title: Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases.
abstract: 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 [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 ORadjof 1.86 (95% CI 1.08-3.21) for amoxicillin to the highest ORadjof 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.
authors.affiliation: 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. carmen.ferrajolo@unina2.it.|Department of Medical Informatics, Erasmus University Medical Centre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands. carmen.ferrajolo@unina2.it.
authors.forename: Carmen
authors.identifier: 0000-0002-6228-6548
authors.initials: C
authors.lastname: Ferrajolo
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Centre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
authors.forename: Katia M C
authors.initials: KM
authors.lastname: Verhamme
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Centre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.|Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Trifirò
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Centre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.|Department of Paediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Geert W
authors.initials: GW
authors.lastname: 't Jong
authors.affiliation: Pedianet-Società Servizi Telematici SRL, Padua, Italy.
authors.forename: Gino
authors.initials: G
authors.lastname: Picelli
authors.affiliation: Pedianet-Società Servizi Telematici SRL, Padua, Italy.|Department of Paediatrics, University of Padua, Padua, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Giaquinto
authors.affiliation: Health Search-IMS HEALTH LPD (Longitudinal Patient Database), Italian College of General Practitioners, Florence, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: Mazzaglia
authors.affiliation: Department of Epidemiology and Biostatistics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.affiliation: 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.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capuano
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Centre, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.|Department of Epidemiology and Biostatistics, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Miriam C J M
authors.initials: MC
authors.lastname: Sturkenboom
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D057225:Data Mining / Q000379:methods*; D016208:Databases, Factual / Q000706:statistics & numerical data*; D005260:Female; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D011320:Primary Health Care; D018570:Risk Assessment / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents