Can pharmacokinetic/pharmacodynamic targets be achieved with voriconazole in the treatment of urinary tract infections caused by Candida spp. with reduced susceptibility to fluconazole?

BACKGROUND

Treating Candida spp. urinary tract infections (UTIs) are challenging when isolates have reduced susceptibility to fluconazole. Voriconazole may be a therapeutic alternative despite its low urinary excretion as an unchanged compound.

OBJECTIVES

To quantify voriconazole and its main metabolite, voriconazole N-oxide, in urine and plasma, determine minimum inhibitory concentrations (MICs) of voriconazole and voriconazole N-oxide, and assess the antifungal activity of urine from voriconazole-treated patients.

METHODS

Sixty patients receiving oral voriconazole were prospectively included. Voriconazole and voriconazole N-oxide concentrations in urine (12-h urine volume) and plasma were measured by liquid chromatography-tandem mass spectrometry. MICs were determined by broth microdilution according to EUCAST guidelines. Urinary antifungal activity was assessed using a disk diffusion bioassay, including against N. glabratus. A pharmacokinetic/pharmacodynamic target concentration/MIC >1 in urine was defined.

RESULTS

Median voriconazole urinary concentration was 1.9 mg/L [1.1-3.1], similar to plasma trough concentration (2.2 mg/L) and positively correlated (R2 = 0.82). Voriconazole N-oxide urinary concentrations (median 20.4 mg/L) were substantially higher than plasma trough concentrations (median 2.1 mg/L). Voriconazole MICs ranged from 0.155 to 0.75 mg/L, while voriconazole N-oxide MICs were 32-48 mg/L for reduced susceptibility to fluconazole isolates. Urine with voriconazole concentrations above 3 mg/L was more likely to inhibit N. glabratus. The median urinary voriconazole concentration/MIC ratio of 4.75 supports potential clinical efficacy.

CONCLUSIONS

Voriconazole can achieve therapeutically relevant urinary concentrations for treating UTIs with reduced susceptibility to fluconazole. Therapeutic drug monitoring may facilitate individualized dosing and optimize treatment outcomes.