title: Systematic Review and Meta-Analysis: Macrolides- and Amoxicillin/Clavulanate-induced Acute Liver Injury.
abstract: 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.
authors.affiliation: Foundation Catalan Institute of Pharmacology, Barcelona, Spain.
authors.forename: Pili
authors.initials: P
authors.lastname: Ferrer
authors.affiliation: Amgen Ltd, 1 Uxbridge Business Park, Uxbridge, UK.
authors.forename: Justyna
authors.initials: J
authors.lastname: Amelio
authors.affiliation: Foundation Catalan Institute of Pharmacology, Barcelona, Spain.|Department of Clinical Pharmacology, University Hospital Vall d'Hebron, Barcelona, Spain.|Department of Pharmacology, Toxicology and Therapeutics, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Ballarín
authors.affiliation: Foundation Catalan Institute of Pharmacology, Barcelona, Spain.|Department of Clinical Pharmacology, University Hospital Vall d'Hebron, Barcelona, Spain.|Department of Pharmacology, Toxicology and Therapeutics, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Sabaté
authors.affiliation: Foundation Catalan Institute of Pharmacology, Barcelona, Spain.|Department of Clinical Pharmacology, University Hospital Vall d'Hebron, Barcelona, Spain.|Department of Pharmacology, Toxicology and Therapeutics, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Xavi
authors.initials: X
authors.lastname: Vidal
authors.affiliation: Institute for Medical Information Sciences, Biometry and Epidemiology, Ludwig-Maximilians Universitaet-Muenchen, Munich, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Rottenkolber
authors.affiliation: Philipp Klee-Institute for Clinical Pharmacology, Helios Klinik Wuppertal, Wuppertal, Germany.|Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten-Herdecke University, Witten, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Schmiedl
authors.affiliation: Foundation Catalan Institute of Pharmacology, Barcelona, Spain.|Department of Clinical Pharmacology, University Hospital Vall d'Hebron, Barcelona, Spain.|Department of Pharmacology, Toxicology and Therapeutics, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Joan-Ramon
authors.initials: JR
authors.lastname: Laporte
authors.affiliation: Foundation Catalan Institute of Pharmacology, Barcelona, Spain.|Department of Clinical Pharmacology, University Hospital Vall d'Hebron, Barcelona, Spain.|Department of Pharmacology, Toxicology and Therapeutics, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ibáñez
mesh_terms: D000658:Amoxicillin / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D019818:Clavulanic Acid / Q000009:adverse effects*; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D018942:Macrolides / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic
chemical_list: D018942:Macrolides; D019818:Clavulanic Acid; D000658:Amoxicillin