Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases

Abstract

IntroductionAntibiotics 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.ObjectiveWe assessed risk estimates of liver injury associated with antibiotic use in children and adolescent outpatients.MethodsA 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]).ResultsWe 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 [ORadj] 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 ORadj of 1.86 (95% CI 1.08–3.21) for amoxicillin to the highest ORadj 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.ConclusionAntibiotic-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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-016-0493-y) contains supplementary material, which is available to authorized users.

Drug-Induced Liver Diseases in Children and Adolescents

“…Gender role in development of DILD is different from one study data to others: in one study [4] such dependency was low due to a little bit bigger number of boys (58%), but in the other study [5] -girls were significantly predominant (70%).…”

“…Activity The essential role in development of DILD in children belongs to age-dependent maturation of cytochrome P450 system (initially its activity corresponds to 50% of adults level) and in particular its isoenzyme 3A4 that participates in metabolism of 50% of all drugs [4] including those that have evident hepatototoxic effect -erythromycin, co-trimoxazol. In addition the activity of 3A4 being insufficient in children decreases in condition of acid-base balance disturbance and hypoxia and also in case of use of inhibitors of this enzymeclarithromycin, fliconazole or omeprazole [18].…”

“…This phenomenon could be related to slower development of immunological reaction or long-term retention of the drug in the body (slow metabolizers). It is emphasized that amoxicillin itself has rather weak hepatotoxic potential and in particular the addition of clavulanic acid (750 mg per day) makes this drug hepatotoxic [4].…”

“…Comparing the liver toxicity of AB of different groups the lowest risk of DILD belongs to penicillins and the highest -to fluoroquinolones. The second place in frequency of DILD in children belongs to psychotropics (40% of all DILD) -anticonvulsants, antidepressants, agents for treatment of hyperactive child syndrome with attention deficiency [3][4][5]. In accordance with data [6][7][8] NSAIDs are also part of the leader group of drugs caused DILD but it's necessary to notify that ibuprofen together with paracetamol are the main antipyretic drugs in children.…”

A Case of Multiple Antibiotic-Associated Hepatotoxicity in an Infant

“…В настоящее время известно более 1200 ЛС практически всех фармакологических групп, способных вызвать ЛПП, при этом частота поражения печени для каждого из препаратов варьирует от 1:1000 до 1:100 000. Антибактериальные препараты относятся к числу часто назначаемых (нередко избыточно) детям и, может быть, в силу этого наиболее часто упоминаются как ЛС, вызывающие ЛПП [1,3]. На долю антибиотиков приходится около 45 % всех случаев лекарственной гепатотоксичности.…”