Pharmacodynamic and immunological interactions of amphotericin B formulations and voriconazole with human neutrophils against mature Scedosporium apiospermum and Fusarium spp. biofilms.

Abstract

Mould infections caused by Scedosporium apiospermum and Fusarium solani species complex (FSSC) biofilms are rising among immunocompromised and immunocompetent patients. Little is known about the immunomodulatory effects of antifungal agents against these moulds. We examined the effects of deoxycholate and liposomal amphotericin B (DAmB, LAmB) and voriconazole on antifungal activities and immune responses of neutrophils (PMNs) against mature biofilms compared with their planktonic counterparts. Antifungal activity of human PMNs exposed to mature biofilms and planktonic cells for 24 h was determined at effector-to-target ratios of 2:1 and 5:1, alone or combined with DAmB, LAmB and voriconazole, assessed as fungal damage by XTT assay. Cytokine production was evaluated by multiplex ELISA, following PMN stimulation with biofilms in the presence/absence of each drug. All drugs showed additive or synergistic effects with PMNs against S. apiospermum at 0.03-32 mg/L. They showed antagonism primarily against FSSC at 0.06-64 mg/L. Increased IL-8 was produced by PMNs exposed to S. apiospermum biofilms plus DAmB or voriconazole compared with PMNs exposed to biofilms alone (P < 0.01). During combined exposure, IL-1β was increased, an effect only counteracted by increased levels of IL-10 caused by DAmB (P < 0.01). LAmB and voriconazole caused similar IL-10 levels with those released by biofilm-exposed PMNs. The synergistic, additive or antagonistic effects of DAmB, LAmB or voriconazole on biofilm-exposed PMNs are organism-specific, with FSSC exhibiting greater resilience than S. apiospermum to antifungals. Biofilms of both moulds caused dampened immune responses. The drug-mediated immunomodulating effect on PMNs, evidenced by IL-1β, enhanced host protective functions.