Enhanced efficacy of synergistic combinations of antimicrobial peptides with caspofungin versus Candida albicans in insect and murine models of systemic infection.

Purpose: The objective of this present study was to determine if combinations of antimicrobial peptides (AMPs) with caspofungin display enhanced antifungal activity versus Candida albicans in vitro and in vivo.
Methods: Three conventional AMPs that satisfied criteria favouring their potential development as novel antifungals were selected for investigation. Colistin sulphate was also included as a lipopeptide antibiotic used in the clinic. Minimal inhibitory concentrations were determined for each antifungal agent and checkerboard assays were used to determine fractional inhibitory concentration indices for dual combinations of AMPs or colistin with caspofungin. Viability assays were performed for the same combinations to investigate fungicidal interactions. Synergistic antifungal combinations were then tested for efficacy in vivo and compared to monotherapies in wax moth larva and murine models of systemic C. albicans infection.
Results: In combination with caspofungin, each of the AMPs [hMUC7-12, DsS3(1-16), hLF(1-11)] and colistin were synergistic and candidacidal in vitro. Treatment of infected wax moth larvae with combinations of caspofungin with hMUC7-12, DsS3(1-16) or colistin resulted in significant enhancements in survival compared to treatment with monotherapies. Notably, treatment of C. albicans-infected mice with a combination of caspofungin and DsS3(1-16) resulted in enhancement of survival compared to groups treated with just the individual agents.
Conclusions: This study demonstrates that combination therapies containing caspofungin and AMPs or colistin merit further development as potential novel treatments for C. albicans infections.