In vitro Pharmacodynamics and PK/PD in Animals

Area of Science:

• Pharmacology
• Microbiology
• Infectious Diseases

Background:

• Polymyxins are critical antibiotics for treating multidrug-resistant Gram-negative infections.
• Identifying the correct pharmacokinetic/pharmacodynamic (PK/PD) index is essential for optimizing polymyxin therapy.
• Previous research has explored various PK/PD indices to define polymyxin efficacy.

Purpose of the Study:

• To identify the most predictive pharmacokinetic/pharmacodynamic (PK/PD) index for polymyxin antimicrobial activity.
• To evaluate the impact of dosing schedules on polymyxin efficacy and resistance.
• To determine the optimal PK/PD target for colistin against specific pathogens.

Main Methods:

• Utilized dose-fractionation studies in hollow-fiber models.
• Assessed the relationship between PK/PD indices and bacterial killing/resistance.
• Correlated in vivo efficacy with various PK/PD indices for colistin.

Main Results:

• Altering dosing schedules had minimal impact on bacterial killing or resistance emergence.
• The area under the concentration-time curve to the minimum inhibitory concentration (AUC/MIC) ratio best described polymyxin activity in vitro.
• The free AUC/MIC (ƒAUC/MIC) ratio was the most predictive PK/PD index for in vivo colistin efficacy against *P. aeruginosa* and *A. baumannii*.

Conclusions:

• The ƒAUC/MIC ratio is the key PK/PD index for predicting colistin efficacy in vivo.
• Optimizing colistin dosing based on the ƒAUC/MIC ratio is crucial for effective treatment of challenging infections.
• Understanding polymyxin PK/PD is vital for combating antimicrobial resistance.