What antifungal medications are suitable for patients with abnormal Liver Function Tests (LFTs)?

From the Guidelines

Echinocandins are the safest first-line option for antifungal therapy in patients with deranged liver function tests (LFTs). Specifically, caspofungin (70mg loading dose followed by 50mg daily), micafungin (100mg daily), or anidulafungin (200mg loading dose followed by 100mg daily) can be used without dose adjustment in mild to moderate liver dysfunction, as recommended by the Infectious Diseases Society of America 1. For severe hepatic impairment, consider reducing caspofungin to 35mg daily after the loading dose, while micafungin and anidulafungin typically don't require dose adjustments. Some key points to consider when managing antifungal therapy in patients with deranged LFTs include:

• Avoiding azole antifungals like voriconazole, itraconazole, and posaconazole when possible, as they undergo extensive hepatic metabolism and may further worsen liver function 1
• If an azole is absolutely necessary, fluconazole is preferred as it has less hepatotoxicity, though dose reduction (by 50%) is recommended in severe liver dysfunction
• Amphotericin B formulations (liposomal amphotericin B at 3-5mg/kg/day) can be considered as they don't require hepatic metabolism, but they carry risks of nephrotoxicity and electrolyte disturbances
• Regular monitoring of LFTs (at least twice weekly) is essential during antifungal therapy, and treatment should be reassessed if there's further deterioration in liver function The safety profile of echinocandins in liver dysfunction relates to their minimal hepatic metabolism and low drug interaction potential compared to azoles, making them a preferred choice for patients with deranged LFTs 1.

From the FDA Drug Label

The overall incidence of transaminase increases >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17. 7% (268/1514) in adult subjects treated with voriconazole tablets for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy. Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death Most of these patients had other serious underlying conditions. Liver function tests should be evaluated at the start of and during the course of voriconazole tablets therapy. Patients who develop abnormal liver function tests during voriconazole tablets therapy should be monitored for the development of more severe hepatic injury Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole tablets must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole tablets

Voriconazole can cause liver damage, and liver function tests should be monitored during treatment. The incidence of liver function test abnormalities is higher in patients with higher plasma concentrations and/or doses. Most cases of abnormal liver function tests resolve with dose adjustment or discontinuation of therapy. However, voriconazole has been associated with rare cases of serious hepatic toxicity, including hepatitis and hepatic failure.

• Key points:
  • Monitor liver function tests during treatment with voriconazole
  • Discontinue voriconazole if clinical signs and symptoms of liver disease develop
  • Higher plasma concentrations and/or doses may increase the risk of liver function test abnormalities
  • Most cases of abnormal liver function tests resolve with dose adjustment or discontinuation of therapy
  • Voriconazole has been associated with rare cases of serious hepatic toxicity 2

From the Research

Antifungal Agents and Liver Function

• Antifungal agents can cause hepatic toxicity, ranging from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure 3.
• The risk of clinical acute liver injury among users of oral antifungals in the general population is rare, but the prognosis is often good with swift discontinuation of the drug and proper treatment 4.

Management of Antifungal-Induced Liver Dysfunction

• Liver function evaluation before treatment and periodic monitoring every three to six weeks after commencement of treatment is suggested to minimize the risk of antifungal-induced liver dysfunction 4.
• Anidulafungin, an echinocandin antifungal, has been shown to be safe and effective in the treatment of invasive fungal infections in patients with moderate to severe abnormal liver function tests or multiorgan failure 5.
• Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead 6.

Switching Antifungals in Cases of Liver Dysfunction

• Switching to an alternative antifungal, such as isavuconazole, may lead to a reduction in LFTs in patients who develop elevated LFTs while on posaconazole therapy 7.
• However, the development of LFT abnormalities while on posaconazole therapy may not warrant a switch to an alternative antifungal, as hepatotoxicity is often multifactorial and generally resolves with time in the majority of patients 7.