High Intracellular Concentrations of Posaconazole Do Not Impact on Functional Capacities of Human Polymorphonuclear Neutrophils and Monocyte-Derived Macrophages In Vitro

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 6; pp. 3533 - 3539
• Main Authors: Farowski, Fedja, Cornely, Oliver A, Hartmann, Pia
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.06.2016
• Subjects: Antifungal Agents; Antifungal Agents - adverse effects; Antifungal Agents - pharmacology; Aspergillosis; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - immunology; Cell Movement - drug effects; Cell Movement - immunology; Cells, Cultured; Humans; Macrophages; Macrophages - drug effects; Macrophages - immunology; Mechanisms of Action: Physiological Effects; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Reactive Oxygen Species - metabolism; Spores, Fungal; Spores, Fungal - drug effects; Spores, Fungal - growth & development; Triazoles; Triazoles - adverse effects; Triazoles - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02060-15

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.