What is the treatment approach for Candida glabrata infections using Voriconazole?

Treatment of Candida glabrata Infections with Voriconazole

For Candida glabrata infections, voriconazole should only be used when susceptibility testing confirms the isolate is voriconazole-susceptible, and it should primarily be considered as step-down oral therapy after initial treatment with an echinocandin. 1

First-line Treatment Approach for C. glabrata Infections

• An echinocandin (caspofungin, micafungin, or anidulafungin) is the preferred first-line therapy for C. glabrata infections due to increasing fluconazole resistance in this species 1
• Lipid formulation of amphotericin B (3-5 mg/kg daily) is an effective but less attractive alternative due to toxicity concerns 1
• Fluconazole is not recommended as initial therapy for C. glabrata infections due to high rates of resistance 1

Role of Voriconazole for C. glabrata Infections

• Voriconazole does not provide predictable activity against fluconazole-resistant C. glabrata strains 1
• For C. glabrata infections, transition to voriconazole (200-300 mg or 3-4 mg/kg twice daily) should only be considered for patients with documented voriconazole-susceptible isolates 1
• Voriconazole can fill an important niche for patients with fluconazole-resistant C. glabrata that are voriconazole-susceptible who are ready for transition from an echinocandin or amphotericin B to oral therapy 1

Susceptibility Testing Requirements

• Testing for azole susceptibility is strongly recommended for all bloodstream and clinically relevant Candida isolates 1
• Testing for echinocandin susceptibility should be considered in patients who have had prior treatment with an echinocandin, particularly with C. glabrata infections 1
• Potential cross-resistance within the azole class has been noted for some strains of C. glabrata (5.5%) that present high MIC values for all tested azoles 2

Dosing Recommendations When Using Voriconazole

• For C. glabrata infections when transitioning to voriconazole: 200-300 mg (3-4 mg/kg) twice daily 1
• Oral voriconazole should be administered at least one hour before or after a meal 3
• For invasive candidiasis, the recommended loading dose is 400 mg (6 mg/kg) twice daily for 2 doses, followed by the maintenance dose 3

Treatment Duration and Monitoring

• Treatment should continue for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer 3
• Follow-up blood cultures should be performed every day or every other day to establish clearance of candidemia 1
• All non-neutropenic patients with candidemia should have a dilated ophthalmological examination within the first week after diagnosis 1

Clinical Evidence for Voriconazole Against C. glabrata

• In vitro studies have shown voriconazole to be active against many C. glabrata isolates with MIC90 of 0.5 μg/ml, though this activity is not consistent against fluconazole-resistant strains 2
• Limited clinical data exists specifically for voriconazole treatment of C. glabrata infections, with most evidence coming from in vitro studies and case reports 4, 5
• Intracellular killing studies show that voriconazole can be effective against C. glabrata within macrophages, but requires higher concentrations (5× MIC) compared to other Candida species 6

Important Considerations and Precautions

• Voriconazole has numerous drug interactions that may limit its usefulness in some patients 7
• Long-term voriconazole therapy is associated with periostitis and bone pain due to fluoride excess from voriconazole metabolism 8
• Common polymorphisms in the gene encoding the primary metabolic enzyme for voriconazole result in wide variability of serum levels, which may affect efficacy 1
• Voriconazole does not accumulate in active form in the urine and thus should not be used for urinary candidiasis 1

Management Algorithm for C. glabrata Infections

1. Start with an echinocandin as first-line therapy 1
2. Obtain susceptibility testing for azoles and echinocandins 1
3. For stable patients who have responded to initial therapy:
   • If isolate is voriconazole-susceptible, consider transition to oral voriconazole 200-300 mg twice daily 1
   • If isolate is fluconazole-susceptible, consider high-dose fluconazole (800 mg daily) 1
4. For patients with suspected or proven azole and echinocandin resistance, use lipid formulation amphotericin B (3-5 mg/kg daily) 1