A combination approach to treating fungal infections

Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans. Their extensive use has led to the emergence of drug resistance, complicating antifungal therapy for yeast infections in critically ill patients. Combination therapy has become popular in clinical practice as a potential strategy to fight resistant fungal isolates. Recently, amphiphilic tobramycin analogues, C(12) and C(14), were shown to display antifungal activities. Herein, the antifungal synergy of C(12) and C(14) with four azoles, fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR), was examined against seven Candida albicans strains. All tested strains were synergistically inhibited by C(12) when combined with azoles, with the exception of C. albicans 64124 and MYA-2876 by FLC and VOR. Likewise, when combined with POS and ITC, C(14) exhibited synergistic growth inhibition of all C. albicans strains, except C. albicans MYA-2876 by ITC. The combinations of FLC-C(14) and VOR-C(14) showed synergistic antifungal effect against three C. albicans and four C. albicans strains, respectively. Finally, synergism between C(12)/C(14) and POS were confirmed by time-kill and disk diffusion assays. These results suggest the possibility of combining C(12) or C(14) with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency.