Hepatotoxicity from the extensively used combination of amoxicillin and clavulanic acid is widely recognized and is attributed to the clavulanic acid component. Amoxicillin–clavulanate is among the most frequently identified drugs causing liver injury.
The frequency of hepatic injury from amoxicillin–clavulanate is low (∼1–3 in 100,000), and the range of clinical and laboratory manifestations is broad. The drug is generally used as short duration therapy (7–10 days). The appearance of evidence of liver injury is often delayed for days to weeks after initiation of therapy; therefore, many cases of hepatic injury appear well after the course of the therapy has been completed, and the pivotal role of amoxicillin–clavulanate may be overlooked. The types of liver injury from amoxicillin–clavulanate include hepatocellular necrosis, cholestatic reactions, and, in some patients, a mixed hepatocellular-cholestatic presentation. Some patients (one to two-thirds) have signs of hypersensitivity, with rash and fever at the time hepatic injury is recognized, whereas others present with jaundice and evidence of a bland cholestasis. In general, the liver injury from amoxicillin–clavulanate is mild and self-limiting, with a gradual and complete resolution of the process over several days to weeks.
Advancing age and prolonged therapy are factors associated with the development of the cholestatic injury. Predominantly hepatocellular injury is more frequent in younger patients. A few instances of severe hepatocellular injury leading to death or the need for transplantation have been reported.