Last update:
04-Apr-2013

OBJECTIVE Although strains of Aspergillus fumigatus with reduced in vitro susceptibility to voriconazole have been described, clinical breakpoints have not yet been defined. The aim of this study was to correlate the results of the new in vitro pharmacokinetic-pharmacodynamic (PK-PD) model with previous results from animal models and to investigate the efficacy of voriconazole against A. fumigatus isolates, determining susceptibility breakpoints.

METHOD Four clinical A. fumigatus isolates were studied: one wild-type control with MIC 0.25 mg/L and three strains with defined CYP51A mutations with MICs 0.125, 0.25 and 2 mg/L, previously tested in animal models. The in vivo voriconazole dosages of 10, 40 and 80 mg/kg that were used in animal model were simulated in the in vitro PK-PD model with maximum concentrations of 1.60, 11.09 και 36.49 mg/L, respectively and an average half-life of 6 hours. The area under the drug concentration-time curve AUC (PK parameter) and the area under the galactomannan concentration-time curve AUCGI (PD parameter) were determined for each dose and isolate. The in vitro relationship of % antifungal activity-AUC/MIC was correlated with the in vivo survival-AUC/MIC. Monte Carlo simulation analysis was performed for 100 patients receiving standard voriconazole dosage of 4 mg/kg qd and the % of patients attaining the pharmacodynamic target FAUC/MIC associated with near maximal antifungal activity was calculated for A. fumigatus isolates with different MICs.

RESULTS The in vitro pharmacokinetic parameters and % of antifungal efficacy were similar to those previously observed in animal models (paired t test p=0.4). The in vitro % fungal growth-AUC/MIC followed a sigmoid curve similar to that derived from the animal model (R²=0.91). The PK/PD parameter FAUC0−24/MIC corresponding to 50% of maximal antifungal efficacy was 11.53 (range 8−16) in the in vitro model, close to the in vivo FAUC₀₋₂₄/MIC of 10.5 observed in animals. Monte Carlo simulation analysis showed that the pharmacodynamic target of 56 FAUC₀₋₂₄/MIC associated with maximal antifungal efficacy was attained in >80% of patients receiving standard voriconazole dosing for isolates with MIC <=0.25, which can be considered as susceptible, whereas the % of target attainment for isolates with MIC >=1 was <5%, indicating resistance.

CONCLUSIONS The results of the new in vitro PK-PD model were comparable with those derived from animal models. Study of voriconazole activity in the new in vitro PK-PD model indicates susceptibility breakpoints of <=0.25, 0.5, >=1 which could be used to detect susceptible, intermediately susceptible and resistant A. fumigatus isolates, respectively.

Key words: Aspergillus fumigatus, Monte Carlo simulation, Resistance, Susceptibility breakpoints, Voriconazole.