Propofol lipidic infusion promotes resistance to antifungals by reducing drug input into the fungal cell

BACKGROUND: The administration of non-antifungal drugs during patient hospitalization might be responsible for discrepancies between in vitro and in vivo susceptibility to antifungals. Propofol is often administered to intensive care units as a sedative. The purpose of this study was to evaluate the effect of propofol lipidic infusion upon the growth and susceptibility profile of pathogenic fungi. Candida and Aspergillus were studied regarding the ability to grow and its susceptibility profile to antifungals in the presence of propofol infusion (Fresenius(®)) (1.25, 2.5 and 5 mg.ml(-1)) and its lipidic vehicle. The intensity of fluorescence after staining with FUN1, in the presence and absence of propofol infusion, was determined by flow cytometry. Radioactivity assays were also performed in order to quantify the input of [(3)H]- itraconazole into the fungal cell in the presence of propofol. Assays were repeated after addition of sodium azide, in order to block efflux pumps. RESULTS: Propofol infusion promoted budding of Candida and the germination of Aspergillus, latter forming a lipid layer around the hypha. An increase of minimal fungicidal concentrations regarding both Candida and Aspergillus strains was found for all antifungals when incubated simultaneously with propofol infusion. A decrease of the intensity of fluorescence of Candida cells was systematically observed, as well as a significant reduced intracellular uptake of [(3)H] itraconazole in cells treated with propofol infusion, even after the blockade of efflux pumps. The results obtained when testing with the lipid vehicle were similar. CONCLUSION: Propofol infusion, due to its lipidic vehicle, increased the fungal germination and promoted resistance to antifungals. This effect seems to be related to the reduced access and/or permeabilization to fungal cells by antifungals.