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Antimicrobial Agents and Chemotherapy, June 1998, p. 1382-1386, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Assessment of Antifungal Activities of Fluconazole and Amphotericin B Administered Alone and in Combination against Candida albicans by Using a Dynamic In Vitro Mycotic Infection Model

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

University of Iowa Colleges of Pharmacy1 and Medicine,2 Iowa City, Iowa

Received 27 January 1998/Returned for modification 25 February 1998/Accepted 17 March 1998

We evaluated the pharmacodynamic activities of fluconazole and amphotericin B given alone and in combination against Candida albicans by using an in vitro model of bloodstream infection that simulates human serum pharmacokinetic parameters for these antifungals. Fluconazole was administered as a bolus into the model to simulate regimens of 200 mg every 24 h (q24h) and 400 mg q24h. Amphotericin B was administered at doses producing the peak concentration (2.4 µg/ml) observed with a regimen of 1 mg/kg of body weight q24h. A combination regimen of fluconazole (400 mg q24h) and amphotericin B (1 mg/kg q24h) administered simultaneously and as a staggered regimen (amphotericin B bolus given 8 h after fluconazole bolus) was also simulated in the model to characterize possible antagonism between these agents. Fluconazole alone and amphotericin B alone demonstrated fungistatic (<99.9% reduction in numbers of CFU per milliliter from the starting inoculum) and fungicidal (>99.9% reduction) activity, respectively. When fluconazole and amphotericin B were administered simultaneously, fungicidal activity similar to that observed with amphotericin B alone was observed. Staggered administration of fluconazole and amphotericin B, however, resulted in a substantial reduction of the fungicidal activity of amphotericin B, producing fungistatic activity similar to that observed with noncombination fluconazole regimens. These results demonstrate the usefulness of this model for comparing the in vitro pharmacodynamic characteristics of different antifungal regimens and support the theory of azole-polyene antagonism. The effects of this antagonism on the in vivo activity and clinical usefulness of combination antifungal therapy, however, remain to be determined.

* Corresponding author. Mailing address: S412 Pharmacy Building, University of Iowa, College of Pharmacy, Iowa City, IA 52242-1112. Phone: (319) 335-9737. Fax: (319) 353-5646. E-mail: michael-klepser{at}uiowa.edu.

Antimicrobial Agents and Chemotherapy, June 1998, p. 1382-1386, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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