What antibiotics are associated with liver dysfunction (abnormal liver function)?

From the Guidelines

Antibiotics such as rifampin, isoniazid, and pyrazinamide can cause liver derangement, and patients with pre-existing liver disease should be closely monitored for signs of liver dysfunction while taking these medications. Several antibiotics can cause liver derangement, with some posing higher risks than others. The most common hepatotoxic antibiotics include amoxicillin-clavulanate, which typically causes cholestatic injury within 1-4 weeks of treatment; fluoroquinolones like ciprofloxacin and levofloxacin; macrolides such as erythromycin and azithromycin; tetracyclines, particularly minocycline; sulfonamides including trimethoprim-sulfamethoxazole; and rifampin, which can cause dose-dependent hepatotoxicity 1.

Key Points to Consider

• Patients taking these medications should be monitored for signs of liver dysfunction including jaundice, abdominal pain, nausea, fatigue, and abnormal liver function tests.
• Risk factors for antibiotic-induced liver injury include advanced age, pre-existing liver disease, alcohol use, and genetic factors affecting drug metabolism.
• The mechanism of liver injury varies by antibiotic class but generally involves either direct hepatotoxicity or immune-mediated reactions.
• If liver derangement occurs, the offending antibiotic should be promptly discontinued, and liver function should be monitored until normalization.
• Alternative antibiotics with lower hepatotoxicity profiles should be considered when treating patients with pre-existing liver conditions, such as using a regimen with only one hepatotoxic agent, generally RIF plus EMB, for 12 months, preferably with another agent, such as a fluoroquinolone, for the first 2 months 1.
• For patients with severe liver disease, a regimen with little or no potential hepatotoxicity, such as EMB combined with a fluoroquinolone, cycloserine, and second-line injectable for 18–24 months, can be considered 1.

Monitoring and Management

• Frequent clinical and laboratory monitoring should be performed to detect drug-induced hepatic injury in patients with preexisting liver disease 1.
• Monitoring liver function at the start of therapy seems a sensible precaution, especially when using macrolide antibiotics, which can cause asymptomatic elevation of serum amino-transaminase levels 1.

From the FDA Drug Label

Hepatotoxicity Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin.

Azithromycin can cause liver derangement, including abnormal liver function, hepatitis, and hepatic failure. If signs and symptoms of hepatitis occur, azithromycin should be discontinued immediately 2.

• Key liver-related adverse reactions include:
  • Abnormal liver function
  • Hepatitis
  • Cholestatic jaundice
  • Hepatic necrosis
  • Hepatic failure It is essential to monitor patients for signs of liver derangement when taking azithromycin 2.

From the Research

Antibiotics and Liver Derangement

• Antibiotics are a common cause of drug-induced liver injury (DILI), with amoxicillin-clavulanate being the most frequent cause of DILI-related hospitalizations 3, 4, 5.
• The severity of antibiotic-induced DILI varies widely, with hepatitis-like damage tend to be more severe than cholestatic/mixed type 3.
• The pattern of liver injury is influenced by age, and some antibiotics like telithromycin can cause abrupt commencement of fever, abdominal pain, jaundice, and ascites 3.
• Genetic-association studies have identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity 3.

Specific Antibiotics and Liver Injury

• Amoxicillin-clavulanate is associated with a high risk of liver injury, particularly in older adults 4, 6, 5.
• Flucloxacillin is also a common cause of DILI, ranking as the second highest cause in many countries 3.
• Other antibiotics like sulfamethoxazole/trimethoprim, minocycline, and nitrofurantoin can also cause significant hepatotoxicity 4, 6.
• Cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion 6.

Clinical Implications

• Early suspicion of hepatocellular injury in the setting of antimicrobial exposure should prompt cessation of therapy and avoidance of rechallenge 4, 6.
• Patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation 6.
• The indication for antibiotics should be evidence-based, and symptoms and signs of liver injury should lead to prompt cessation of therapy 6, 5.