title: Fluconazole plus cyclosporine: a fungicidal combination effective against experimental endocarditis due to Candida albicans.
abstract: Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicans experimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and >10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal 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 decreased fungal densities compared to all groups, including amphotericin B (P < 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P < 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Marchetti
authors.forename: J M
authors.initials: JM
authors.lastname: Entenza
authors.forename: D
authors.initials: D
authors.lastname: Sanglard
authors.forename: J
authors.initials: J
authors.lastname: Bille
authors.forename: M P
authors.initials: MP
authors.lastname: Glauser
authors.forename: P
authors.initials: P
authors.lastname: Moreillon
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D004696:Endocarditis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D016572:Cyclosporine; D015725:Fluconazole