In Vitro Combination Therapy with Isavuconazole against Candida spp

V. Petraitis, M. McCarthy, J. Meletiadis, A. Katragkou, P.W. Moradi, G.E. Strauss, K.L. Myint, K. Hussain, L.L. Kovanda, M.M. Fouant, E. Roilides, R. Petraitiene, T.J. Walsh


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.

abstract No: 

    • ICAAC 54th (2014)