A new marker of echinocandins activity in an in vitro PK/PD model correlates with an animal model of Aspergillus fumigatus infection [PublishAheadOfPrint]

The lack of a quantifiable marker for echinocandins activity hinders in vitro PK/PD studies for Aspergillus spp. We developed an in vitro PK/PD model simulating anidulafungin pharmacokinetics and assessing its pharmacodynamics against A. fumigatus with a new easily quantifiable, sensitive and reproducible marker. Two clinical A. fumigatus isolates previously used in animals (AZN8196,V52-35) with identical anidulafungin EUCAST (0.03 μg/ml) and CLSI (0.015 μg/ml) MEC and one (AFU79728) with MEC>16 μg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane tube (DM) inoculated with 10³ cfu/mL. During anidulafungin exposure, two types of fungal forms were observed inside the DM, floating conidia that were quantified by cultures and attached aberrant mycelia that were quantified by the vertical height of the mycelia covering the DM. No aberrant mycelia were found for the resistant isolate and in the drug-free controls. In vitro exposure-effect relationship was similar with that found in animals using survival as an endpoint with fAUC_0-24 (range) associated with 50% of maximal activity of 2.21 (1.81-2.71) vs 2.62 (1.88-3.65) (p=0.41), respectively. The Hillslopes were also similar, 1.96 vs 1.34 (p=0.29). Analysis of each isolate separately showed increased antifungal susceptibility between AZN8196 and V52-35 (p<0.001) despite the same CLSI and EUCAST MECs but 2 two-fold lower MICs using Etest and XTT method. Dose fractionation studies with all three echinocandins showed that their activity is best described by fAUC rather than fC_max. The new marker correlated with in vivo outcome and can be used for in vitro PK/PD studies exploring pharmacodynamics of echinocandins against Aspergillus spp.

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