Evaluation of an in vivo pulmonary aspergillosis model for triazole susceptibility breakpoint development

Use of mouse infection models for antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) analysis can assist in dosing regimen design and susceptibility breakpoint development. A major hurdle for clinical translation of in vivo study output is defining the model endpoint linked to clinical success. Validation of the in vivo endpoint requires a clinical data set composed of success or failure linked to minimum inhibitory concentration (MIC), dosing regimen, and if possible human pharmacokinetic measures. The present studies utilized a clinical library of eight Aspergillus fumigatus strains in a mouse pneumonia model to define the endpoint associated with humanized treatment regimens of the triazole, posaconazole. This includes wild-type strains associated with successful treatment and strains with resistance mutations leading to elevated MICs and associated with treatment failure. We found humanized posaconazole exposures resulted in a net stasis or net decrease in organism burden in the animal model compared to the start of therapy for all wild-type strains. However, a net increase in organism burden despite treatment with the humanized regimen was noted for strains with higher MIC values and defined Cyp51 mutations. The ratio of posaconazole free-drug area under the concentration-time curve to the MIC (AUC/MIC) associated with a stasis endpoint in the mouse model was then utilized with in vitro surveillance data and a human posaconazole population pharmacokinetic model to perform simulations and PK/PD target attainment analyses. The results of these analyses demonstrated >90% probability of PK/PD target attainment for A. fumigatus strains with MICs of ≤0.5 mg/L, thus supporting this susceptible breakpoint threshold.