title: High Intracellular Concentrations of Posaconazole Do Not Impact on Functional Capacities of Human Polymorphonuclear Neutrophils and Monocyte-Derived Macrophages In Vitro.
abstract: Posaconazole is a commonly used antifungal for the prophylaxis and treatment of invasive fungal infections. We previously demonstrated that the intracellular concentration of posaconazole in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) was greatly increased compared to the plasma concentration. As these professional phagocytes are crucial to combat fungal infections, we set out to investigate if and how, beneficial or deleterious, this high loading of intracellular posaconazole impacts the functional capacities of these cells. Here, we show that high intracellular concentrations of posaconazole do not significantly impact PMN and monocyte-derived macrophage function in vitro In particular, killing capacity and cytoskeletal features of PMN, such as migration, are not affected, indicating that these cells serve as vehicles for posaconazole to the site of infection. Moreover, since posaconazole as such slowed the germination of Aspergillus fumigatus conidia, infected neutrophils released less reactive oxygen species (ROS). Based on these findings, we propose that the delivery of posaconazole by neutrophils to the site of Aspergillus species infection warrants control of the pathogen and preservation of tissue integrity at the same time.
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany Fedja.Farowski@uk-koeln.de.
authors.forename: Fedja
authors.initials: F
authors.lastname: Farowski
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany Clinical Trials Centre Cologne, ZKS Köln, University of Cologne, Cologne, Germany Center for Integrated Oncology (CIO) KölnBonn, University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne, Cologne, Germany Department of Hospital Hygiene and Infection Control, University of Cologne, Cologne, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Hartmann
mesh_terms: D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013172:Spores, Fungal / Q000187:drug effects / Q000254:growth & development*; D014230:Triazoles / Q000009:adverse effects* / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D017382:Reactive Oxygen Species; D014230:Triazoles; C101425:posaconazole