Exposure times and serum concentrations in humans after treatment with multiple doses of fluconazole have been studied to measure: (a) the postantifungal effect (PAFE) on Candida albicans, at two concentrations of the drug in the presence or absence of 10% human serum; (b) the activity of low concentrations of the drug on yeasts previously exposed to fluconazole with or without 10% human serum; and (c) the effect of fluconazole pretreatment on the fungicidal activity of leucocytes and serum against C. albicans. Fluconazole showed no PAFE against C. albicans between -0.1 and -0.7 h, but when the assays were performed in the presence of serum, concentration dependent PAFEs were obtained (1.1 h-3.6 h). Pretreated yeasts were more susceptible than untreated yeasts to low concentrations of the drug. The decrease in growth was dependent on the concentration used in pretreatment. Growth delay was also more marked when the yeast cells were tested in the presence of serum. Pretreatment of the growing C. albicans cells with fluconazole increased their vulnerability to killing by leucocytes mainly in the first hour (P < 0.05). These results could partially explain why fluconazole has more activity in vivo than in vitro.

This study evaluates the influence of both fresh and heated human serum on the postantifungal effect (PAFE) induced by different concentrations of amphotericin B (AmB), 5-fluorocytosine (5-Fc), Ketoconazole (Kz) and fluconazole (Flu) on two strains of Candida albicans. The concentrations were selected in harmony with the pharmacokinetic properties and toxicity of the drugs. Without serum there was no delay in the growth of yeast cultures pretreated with Kz or Flu, leading to negative PAFEs, however with AmB and 5-Fc the PAFEs were positive. When assays were made in the presence of 10% fresh human serum, the duration of the PAFEs increased with all drugs tested, and those induced by azolic agents became positive. In the presence of 10% human serum heated at 56°C for 30 min, the PAFEs of the antifungal agents were similar to those obtained in the absence of serum. Our results suggest that fresh serum positively influenced PAFE which may be an important factor in determining the dosing regimen for infection by yeasts.

The objective of the study was to assess (a) the postantifungal effect (PAFE) of amphotericin B (AmB) and fluconazole (Flu) on two Candida albicans strains, and (b) the effect of low concentrations of AmB or Flu on yeasts previously exposed to AmB or Flu, respectively, in the presence or absence of 10% human serum. In the absence of serum, AmB exerted a positive effect (at 0.5-5.0 h) depending on the concentration and the strain used. Flu, however, produced negative effects (at -1.2 to -0.1 h). When the experiment was conducted in the presence of serum, the duration of all PAFEs increased significantly, especially those induced by Flu that became positive. Pretreated yeasts were more susceptible than untreated controls to the antifungal activity of low concentrations of the drugs. Growth delay was more pronounced with Flu (up to 5.2 h), whereas the greatest decrease in log10 at 12 h was slightly more pronounced for AmB. A knowledge of PAFEs and the effects of low drug concentrations on pretreated yeasts and the effects of serum on these is important in order to gain more insight into the in vivo activity of the study drugs.

The aim of this work was to measure the susceptibility of Candida albicans pretreated for 2 or 6 h with fluconazole (Flu), ketoconazole (Ktz), amphotericin B (AmB) and 5-fluorocyto-sine (5-Fc) to the fungicidal action of human polymorphic leukocytes. The influence of pretreatment was measured by comparing the delay (in hours) and reduction (logio) in growth of pretreated cultures in the presence of leukocytes and serum with that of non-pretreated control cultures. Six-hour pretreat-ments with Flu, Ktz, AmB and 5-Fc led to growth delays of 1, 3, 3 and 3 h, respectively. No significant differences were found when pretreatment lasted only 2 h. With respect to a reduction in growth, this was larger when the preincubation was 6 h, mainly for 5-Fc and AmB. 5-Fc was seen to be the most effective, followed by Ktz, AmB and finally Flu. It may be concluded that antifungal pretreatment renders this yeast more susceptible to the action of leukocytes. The degree of susceptibility achieved is dependent on the antifungal agent employed.

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