title: A combination approach to treating fungal infections.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596, USA.
authors.forename: Sanjib K
authors.initials: SK
authors.lastname: Shrestha
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596, USA.
authors.forename: Marina Y
authors.initials: MY
authors.lastname: Fosso
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D013045:Species Specificity; D014031:Tobramycin / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D015725:Fluconazole; D065819:Voriconazole; D014031:Tobramycin