题，目的是得出美罗培南、替考拉宁、利奈唑胺、哌拉西林/他唑巴坦、左氧氟沙星和阿昔洛韦治疗美罗培南、替考拉宁、利奈唑胺、左氧氟沙星和阿昔洛韦的体外治疗效果和临床患者特征。有了这些相关的结果，抗感染药物的适当剂量可能会在未来的危重患者的体外治疗中得到改善。

About 70% of critically ill patients require antiinfective therapy. Optimal antibiotic dosing is key to improve patient survival, reduce toxic effects and minimise the emergence of bacterial resistance. However, there is a growing body of evidence demonstrating the existence of significant changes in pharmacokinetics (PK) in intensive care patients, particularly those with extracorporeal therapy (extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT)). Existing antiinfective dosing regimens assume a "normal" PK; currently there are no evidence-based antiinfective dosing guidelines for critically ill patients available. The current recommendations of the Paul-Ehrlich Society and the Surviving Sepsis Campaign therefore recommend explicitly appliance of a therapeutic drug monitoring (TDM) for intensive care patients to individually adjust dosing and to avoid potential over- or underdosing.To characterize the effects of extracorporal therapy for critically ill patients, we designed a prospective pilot observational study using a drug monitoring. Six antiinfectives (meropenem, teicoplanin, linezolid, piperacillin / tazobactam, levofloxacin and aciclovir) will be investigated as index substances for the various antiinfective groups. A total of 100 patients, divided into 5 groups of 20 patients, will be examined in this study: 1. venovenous (vv)-ECMO, 2. venoarterial (va)-ECMO, 3. vv-ECMO + CRRT, 4. va-ECMO + CRRT, 5. control group. Sampling for determination of trough and peak levels of the study substances will take place during the different dosing intervals. Patients will be included at the beginning of ECMO therapy within 24-48h after start of an antiinfective therapy with at least one of the index-substances; observation period will be a total of 5 days. The collected data will be analyzed to identify covariates associated with changes in PK for the 6 different antiinfectives in critically ill patients receiving extracorporeal therapy. Using the comprehensive data set collected, the pharmacokinetic profile of the 6 antiinfectives as well as other influencing factors will be constructed to assess the need for dose adjustment of antiinfective agents in these patients. This prospective observational trial addresses the current knowledge deficiency with the aim to derive relevant effects of extracorporeal therapy and clinical patient characteristics for the treatment with meropenem, teicoplanin, linezolid, piperacillin/tazobactam, levofloxacin and acyclovir. With these relevant results, adapted dosing of antiinfectives can probably be improved in critically ill patients with extracorporeal therapy in future.