Can Clarithromycin, Ceftriaxone, and Nitrofurantoin cause acute liver injury?

Hepatotoxicity Risk of Clarithromycin, Ceftriaxone, and Nitrofurantoin

Yes, all three antibiotics—clarithromycin, ceftriaxone, and nitrofurantoin—can cause acute liver injury, though the risk profile, severity, and clinical patterns differ substantially among them.

Clarithromycin

Clarithromycin carries a well-established risk of hepatotoxicity that is specifically contraindicated in patients with pre-existing cholestatic jaundice or hepatic dysfunction. 1

• The FDA drug label explicitly lists "cholestatic jaundice/hepatic dysfunction" as a contraindication, indicating this is a recognized and clinically significant adverse effect 1
• Hepatotoxicity is listed as a specific warning requiring monitoring during treatment 1
• The clinical pattern typically presents as cholestatic or mixed liver injury 2
• Macrolides as a class, including clarithromycin, have well-documented potential to cause primarily cholestatic hepatitis 2, 3
• Dose adjustment is required in patients with severe renal impairment (reduce by 50% if CrCl <30 mL/min), which may indirectly reduce hepatotoxicity risk 4

Key clinical consideration: The hepatotoxicity mechanism appears to be hypersensitivity-mediated rather than dose-dependent, meaning it can occur unpredictably in susceptible individuals 3

Ceftriaxone

Ceftriaxone has relatively low hepatotoxicity compared to other antibiotics, but acute liver injury can occur and has been documented in case reports. 5, 2

• A 2022 case report documented acute non-cholestatic liver injury occurring within 48 hours of ceftriaxone administration, confirmed by RUCAM scoring 5
• The hepatotoxicity pattern was hepatocellular rather than cholestatic 5
• Cephalosporins as a class have minimal hepatotoxicity, making ceftriaxone-induced liver injury rare but clinically important when it occurs 2, 3
• The injury typically manifests acutely (within days) rather than with delayed onset 5
• Ceftriaxone is recommended for short-term use (maximum 7 days) in specific clinical contexts such as variceal hemorrhage prophylaxis, which limits cumulative exposure 4

Critical pitfall: Because ceftriaxone hepatotoxicity is rare, it may be overlooked as a cause of acute liver injury unless other etiologies are systematically excluded 5

Nitrofurantoin

Nitrofurantoin poses the most severe hepatotoxicity risk among these three antibiotics, capable of causing both acute liver failure and chronic autoimmune-like hepatitis, potentially requiring liver transplantation. 6, 7

• Nitrofurantoin can cause acute cholestatic reactions, acute hepatocellular injury, AND chronic hepatitis mimicking autoimmune hepatitis 2, 3
• The temporal pattern is highly variable—liver injury can occur after just a few weeks OR after years of chronic prophylactic use 6
• A documented case resulted in endstage liver disease requiring orthotopic liver transplantation after only one month of therapy 7
• Patients with jaundice from antibiotic-induced liver injury have approximately 10% risk of death or need for liver transplantation 6
• The mechanism may be immunoallergic or metabolic in origin 7

Most dangerous characteristic: Unlike most drug-induced liver injuries that resolve with discontinuation, nitrofurantoin can cause progressive chronic liver disease even after stopping the medication 6, 7

Comparative Risk Assessment

Among these three antibiotics, nitrofurantoin carries the highest risk for severe, potentially irreversible liver injury, followed by clarithromycin (which has FDA contraindications for hepatic dysfunction), with ceftriaxone having the lowest but still documented risk. 6, 2

• In major DILI studies, antibiotics are consistently the most common drug class implicated 6
• The clinical phenotype varies: clarithromycin typically causes cholestatic injury, ceftriaxone causes hepatocellular injury, and nitrofurantoin can cause either pattern plus chronic hepatitis 5, 2, 3
• Immediate discontinuation is mandatory when hepatotoxicity is suspected, as continued exposure significantly worsens outcomes 6, 7

Monitoring Recommendations

• Baseline liver function tests should be obtained before initiating any of these antibiotics, particularly for prolonged courses 8
• Monitor for symptoms of liver dysfunction including unusual fatigue, anorexia, nausea/vomiting, dark urine, and jaundice 9
• If ALT rises ≥3× ULN with total bilirubin ≥2× baseline, immediately discontinue the antibiotic and repeat testing within 2-5 days 8
• For nitrofurantoin specifically, any signs of jaundice warrant immediate cessation given the risk of progression to liver failure 7