Leven Cyril, Fillâtre Pierre, Petitcollin Antoine, Verdier Marie-Clémence, Laurent Jérôme, Nesseler Nicolas, Launey Yoann, Tattevin Pierre, Bellissant Eric, Flécher Erwan, Lemaitre Florian
*Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital; †Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, Rennes 1 University; ‡Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France; §Department of Biochemistry, Pharmacology and Toxicology, Brest University Hospital, Brest, France; Departments of ¶Infectious Diseases and Intensive Care Unit, ‖Thoracic and Cardio-Vascular Surgery, and **Surgical Intensive Care Unit, Rennes University Hospital; ††Inserm 1099, CIC-IT, Clinical Investigation Centre, Rennes, France.
Ther Drug Monit. 2017 Apr;39(2):180-184. doi: 10.1097/FTD.0000000000000369.
As a consequence of drug sequestration, increase in volume of distribution, or alteration of elimination, extracorporeal membrane oxygenation (ECMO) might lead to inadequate plasma concentrations of vital drugs. The aim of this experimental study was to develop an ex vivo model to better characterize the impact of ECMO procedure on beta-lactam antibiotics pharmacokinetics.
Plasma concentrations of cefotaxime, ceftazidime, cefepime, piperacillin, oxacillin, amoxicillin, and ceftriaxone were measured in an ex vivo ECMO circuit primed with whole human blood and compared with controls stored in glass tubes and polyvinyl chloride tubing. Serial blood samples were collected over 48 hours, and the concentrations of beta-lactam antibiotics were quantified using a validated high-performance liquid chromatography assay. The concentrations' decay rate over time was compared between the ECMO circuits and controls using nonlinear mixed-effect modeling.
Cefotaxime concentrations decreased markedly: 86% of the initial concentration remained after 4 hours and only 21% after 48 hours (P < 0.05 for the comparison in rate of decrease with both glass and polyvinyl chloride controls). There was no difference in the rate of decrease between ECMO circuit and controls for the other beta-lactam antibiotics. The average drug recoveries from the ECMO circuits at 48 hours were as follows: ceftazidime, 73%; cefepime, 67%; piperacillin, 71%; oxacillin, 46%; and amoxicillin, 72%. Concentrations of ceftriaxone remained stable throughout the 48-hour study both in ECMO circuits and in controls.
Significant losses of cefotaxime were observed, whereas ceftazidime, cefepime, piperacillin, oxacillin, and amoxicillin decrease was moderate and similar to that of the control group, and ceftriaxone concentrations remained unchanged. These results are reassuring for the use of beta-lactam antibiotics in critically ill patients treated with ECMO.
由于药物隔离、分布容积增加或消除改变，体外膜肺氧合（ECMO）可能导致重要药物的血浆浓度不足。本实验研究的目的是建立一种体外模型，以更好地描述ECMO程序对β-内酰胺类抗生素药代动力学的影响。
在用人全血预充的体外ECMO回路中测量头孢噻肟、头孢他啶、头孢吡肟、哌拉西林、苯唑西林、阿莫西林和头孢曲松的血浆浓度，并与储存在玻璃管和聚氯乙烯管中的对照进行比较。在48小时内采集系列血样，使用经过验证的高效液相色谱法对β-内酰胺类抗生素的浓度进行定量。使用非线性混合效应模型比较ECMO回路和对照组中浓度随时间的衰减率。
头孢噻肟浓度显著下降：4小时后仍保留初始浓度的86%，48小时后仅为21%（与玻璃和聚氯乙烯对照组相比，下降速率的比较P<0.05）。其他β-内酰胺类抗生素在ECMO回路和对照组之间的下降速率没有差异。48小时时从ECMO回路中的平均药物回收率如下：头孢他啶73%；头孢吡肟67%；哌拉西林71%；苯唑西林46%；阿莫西林72%。在整个48小时的研究中，头孢曲松在ECMO回路和对照组中的浓度均保持稳定。
观察到头孢噻肟有显著损失，而头孢他啶、头孢吡肟、哌拉西林、苯唑西林和阿莫西林的下降幅度适中且与对照组相似，头孢曲松浓度保持不变。这些结果对于在接受ECMO治疗的重症患者中使用β-内酰胺类抗生素是令人放心的。
