Abstract
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, C12 and C14, were shown to display antifungal activities. Herein, the antifungal synergy of C12 and C14 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 C12 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, C14 exhibited synergistic growth inhibition of all C. albicans strains, except C. albicans MYA-2876 by ITC. The combinations of FLC-C14 and VOR-C14 showed synergistic antifungal effect against three C. albicans and four C. albicans strains, respectively. Finally, synergism between C12/C14 and POS were confirmed by time-kill and disk diffusion assays. These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency.
Highlights
Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans
These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency
When compared to C12 and C14, FLC, ITC, POS, and VOR displayed higher MIC values against the majority of the yeast strains tested (MIC values ranged from ≥ 25 μ g/mL, 12.5- > 25 μ g/mL, 10- > 20 μ g/mL, and ≥ 10 μ g/mL, respectively), with the exception of the C. albicans American Type Culture Collection (ATCC) 10231 (A) strain where ITC, POS, and VOR had MIC values of 0.78 μ g/mL, 0.62 μ g/mL, and 0.31 μ g/mL, respectively
Summary
Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans. Synergism between C12/C14 and POS were confirmed by time-kill and disk diffusion assays These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency. Echinocandins, allylamines, and polyenes are the four major classes of antifungal agents that are used to treat candidiasis as well as other type of fungal infections in humans Among these four, azoles such as fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR) are considered first line drugs to treat refractory fungal diseases (Fig. 1)[5]. The fungistatic nature and prolonged use of azoles to treat fungal infections, has promoted the selection and emergence of drug resistant fungal strains. We have determined the in vitro cytotoxicity effect of TOB analogues and azoles in combination against mammalian cells
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