Evaluation of theIn VitroActivity of Voriconazole As Predictive ofIn VivoOutcome in a Murine Aspergillus fumigatus Infection Model
ABSTRACTWe have evaluated thein vitroactivity of voriconazole against 61 strains ofAspergillus fumigatusby using broth microdilution, disk diffusion, and minimal fungicidal concentration procedures. We observed an excellent correlation between the results obtained with the three methods. Five percent of the strains showed MICs greater than or equal to the epidemiological cutoff value (ECV; 1 μg/ml). To assess whether MICs were predictive ofin vivooutcome, we tested the efficacy of voriconazole at 25 mg/kg of body weight daily in an immunosuppressed murine model of disseminated infection using 10 strains representing various patterns of susceptibility to the drug as determined by thein vitrostudy. Voriconazole prolonged survival and reduced fungal load in the kidneys and brain in those mice infected with strains with MICs of ≤0.25 μg/ml, while in mice infected with strains with MICs of 0.5 to 2 μg/ml, the efficacy was varied and strain dependent and in mice infected with the strain with a MIC of 4 μg/ml, the antifungal did not show efficacy. Voriconazole reduced galactomannan antigenemia against practically all strains with a MIC of <4 μg/ml. Our results demonstrate that some relationship exists between voriconazole MICs andin vivoefficacy; however, further studies testing additional strains are needed to better ascertain which MIC values can predict clinical outcome.