Synergistic interaction between antifungal agents against Candida guilliermondii using pharmacodynamics-modelling approach

International audience ; Candida guilliermondii is a yeast species involved in candidemia. It presents high MICs for echinocandins, the first-line treatment and several strains showed tolerance to amphotericin B. In this context, azole antifungal agents are frequently used. However, azole-resistant strains have been described. Combination of antifungal drugs could be interesting to improve efficacy and prevent the emergence of resistance. The aim of this study was to test in vitro combinations of azoles and amphotericin B (AmB) against several clinical isolates of C. guilliermondii. Ten isolates of C. guilliermondii (6 azole-susceptible and 3 azole-resistant) and the ATCC 6260 reference strain were studied. Checkerboards were performed to study combination of fluconazole or voriconazole and AmB following EUCAST recommendations (1). Since MIC interpretative criteria are different for AmB (90% of inhibition) and azoles (50% of inhibition), we developed a model to interpret these checkerboards. Growth inhibition was modelled using Bliss independence modified by the GDPI model (2). The GPDI interaction model was used to evaluate interactions between antifungal drugs (synergy, additivity or antagonism). Parameters were estimated by nonlinear least-squares regression in R. The Emax model successfully described the effect of the three monotherapies against the 10 strains of C. guilliermondii (representative fit for one strain: Figure 1). The GPDI model successfully described the effect of the two combination therapies against the 10 strains (representative fit for one strain: Figure 2). In this GPDI model, we observed statistically significant synergy against the 10 strains for AmB/fluconazole. For AmB/voriconazole we observed synergy against 7 strains and additivity against 3 strains. An AmB concentration of 0.125 mg/L was able to decrease the MIC of fluconazole and voriconazole by an average factor of 8 and 3 respectively. This concentration of AmB dropped the MICs of azole-resistant strains below the breakpoint of ...