Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

doi:10.1128/AAC.44.11.2932-2938.2000

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Antimicrobial Agents and Chemotherapy, November 2000, p. 2932-2938, Vol. 44, No. 11
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

O. Marchetti,¹ J. M. Entenza,¹ D. Sanglard,² J. Bille,² M. P. Glauser,¹ and P. Moreillon¹^,^*

Division of Infectious Diseases, Department of Internal Medicine,¹ and Institute of Microbiology,² Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

Received 2 May 2000/Returned for modification 15 June 2000/Accepted 5 August 2000

Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro.This combination was tested in rats with C. albicans experimentalendocarditis. The MICs of fluconazole and Cy for the test organismwere 0.25 and >10 mg/liter, respectively. Rats were treated for5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy.Although used at high doses, the peak concentrations of fluconazolein the serum of rats (up to 4.5 mg/liter) were compatible withhigh-dose fluconazole therapy in humans. On the other hand, Cyconcentrations in serum (up to 4.5 mg/liter) were greater thanrecommended therapeutic levels. Untreated rats demonstrated massivepseudohyphal growth in both the vegetations and the kidneys. However,only the kidneys displayed concomitant polymorphonuclear infiltration.The therapeutic results reflected this dissociation. In the vegetations,only the fungicidal fluconazole-Cy combination significantly decreasedfungal densities compared to all groups, including amphotericinB (P < 0.0001). In the kidneys, all regimens except the Cy regimenwere effective, but fluconazole-Cy remained superior to amphotericinB and fluconazole alone in sterilizing the organs (P < 0.0001).While the mechanism responsible for the fluconazole-Cy interactionis hypothetical, this observation opens new perspectives for fungicidalcombinations between azoles and otherdrugs.

^* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Internal Medicine, Centre HospitalierUniversitaire Vaudois, 1011 Lausanne, Switzerland. Phone: 41-21-314-10-26.Fax: 41-21-314-10-36. E-mail: pmoreill{at}chuv.hospvd.ch.

Antimicrobial Agents and Chemotherapy, November 2000, p. 2932-2938, Vol. 44, No. 11
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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