Comparative pharmacodynamic interaction analysis of triple combinations of caspofungin and voriconazole or ravuconazole with subinhibitory concentrations of amphotericin B against Aspergillus spp

Abstract

Triple combination therapy with an antifungal triazole, echinocandin and amphotericin B (AmB) is used in some centres to treat refractory aspergillosis. The objective of this study was to investigate the effect of subinhibitory concentrations of AmB on the double combinations of caspofungin (CAS) + voriconazole (VOR) or ravuconazole (RAV) against Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. Isolates were studied in triplicate against CAS/VOR and CAS/RAV combinations by chequerboard broth microdilution. AmB was added to each double combination at concentrations of 0, 0.1 and 0.2 microg ml(-1). The fractional inhibitory concentration (FIC) index was calculated for the double and triple combinations. Comparative analysis was performed by repeated measures analysis followed by Dunnett's post-test. The double combinations of CAS/RAV and CAS/VOR were synergistic or additive in most conditions. Addition of AmB to the double combinations resulted in increased FIC indices for A. fumigatus and A. flavus. By contrast, AmB increased the synergism of the double combinations decreasing FIC indices for A. terreus (P < 0.05). RAV and VOR displayed similar synergistic activity with CAS. The addition of sub-inhibitory amphotericin B concentrations reduced but did not eliminate the synergistic interaction between the echinocandin and triazole against A. fumigatus and A. flavus, while it increased the synergy against A. terreus.

Figure 1

Comparative pharmacodynamic analysis of the effect of different triazoles in the triple combinations of VOR + CAS + AmB and RAV + CAS + AmB. Studies are performed at near MIC concentrations using the fractional inhibitory concentration (FIC) index analysis. Box-plots depict differences between FIC indices at 0.1 and 0.2 μg ml⁻¹ of AMB with the FIC indices at 0 μg ml⁻¹ of AMB for VOR + CAS and RAV + CAS combinations. P-values were analysed by anova followed by Dunnett’s post-test for repeated measures.