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Antimicrobial Agents and Chemotherapy, May 1998, p. 1207-1212, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Influence of Test Conditions on Antifungal Time-Kill Curve Results: Proposal for Standardized Methods

Michael E. Klepser,1,* Erika J. Ernst,1 Russell E. Lewis,1 Michael E. Ernst,1 and Michael A. Pfaller2

College of Pharmacy, The University of Iowa,1 and Department of Pathology, The University of Iowa Hospitals and Clinics,2 Iowa City, Iowa 52242

Received 5 January 1998/Returned for modification 4 February 1998/Accepted 9 March 1998

This study was designed to examine the effects of antifungal carryover, agitation, and starting inoculum on the results of time-kill tests conducted with various Candida species. Two isolates each of Candida albicans, Candida tropicalis, and Candida glabrata were utilized. Test antifungal agents included fluconazole, amphotericin B, and LY303366. Time-kill tests were conducted in RPMI 1640 medium buffered with morpholinepropanesulfonic acid (MOPS) to a pH of 7.0 and incubated at 35°C. Prior to testing, the existence of antifungal carryover was evaluated at antifungal concentrations ranging from 1× to 16× MIC by four plating methods: direct plating of 10, 30, and 100 µl of test suspension and filtration of 30 µl of test suspension through a 0.45-µm-pore-size filter. Time-kill curves were performed with each isolate at drug concentrations equal to 2× MIC, using a starting inoculum of approximately 105 CFU/ml, and incubated with or without agitation. Last, inoculum experiments were conducted over three ranges of starting inocula: 5 × 102 to 1 × 104, >1 × 104 to 1 × 106, and >1 × 106 to 1 × 108 CFU/ml. Significant antifungal carryover (>25% reduction in CFU/milliliter from the control value) was observed with amphotericin B and fluconazole; however, carryover was eliminated with filtration. Agitation did not appreciably affect results. The starting inoculum did not significantly affect the activity of fluconazole or amphotericin B; however, the activity of LY303366 may be influenced by the starting inoculum. Before antifungal time-kill curve methods are routinely employed by investigators, methodology should be scrutinized and standardized procedures should be developed.

* Corresponding author. Mailing address: The University of Iowa College of Pharmacy, S412 Pharmacy Building, Iowa City, IA 52242-1112. Phone: (319) 335-8861. Fax: (319) 353-5646. E-mail: michael-klepser{at}uiowa.edu.

Antimicrobial Agents and Chemotherapy, May 1998, p. 1207-1212, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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