In an adult patient without severe hepatic impairment who has a Candida infection, when is voriconazole indicated and what is the recommended dosing regimen (including loading and maintenance doses, hepatic dose adjustments, treatment duration, and monitoring)?

Voriconazole for Candida Infections: Indications and Dosing

Voriconazole is NOT a first-line agent for most Candida infections; echinocandins are preferred for candidemia and invasive candidiasis in both neutropenic and non-neutropenic patients. 1

Primary Indications for Voriconazole in Candida Infections

Voriconazole has limited but specific roles in Candida management:

Step-Down Therapy After Initial Echinocandin

• Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then 200-300 mg (3-4 mg/kg) twice daily can be used as step-down oral therapy in clinically stable patients with documented bloodstream clearance and voriconazole-susceptible isolates 1
• This transition is appropriate only after 5-7 days of initial therapy when repeat blood cultures are negative 1

C. krusei Infections

• Voriconazole is recommended as one of three acceptable options (alongside echinocandins and lipid formulation amphotericin B) for C. krusei, which is inherently fluconazole-resistant 1
• Dosing: 400 mg (6 mg/kg) twice daily for 2 doses, then 200-300 mg (3-4 mg/kg) twice daily 1

Neutropenic Patients Requiring Mold Coverage

• Voriconazole can be used when additional mold coverage is desired in neutropenic patients with candidemia, though this represents a weak recommendation 1
• Dosing: 400 mg (6 mg/kg) twice daily for 2 doses, then 200-300 mg (3-4 mg/kg) twice daily 1

Fluconazole-Resistant Candida (Europe Only)

• Voriconazole is licensed in Europe (but NOT in the United States) for treatment of fluconazole-resistant serious invasive Candida infections 1
• This represents salvage therapy based on open-label data 1

Dosing Regimens

Standard Adult Dosing 2

• Loading dose: 400 mg (6 mg/kg) IV or PO every 12 hours for 2 doses (first 24 hours)
• Maintenance dose: 200 mg (3 mg/kg) IV or PO every 12 hours
• Alternative maintenance: 200-300 mg (3-4 mg/kg) twice daily depending on clinical response 1
• Patients <40 kg: Reduce maintenance to 100-150 mg every 12 hours 2

Hepatic Dose Adjustments 2

• Mild to moderate hepatic impairment (Child-Pugh A and B): Use half the standard maintenance dose (loading dose unchanged)
• Severe hepatic impairment (Child-Pugh C): Not adequately studied; use only if benefit outweighs risk with close monitoring 2
• A recent study suggests even lower doses may be appropriate: 50 mg q12h or 100 mg q24h for Child-Pugh C patients 3

Renal Considerations 2

• Avoid IV formulation in patients with moderate to severe renal impairment (CrCl <50 mL/min) due to accumulation of the solubilizing excipient (SBECD) 2, 4
• Oral formulation is preferred in renal dysfunction 2, 4

Treatment Duration

• Candidemia without metastatic complications: Continue for 2 weeks after documented bloodstream clearance and resolution of symptoms 1
• Neutropenic patients: Continue for 2 weeks after clearance, resolution of symptoms, AND resolution of neutropenia 1

Monitoring Requirements

Therapeutic Drug Monitoring

• Target trough concentration (Cmin): 2-6 mg/L 3
• Monitor closely in hepatic dysfunction to avoid toxicity 3

Visual Function Monitoring

• Monitor visual function if treatment continues beyond 28 days due to risk of optic neuritis and papilledema 2
• Transient visual disturbances occur in approximately 30% of patients 4

Hepatic Function

• Evaluate liver function tests at start of therapy and during treatment 2
• Hepatic enzyme elevations occur in ≤20% of patients 4

Follow-Up Blood Cultures

• Perform every day or every other day to establish clearance timepoint 1

Critical Pitfalls and Contraindications

Drug Interactions

• Voriconazole is metabolized by CYP2C19, CYP3A4, and CYP2C9, creating high potential for drug interactions 4, 5
• Contraindicated with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, St. John's Wort, cisapride, pimozide, quinidine, and sirolimus 2

Species-Specific Cautions

• C. glabrata: Voriconazole should only be used if isolate is confirmed voriconazole-susceptible; echinocandins remain strongly preferred 1
• C. parapsilosis: Echinocandins have decreased in vitro activity; if voriconazole is used, ensure susceptibility testing confirms activity 1
• C. tropicalis: Consider alternative agents or combination therapy if MIC ≥2 mg/L 3

Pregnancy

• Voriconazole can cause fetal harm and is contraindicated in pregnancy 2
• Amphotericin B formulations are preferred in pregnant patients 6

Common Adverse Effects

• Visual abnormalities (30%), skin reactions (20%), hepatic enzyme elevations (≤20%) 4
• Photosensitivity: Avoid sunlight exposure 2
• Risk of fluorosis and periostitis with long-term therapy 2

Why Voriconazole Is NOT First-Line

Echinocandins (caspofungin, micafungin, anidulafungin) are strongly recommended as initial therapy for candidemia and invasive candidiasis in both neutropenic and non-neutropenic patients based on superior efficacy, safety profile, and strong evidence 1. Voriconazole offers no advantage over fluconazole as initial therapy for most Candida species and has more drug interactions and monitoring requirements 1.