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. Posaconazole is a broad-spectrum triazole antifungal approved for prophylaxis and treatment of opportunistic invasive fungal infections (IFI) in immunocompromised patients. The majority of all IFI (probably more than 95%) are attributable to Aspergillus spp. and Candida spp. (1, 2). Aspergillus spp. are ubiquitous soil-dwelling fungi, often found in walls and dust. Due to their small size (2-to 4-m diameter), Aspergillus conidia (spores) tend to remain airborne. It is estimated that all humans inhale at least several hundred Aspergillus fumigatus conidia per day (3). Upon inhalation, these conidia may germinate at body temperature in the terminal airways and alveoli, causing invasive pulmonary aspergillosis (3). Alveolar macrophages constitute the first line of defense against invading conidia. They immediately phagocytize conidia, thereby restricting their initial spread into the alveoli. The process of phagocytosis is accompanied by secretion of proinflammatory cytokines, leading to autocrine activation of the macrophage and attraction of other immune cells to the site of infection (4). It has been shown that recruitment of neutrophils is essential for efficient clearing of Aspergillus fumigatus conidia (5). Moreover, one of the most disposing risk factors for invasive aspergillosis is a depletion and/or functional impairment of neutrophils (6-8). Killing of Aspergillus fumigatus by neutrophils is mediated by the release of reactive oxygen species and neutrophil granular content (9-12).Therapeutic substances are differentially distributed to various compartments of the human body, which impacts their pharmacokinetics and pharmacodynamics. With regard to the question of whether cells of the peripheral blood constitute a relevant compartment f...

Posaconazole-Loaded Leukocytes as a Novel Treatment Strategy Targeting Invasive Pulmonary Aspergillosis

“…In this study, the viability and chemotaxis of primary human neutrophils in vitro was preserved following exposure to posaconazole concentrations as high as 1.2 μg/mL (186). In contrast to our findings however, posaconazole-loaded primary human neutrophils did not exhibit enhanced killing of A. fumigatus conidia as determined by quantitative culture (186). It is likely that this observation reflects the fact that posaconazole is fungistatic rather than fungicidal.…”

“…Posaconazole is a broad-spectrum triazole that is highly active against (186). In this study, the viability and chemotaxis of primary human neutrophils in vitro was preserved following exposure to posaconazole concentrations as high as 1.2 μg/mL (186).…”

Kinsenoside screening with a microfluidic chip attenuates gouty arthritis through inactivating NF-κB signaling in macrophages and protecting endothelial cells

“…Previous researches revealed that inflammatory cells could serve as potential targets to achieve desirable efficacy during the treatments of tumor, microbial infection and inflammatory bone diseases. 55 , 56 , 57 , 58 Therefore, we consider that the treatment of Kin could be applied in the therapies of cancer, microbial infection and inflammatory diseases, which require future in-depth work.…”

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…The finding that posaconazole accumulates in human peripheral blood mononuclear cells and polymorphonuclear leukocytes triggered an investigation on the impact of posaconazole-loaded leukocytes on the antifungal activity and functional capacity of different leukocytes [116][117][118][119]. High posaconazole intracellular concentrations did not show a significant impact on the functional capacities of human neutrophils and macrophages in vitro [117]. Natural killer cells also have proven to still be viable and they maintained their capacity under therapeutic concentrations of posaconazole [119].…”