Effects of Lipid Formulations of Amphotericin B on Activity of Human Monocytes against Aspergillus fumigatus

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Abstract
The immunomodulatory effects of liposomal amphotericin B (LAMB), amphotericin B lipid complex, and amphotericin B colloidal dispersion (ABCD) on antifungal activity of human monocytes (MNCs), an important component of antifungal host defense, against Aspergillus fumigatus were compared to those of deoxycholate amphotericin B (DAMB). MNCs from healthy volunteers were incubated with 1 or 5 μg/ml DAMB and 5 or 25 μg/ml lipid formulations for 22 h. Drug-pretreated or untreated MNCs were then washed and assayed for the following: (i) activity against A. fumigatus hyphae by XTT assay at MNC:hypha ratios of 10:1 and 20:1; (ii) production of superoxide anion (O 2 − ) from MNCs in response to hyphae by cytochrome c reduction; (iii) production of hydrogen peroxide (H 2 O 2 ) and H 2 O 2 -dependent intracellular intermediates (DIIs), such as OH − and HOCl, from MNCs in response to A. fumigatus culture supernatant by flow cytometric measurement of dihydrorhodamine-1,2,3 oxidation. With the exception of 1 μg/ml DAMB and 5 μg/ml LAMB or ABCD at 10:1, all amphotericin B formulations at both concentrations and MNC:hypha ratios enhanced MNC-induced damage of A. fumigatus hyphae compared to results with untreated cells ( P < 0.01). While MNC O 2 − production upon hyphal challenge, an early event in oxidative burst, was not affected by the drugs, production of H 2 O 2 and DIIs, late events, were significantly increased by all four drugs ( P < 0.01). At clinically relevant concentrations, both conventional amphotericin B and its lipid formulations enhance antihyphal activity of MNCs against A. fumigatus in association with significant augmentation of H 2 O 2 and DIIs but not O 2 − , further demonstrating the immunomodulatory antifungal activities of these agents.