Amoxicillin is considered a third generation or aminopenicillin and is one of the most commonly prescribed antibiotics. Amoxicillin and other aminopenicillins have been linked with idiosyncratic liver injury, but only rarely and in isolated case reports.
Amoxicillin (a mox' i sil' in) is an orally available aminopenicillin that has been available in the United States since 1980, for which currently more than 50 million prescriptions are filled yearly. Amoxicillin is used to treat mild to moderate infections caused by susceptible agents, such as (but not limited to) Escherichia coli, Hemophilis influenzae, Listeria monocytogenesis, Neisseria gonorrhoeae, Proteus mirabilis, Salmonella, Shigella, Staphylococcus aureus (non-penicillinase producing), Staphyloccocus epidermidis, and Streptococcus pneumoniae. Amoxicillin is available in multiple generic formulations as tablets or capsules of 250, 500 and 875 mg and is usually given in doses of 250 to 850 mg every 8 hours for 7 to 14 days. Pediatric formulations in liquid suspension and chewable tablets are also available.
Rare instances of idiosyncratic liver injury have been reported in persons receiving the aminopenicillins including amoxicillin. Cases are characterized by a short latency period of a few days to as long as two weeks. The onset of liver injury can occur after the antibiotic is stopped. The serum enzyme pattern associated with aminopenicillin liver injury has included a hepatocellular pattern with marked elevations in ALT and AST, and minimal elevations in alkaline phosphatase and rapid recovery after withdrawal. In addition, cholestatic forms of hepatic injury with marked alkaline phosphatase elevations (as also seen with penicillin-induced liver injury) have also been described, some of which have been associated with prolonged cholestasis (Case 1). The onset of hepatic injury may be accompanied by signs or symptoms of hypersensitivity such as eosinophilia, rash and arthralgias, and in some cases is accompanied by toxic epidermal necrolysis or Stevens Johnson syndrome.
Likelihood score: B (highly likely but rare cause of clinically apparent liver injury).
Much more common than liver injury from amoxicillin alone is the typically cholestatic hepatitis that occurs after treatment with the combination of amoxicillin and clavulanate. Indeed, this combination is currently the most common cause of idiosyncratic acute liver injury in the United States, Europe and Australia. The injury, however, is usually attributed to the clavulanate rather than amoxicillin. The clinical features are similar but perhaps not completely the same. In cases of liver injury seeming due to amoxicillin, an extra effort should be made to make sure that it was not amoxicillin/clavulanate [Augmentin] that was taken.
Mechanism of Injury
The cause of the liver injury associated with amoxicillin use is probably hypersensitivity or allergy. Recurrence with reexposure is highly likely, but intentional rechallenge has not been described.
Outcome and Management
In the few cases that have been described, the majority of patients have recovered, although recovery has been slow in some cholestatic instances (2 to 6 months). Rare instances of acute liver failure and several cases of vanishing bile duct syndrome have been reported with aminopenicillin induced liver injury. Corticosteroids have often been used to treat the allergic manifestations of penicillin related immunoallergic hepatitis; while corticosteroid therapy may improve fever and rash promptly, their efficacy in ameliorating the accompanying liver disease has not been shown. Instances of recurrence of liver injury with unintentional reexposure to aminopenicillins and recurrence with exposure to cephalosporins have been reported. Patients with aminopenicillin induced hepatitis should avoid reexposure to other penicillins and should take cephalosporins with caution.
References to the hepatotoxicity and safety of amoxicillin are given in the Overview section on the aminopenicillins.
Drug Class: Antiinfective Agents, Aminopenicillins
Other Drugs in the Subclass, Aminopenicillins: Amoxicillin/Clavulanate, Ampicillin, Ampicillin-Sulbactam, Bacampicillin, Pivampicillin
Case 1. Cholestatic hepatitis due to amoxicillin therapy.
|Medication:||Amoxicillin (1500 mg daily for 10 days)|
|Severity:||3+ (jaundice and hospitalization)|
|Days After Starting||Days After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|Amoxicillin 1500 mg/day for 10 days for pharyngitis|
|20||10||30||314||10.5||AMA, ANA, pANCA negative|
|DRUG||CAS REGISTRY NO||MOLECULAR FORMULA||STRUCTURE|