Ferrajolo Carmen, Verhamme Katia M C, Trifirò Gianluca, 't Jong Geert W, Picelli Gino, Giaquinto Carlo, Mazzaglia Giampiero, Stricker Bruno H, Rossi Francesco, Capuano Annalisa, Sturkenboom Miriam C J M
Department of Experimental Medicine, Pharmacology Section, Campania Regional Centre of Pharmacovigilance and Pharmacoepidemiology, University of Campania, Via Santa Maria di Costantinopoli, 16, 80138, Naples, Italy.
Department of Medical Informatics, Erasmus University Medical Centre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
Drug Saf. 2017 Apr;40(4):305-315. doi: 10.1007/s40264-016-0493-y.
Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury.
We assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients.
A large, multi-database, population-based, case-control study was performed in people <18 years of age from two European countries (Italy and The Netherlands) during the period 2000-2008. All potential cases of liver injury were automatically extracted from three databases and then manually validated based on Council for International Organizations of Medical Sciences (CIOMS) criteria and by exclusion of all competing causes for liver injury. Up to 100 control participants were sampled for each case and were matched on index date of the event, age, sex and database. Based on prescription data, antibiotic exposure was categorized as current, recent or past use by calculating the time period between the end of prescription and the index date. Multivariate conditional logistic regression analyses were applied to calculate odds ratios (ORs) as a measure of the association (with 95% confidence interval [CI]).
We identified 938 cases of liver injury and matched to 93,665 controls. Current use of overall antibiotics is associated with a threefold increased risk of liver injury compared with past use (adjusted OR [OR] 3.22, 95% CI 2.57-4.03). With regard to individual antibiotics, the risk is significantly increased for current use of each antibiotic (p < 0.005), except for azithromycin. Risk estimates vary from the lowest OR of 1.86 (95% CI 1.08-3.21) for amoxicillin to the highest OR of 24.16 (95% CI 11.78-49.54) for cotrimoxazole (i.e. sulphamethoxazole/trimethoprim) and 26.70 (95% CI 12.09-58.96) for ceftriaxone. Sensitivity analyses confirm the associations for ceftriaxone, cotrimoxazole, and clarithromycin.
Antibiotic-induced liver injury in children is heterogeneous across the use of individual antibiotics. When prescribing ceftriaxone, cotrimoxazole and clarithromycin in children, paediatricians should definitely be aware of their potential risk of liver injury, even if for short periods.
抗生素是儿童中最常用的药物类别。对儿科人群的真实世界数据挖掘显示抗生素使用与急性肝损伤之间存在潜在关联。
我们评估了儿童和青少年门诊患者中抗生素使用相关肝损伤的风险估计值。
在2000年至2008年期间，对来自两个欧洲国家（意大利和荷兰）年龄小于18岁的人群进行了一项大型、多数据库、基于人群的病例对照研究。所有潜在的肝损伤病例均从三个数据库中自动提取，然后根据国际医学科学组织理事会（CIOMS）标准并排除所有肝损伤的竞争病因进行人工验证。每个病例抽取多达100名对照参与者，并根据事件的索引日期、年龄、性别和数据库进行匹配。根据处方数据，通过计算处方结束至索引日期之间的时间段，将抗生素暴露分类为当前、近期或过去使用。应用多变量条件逻辑回归分析来计算比值比（OR）作为关联的度量（95%置信区间[CI]）。
我们识别出938例肝损伤病例，并匹配了93,665名对照。与过去使用相比，当前使用总体抗生素与肝损伤风险增加三倍相关（调整后OR 3.22，95% CI 2.57 - 4.03）。就个别抗生素而言，除阿奇霉素外，每种抗生素当前使用的风险均显著增加（p < 0.005）。风险估计值从阿莫西林的最低OR 1.86（95% CI 1.08 - 3.21）到复方新诺明（即磺胺甲恶唑/甲氧苄啶）的最高OR 24.16（95% CI 11.78 - 49.54）以及头孢曲松的26.70（95% CI 12.09 - 58.96）不等。敏感性分析证实了头孢曲松、复方新诺明和克拉霉素之间的关联。
儿童抗生素诱导的肝损伤在个别抗生素的使用方面存在异质性。在给儿童开具头孢曲松、复方新诺明和克拉霉素时，儿科医生应明确意识到它们潜在的肝损伤风险，即使是短期使用。
