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Antimicrobial Agents and Chemotherapy, March 2004, p. 985-991, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.985-991.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Amphotericin B and Fluconazole, a Potent Combination Therapy for Cryptococcal Meningitis

Robert A. Larsen,1* Madeline Bauer,1 Ann M. Thomas,2 and J. Richard Graybill3

Department of Medicine (Infectious Diseases), University of Southern California, Los Angeles, California,1 Department of Statistics, University of Northern Colorado, Greeley, Colorado,2 Department of Medicine/Division of Infectious Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas3

Received 25 March 2003/ Returned for modification 7 July 2003/ Accepted 10 November 2003

We evaluated the antifungal activities of amphotericin B, fluconazole, and flucytosine, alone and in combination, in a murine model of cryptococcal meningitis. The objectives were to determine the greatest antifungal effects achievable with these drugs alone or in combination. Meningitis was established in male BALB/c mice weighing 23 to 25 g by intracerebral injection of Cryptococcus neoformans. Treatment was started on day 2. Amphotericin B was tested at 0.3 to 1.3 mg/kg of body weight/day by slow intravenous injection. Fluconazole at 10 to 40 mg/kg/day and flucytosine at 20 to 105 mg/kg/day were administered in the sole source of drinking water. The mice were killed at 16 days, and the numbers of fungal colonies in the brain were quantified. The association between the response and the dose combination was evaluated by local nonparametric response surface methods; 99% confidence intervals were used to evaluate the antifungal effects. Ninety-five percent of the mice treated with amphotericin B at 0.5 mg/kg survived to the end of the experiment, regardless of the fluconazole or flucytosine dose used. The greatest activity was seen with amphotericin B plus fluconazole with or without flucytosine. However, the addition of flucytosine did not increase the antifungal activity. Given the widespread availability of amphotericin B and fluconazole and the relative safety profile of fluconazole compared to that of flucytosine, the full potential of this two-drug combination deserves further evaluation.

* Corresponding author. Mailing address: Department of Medicine (Infectious Diseases), 2020 Zonal Ave., IRD Room 632, MC 9520, University of Southern California, Los Angeles, CA 90033. Phone: (323) 226-7556. Fax: (323) 226-2775. E-mail: rlarsen{at}usc.edu.

Antimicrobial Agents and Chemotherapy, March 2004, p. 985-991, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.985-991.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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