利奈唑胺严重与致死性不良反应--案例报道的汇总分析

Severe and lethal adverse reactions of linezolid--a summary analysis of case reports

本研究通过系统汇总,对利奈唑胺(Linezolid)引起不良反应(Adverse Drug Reactions,ADRs)的案例报告进行评价,利奈唑胺ADRs对人体器官或系统的影响及其严重程度。检索Pub Med、Embase、Cochrane图书馆、CINAH等电子数据库,时间从数据库建立到2019年12月31日,以“linezolid”+“case reports”和“利奈唑胺”+“案例”为检索词,收集关于利奈唑胺ADRs的案例报告。共纳入个案报道159篇,共计189例患者,男女比例为0.89:1,平均年龄(52.42±23.43)岁。结果显示,利奈唑胺引起的严重的ADRs主要发生在神经系统(n=86)和血液系统(n=44)中,其次是代谢系统(n=31)和胃肠道系统(n=18),其它系统的报道较少如皮肤组织(n=6),肾和泌尿系统(n=3),心血管系统(n=2)和肝胆系统(n=2)。报道最多的ADRs是5-羟色胺综合征(n=40),其次是视神经病变(n=25)和血小板减少症(n=22),最严重的ADR是乳酸酸中毒(n=29,死亡占比达31.0%)。有11例血液系统ADRs患者基础即存在肾功能损伤的问题,其中4例死亡;血小板减少症的22例患者主要为65岁以上的老年人(n=17),还有1例新生儿和2例儿童。我们首次报道,乳酸性酸中毒和血液系统ADRs多发生在28天内,神经系统ADRs多发生在28天后;而不可逆的听神经病变(n=1)、低磷血症(n=1)、心动过缓(n=1)和未成年人牙齿变色(n=5)是利奈唑胺说明书、相关指南和临床试验中没有描述过的ADRs。案例报道提示,利奈唑胺最严重的ADRs是乳酸性酸中毒且多发生在28天内;肾功能损伤和特殊人群可能是利奈唑胺发生血液系统ADRs的主要危险因素;利奈唑胺相关ADRs罕见但已有听神经病变、低磷血症、心动过缓和未成年人牙齿变色的个案。

A systematic summary was used to evaluate case reports of adverse drug reactions(ADRs)caused by linezolid,and to explore the effects and severity on human organs or systems in the real world.The databases,such as PubMed,Embase,Cochrane Library,and CINAHL,were searched using“linezolid”+“case reports”as search terms from the establishment of each database to 31 st December 2019,and the case reports on ADRs related to linezolid were collected.A total of 159 case reports were finally included in the analysis,including 189 patients.The ratio of male to female was 0.89:1,and the average age was(52.42±23.43)years old.The results showed that linezolid-related severe ADRs mainly occurred in the nervous system(n=86)and blood system(n=44),followed by the metabolic system(n=31)and gastrointestinal system(n=18).Other systems reported less frequently were the skin tissue(n=6),renal and urinary system(n=3),cardiovascular systems(n=2),and hepatobiliary system(n=2).The most common linezolid-related ADRs were serotonin syndrome(n=40),followed by optic neuropathy(n=25)and thrombocytopenia(n=22).The most severe ADR was lactic acidosis(n=29),and its death rate was as high as 31.0%.In the blood system ADRs,11 cases had underlying diseases of renal impairment,and four of them died.Moreover,22 cases with thrombocytopenia were mainly elderly over 65 years old(n=17),and there were also one infant and one child with thrombocytopenia.We first reported that lactic acidosis and blood system ADRs mostly occurred within 28 d,and the nervous system ADRs mostly occurred after 28 d.Besides,irreversible auditory neuropathy(n=1),hypophosphatemia(n=1),bradycardia(n=1),and tooth discoloration mostly occurring in minors(n=5)were the linezolid-related ADRs,which were not described in the instructions,related guidelines,and clinical trials of linezolid.The most severe linezolid-related ADRs was lactic acidosis that occurred within 28 d.Renal damage and special populations might be the main risk factors in the blood system ADRs.Minor linezolid-related ADRs were rare,while there were still some cases of auditory neuropathy,hypophosphatemia,bradycardia,and tooth discoloration.