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Comment: History of Drug-Induced Hepatitis and Risk of Amoxicillin/Clavulanate—Induced Hepatotoxicity

TO THE EDITOR: The letter from Schey et al.,1 in which they commented that few cases of liver damage in association with the combination of amoxicillin and clavulanic acid have been reported is surprising. Hepatic dysfunction in association with amoxicillin/clavulanate is well recognized, and there have been scores of case reports on such dysfunction.2 Amoxicillin/clavulanate is the second most common suspected cause of hepatotoxicity reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC), which has now received almost 500 spontaneous reports of the association. The reaction has been well characterized as displaying a predominantly cholestatic profile and often has an onset of 10–14 days after cessation of the antibiotic treatment.3,4 Of the 494 reports of hepatic dysfunction in association with the combination reported to ADRAC, 319 have described jaundice or cholestatic hepatitis. This reaction is generally reversible after the drug is withdrawn; however, 13 patients reported to ADRAC have died from liver failure or complications associated with liver disease. A retrospective case–control study5 was performed to identify risk factors for the reaction and found that increasing age was a risk factor, with patients >55 years old having an odds ratio of 16.1 (CI 2.9 to 88.9), compared with patients aged <30 years. Schey et al.1 also refer to a prevalence of 1/100 000 for the association of hepatic dysfunction with the combination. In a retrospective cohort study using the General Practice Research Database in the UK, Garcia Rodriguez et al.2 found that the incidence rate for the development of acute liver injury in association with amoxicillin/clavulanate was 1.7 per 10 000 prescriptions. This group also found that the risk increased with increasing age and with consecutive prescriptions.