Influence of human serum on antifungal pharmacodynamics with Candida albicans

Antifungal susceptibilities (NCCLS, approved standard M27-A, 1997) were det ermined for the reference strain ATCC 90028 and 21 clinical isolates of Can dida albicans,vith varying levels of fluconazole susceptibility using RPMI 1640 (RPMI) and 80% fresh human serum-20% RPMI (serum). Sixty-four percent (14 of 22) of the isolates tested demonstrated significant decreases (great er than or equal to4-fold) in fluconazole MICs in the presence of serum, an d the remaining eight isolates exhibited no change. Itraconazole and ketoco nazole, two highly protein-bound antifungal agents, had MICs in serum that were increased or unchanged for 46% (10 of 22) and 41% (9 of 22) of the iso lates, respectively. All 10 isolates tested against an investigational anti fungal agent, LY303366, demonstrated significant increases in the MIC requi red in serum, while differences in amphotericin B MICs in the two media wer e not observed. Four of 10 isolates tested demonstrated fourfold higher flu cytosine MICs in serum than in RPMI. Postantifungal effects (PAFEs) and 24- h kill curves were determined by standard methods for selected isolates. At the MIG, fluconazole, itraconazole, ketoconazole, flucytosine, and LY30336 6 kill curves and PAFEs in RPMI were similar to those in serum. Isolates of fluconazole-resistant C. albicans required lower MICs in serum than in RPM I, without relative increases in fungal killing or PAFEs. Isolates tested a gainst amphotericin B demonstrated significantly reduced killing and shorte r PAFEs in serum than in RPMI without observable changes in MIG. In conclus ion, antifungal pharmacodynamics in RPMI did not consistently predict antif ungal activity in serum for azoles and amphotericin IZ. Generally speaking, antifungal agents with high protein binding exhibited some form of reduced activity (MIC, killing, or PAFE) in the presence of serum compared to thos e with low protein binding.