Pharmacodynamics of Voriconazole in a Novel In Vitro Model of Aspergillus flavus Acute Invasive Sinusitis

C. E. Negri1, H. Box2, J. L. Livermore2, S. S. Gonçalves1, A. L. Colombo1, W. W. Hope2;

Author address: 

Univ.e Federal de Sao Paulo, Sao Paulo, Brazil, 2Univ. of Liverpool, Liverpool, United Kingdom

Abstract: 

Background: 

Invasive fungal sinusitis is an aggressive infection associated with high mortality that generally occurs in immunocompromised individuals. A. flavus is a leading cause of fungal sinusitis in some series. The treatment is difficult, and usually requires surgery and use of antifungal agents. There is relatively little information on the PK and PD of voriconazole (VCZ) against A. flavus. The aim of this study was to evaluate the VCZ PD in novel in vitro models of acute invasive sinusitis caused by A. flavus

Methods:

 A cellular bilayer was constructed using human nasal epithelial and pulmonary artery endothelial cells cultured on a semipermeable polyester membrane. The bilayer was used in a static and dynamic model that enabled simulation of human-like PK. The bilayer was inoculated with A. flavus conidial suspension on the epithelial surface. The primary challenge strain was ATCC 204304 and a further 3 strains from Brazilian patients with proven invasive aspergillosis were studied. VCZ was diluted to obtain concentrations that ranged from 0.03 to 2 mg/L for both models. Samples were obtained throughout the dosing interval until 48 and 72 hours for static and dynamic model, respectively. Galactomannan (GM) was used as the model readout. 

Results: 

The cellular bilayer was impermeable to Dextran Blue. Histopathological studies confirmed infection and invasion of the cellular bilayer. For the ATCC strain, after 48h exposure in 0.5 mg/L VCZ, the GM index decreased from 9.34 to 0.73 in the nasal compartment (NC) and 4.50 to 0.56 in the endothelial compartment (EC). In addition, for LEMI1049 strain, 0.5 mg/L of VCZ was sufficient to decrease GM index from 11.01 to 7.98 in NC and from 2.72 to 0.57 in EC. However, for LEMI764 and LEMI1024 strains 1 mg/L was more effective, decreasing GM index from NC from 9.365 and 10.77 to 1.41 and 4.81 and EC from 5.81 and 5.19 to 1.46 and 0.54, respectively. Using the dynamic model VCZ induced a dose-dependent reduction in circulating GM concentrations. A concentration of 2 mg/L was required to suppress GM, while lowest concentrations resulted in breakthrough infection. 

Conclusions: 

These new in vitro models can be used to study and elucidate the PK-PD of existing and new antifungal agents for invasive fungal sinusitis caused by A. flavus.

abstract No: 

A-016
    • ICAAC 55th (2015)