利奈唑胺联合常规抗结核药物治疗结核性脑膜炎有效性与安全性的Meta分析

文朋 程登贵 蒋其俊 罗雪 陈欢

摘 要 目的：系统评价利奈唑胺（LZD）联合常规抗结核药治疗结核性脑膜炎（TBM）的疗效和安全性，为临床用药提供循证参考。方法：计算机检索PubMed、Cochrane图书馆、Embase、中国知网、万方数据等，收集LZD联合常规抗结核药物（试验组）对比常规抗结核药物（对照组）的随机对照试验（RCT），检索时限均为建库起至2020年1月。筛选文献、提取资料后，采用Cochrane 系统评价员手册5.2 推荐的偏倚风险评估工具对纳入文献质量进行评价，采用Rev Man 5.3软件进行Meta分析，并对结果进行敏感性分析和发表偏倚分析。结果：共纳入9项RCT，共计602例患者。Meta分析结果显示，试验组患者总有效率[OR=4.05，95%CI（2.26，7.26），P<0.000 01]、脑脊液蛋白含量变化幅度[MD=0.48，95%CI（0.20，0.77），P=0.000 8]、脑脊液白细胞计数变化幅度[MD=44.43，95%CI（20.06，68.81），P=0.000 4]、脑脊液糖/同步血糖变化幅度[MD=0.09，95%CI（0.05，0.14），P<0.000 1]均显著高于对照组，两组患者脑脊液氯化物含量变化幅度[MD=8.08，95%CI（-0.64，16.80），P=0.07]和不良反应发生率[OR=1.34，95%CI（0.57，3.11），P=0.50] 比较，差异均无统计学意义。以脑积液蛋白含量变化幅度、脑脊液糖/同步血糖变化幅度为指标的敏感性分析结果显示，与剔除前比较有显著性差异;以脑脊液白细胞计数变化幅度、脑脊液氯化物含量变化幅度为指标的敏感性分析结果显示，与剔除前比较无显著性差异。发表偏倚分析结果显示，本研究存在一定的发表偏倚。结论：LZD联合常规抗结核药治疗TBM的疗效和安全性均较好。由于敏感性分析结果不一致，且存在发表偏倚，故所得结论尚需更多大样本、多中心研究进一步证实。

关键词 利奈唑胺;抗结核药物;结核性脑膜炎;Meta分析;疗效;安全性

中圖分类号 R529.3 文献标志码 A 文章编号 1001-0408（2020）22-2781-05

DOI 10.6039/j.issn.1001-0408.2020.22.16

ABSTRACT   OBJECTIVE： To systematically evaluate the efficacy and safety of linezolid （LZD） combined with routine anti- tuberculosis drugs in the treatment of tuberculous meningitis （TBM）， so as to provide evidence-based reference for clinical medi- cation. METHODS： Retireved from PubMed， Cochrane Library， Embase， CNKI and Wanfang database， randomized controlled trials （RCT） of LZD combined with routine anti-tuberculosis drugs （trial group） versus routine anti-tuberculosis drugs （control group） were collected from the inception to Jan. 2020. After literature screening and data extraction，  the quality of the included literature were evaluated with bias risk assessment tool recommended by Cochrane system evaluator handbook 5.2. Meta-analysis was conducted by using Rev Man 5.3 software， and sensitivity analysis and publication bias analysis were performed. RESULTS： Totally 9 RCTs involving 602 patients were included. Meta-analysis showed that total response rate [OR=4.05， 95%CI （2.26， 7.26）， P<0.000 01]，  changes of protein content of cerebrospinal fluid [MD=0.48，95%CI（0.20，0.77），P=0.000 8]， changes of white blood cells count of cerebrospinal fluid [MD=44.43， 95%CI （20.06， 68.81）， P=0.000 4]， changes of cerebrospinal fluid glucose/synchronous blood glucose [MD=0.09，95%CI（0.05，0.14），P<0.000 1] of trial group were significantly higher than those of control group. There was no statistical significance in the changes of chloride content of cerebrospinal fluid [MD=8.08，95%CI（-0.64，16.80），P=0.07] and the incidence of ADR [OR=1.34，95%CI（0.57，3.11），P=0.50] between 2 groups. The results of sensitivity analysis showed that there were significant differences comparison with before exclusion when the change of protein content in cerebrospinal fluid and the change of glucose/synchronous blood glucose in cerebrospinal fluid were taken as indexes， and there was no significant difference comparison with before exclusion when the changes of white blood cell count and chloride content in cerebrospinal fluid were taken as indexes. The results of publication bias analysis showed that there was a certain publication bias in this study. CONCLUSIONS： LZD combined with conventional anti-tuberculosis drugs is effective and safe for TBM. Because the inconsistent results of sensitivity analysis and publication bias exists in publication bias analysis， the conclusions need to be further confirmed by more large sample and multi-center studies.

KEYWORDS   Linezolid; Anti-tuberculosis drugs; Tuber- culous meningitis; Meta-analysis; Therapeutic efficacy; Safety

结核性脑膜炎（Tuberculous meningitis，TBM）是由结核分枝杆菌入侵蛛网膜下腔引起软脑膜、蛛网膜感染进而累及脑血管，同时部分可累及脑实质和脊髓的中枢神经系统感染，主要症状为发热、抽搐、颈项强直和恶心呕吐;当进展为重症TBM时，其具有病情重、起病急和患者预后差的特点，且发病率和致死率均较高[1]。临床常用治疗TBM的药物有异烟肼、吡嗪酰胺、乙胺丁醇和利福平，但疗效欠佳、患者预后差[2]。利奈唑胺（Linezolid，LZD）属噁唑烷酮类抗菌药物，对结核分枝杆菌有一定的抑制活性[3]。有研究认为，该药可较好地透过血脑屏障，可在脑脊液中维持较高的药物浓度[4]，现已被《热病：桑德福抗微生物治疗指南（第48版）》[5]推荐用于多耐药肺结核的治疗。近年来多项研究表明，LZD联合常规抗结核药治疗TBM具有一定的疗效，但这些研究大多均为小样本的临床研究[6-8]。……