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Antimicrobial Agents and Chemotherapy, July 2001, p. 2018-2022, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2018-2022.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Influence of Human Serum on Antifungal Pharmacodynamics with Candida albicans

George G. Zhanel,1,2,3,4,* David G. Saunders,4 Daryl J. Hoban,1,4 and James A. Karlowsky1,2,4

Faculty of Medicine1 and Faculty of Pharmacy,2 Department of Medical Microbiology, University of Manitoba, and Departments of Medicine3 and Clinical Microbiology,4 Health Sciences Centre, Winnipeg, Manitoba, Canada

Received 13 April 2000/Returned for modification 19 August 2000/Accepted 15 March 2001

Antifungal susceptibilities (NCCLS, approved standard M27-A, 1997) were determined for the reference strain ATCC 90028 and 21 clinical isolates of Candida albicans with 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 (>= 4-fold) in fluconazole MICs in the presence of serum, and the remaining eight isolates exhibited no change. Itraconazole and ketoconazole, 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 isolates, respectively. All 10 isolates tested against an investigational antifungal agent, LY303366, demonstrated significant increases in the MIC required in serum, while differences in amphotericin B MICs in the two media were not observed. Four of 10 isolates tested demonstrated fourfold higher flucytosine MICs in serum than in RPMI. Postantifungal effects (PAFEs) and 24-h kill curves were determined by standard methods for selected isolates. At the MIC, fluconazole, itraconazole, ketoconazole, flucytosine, and LY303366 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 RPMI, without relative increases in fungal killing or PAFEs. Isolates tested against amphotericin B demonstrated significantly reduced killing and shorter PAFEs in serum than in RPMI without observable changes in MIC. In conclusion, antifungal pharmacodynamics in RPMI did not consistently predict antifungal activity in serum for azoles and amphotericin B. 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 those with low protein binding.

* Corresponding author. Mailing address: Department of Clinical Microbiology, Health Sciences Centre, MS673---820 Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada. Phone: (204) 787-4902. Fax: (204) 787-4699. E-mail: ggzhanel{at}pcs.mb.ca.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2018-2022, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2018-2022.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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