What antibiotics can cause elevated liver enzymes?

Antibiotics That Can Cause Elevated Liver Enzymes

Macrolide antibiotics (erythromycin, clarithromycin), amoxicillin-clavulanate, penicillinase-resistant penicillins (flucloxacillin, oxacillin, dicloxacillin), sulfonamides (sulfamethoxazole), and fluoroquinolones are the most common antibiotics associated with liver enzyme elevations. 1, 2, 3

Common Hepatotoxic Antibiotics

Macrolide Antibiotics

• Erythromycin: Can cause hepatocellular and/or cholestatic hepatitis with or without jaundice 1
• Clarithromycin: Associated with hepatic dysfunction including increased liver enzymes and hepatocellular/cholestatic hepatitis 2
• Azithromycin: Can cause periodic elevations in alkaline phosphatase, AST, and ALT 4

Beta-lactams

• Amoxicillin-clavulanate: Most frequently associated with hepatotoxicity among penicillins, primarily causing cholestatic hepatitis 3, 5
• Flucloxacillin, oxacillin, dicloxacillin: Can cause predominantly cholestatic hepatitis, sometimes protracted 3, 6

Sulfonamides

• Sulfamethoxazole/trimethoprim: Can cause severe hepatotoxicity, especially in patients with AIDS 3
• Trimethoprim alone: Also reported as a possible cause of acute liver injury 6

Fluoroquinolones

• Ciprofloxacin: Associated with serious hepatitis 6
• Other fluoroquinolones: Can cause cholestasis 3

Other Antibiotics

• Tetracyclines: Historically associated with acute fatty liver syndrome (rare with current dosing) 3
• Nitrofurantoin: Can cause both acute cholestatic/hepatocellular reactions and chronic hepatitis 3

Patterns of Liver Injury

1. Hepatocellular pattern: Predominantly elevated ALT/AST

   • More common with: Isoniazid, tetracyclines, nitrofurantoin

2. Cholestatic pattern: Predominantly elevated alkaline phosphatase and bilirubin

   • More common with: Amoxicillin-clavulanate, flucloxacillin, erythromycin

3. Mixed pattern: Features of both hepatocellular and cholestatic injury

   • Common with: Macrolides, sulfonamides

Monitoring Recommendations

• Baseline testing: Obtain liver function tests before initiating potentially hepatotoxic antibiotics 7

• Routine monitoring:

  • For normal baseline liver function: Not routinely required unless symptoms develop 7
  • For pre-existing liver disease: Monitor weekly for two weeks, then every two weeks for the first two months 7

• Management of elevations:

  • AST/ALT <2× ULN: Repeat LFTs in 2 weeks
  • AST/ALT 2-5× ULN: Monitor weekly, consider dose adjustment or alternative antibiotics
  • AST/ALT >5× ULN: Consider discontinuation 7

Risk Factors for Antibiotic-Induced Liver Injury

• Advanced age (especially >65 years) 2
• Pre-existing liver disease
• Alcohol consumption 4
• Concomitant hepatotoxic medications
• Genetic factors (recently identified for flucloxacillin and amoxicillin-clavulanate) 5

Clinical Pearls and Pitfalls

• Important caveat: The relative risk of antibiotic-related hepatotoxicity is generally low despite being the most common cause of drug-induced liver injury 5
• Timing: Liver injury can occur even after the antibiotic has been discontinued 5
• Drug interactions: Macrolides can inhibit CYP3A4, potentially increasing levels of other hepatotoxic drugs 1, 2
• Don't assume: Not all liver enzyme elevations in patients on antibiotics are due to the antibiotics; consider other causes including the infection itself 7
• Special populations: Elderly patients may be more susceptible to drug-associated hepatotoxicity 2

When liver injury is suspected, prompt discontinuation of the offending antibiotic and close monitoring are essential to prevent progression to more severe liver damage.