Divala Titus H, Fielding Katherine L, Kandulu Chikondi, Nliwasa Marriott, Sloan Derek J, Gupta-Wright Ankur, Corbett Elizabeth L
TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Helse Nord Tuberculosis Initiative, University of Malawi College of Medicine, Blantyre, Malawi; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.
TB Centre, London School of Hygiene & Tropical Medicine, London, UK; School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.
Lancet Infect Dis. 2020 Sep;20(9):1089-1098. doi: 10.1016/S1473-3099(20)30143-2. Epub 2020 May 18.
Suboptimal diagnostics for pulmonary tuberculosis drive the use of the so-called trial of antibiotics, a course of broad-spectrum antibiotics without activity against Mycobacterium tuberculosis that is given to patients who are mycobacteriology negative but symptomatic, with the aim of distinguishing pulmonary tuberculosis from bacterial lower respiratory tract infection. The underlying assumption-that patients with lower respiratory tract infection will improve, whereas those with pulmonary tuberculosis will not-has an unclear evidence base for such a widely used intervention (at least 26·5 million courses are prescribed per year). We aimed to collate available evidence on the diagnostic performance of the trial of antibiotics.
In this systematic review and meta-analysis we searched the MEDLINE, Embase, and Global Health databases for studies published up to March 15, 2019, that investigated the sensitivity and specificity of the trial of antibiotics against mycobacteriology tests in adults (≥15 years) with tuberculosis symptoms. We used the QUADAS-2 tool to assess the risk of bias. We estimated pooled values for sensitivity and specificity of trial of antibiotics (as the index text) versus mycobacteriology tests (as the reference standard) using random-effects bivariate modelling, and we used the I statistic to assess heterogeneity between studies contributing to these estimates. This study is registered with PROSPERO, number CRD42017083915.
Of the 9410 articles identified by our search, eight studies were eligible for inclusion. The studies were from seven countries in Africa, South America, and Asia, and involved 2786 participants. Six studies used mycobacterial culture as the reference standard, and six used penicillins for the trial of antibiotics. The treatment duration, number of antimicrobial courses, and definition of what constituted response to treatment varied substantially between studies. The pooled sensitivity (67%, 95% CI 42-85) and specificity (73%, 58-85) of the trial of antibiotics versus mycobacteriology tests were below internationally defined minimum performance profiles for tuberculosis diagnostics and had substantial heterogeneity (I was 96% for sensitivity and 99% for specificity). Each included study failed on one or more domain of the QUADAS-2 tool.
Current policy and practice regarding the trial of antibiotics appear inappropriate, given the weak evidence base, poor diagnostic performance, potential contribution to the global antimicrobial resistance crisis, and adverse individual and public health consequences from the misclassification of tuberculosis status. Antibiotic strategies during tuberculosis investigations should instead optimise clinical outcomes, ideally guided by clinical trials in both inpatient and outpatient groups.
Helse Nord RHF, Wellcome Trust, and the UK Commonwealth Scholarship Commission.
肺结核的诊断方法欠佳，促使人们使用所谓的抗生素试验，即给予痰涂片抗酸杆菌阴性但有症状的患者一个疗程的对结核分枝杆菌无活性的广谱抗生素，目的是区分肺结核与细菌性下呼吸道感染。其潜在假设是，下呼吸道感染患者病情会改善，而肺结核患者则不会，但这种广泛使用的干预措施（每年至少开出2650万疗程）的证据基础并不明确。我们旨在整理关于抗生素试验诊断性能的现有证据。
在这项系统评价和荟萃分析中，我们检索了MEDLINE、Embase和全球卫生数据库，以查找截至2019年3月15日发表的研究，这些研究调查了抗生素试验对有结核病症状的成年人（≥15岁）相对于分枝杆菌学检测的敏感性和特异性。我们使用QUADAS - 2工具评估偏倚风险。我们使用随机效应双变量模型估计抗生素试验（作为索引文本）相对于分枝杆菌学检测（作为参考标准）的敏感性和特异性的合并值，并使用I²统计量评估对这些估计有贡献的研究之间产生的异质性。本研究已在国际前瞻性系统评价注册库（PROSPERO）注册，注册号为CRD42017083915。
我们检索到的9410篇文章中，有8项研究符合纳入标准。这些研究来自非洲、南美洲和亚洲的7个国家，涉及2786名参与者。6项研究使用分枝杆菌培养作为参考标准，6项研究使用青霉素进行抗生素试验。不同研究之间的治疗持续时间、抗菌疗程数量以及治疗反应的定义差异很大。抗生素试验相对于分枝杆菌学检测的合并敏感性（67%，95%CI 42 - 85）和特异性（73%，58 - 85）低于国际定义的结核病诊断最低性能指标，并且存在很大的异质性（敏感性的I²为96%，特异性的I²为99%）。每项纳入研究在QUADAS - 2工具的一个或多个领域存在缺陷。
鉴于证据基础薄弱、诊断性能不佳、对全球抗菌药物耐药性危机的潜在影响以及结核病状态误分类对个人和公共健康造成的不良后果，目前关于抗生素试验的政策和实践似乎并不恰当。在结核病调查期间，抗生素策略应改为优化临床结局，理想情况下应以住院和门诊患者组的临床试验为指导。
挪威北部健康信托基金、惠康信托基金会和英国英联邦奖学金委员会。
