How should Augmentin (amoxicillin/clavulanate) be used in patients with liver disease?

Augmentin Use in Liver Disease

Augmentin (amoxicillin/clavulanate) should be used with extreme caution in patients with liver disease and is contraindicated in patients with a previous history of cholestatic jaundice or hepatic dysfunction associated with this medication. 1

Contraindications and Risks

• Augmentin is explicitly contraindicated in patients with a previous history of cholestatic jaundice or hepatic dysfunction associated with amoxicillin/clavulanate 1
• Hepatic dysfunction, including hepatitis and cholestatic jaundice, has been associated with Augmentin use, and while usually reversible, deaths have been reported 1
• Jaundice can develop several weeks after completing treatment with Augmentin, making the association difficult to recognize immediately 2

Mechanism of Hepatotoxicity

• The hepatotoxicity appears to be primarily related to the clavulanic acid component rather than amoxicillin alone 2, 3
• The mechanism is likely a hypersensitivity reaction to clavulanic acid or an idiosyncratic metabolic reaction 4
• Histological findings typically show cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes 1
• In some cases, a distinctive focal destructive cholangiopathy has been observed 5

Monitoring Recommendations

• Hepatic function should be monitored at regular intervals in patients with hepatic impairment who are taking Augmentin 1
• Baseline liver function tests should be obtained before starting treatment 1
• More frequent monitoring is warranted during treatment in patients with pre-existing liver disease 1
• Monitor for signs of hepatotoxicity including jaundice, pruritus, fatigue, and elevated liver enzymes 6

Clinical Presentation of Augmentin-Induced Liver Injury

• Typically presents as cholestatic jaundice, which may appear up to 6 weeks after stopping therapy 2, 6
• Symptoms include jaundice, pruritus, fatigue, and occasionally rash 6
• Laboratory findings show elevated alkaline phosphatase, bilirubin, and transaminases 1
• The illness can be protracted over many weeks but is usually reversible 2

Management of Patients with Liver Disease

• For patients with known liver disease who require Augmentin:

  • Consider alternative antibiotics if possible 2
  • If no alternatives exist, use the lowest effective dose for the shortest duration 2
  • Monitor liver function tests more frequently during treatment 1
  • Discontinue immediately if signs of hepatotoxicity develop 1

• For patients who develop hepatotoxicity while on Augmentin:

  • Discontinue the medication immediately 1
  • Monitor liver function tests until normalization 1
  • Avoid rechallenge with Augmentin, as recurrence of hepatotoxicity has been documented 3
  • Note that amoxicillin alone may be safely used in patients who have experienced Augmentin-induced hepatotoxicity 3

Severity and Outcomes

• Most cases of Augmentin-induced liver injury are reversible upon discontinuation 2
• However, severe cases progressing to hepatic failure have been reported 6
• In rare instances, Augmentin-induced hepatotoxicity has been associated with progression to Stevens-Johnson syndrome and death 6
• One report noted development of chronic liver disease with persistent cholestatic liver biochemical abnormalities 5

Risk Factors

• Older age and male gender appear to be associated with increased risk of hepatotoxicity 1
• Prolonged treatment duration may increase risk 1
• Previous history of drug-induced liver injury may predispose patients to Augmentin hepatotoxicity 1

Clinical Recommendations

• Reserve Augmentin for severe infections where amoxicillin alone is unsuitable 2
• Consider using amoxicillin without clavulanic acid when possible, especially in patients with liver disease 3
• Educate patients about the potential for delayed hepatotoxicity and instruct them to report jaundice, dark urine, or pruritus, even weeks after completing therapy 2
• Ensure that patients with liver disease are informed about the signs and symptoms of hepatotoxicity 1