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Luis A. García Rodríguez, MD, MSc; Bruno H. Stricker, MD; Hyman J. Zimmerman, MD

Arch Intern Med. 1996;156(12):1327-1332.

Abstract
Background
Amoxicillin—clavulanic acid combination— associated hepatitis and jaundice was first identified in 1988. Numerous case reports and case series have been published since then, but there is no precise estimate of this risk.

Methods
A retrospective cohort study in the United Kingdom to estimate the risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid and compare it with the one of amoxicillin alone. Data were derived from a cohort of 93 433 users of the combination drug amoxicillin—clavulanic acid and 360 333 users of amoxicillin alone who were aged between 10 and 79 years and who were followed up from 1991 through 1992. After reviewing the information on subjects with suspected liver injury that was recorded on computer files, the clinical records of 177 patients from the attending general practitioners were requested.

Results
They were 35 cases of idiopathic acute liver injury. None was fatal. There were 14 cases of acute liver injury among users of amoxicillin alone. The type of liver injury was hepatocellular in half the cases. There were 21 cases of acute liver injury among users of amoxicillin and clavulanic acid together. The type of liver injury was cholestatic in three quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of developing acute liver injury associated with the combination of amoxicillin and clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (0.2-0.5) per 10 000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver injury for amoxicillin and clavulanic acid together compared with amoxicillin alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients presenting with jaundice. Among users of amoxicillin and clavulanic acid together, the risk of developing acute liver injury was more than 3 times greater after a course of 2 or more consecutive prescriptions than after a single course of therapy. The risk also increased with age among users of amoxicillin and clavulanic acid together. The combination of advancing age and repeated prescriptions resulted in a risk of developing acute liver injury greater than 1 per 1000 users of amoxicillin and clavulanic acid together.

Conclusions
Use of the combination of amoxicillin and clavulanic acid is associated with a higher incidence of acute hepatic injury than the use of amoxicillin alone. The injury is mostly cholestatic. The greatest absolute risk of developing acute liver injury in users of amoxicillin and clavulanic acid together is among elderly patients who are receiving continuous therapy.

(Arch Intern Med. 1996;156:1327-1332)

Author Affiliations
From the Centro Español de Investigación Farmacoepidemiológica, Universidad Complutense de Madrid, Madrid, Spain (Dr García Rodríguez), Department of Internal Medicine II, Academic Hopsital Dijkzigt, Rotterdam, and the Netherlands Center for Monitoring of Adverse Reactions to Drugs, Rijswijk (Dr Stricker), the Netherlands, and the Department of Medicine, The George Washington University Medical Center, and the American Registry of Pathology, Washington, DC (Dr Zimmerman).

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