Chitosan Enhanced Anti-Candida Activity of Antifungal Drugs

Objectives: Drug-resistant fungal infections have become an important problem worldwide. Therefore, novel alternative and/or adjunctive antifungal agents are greatly needed. Previously, we showed that high molecular-weight water-soluble chitosan (HMWC), a derivative of chitin from crustacean shells, is active against several Candida species. We also found that a genetic defect in membrane ergosterol biosynthesis, the target of azole drugs, resulted in chitosan hypersensitivity. Thus, we hypothesize that combining chitosan with antifungal drugs that target the cell membrane may enhance the antifungal activity.

Methods: The minimum inhibitory concentrations (MIC) of 2 antifungal drugs, fluconazole and amphotericin B, for 5 Candida species (C.albicans, C.krusei, C.parapsilosis, C.tropicalis, and C.dubliniensis) were evaluated by standard drug susceptibility test (E-test^®) in the presence and absence of sublethal concentrations of HMWC. Similar tests were performed for 4 fluconazole-resistant C.albicans strains isolated from HIV-infected patients.

Results: The MIC of fluconazole against most species (except C.krusei), and that of amphotericin B against C.krusei and C.tropicalis, were decreased by 1.5-4 fold in the presence of HMWC. These results suggested that chitosan could enhance the activity of fluconazole and amphotericin B. Moreover, the addition of chitosan could reduce the MIC levels of 4 fluconazole-resistant C.albicans isolates from “resistant” (>256 ug/ml) to “susceptible” (≤ 2 ug/ml).

Conclusions: HMWC could enhance the antifungal activity of fluconazole and amphotericin B against certain Candida species. In addition, it could enable fluconazole to kill drug-resistant C.albicans clinical isolates, suggesting that combination therapy may be beneficial for the treatment of drug-resistant Candida infection.