Effect of Cell-Associated Antifungal Agents on Inhibiting Aspergillus fumigatus

Ref ID: 18652

Author:

P. CAMPOLI1, M. LAVERDIERE 2, R. ROBITAILLE 2, D. SHEPPARD 1;

Author address:

1McGill Univ., Montreal, Canada, 2Hôpital Maisonneuve-Rosemont, Montreal, Canada.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Pharmacokinetic studies have found that the ratio of cellular to serum concentrations differ significantly between antifungal agents. As intracellular penetration by A. fumigatus (AF) is an early event in the development of invasive aspergillosis, we hypothesized that that the degree of concentration of antifungals within pulmonary epithelial cells is a critical determinant of efficacy during prophylaxis. Methods: A549 pulmonary epithelial cells were exposed to varying concentrations of posaconazole, voriconazole, caspofungin or amphotericin B for 4 hrs. The drug was then removed, the cells were washed and then infected with conidia of AFstrain Af293 in a microtiter assay. Minimal inhibitory concentrations were determined for cells exposed to antifungals and compared with the MICs of free drug in RPMI medium. Results: Epithelial cells exposed for four hours to posaconazole at 2 ug/ml or greater inhibited the growth of AF. In contrast, none of the other antifungal exposed cells inhibited fungal growth to any degree including: caspofungin (256ug/ ml), voriconazole (8ug/ml), and Amphotericin B (8ug/ml). Blocking epithelial cell endocytosis of conidia with cytochalasin D did not affect the ability of posaconazole loaded cells to inhibit fungal growth. Thus, posaconazole may remain associated with the epithelial cell membrane rather than the intracellular compartment. Conclusion: These results suggest that cell-associated antifungals may be an important reservoir within the lung and can play an important role in preventing the initiation of infection during prophylaxis. These data may also provide an explanation for the efficacy of posaconazole in prophylaxis despite the lower serum levels reported with this agent.

Abstract Number: M-1090

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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