Pharmacodynamics of Voriconazole (VCZ) in a Novel Dynamic in vitro Model of invasive Pulmonary Aspergillosis (IPA): Implications for in vitro Susceptibility Breakpoints and Targets for therapeutic Drug Monitoring (TDM)

Ref ID: 18653

Author:

A. R. Jeans, MD (Doctor of Medicine) – Clinical Fellow, S. J. Howard – Research Associate, Z. Al-Nakeeb – MRES student, J. Goodwin – Research Assistant, L. Gregson – Research Technician, P. A. Warn – Senior Lecturer, W. W. Hope – Clinical Senior Lect

Author address:

The Univ. of Manchester, Manchester, United Kingdom.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: VCZ is a first-line agent for IPA. Isolates of Aspergillus fumigatus with elevated VCZ MICs are increasingly seen. In vitro susceptibility breakpoints have not been defined. Methods: A novel dynamic in vitro model of the human alveolus was used. Human-like VCZ concentration-time profiles were generated using pumps. Four strains of Aspergillus fumigatus with CLSI MICs 0.5-16 mg/L and defined resistance mechanisms were studied. Conidia were inoculated into the alveolar compartment. Fungal growth and the antifungal effect of VCZ were estimated using circulating galactomannan (GM) concentrations. VCZ was injected into the circuit every 12 hours. Treatment was initiated 6 hours post inoculation and continued for 48 hours. A mathematical PK-PD model was fitted to the data and used to link AUC:MIC with GM. The VCZ AUC:MIC and trough concentration:MIC that suppressed fungal growth were determined. The implications for humans were explored using a VCZ population PK model fitted to patient data and Monte Carlo simulations. Results: Fungal growth was progressively inhibited with higher drug exposures. Strains with higher MICs required proportionally greater drug exposures to achieve a comparable antifungal effect. The AUC:MIC and trough:MIC associated with suppression of GM were 60 and 2, respectively. Monte Carlo simulations suggested that 64% of simulated patients receiving standard IV therapy would have adequate drug exposure if infected by a strain with an MIC of 1 mg/L. Adequate exposure would be achieved in only 28% if the MIC increased to 2 mg/L. Target attainment was unacceptably low for strains with higher MICs. The overall fractional target attainment rate was 89%. Conclusions: Aspergillus fumigatus with VCZ CLSI MICs ≥ 2 mg/L should be classified as resistant. Resistance mechanisms can be overcome with elevated drug exposures, but these are likely to be associated with clinical toxicity. A trough:MIC of 2 is a potential target for TDM.

Abstract Number: A2-583

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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