Activity of Voriconazole: post-antifungal effect, effects of low concentrations and of pretreatment on the susceptibility of Candida albicans to leucocytes

Abstract

This study examined: (i) the post-antifungal effect (PAFE) of Voriconazole (UK( 109,496) on Candida albicans, at 2 concentrations (MIC and 4 x MIC) in the presence or absence of 10% human serum: (ii) the activity of low concentrations of the drug (1/4 x MIC) on yeasts that had previously been exposed to Voriconazole (PAFSE) with or without 10% human serum; and (iii) the effect of Voriconazole pretreatment on the fungicidal activity of leucocytes and serum against C. albicans (PALE). Two concentrations (0.25 and 1 mg/l) of Voriconazole induced no PAFE against C. albicans between -4.3 and -1.4 h, but when the assays were performed in the presence of serum, positive and concentration-dependent PAFEs were obtained (0.2-4.1 h). Pretreated yeasts were more susceptible than untreated yeasts to low concentrations (0.0625 mg/l) of Voriconazole, so the drug showed positive PAFSE that was dependent on the concentration used in pretreatment without serum (0.3-1.9 h) or with 10% human serum (0.5-2.5 h). Pretreatment of the growing C. albicans cells with Voriconazole (0.25 mg/l) increased their vulnerability to killing by leucocytes during the last 2 h (p < 0.05), leading to PALE of 2 h. The results suggest that these effects might be used to evaluate the in vivo activity of an antifungal agent. The sum of the durations of these effects (PAFE, PAFSES and PALE) cause a considerable delay in yeast growth in treated cultures compared with control cultures.