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Antimicrobial Agents and Chemotherapy, October 2000, p. 2664-2671, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vivo Activity of Amphotericin B Lipid Complex in Immunocompromised Mice against Fluconazole-Resistant or Fluconazole-Susceptible Candida tropicalis

P. A. Warn,1 J. Morrissey,1 C. B. Moore,2 and D. W. Denning1,3,*

Department of Medicine, Section of Infectious Diseases, Hope Hospital, University of Manchester,1 and Department of Microbiology, Salford Royal Hospital NHS Trust,2 Salford, Manchester M6 8HD and Department of Infectious Diseases & Tropical Medicine, North Manchester General Hospital, Manchester M8 6RB,3 United Kingdom

Received 8 February 2000/Returned for modification 5 April 2000/Accepted 27 June 2000

We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 µg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.

* Corresponding author. Mailing address: Department of Infectious Diseases & Tropical Medicine, North Manchester General Hospital, Delaunays Rd., Manchester M8 6RB, United Kingdom. Phone: 0161 720 2734. Fax: 0161 720 2732. E-mail: ddenning{at}fs1.ho.man.ac.uk.

Antimicrobial Agents and Chemotherapy, October 2000, p. 2664-2671, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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