The frequency of invasive fungal infections caused by filamentous fungi have been increased the last decades as the population of profound and prolong immunocompromised patients (transplant recipients, patients with cancer, AIDS or other immunodeficiencies) has been expanded. These infections are associated with high mortality (up to 90%) despite antifungal therapy and for difficult-to-treat mould infections surgical debridement is the only effective therapeutic approach. In search of alternative effective chemotherapeutic approaches, the interest on antifungal combination therapy with two or more antifungal agents have been increased given the availability of more systemic antifungal agents with different mechanisms of action. The objective of this proposal is the development of an in vitro pharmacokinetic/pharmacodynamic system for filamentous fungi that will simulate the microenvironment at the site of infection accounting for drug-host-fungus factors and their interactions. In this model drug concentrations will fluctuate over time simulating in vivo plasma pharmacokinetics, epithelial/endothelial barriers and host defense cells will be included to simulate the pathophysiology of fungal infections at different tissues and various clinical isolates with different microbiological characteristics will be tested in order to simulate differences in virulence factors, growth rates and drug susceptibilities. This system will help to study the efficacy of various combination dosing regimens and schedules against filamentous fungi and to aid the regimen design process for in vivo studies and clinical trials, which otherwise would be not easily feasible. Finally, the grant will promote reintegration of Dr. Joseph Meletiadis into European scientific community, scientific excellence in medical microbiology, knowledge transfer to Attikon Hospital of University of Athens in Greece and development of a lasting co-operation with the National Institutes of Health in the USA.
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