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Antimicrobial Agents and Chemotherapy, September 2000, p. 2373-2381, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans

Oscar Marchetti,1 Philippe Moreillon,1 Michel P. Glauser,1 Jacques Bille,2 and Dominique Sanglard2,*

Division of Infectious Diseases1 and Institute of Microbiology,2 University Hospital, Lausanne, Switzerland

Received 18 January 2000/Returned for modification 16 March 2000/Accepted 24 May 2000

Several types of drugs currently used in clinical practice were screened in vitro for their potentiation of the antifungal effect of the fungistatic agent fluconazole (FLC) on Candida albicans. These drugs included inhibitors of multidrug efflux transporters, antimicrobial agents, antifungal agents, and membrane-active compounds with no antimicrobial activity, such as antiarrhythmic agents, proton pump inhibitors, and platelet aggregation inhibitors. Among the drugs tested in an agar disk diffusion assay, cyclosporine (Cy), which had no intrinsic antifungal activity, showed a potent antifungal effect in combination with FLC. In a checkerboard microtiter plate format, however, it was observed that the MIC of FLC, as classically defined by the NCCLS recommendations, was unchanged when FLC and Cy were combined. Nevertheless, if a different reading endpoint corresponding to the minimal fungicidal concentration needed to decrease viable counts by at least 3 logs in comparison to the growth control was chosen, the combination was synergistic (fractional inhibitory concentration index of <1). This endpoint fitted to the definition of MIC-0 (optically clear wells) and reflected the absence of the trailing effect, which is the result of a residual growth at FLC concentrations greater than the MIC. The MIC-0 values of FLC and Cy tested alone in C. albicans were >32 and >10 µg/ml, respectively, and decreased to 0.5 and 0.625 µg/ml when the two drugs were combined. The combination of 0.625 µg of Cy per ml with supra-MICs of FLC resulted in a potent antifungal effect in time-kill curve experiments. This effect was fungicidal or fungistatic, depending on the C. albicans strain used. Since the Cy concentration effective in vitro is achievable in vivo, the combination of this agent with FLC represents an attractive perspective for the development of new management strategies for candidiasis.

* Corresponding author. Mailing address: Institut de Microbiologie, Rue du Bugnon 44, CH-1011 Lausanne, Switzerland. Phone: 41-21-3144083. Fax: 41-21-3144060. E-mail: Dominique.Sanglard{at}chuv.hospvd.ch.

Antimicrobial Agents and Chemotherapy, September 2000, p. 2373-2381, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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