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.
Cyclosporin A showed potent synergism when combined with the three azoles, especially against azole-R C. albicans strains, and there was good agreement between various methods used in this study.
Candida albicans is the most common candidal pathogen, causing serious systemic disease in immunocompromised patients. Azoles are widely applied and largely effective; however, they are generally fungistatic and clinically resistant isolates are emerging increasingly. The present study provided in vitro evidence using a chequerboard technique that amiodarone is strongly synergistic with azoles against resistant C. albicans, with mean fractional inhibitory concentration indices of 0.01 and high-percentage synergistic interactions of 1250 %. A time–kill study performed by both colony counting and a colorimetric reduction assay confirmed the synergistic interaction, with a ≥2 log10 decrease in c.f.u. ml−1 compared with the corresponding azoles alone. These results suggest the possibility of supplementing azoles with amiodarone to treat resistant C. albicans infections.
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