What is the most appropriate oral voriconazole (Voriconazole) dosing regimen for a patient with a complicated intra-abdominal infection caused by echinocandin- and fluconazole-resistant Candida glabrata, transitioning from intravenous (IV) to oral therapy?

Voriconazole Dosing for Transition from IV to Oral Therapy in Echinocandin-Resistant C. glabrata Infection

Initiate voriconazole 200 mg PO every 12 hours, with a voriconazole trough concentration measured 2-5 days after switching formulations.

Rationale for Oral Voriconazole Dosing

For patients with echinocandin- and fluconazole-resistant Candida glabrata infections transitioning from IV to oral therapy, the appropriate dosing strategy must consider both efficacy and monitoring requirements:

1. Dose Selection:

   • The IDSA guidelines recommend voriconazole 200-300 mg (3-4 mg/kg) twice daily for C. glabrata infections with voriconazole-susceptible isolates 1
   • The standard oral maintenance dose that corresponds to the IV dose of 4 mg/kg every 12 hours is 200 mg every 12 hours 2

2. Bioavailability Considerations:

   • While voriconazole has high theoretical bioavailability (>90%), clinical studies show significant variability in actual bioavailability 3
   • When switching from IV to oral administration with the same dose, median serum concentration decreases to approximately 82.7% of IV levels, with wide inter-individual variability (range 27.2-333.3%) 3

Therapeutic Drug Monitoring Requirements

Therapeutic drug monitoring (TDM) is essential when transitioning from IV to oral voriconazole for several reasons:

• Pharmacokinetic Variability: Voriconazole exhibits nonlinear pharmacokinetics due to capacity-limited elimination 4
• Genetic Polymorphisms: CYP2C19 polymorphisms can significantly affect voriconazole metabolism 1
• Route of Administration Change: Switching from IV to oral administration results in significant changes in serum concentrations 3

The timing of TDM should be 2-5 days after switching formulations to ensure adequate drug exposure, as steady state is typically reached within 5 days of oral administration 4.

Management Algorithm for Transitioning to Oral Therapy

1. Initial Oral Dosing:

   • Discontinue IV voriconazole (4 mg/kg every 12 hours)
   • Initiate oral voriconazole at 200 mg every 12 hours

2. Monitoring:

   • Measure voriconazole trough concentration 2-5 days after switching to oral formulation
   • Target trough concentration: 1-5.5 mg/L 2

3. Dose Adjustment Based on TDM:

   • If trough concentration is below target: Increase dose to 300 mg every 12 hours
   • If trough concentration is within target: Continue current dose
   • If trough concentration is above target: Reduce dose or frequency

Important Considerations

• Drug Interactions: Voriconazole is both a substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4, requiring careful review of concomitant medications 4
• Absorption: Taking oral voriconazole with food may improve absorption 1
• Duration of Therapy: For complicated intra-abdominal Candida infections, treatment should continue for at least 14 days after resolution of symptoms and negative cultures 1

Potential Pitfalls

• Inadequate Monitoring: Failure to perform TDM after switching to oral therapy may result in subtherapeutic levels and treatment failure
• Ignoring Drug Interactions: Concomitant medications metabolized by CYP enzymes may significantly affect voriconazole levels
• Assuming Equivalent Bioavailability: Despite theoretical high bioavailability, actual serum concentrations after oral administration are often lower and more variable than with IV administration 3

This approach ensures optimal treatment of this resistant Candida glabrata infection while managing the transition from inpatient to outpatient care appropriately.