Ferrer Pili, Amelio Justyna, Ballarín Elena, Sabaté Mònica, Vidal Xavi, Rottenkolber Marietta, Schmiedl Sven, Laporte Joan-Ramon, Ibáñez Luisa
Foundation Catalan Institute of Pharmacology, Barcelona, Spain.
Amgen Ltd, 1 Uxbridge Business Park, Uxbridge, UK.
Basic Clin Pharmacol Toxicol. 2016 Jul;119(1):3-9. doi: 10.1111/bcpt.12550. Epub 2016 Feb 3.
Antibacterials are frequently associated with idiosyncratic drug-induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta-analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials.gov, Livertox and Toxline (1980-2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non-user comparator. We summarized the evidence with a random-effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case-control, one cohort and one case-population studies) and 9 (case-population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 [95% confidence interval (CI) 1.81-4.47], p < 0.0001, I(2) = 57%. Three studies were perceived to be missing in the area of low statistical significance. Year of study and selected exposure window partly explained the variability between studies. For AMC, the risk of DILI was 9.38 (95% CI 0.65-135.41) p = 0.3, I2 = 95%. In conclusion, although spontaneous reports and case series have long established an association between macrolides and AMC with acute liver injury, these SR and MA have assessed the magnitude of this association. The low incidence of DILI and the therapeutic place of these antibiotics might tilt the balance in favour of their benefits.
抗菌药物常与特异质性药物性肝损伤（DILI）相关。本研究的目的是评估大环内酯类药物和阿莫西林/克拉维酸（AMC）导致DILI的风险。我们对从PubMed、Cochrane图书馆升级版、Web of Knowledge、clinicaltrials.gov、Livertox和Toxline（1980 - 2014年）检索到的研究进行了系统评价（SR）和荟萃分析（MA）。我们搜索了大环内酯类药物、AMC以及DILI的医学主题词（MeSH）和同义词。我们纳入了除病例报告/系列研究外的所有研究设计、所有年龄段人群以及有安慰剂/非使用者对照的研究。我们采用随机效应荟萃分析总结证据。研究质量通过为不良反应系统评价制定的清单进行评估。使用不同的探索性工具评估异质性和发表偏倚。最终，我们在系统评价中纳入了10篇文章（2篇随机临床试验、6篇病例对照研究、1篇队列研究和1篇病例 - 人群研究），在荟萃分析中纳入了9篇文章（排除病例 - 人群研究）。大环内酯类药物导致DILI的总体汇总相对风险为2.85 [95%置信区间（CI）1.81 - 4.47]，p < 0.0001，I² = 57%。在统计学意义较低的领域，有三项研究被认为缺失。研究年份和选定的暴露窗口部分解释了研究之间的变异性。对于AMC，DILI的风险为9.38（95% CI 0.65 - 135.41），p = 0.3，I² = 95%。总之，尽管自发报告和病例系列研究早就证实了大环内酯类药物和AMC与急性肝损伤之间的关联，但这些系统评价和荟萃分析评估了这种关联的程度。DILI的低发病率以及这些抗生素的治疗地位可能使利弊平衡倾向于其益处。
