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Updated: Feb 1, 2026
Detection of Invasive Pulmonary Aspergillosis in Haematological Malignancy Patients by using Lateral-flow Technology
Published on: March 22, 2012
Evaluation of an in vivo pulmonary aspergillosis model for triazole susceptibility breakpoint development
Alex Lepak1, Sujata M Bhavnani2, Mariana Castanheira3
1University of Wisconsin, Madison, Wisconsin, USA.
Abstract:
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.
Insights
Mouse infection models help design antimicrobial dosing. Defining endpoints linked to clinical success is key. This study validated posaconazole breakpoints for Aspergillus fumigatus, establishing a MIC threshold of ≤0.5 mg/L for effective treatment.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Pharmacokinetics/Pharmacodynamics
Background:
- Mouse infection models are crucial for antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) analysis, aiding dosing regimen design and susceptibility breakpoint development.
- A significant challenge in translating in vivo study findings to clinical practice is defining the model endpoint that correlates with clinical success.
- Validating in vivo endpoints requires clinical data linking treatment outcomes (success/failure) to minimum inhibitory concentration (MIC), dosing regimens, and human pharmacokinetic measures.
Purpose of the Study:
- To define the in vivo endpoint in a mouse pneumonia model for posaconazole treatment.
- To validate the clinical utility of established pharmacokinetic/pharmacodynamic (PK/PD) targets for Aspergillus fumigatus infections.
- To establish a susceptible breakpoint for Aspergillus fumigatus based on posaconazole PK/PD targets.
Main Methods:
- Utilized a panel of eight Aspergillus fumigatus strains (wild-type and resistant mutants) in a mouse pneumonia model.
- Administered humanized posaconazole dosing regimens to infected mice.
- Determined the ratio of posaconazole free-drug area under the concentration-time curve to MIC (AUC/MIC) associated with a stasis endpoint.
Main Results:
- Humanized posaconazole exposures achieved stasis or reduction in fungal burden for wild-type strains.
- Increased fungal burden was observed for strains with higher MICs and Cyp51 mutations despite treatment.
- Simulations indicated >90% probability of PK/PD target attainment for Aspergillus fumigatus strains with MICs ≤0.5 mg/L.
Conclusions:
- The posaconazole AUC/MIC ratio associated with a stasis endpoint in the mouse model can predict treatment success.
- A minimum inhibitory concentration (MIC) breakpoint of ≤0.5 mg/L is supported for Aspergillus fumigatus susceptibility to posaconazole.
- This study provides a framework for validating in vivo models and establishing clinical breakpoints for antifungal therapies.
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