治疗药物监测在ICU重症感染患者抗菌药物联用的作用

Multiple antimicrobial therapeutic drug monitoring in adult critically infection patients:a clinical analysis

目的:通过分析不同药物组合下的药物浓度达标率和治疗反应以及影响药物浓度变化,探讨抗菌药物治疗药物监测(TDM)优化临床给药方案,对重症感染患者完全缓解率和疗效评价时间的影响。方法:前瞻性研究纳入2019年1月-2022年4月我科收治的重症感染患者,随机分为TDM组(82例)和非TDM组(77例)。建立液相色谱串联质谱法(LC-MS)检测平台,进行碳青霉烯类、β-内酰胺类、糖肽类、抗真菌药等8种抗菌药物联合(至少2药联合使用)治疗重症感染的TDM,确定抗菌药物TDM是否与治疗反应、药物相关不良反应有关,多因素logistic回归分析药物浓度变化的相关危险因素。结果:(1)初始血药浓度检测,TDM组整体不合格率91.5%,其中哌拉西林-他唑巴坦不合格率达100%,氟康唑、万古霉素、美罗培南的不达标率分别为79.2%、75.0%、70.9%,显著高于文献报道的单药使用;(2)TDM组完全缓解率高,疗效评价时间短,与非TDM组比较,差异有统计学意义(P<0.05);(3)TDM组药物相关不良反应的整体发生率低于非TDM组(8.5%vs.22.1%,P=0.004),亚组分析示神经毒性/脑病和肾毒性的发生率显著降低;(4)药物浓度变化的相关因素有年龄(OR=1.221,95%CI:1.042~1.431)、肌酐清除率(万古霉素和美罗培南)、红细胞压积(哌拉西林-他唑巴坦)。结论:多种抗菌药物TDM优化给药方案,可能改善ICU重症感染患者的临床结局,降低药物相关不良反应发生率。

Objective:Therapeutic drug monitoring(TDM)is recommended to optimise the use of antimicrobial agents for patients with severe infections in ICU.However,TDM data about combination of multiple antibiotics is still absent.Methods:Eight antibiotics TDM were performed including carbapenems,β-lactam,glycopeptides and antifungal drugs by using Liquid chromatography tandem mass spectrometry(LC-MS)platform to determine whether TDM was associated with antimicrobial treatment response and drug-related adverse reactions.And Multivariate logistic regression analysis was used to analyze the risk factors of drug concentration changes.Results:A total of 159 critically ill patients were included in this prospective study from January 2019 to April 2022 and randomly divided into two groups:those underwent TDM(TDM group,n=82)or did not undergo TDM(non-TDM group,n=77).The results showed as follows:(1)91.5%patients were with inappropriate initial concentration.Among them,inappropriate initial concentration was found in 100%patients that received piperacillin-tazobactam,and 79.2%,75.0%and 70.9%patients that received fluconazole,vancomycin and meropenem treatment,respectively,which were significantly higher than those patients that received single drug reported in the literature.(2)TDM group had higher complete remission rate and shorter efficacy evaluation time than non-TDM group(P<0.05).(3)The overall incidence of drug-related adverse reactions in TDM group was lower than that in non-TDM group(8.5%vs.22.1%,P=0.004),and the incidence of neurotoxicity/encephalopathy and nephrotoxicity was significantly lower in subgroup analysis.(4)Age(OR=1.221,95%CI:1.042-1.431),creatinine clearance(vancomycin and meropenem),and hematocrit(piperacillin-tazobactam)were associated with the change of drug concentration.Conclusion:Multiple antimicrobial TDM in adult critical infection patients may improve the clinical outcome and decrease the incidence of drug-related adverse events.