This combination of drugs is an oral antibiotic widely used in the treatment of mild to moderate bacterial infections.
This combination is currently the most common cause of clinically apparent acute hepatic injury induced by drugs, both in the United States and in Europe.
The combination consists of amoxicillin, a semisynthetic third-generation penicillin and clavulanate that is a beta-lactam that acts as a beta-lactamase inhibitor.
The main bacterial enzyme responsible for resistance to penicillin.
Amoxicillin clavulanate was approved for use in the United States in 1984 and, currently, 2 to 5 million prescriptions are filled annually, making it one of the most commonly used antibiotic regimens.
Current indications are for mild to moderate bacterial infections due to known or suspected gram-positive or gram-negative organisms resistant to penicillinase.
This combination is provided in multiple dose combinations, typically as 250 to 875 mg of amoxicillin with 125 mg of clavulanate, two to three times a day for 7 to 10 days.
Amoxicillin clavulanate is available in multiple generic formulations and under the brand name Augmentin. Common side effects include gastrointestinal upset, diarrhea and rash.
Amoxicillin clavulanate has been implicated in hundreds of cases of clinically apparent acute liver injury.
This combination is currently the most common cause of drug-induced liver disease in most large case series in the United States and Europe.
The onset of the injury usually lasts a few days or up to 8 weeks, after the start of therapy often occurs after the antibiotic cycle is completed; the delay is a few days or up to six weeks.
The onset is usually fatigue, low fever, nausea and abdominal pain, followed by pruritus and jaundice .
The pattern of elevations of liver enzymes is typically cholestatic with marked elevations in alkaline phosphatase and gamma glutamyl transpeptidase.
In some cases, aminotransferase levels are markedly elevated giving a mixed or hepatocellular pattern, particularly in younger patients with an earlier onset of the lesion.
In children, amoxicillin-clavulanic hepatotoxicity is typically anicteric and occurs with nausea, vomiting and abdominal pain instead of jaundice and itching.
The pattern of elevations of serum enzymes is also much more likely to be hepatocellular in children, but the course of the disease is usually benign.
Because liver injury can occur days or weeks after stopping treatment, the association of liver injury with the reception of amoxicillin / clavulanic acid may go unnoticed.
Immunoallergic features (fever, rash, eosinophilia ) may occur, but they are not invariably present and are generally not prominent.
The formation of autoantibodies is not common. The liver injury is idiosyncratic and is estimated to occur after 1 week in 2,500 prescriptions. Injury is more common in men than in women, in the elderly and after multiple courses.
The cause of amoxicillin clavulanic hepatotoxicity is unknown, but probably of immunoallergic origin.
Allergic manifestations can occur and include rash, fever, arthralgias and eosinophilia.
An independent HLA Class I association has also been made with HLA-A * 02: 01. Liver injury appears to be due to clavulanate rather than amoxicillin, since re-exposure to amoxicillin alone has not been associated with recurrence.
While re-exposure to the combination is often followed by a more rapid onset of a more severe liver injury that may include prolonged cholestasis and development of cirrhosis.
Other beta-lactamase inhibitors (tazobactam and subactame) have not been reported to cause a similar hepatic injury.
Although it has been reported with other penicillins when combined with clavulanate (ticarcillin / clavulanate).
Result and management
Hepatic injury caused by amoxicillin-clavulanate is typically associated with jaundiceand can be severe and prolonged (with jaundice lasting from 4 to 24 weeks).
But it rarely results in a lasting injury or death. Deaths from amoxicillin-hepatic clavulanate injury have been reported, but largely in patients with other comorbidities, including cirrhosis or multiple exp.