基于FAERS的头孢他啶／阿维巴坦致神经系统异常的不良反应信号挖掘与分析

目的：通过对头孢他啶/阿维巴坦（ceftazidime/avibactam， CAZ/AVI）导致神经系统异常相关药物不良反应（adverse drug reactions， ADRs）信号的挖掘分析，为临床安全合理用药提供依据。方法：基于2015年1月至2021年6月美国食品药品监督管理局的不良事件报告系统（FAERS），采用报告比值比法（reporting odds ratio， ROR）和贝叶斯法判别可信区间产比神经网络法（bayesian confidence propagation neural network， BCPNN）进行数据挖掘，筛选CAZ/AVI给药后导致神经系统异常的相关ADRs，并将其与美罗培南、亚胺培南/西司他丁和头孢他啶进行比较。结果：该研究共收集到CAZ/AVI相关ADRs共694例，其中88例与神经系统异常相关。女性患者比例稍高于男性（54.55% vs.34.09%），65岁以上患者所占比例较高（15.91%），用药后中位发病时间为6.5 d。CAZ/AVI与美罗培南和头孢他啶相比，致神经系统异常的风险增加[ROR=1.66（95%CI：1.28~2.13），IC025=0.46；ROR=1.36（95%CI：1.02~1.81），IC025=0.21]。CAZ/AVI与美罗培南、亚胺培南/西司他丁和头孢他啶相比，CAZ/AVI发生脑病[ROR=2.73（95%CI：1.85~4.04），IC025=0.81；ROR=2.26（95%CI：1.46~3.51），IC025=0.52；ROR=1.81（95%CI：1.15~2.84），IC025=0.34]、肌阵挛[ROR=4.74（95%CI：2.56~8.81），IC025=0.97；ROR=4.31（95%CI：2.04~9.10），IC025=0.63]、昏迷[ROR=2.77（95%CI：1.26~6.08），IC025=0.57；ROR=2.69（95%CI：1.08~6.71），IC025=0.39]和癫痫[ROR=1.67（95%CI：1.05~2.67），IC025=0.30]的风险增加。结论：该研究表明CAZ/AVI具有增加神经系统异常风险的倾向，这些不良反应应引起临床注意，特别是用于有中枢神经系统病史的患者，从而为临床安全用药提供参考，或避免用于高风险人群。

Signal mining and analysis of adverse drug reactions associated with nervous system disorders induced by ceftazidime/avibactam based on FAERS database

OBJECTIVE To provide reference for rational and safe clinical practice through signal mining and analysis of the adverse drug reactions (ADRs) associated with nervous system disorders incuded by ceftazidime/avibactam (CAZ/AVI).METHODS Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) analysis were used for data mining to screen the ADRs associated with nervous system disorders after the administration of CAZ/AVI based on Food and Drug Administration's Adverse Event Reporting System (FAERS) from January 2015 to June 2021, and compared CAZ/AVI with meropenem, cilastatin sodium/imipenem and ceftazidime.RESULTS A total of 694 adverse reaction reports of CAZ/AVI were collected, and among them, 88 ones were related to nervous system disorders. The proportion of female patients was slightly higher than that of male patients (54.55% vs. 34.09%), and the proportion of patients over 65 years old was higher (15.91%). The ADRs median occurrence time was 6.5 days after CAZ/AVI treatment. CAZ/AVI showed increased risks of nervous system disorders compared with meropenem and ceftazidime[ROR=1.61(95%CI:1.27-2.05), IC025=0.43; ROR=1.46(95%CI:1.01-1.91), IC025=0.25]. Compared with meropenem, cilastatin sodium/imipenem and ceftazidime, CAZ/AVI showed increased risks of encephalopathy[ROR=2.73(95%CI:1.85-4.04), IC025=0.81; ROR=2.26 (95%CI:1.46-3.51), IC025=0.52; ROR=1.81 (95%CI:1.15-2.84), IC025=0.34], myoclonus[ROR=4.74(95%CI:2.56-8.81), IC025=0.97; ROR=4.31(95%CI:2.04-9.10), IC025=0.63], coma[ROR=2.77 (95%CI:1.26-6.08), IC025=0.57; ROR=2.69(95%CI:1.08-6.71), IC025=0.39] and seizure[ROR=1.67(95%CI:1.05-2.67), IC025=0.30].CONCLUSION This study shows CAZ/AVI tends to increase risks of nervous system disorders. The poor clinical outcomes of the events should attract clinical attention, especially for patients with a history of nervous system disorders, which provide reference for clinical safe medication, or it should be avoided to be applied to high risk population.