Fluconazole plus cyclosporine: A fungicidal combination effective against experimental endocarditis due to Candida albicans

Recent observations demonstrated that fluconazole plus cyclosporine (Cy) sy nergistically killed Candida albicans in vitro. This combination was tested in rats with C, albicans experimental endocarditis, The MICs of fluconazol e and Cy for the test organism were 0.25 and >10 mg/liter, respectively, Ra ts were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy, Although used at high doses, the peak concentrations of flu conazole in the serum of rats (up to 4.5 mg/liter) were compatible with hig h-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic lev els. Untreated rats demonstrated massive pseudohyphal growth in both the ve getations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this diss ociation. In the vegetations, only the fungicidal fluconazole-Cy combinatio n significantly decreased fungal densities compared to all groups, includin g amphotericin B (P < 0.0001), In the kidneys, all regimens except the Cy r egimen 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, t his observation opens new perspectives for fungicidal combinations between azoles and other drugs.