In Vitro Interactions between Amphotericin B, Itraconazole, and Flucytosine against 21 Clinical Aspergillus Isolates Determined by Two Drug Interaction Models

Abstract

Combination therapy of flucytosine (5FC) with other antifungal agents could be of use for the treatment of invasive aspergillosis. However, interpretation of the results of in vitro interactions is problematic. The fractional inhibitory concentration (FIC) index is the most commonly used method, but it has several major drawbacks in characterizing antifungal drug interaction. Alternatively, a response surface approach using the concentration-effect relationship over the whole concentration range instead of just the MIC can be used. We determined the in vitro interactions between amphotericin B (AMB), itraconazole, and 5FC against 21 Aspergillus isolates with a broth microdilution checkerboard method that employs the dye MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. FIC indices based on three different MIC endpoints (MIC-0, MIC-1, and MIC-2) and the interaction coefficient alpha were determined, the latter by estimation from the response surface approach described by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995). The value obtained for the FIC index was found to be dependent on the MIC endpoint used and could be either synergistic, indifferent, or antagonistic. The response surface approach gave more consistent results. Of the three combinations tested, the AMB-5FC combination was the most potent in vitro against Aspergillus spp. We conclude that the use of the response surface approach for the interpretation of in vitro interaction studies of antifungals may be helpful in order to predict the nature and intensity of the drug interaction. However, the correlation of these results with clinical outcome remains difficult and needs to be further investigated.

The Strength of Synergistic Interaction between Posaconazole and Caspofungin Depends on the Underlying Azole Resistance Mechanism of Aspergillus fumigatus

“…To capture both synergistic and antagonistic interactions, the FIC min and FIC max were calculated as the minimum and maximum FICi for each isolate and replicate. Synergy and antagonism were concluded when the log 2 FICi values of the three independent replicates were statistically significantly (P Ͻ 0.05) lower than 1 and higher than 1.25, respectively, by Student's t test as proposed previously based on in vitro-in vivo correlation studies (30). In any other case, an additive effect was claimed.…”

Putative Role of β-1,3 Glucans in Candida albicans Biofilm Resistance

“…Four replicates were performed for each drug and each drug combination. The impact of the compounds in combination was assessed using the fractional inhibitory concentration (FIC) index {FIC index ϭ [(ED 50 (5,52). For a planktonic control, cells were grown in RPMI-MOPS at 37°C to log phase.…”

Reduced Biocide Susceptibility in Candida albicans Biofilms

“…Mature biofilms (24 h) were incubated in the presence of the biocide and antifungal combination for 24 h, and the endpoints were assessed as described above. Fractional inhibitory concentration (FIC) indices were used to estimate the impact of each biocide on the activity of fluconazole, as described previously (30,44).…”