Background: Combination therapy is increasingly considered as an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether Isavuconazole (ISA), an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis have not been studied.
Methods: We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of ISA with amphotericin B (AMB) or micafungin (MFG), a representative echinocandin, against strains of Candida albicans (CA), Candida glabrata (CG), Candida tropicalis (CT), Candida parapsilosis (CP), and Candida krusei (CK).
Results: The combination of ISA and MFG resulted in synergistic or indifferent interactions against CA, CG, CT, and CP. The degree of synergy ranged from 1.4% to 37.4% (mean ΔΕ value) with the highest occurring against CA. CK was the only species showing antagonistic interaction (%mean ΔΕ value 45.3 to 62% depending on the strain). The combined interaction between ISA and AMB was concentrationdependent. Synergistic interaction was observed between ISA and low AMB concentrations (mean %ΔΕ value 42.6% and 11.2% against CA and CG, respectively) against CA and CG. The degree of synergy ranged from 0.8% to 53.4% (%mean ΔΕ value) with the highest noted against CT. Antagonism, ranging from -7.3 to -25.2%, was observed for ISA and AmB against CG, CT, CA, and CK. Time-kill assays of ISA and MFG combinations demonstrated concentration-dependent synergy against CA and CP. The combination of ISA and AMB also demonstrated concentration-dependent synergy against CP, while being antagonistic against CK.
Conclusions: ISA in combination with MFG or AMB demonstrated concentration-dependent and species-dependent synergy against CA and CP.
- ICAAC 54th (2014)