Impact of different antimycotics on cytokine levels in an in vitro aspergillosis model in human whole blood

Abstract

Background: Although fungal infections play a central role in severely ill and immunosuppressed patients, in contrast to antibiotics immunomodulatory effects of antifungals have not been sufficiently investigated. The present study sets out to compare the effect of different antimycotics on immunologic reaction towards mold in vitro. Materials/methods: Aspergillus fumigatus ATCC204305 was used to develop a model of invasive aspergillosis in vitro in whole blood. Since autoclaved hyphal suspension demonstrated the most potent cytokine release, they were used for the further study including blood of 20 male volunteers. Impact on IL-6, IL-8 and TNF-α time concentration profiles by 5 mg/mL conventional and liposomal amphotericin B, 20 mg/mL fluconazole, 5 mg/mL voriconazole, 2 mg/mL posaconazole or saline solution was investigated over 4 h of incubation at 37 °C. Results: Compared to baseline, cytokine levels increased by addition of hyphal suspension over 4 h approximately: 54-fold for IL-6, 1000-fold for IL-8 and 270-fold for TNF-α. While conventional amphotericin B further increased IL-6 and to a smaller extent IL-8 levels, this was not the case for its liposomal formulation. Congruently amphotericin B increased cytokines in blood without fungus substantially. Fluconazole reduced cytokine increase for all three cytokines compared to stimulation with hyphae without antifungal agent. Conclusions: Our data indicate significant differences in the immunomodulatory potency of different antimycotics. While fluconazole had the highest anti-inflammatory potential, conventional amphotericin even increased cytokine release. This preliminary information might have clinical implication, since cytokine dysregulation plays a major role in the pathogenesis and outcome of fungal infections. Clinical studies are warranted to confirm our findings.