Antibiotic saving effect of combination therapy through synergistic interactions between well-characterized chito-oligosaccharides and commercial antifungals against medically relevant yeasts.

Berit B. Aam,Vincent G. H. Eijsink,Monica Ganan,Silje B. Lorentzen,Morten Sørlie,Peter Gaustad

doi:10.1371/journal.pone.0227098

Berit B. Aam, Vincent G. H. Eijsink + Show 4 more

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https://doi.org/10.1371/journal.pone.0227098

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Abstract

Combination therapies can be a help to overcome resistance to current antifungals in humans. The combined activity of commercial antifungals and soluble and well-defined low molecular weight chitosan with average degrees of polymerization (DPn) of 17–62 (abbreviated C17 –C62) and fraction of acetylation (FA) of 0.15 against medically relevant yeast strains was studied. The minimal inhibitory concentration (MIC) of C32 varied greatly among strains, ranging from > 5000 μg mL-1 (Candida albicans and C. glabrata) to < 4.9 (C. tropicalis). A synergistic effect was observed between C32 and the different antifungals tested for most of the strains. Testing of several CHOS preparations indicated that the highest synergistic effects are obtained for fractions with a DPn in the 30–50 range. Pre-exposure to C32 enhanced the antifungal effect of fluconazole and amphotericin B. A concentration-dependent post-antifungal effect conserved even 24 h after C32 removal was observed. The combination of C32 and commercial antifungals together or as part of a sequential therapy opens new therapeutic perspectives for treating yeast infections in humans.

Highlights

With the increased competence of medical science to extend the lives of immunocompromised hosts, the incidence of systemic fungal infections has raised dramatically
The in vitro antifungal activity of C32, a chito-oligosaccharide mixture with degrees of polymerization (DPn) 32 and fraction of acetylation (FA) 0.15, was analyzed against clinical-relevant yeast strains, and the effect of the CHOS preparation was determined when combined with five commercial antifungals: amphotericin B (Amp), fluconazole (Flu), voriconazole (Vor), flucytosine (Fcs), and miconazole (Mcz) (Table 1)
In the case of Amp, the minimal inhibitory concentration (MIC) ranged from 0.25 μg mL-1

Summary

Introduction

With the increased competence of medical science to extend the lives of immunocompromised hosts, the incidence of systemic fungal infections has raised dramatically. Amphotericin B has been considered the “gold” standard for the treatment of invasive fungal infections, but toxicity limits its usefulness. Less toxic triazole antifungals, such as fluconazole and itraconazole, are considered reasonable substitutes. In spite of amphotericin B or triazole monotherapy treatments, mortality associated with fungal infections remains to be substantial. There is a great interest in using combined therapies in an attempt of improving survival rates and of reducing fungal resistance. For this reason, a great number of studies have investigated the synergistic activity of commercial antifungals (CA) [1,2,3,4]

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