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Antimicrobial Agents and Chemotherapy, February 2008, p. 409-417, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01070-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vitro Interactions between Tacrolimus and Azoles against Candida albicans Determined by Different Methods

Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, People's Republic of China,¹ School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong Province, People's Republic of China,² The General Surgical Central Laboratory of Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, People's Republic of China³

Received 13 August 2007/ Returned for modification 14 September 2007/ Accepted 16 November 2007

Combination therapy could be of use for the treatment of fungal infections, especially those caused by drug-resistant fungi. However, the methods and approaches used for data generation and result interpretation need further optimizing. The fractional inhibitory concentration index (FICI) is the most commonly used method, but it has several drawbacks in characterizing antifungal drug interaction. Alternatively, some new methods can be used such as the E model (difference between the predicted and measured fungal growth percentages) and the response surface approach, which uses the concentration-effect relationship over the whole concentration range instead of just the MIC. In the present study, in vitro interactions between tacrolimus (FK506) and three azoles—fluconazole (FLC), itraconazole (ITR), and voriconazole (VRC)-against Candida albicans were evaluated by the checkerboard microdilution method and time-killing test. The intensity of the interactions was determined by visual reading and the spectrophotometric method in a checkerboard assay, and the nature of the interactions was assessed by nonparametric models of FICI and E. Colony counting and colorimetric viable detection methods (2,3-bis {2-methoxy-4-nitro-5-[(sulfenylamino) carbonyl]-2H-tetrazolium hydroxide} [XTT] reduction test) were used for evaluating the combination antifungal effects over time. Synergistic and indifferent effects were found for the combination of FK506 and azoles against azole-sensitive strains, while strong synergy was found against azole-resistant strains analyzed by FICI. The E model gave more consistent results with FICI. The positive interactions were also confirmed by the time-killing test. Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and azoles to augment activity against resistant C. albicans.

Published ahead of print on 3 December 2007.