Head-To-Head Comparison Of Inhibitory And Fungicidal Activities Of Fluconazole, Itraconazole, Voriconazole, Posaconazole, And Isavuconazole Against Clinical Isolates Of Trichosporon Asahii

Abstract

Treatment of disseminated Trichosporon infections still remains difficult. Amphotericin B frequently displays inadequate fungicidal activity and echinocandins have no meaningful antifungal effect against this genus. Triazoles are currently the drugs of choice for the treatment of Trichosporon infections. This study evaluates the inhibitory and fungicidal activities of five triazoles against 90 clinical isolates of Trichosporon asahii. MICs (mu g/ml) were determined according to Clinical and Laboratory Standards Institute microdilution method M27-A3 at 24 and 48 h using two endpoints, MIC-2 and MIC-0 (the lowest concentrations that inhibited similar to 50 and 100% of growth, respectively). Minimum fungicidal concentrations (MFCs; mu g/ml) were determined by seeding 100 mu l of all clear MIC wells (using an inoculum of 104 CFU/ml) onto Sabouraud dextrose agar. Time-kill curves were assayed against four clinical T. asahii isolates and the T. asahii ATCC 201110 strain. The MIC-2 (similar to 50% reduction in turbidity compared to the growth control well)/MIC-0 (complete inhibition of growth)/MFC values that inhibited 90% of isolates at 48 h were, respectively, 8/32/64 mu g/ml for fluconazole, 1/2/8 mu g/ml for itraconazole, 0.12/0.5/2 mu g/ml for voriconazole, 0.5/2/4 mu g/ml for posaconazole, and 0.25/1/4 mu g/ml for isavuconazole. The MIC-0 endpoints yielded more consistent MIC results, which remained mostly unchanged when extending the incubation to 48 h (98 to 100% agreement with 24-h values) and are easier to interpret. Based on the time-kill experiments, none of the drugs reached the fungicidal endpoint (99.9% killing), killing activity being shown but at concentrations not reached in serum. Statistical analysis revealed that killing rates are dose and antifungal dependent. The lowest concentration at which killing activity begins was for voriconazole, and the highest was for fluconazole. These results suggest that azoles display fungistatic activity and lack fungicidal effect against T. asahii. By rank order, the most active triazole is voriconazole, followed by itraconazole similar to posaconazole similar to isavuconazole > fluconazole.