A Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis to Predict the Efficacy of Systemic Antifungal Therapy

Ref ID: 15130

Author:

J. B. MAJITHIYA, S. J. HOWARD, L. GREGSON, J. GOODWIN, E. HARRISON, P. A. WARN, W. W. HOPE

Author address:

The Univ. of Manchester, Manchester, United Kingdom.

Full conference title:

50th Annual ICAAC

Date: 12 September 2014

Abstract:

Background: Invasive pulmonary aspergillosis is a leading cause of morbidity and mortality in immunocompromised patients. There are relatively few models of invasive fungal infections that can be used to investigate pathogenesis and therapy of early human infection. Methods: A previously described in vitro model of the human alveolus consisting of a bilayer human alveolar epithelial and endothelial cells was modified to produce an air liquid interface. The bilayer was housed in a bioreactor that was then incorporated in a circuit that enabled the continuous flow of cell culture medium within the endothelial compartment. Aspergillus conidia were inoculated into the alveolar compartment. Samples for galactomannan (GM) and PCR were drawn from the circuit. Various amounts of amphotericin B was introduced into the circuit at 0 and 24 hours post inoculation. Samples were taken from 0-48 hrs post inoculation. Drug free medium was pumped into the circuit with simultaneous removal of drug containing medium, thus simulating first-order pharmacokinetics (PK). Pumps were set to simulate both murine and human PK. Results: Aspergillus conidia germinated and invaded through the bilayer. There was a progressive increase in the concentrations of GM, which became maximal after ~20 hours. The PCR was initially positive after 12 hrs, but thereafter only intermittently and with no consistent relationship with rising galactomannan concentrations. Murine amphotericin B PK for mice receiving 0.1-5 mg/kg were readily simulated. A peak concentration of 2 mg/kg completely suppressed GM in the circuit. A humanized regimen simulating 1 mg/kg suppressed GM within the circuit. Conclusions: This dynamic model enables a variety of antifungal PK profiles to be simulated and allows for continuous monitoring of biomarkers. Such a model could be used for the development of novel antifungal agents and examination of pathogenesis of early fungal infection.

Abstract Number: M-1084

Conference Year: 2010

Link to conference website: NULL

New link: NULL

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