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Antimicrobial Agents and Chemotherapy, March 1998, p. 528-533, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Amphotericin B Colloidal Dispersion Combined with Flucytosine with or without Fluconazole for Treatment of Murine Cryptococcal Meningitis

DeAnn M. Diamond,1 Madeline Bauer,2 Barbra E. Daniel,3 Mary Ann E. Leal,1 Debra Johnson,1 Byron K. Williams,1 Ann M. Thomas,4 James C. Ding,1 Laura Najvar,5 J. Richard Graybill,5 and Robert A. Larsen1,*

Departments of Medicine (Infectious Diseases)1 and Preventive Medicine (Biostatistics),2 University of Southern California, Los Angeles, California; Preclinical Research Department, SEQUUS Pharmaceuticals, Inc., Menlo Park, California3; Department of Statistics, University of Northern Colorado, Greeley, Colorado4; and Division of Infectious Diseases, University of Texas Health Sciences Center, San Antonio, Texas5

Received 24 June 1997/Returned for modification 20 October 1997/Accepted 7 December 1997

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.

* Corresponding author. Mailing address: Department of Medicine (Infectious Diseases), 2020 Zonal Ave., IRD Room 220, University of Southern California, Los Angeles, CA 90033. Phone: (213) 226-7556. Fax: (213) 226-2775.

Antimicrobial Agents and Chemotherapy, March 1998, p. 528-533, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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