What is the treatment for invasive candidiasis with Voriconazole?

Voriconazole in Decompensated Chronic Liver Disease (DCLD)

Voriconazole should be avoided or used with extreme caution in patients with decompensated chronic liver disease due to unpredictable pharmacokinetics, accumulation risk, and lack of dose-adjustment data in severe hepatic impairment. 1

Primary Recommendation for Invasive Candidiasis in DCLD

For invasive candidiasis in patients with decompensated liver disease, an echinocandin (caspofungin, micafungin, or anidulafungin) is the preferred first-line therapy, as these agents do not require hepatic dose adjustment and have superior safety profiles in liver dysfunction. 2, 3

• Echinocandins are the drug of choice for moderately severe to severe invasive candidiasis regardless of hepatic function 3, 4
• These agents have predictable pharmacokinetics even in severe liver disease 2
• Liposomal amphotericin B (3-5 mg/kg daily) is an alternative if echinocandins are contraindicated, though toxicity concerns exist 3

Critical Hepatic Considerations for Voriconazole

Voriconazole undergoes 80% hepatic elimination via CYP2C19, CYP3A4, and CYP2C9, making it highly problematic in decompensated liver disease. 1

• Dose reduction is recommended only for mild to moderate hepatic dysfunction (Child-Pugh class A or B), but no dosing recommendations exist for Child-Pugh class C (decompensated cirrhosis) 1
• Voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance, leading to unpredictable drug accumulation in liver failure 5
• Wide intra- and inter-patient variability in voriconazole levels occurs even in patients with normal hepatic function 5

When Voriconazole Might Be Considered (Rare Scenarios)

Voriconazole may only be considered in DCLD patients under these specific circumstances:

• Fluconazole-resistant Candida krusei infections where the isolate is documented as voriconazole-susceptible 2, 3
• Step-down oral therapy after initial echinocandin treatment once clinically stable, blood cultures cleared, and susceptibility confirmed 3, 4
• CNS candidiasis where voriconazole achieves excellent CSF penetration after initial amphotericin B therapy 4

Mandatory Monitoring if Voriconazole is Used

If voriconazole must be used in a patient with liver disease, therapeutic drug monitoring is absolutely essential to achieve target trough levels of 2-5 μg/mL and avoid toxicity. 5

• Target therapeutic range: 0.25-2 mg/L (lower threshold) to 4-6 mg/L (upper threshold) 5
• Genetic polymorphism of CYP2C19 can cause 4-fold greater drug exposure in poor metabolizers (19% of non-Indian Asians) 5
• Monitor for hepatotoxicity with serial liver function tests 2

Species-Specific Considerations

For Candida glabrata in DCLD, voriconazole should NOT be used as first-line therapy due to unpredictable activity against fluconazole-resistant strains. 3

• Echinocandins remain first-line for C. glabrata regardless of hepatic function 3
• Voriconazole transition only acceptable if isolate is documented voriconazole-susceptible (200-300 mg twice daily) 3

For Candida krusei, voriconazole showed 70% response rate in salvage therapy and may be considered after echinocandin stabilization. 2, 6

Critical Pitfalls to Avoid

• Never use voriconazole for urinary candidiasis as it does not accumulate in active form in urine 3, 4
• Avoid the intravenous formulation in renal dysfunction (CrCl <50 mL/min) due to accumulation of the solubilizing excipient, which is particularly problematic in hepatorenal syndrome 1
• Do not use voriconazole empirically without susceptibility testing in DCLD patients 3
• Long-term voriconazole therapy causes periostitis and bone pain from fluoride accumulation 3

Practical Algorithm for DCLD Patients with Invasive Candidiasis

1. Start echinocandin immediately (caspofungin 70 mg loading, then 50 mg daily) 2
2. Remove central venous catheter if present 2
3. Obtain blood cultures daily until clearance documented 3, 4
4. Send susceptibility testing for both azoles and echinocandins 3
5. Consider voriconazole step-down only if: patient clinically stable, blood cultures cleared, isolate voriconazole-susceptible, and therapeutic drug monitoring available 3, 4
6. Continue therapy for 2 weeks after bloodstream clearance and symptom resolution 4

Adverse Event Profile in Context of Liver Disease

Voriconazole carries additional risks in DCLD:

• Visual disturbances occur in ~30% of patients 1
• Hepatotoxicity with elevated liver enzymes in ≤20% 1
• Skin reactions in ~20% 1
• Higher rate of adverse events compared to fluconazole in comparative studies 2