Is voriconazole (Voriconazole) effective for treating Candida glabrata?

Treatment of Candida glabrata with Voriconazole

Voriconazole should NOT be used as first-line therapy for Candida glabrata infections; echinocandins are the preferred initial treatment, and voriconazole should only be considered as step-down therapy after susceptibility testing confirms the isolate is voriconazole-susceptible. 1, 2

First-Line Treatment Recommendations

• Echinocandins (caspofungin, micafungin, or anidulafungin) are the preferred first-line agents for C. glabrata infections due to increasing fluconazole resistance and unpredictable azole activity in this species 2
• Lipid formulation amphotericin B (3-5 mg/kg daily) serves as an alternative first-line option, though toxicity concerns make it less attractive 2
• Fluconazole is NOT recommended as initial therapy for C. glabrata due to high resistance rates, with recent surveillance showing a dramatic shift from 64% susceptible isolates (1999-2001) to only 19% susceptible (2007) 2, 3

Limited Role of Voriconazole in C. glabrata Treatment

Voriconazole does not provide predictable activity against fluconazole-resistant C. glabrata strains 2

• The primary clinical use of voriconazole for C. glabrata is as step-down oral therapy in patients with documented voriconazole-susceptible isolates who have responded to initial echinocandin treatment 1, 2
• Voriconazole has not been systematically studied in fluconazole-resistant Candida species, and its use is generally discouraged without susceptibility data 1
• In clinical studies, the voriconazole MIC90 for C. glabrata was 4 μg/mL, with 26% of baseline isolates showing resistance (MIC ≥ 4 μg/mL) 4

Critical Requirement: Susceptibility Testing

• Azole susceptibility testing is strongly recommended for all bloodstream and clinically relevant Candida isolates before considering voriconazole therapy 2
• Potential cross-resistance exists within the azole class, with approximately 5.5% of C. glabrata strains presenting high MIC values for all azoles tested 5
• Echinocandin susceptibility testing should also be considered in patients with prior echinocandin exposure 2

Dosing When Voriconazole Is Appropriate

When transitioning to voriconazole for documented voriconazole-susceptible C. glabrata infections 1, 2:

• Oral dosing: Loading dose of 400 mg (6 mg/kg) twice daily for 2 doses, followed by 200-300 mg (3-4 mg/kg) twice daily
• Intravenous dosing: Loading dose of 6 mg/kg every 12 hours for 2 doses, followed by maintenance of 3-4 mg/kg every 12 hours
• Higher maintenance doses (800 mg daily for fluconazole) are often recommended for susceptible C. glabrata, though this principle has not been validated for voriconazole in clinical trials 1

Important Limitations and Caveats

• Voriconazole does NOT accumulate in active form in urine and should never be used for urinary candidiasis 1, 2
• Common polymorphisms in CYP2C19 result in wide variability of serum levels, with poor metabolizers having 4-fold higher exposure than extensive metabolizers 1, 4
• Therapeutic drug monitoring should be performed to optimize efficacy and minimize toxicity 1
• Long-term voriconazole therapy is associated with periostitis, bone pain, visual side effects, photosensitivity, hepatic injury, and CNS effects 1, 2
• Intravenous voriconazole contains cyclodextrin and is not recommended for patients with creatinine clearance <50 mL/minute, though oral formulations do not require renal dose adjustment 1

Treatment Algorithm for C. glabrata Infections

1. Initiate echinocandin therapy immediately (caspofungin, micafungin, or anidulafungin) 2
2. Obtain susceptibility testing for both azoles and echinocandins 2
3. Assess clinical response with daily or every other day blood cultures to establish clearance 2
4. Consider step-down to oral voriconazole (200-300 mg twice daily) only if:
   • Patient is clinically stable and hemodynamically improved 1
   • Blood cultures have cleared 2
   • Isolate is confirmed voriconazole-susceptible 1, 2
   • Infection is NOT in the urinary tract 1, 2
5. Continue therapy for 14 days after documented bloodstream clearance and resolution of symptoms 1

Special Pediatric Considerations

• In children, voriconazole (day 1: 9 mg/kg Q12h, then 8 mg/kg BID) can be used for C. glabrata infections with documented susceptibility (B-I recommendation) 1
• Voriconazole is more potent in vitro against C. glabrata than fluconazole and may be reasonable for these infections in pediatric patients after susceptibility confirmation 1