De Corte Thomas, Verhaeghe Jarne, Dhaese Sofie, Van Vooren Sarah, Boelens Jerina, G Verstraete Alain, Stove Veronique, Ongenae Femke, De Bus Liesbet, Depuydt Pieter, Van Hoecke Sofie, J De Waele Jan
Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium.
Ann Intensive Care. 2023 Apr 29;13(1):35. doi: 10.1186/s13613-023-01129-6.
Several studies have indicated that commonly used piperacillin-tazobactam (TZP) and meropenem (MEM) dosing regimens lead to suboptimal plasma concentrations for a range of pharmacokinetic/pharmacodynamic (PK/PD) targets in intensive care unit (ICU) patients. These targets are often based on a hypothetical worst-case scenario, possibly overestimating the percentage of suboptimal concentrations. We aimed to evaluate the pathogen-based clinically relevant target attainment (CRTA) and therapeutic range attainment (TRA) of optimized continuous infusion dosing regimens of TZP and MEM in surgical ICU patients.
A single center prospective observational study was conducted between March 2016 and April 2019. Free plasma concentrations were calculated by correcting total plasma concentrations, determined on remnants of blood gas samples by ultra-performance liquid chromatography with tandem mass spectrometry, for their protein binding. Break points (BP) of identified pathogens were derived from epidemiological cut-off values. CRTA was defined as a corrected measured total serum concentration above the BP and calculated for increasing BP multiplications up to 6 × BP. The upper limit of the therapeutic range was set at 157.2 mg/L for TZP and 45 mg/L for MEM. As a worst-case scenario, a BP of 16 mg/L for TZP and 2 mg/L for MEM was used.
781 unique patients were included with 1036 distinctive beta-lactam antimicrobial prescriptions (731 TZP, 305 MEM) for 1003 unique infections/prophylactic regimens (750 TZP, 323 MEM). 2810 samples were available (1892 TZP, 918 MEM). The median corrected plasma concentration for TZP was 86.4 mg/L [IQR 56.2-148] and 16.2 mg/L [10.2-25.5] for MEM. CRTA and TRA was consistently higher for the pathogen-based scenario than for the worst-case scenario, but nonetheless, a substantial proportion of samples did not attain commonly used PK/PD targets.
Despite these pathogen-based data demonstrating that CRTA and TRA is higher than in the often-used theoretical worst-case scenario, a substantial proportion of samples did not attain commonly used PK/PD targets when using optimised continuous infusion dosing regimens. Therefore, more dosing optimization research seems warranted. At the same time, a 'pathogen-based analysis' approach might prove to be more sensible than a worst-case scenario approach when evaluating target attainment and linked clinical outcomes.
多项研究表明，常用的哌拉西林-他唑巴坦（TZP）和美罗培南（MEM）给药方案在重症监护病房（ICU）患者中，对于一系列药代动力学/药效学（PK/PD）靶点而言，会导致血浆浓度未达最佳水平。这些靶点通常基于一种假设的最坏情况，可能高估了未达最佳浓度的百分比。我们旨在评估TZP和MEM优化持续输注给药方案在外科ICU患者中基于病原体的临床相关目标达成率（CRTA）和治疗范围达成率（TRA）。
于2016年3月至2019年4月进行了一项单中心前瞻性观察研究。通过校正总血浆浓度来计算游离血浆浓度，总血浆浓度通过超高效液相色谱串联质谱法在血气样本残余物上测定，并对其蛋白结合情况进行校正。已鉴定病原体的断点（BP）源自流行病学截断值。CRTA定义为校正后的实测总血清浓度高于BP，并针对高达6×BP的BP倍数增加进行计算。TZP的治疗范围上限设定为157.2mg/L，MEM为45mg/L。作为最坏情况，TZP的BP为16mg/L，MEM为2mg/L。
纳入了781例独特患者，针对1003种独特感染/预防方案（750种TZP，323种MEM）开具了1036份独特的β-内酰胺类抗菌药物处方（731份TZP，305份MEM）。获得了2810份样本（1892份TZP，918份MEM）。TZP的校正血浆浓度中位数为86.4mg/L [IQR 56.2 - 148]，MEM为16.2mg/L [10.2 - 25.5]。基于病原体的情况，CRTA和TRA始终高于最坏情况，但尽管如此，仍有相当比例的样本未达到常用的PK/PD靶点。
尽管这些基于病原体的数据表明CRTA和TRA高于常用的理论最坏情况，但在使用优化持续输注给药方案时，仍有相当比例的样本未达到常用的PK/PD靶点。因此，似乎有必要进行更多的给药优化研究。同时，在评估目标达成情况及相关临床结局时，“基于病原体的分析”方法可能比最坏情况方法更为合理。
