重症感染患者美罗培南血药浓度与不良反应相关性

目的：评估重症感染患者使用美罗培南造成的不良反应是否与浓度有关并确定造成不良反应发生的浓度阈值。方法：回顾性分析2017年1月至2018年12月间某院重症监护室连续使用美罗培南治疗重症感染并进行了治疗药物监测（therapeutic drug monitoring，TDM）的患者。不良反应的考察包括神经毒性、肾毒性、肝毒性以及抗生素所致的难辨梭菌感染（clostridium difficile infection，CDI）。是否发生美罗培南相关的不良反应是通过观察分级法、临床评估以及血清相关标志物来判断的。最后将获得的不良反应数据和TDM数据进行相关性的回归分析。结果：本研究共获得了87人次美罗培南的药物浓度数据，发生神经毒性反应和肾毒性的患者其美罗培南谷浓度（C_min）都显著性高于未发生的患者（P<0.01），但是未发现肝毒性和CDI的发生与美罗培南谷浓度（C_min）有相关性。进一步通过受试者工作曲线（receiver operating characteristic，ROC）分析得到，神经毒性的美罗培南谷浓度阈值为C_min>27.4 mg·L^-1；而造成肾毒性的阈值为C_min>27.1 mg·L^-1。结论：本研究揭示了重症感染患者美罗培南谷浓度与神经毒性、肾毒性的相关性，并获得了造成毒性反应的美罗培南谷浓度阈值。临床在应用美罗培南治疗重症感染时，一方面要考虑疗效，另一方面也不能忽视美罗培南可能带来的不良反应。运用TDM定期进行药物浓度监测或许是一个有效的减少不良反应发生的手段。

Concentration-toxicity relationships of meropenem in patients with severe infection

OBJECTIVE To evaluate whether the adverse reactions caused by meropenem in patients with severe infection are related to the concentration and to determine the concentration threshold for the occurrence of adverse reactions.METHODS A retrospective analysis was conducted on patients who were continuously treated with meropenem for severe infection and underwent therapeutic drug monitoring (TDM) in the intensive care unit of a hospital from January 2017 to December 2018.Adverse effects include neurotoxicity,nephrotoxicity,hepatotoxicity,and antibiotic-induced clostridium difficile infection (CDI).The occurrence of meropenem-related adverse reactions was judged by observation grading method,clinical evaluation and serum related markers.Finally,the obtained adverse reaction data and TDM data were subjected to regression analysis of the correlation RESULTS A total of 87 drug concentration data of meropenem were obtained in this study.The concentration of meropenem trough (C_min) in patients with neurotoxicity and nephrotoxicity was significantly higher than that in patients without toxicity (P<0.01),but no correlation was found between the occurrence of hepatotoxicity and CDI and the concentration of meropenem trough (C_min).Further receiver operating characteristic (ROC) analysis showed that the threshold of Melopeuran trough concentration for neurotoxicity was C_min>27.4 mg·L^-1;while the threshold for causing nephrotoxicity was C_min>27.1 mg·L^-1.CONCLUSION Our data reveal an association between meropenem trough concentration and neurotoxic/nephrotoxic effects.We have defined threshold concentrations above which these toxicities become more likely.Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.Regular drug concentration monitoring with TDM may be an effective method to reduce the occurrence of adverse reactions.