Optimizing Clinical Use of Polymyxin B: Teaching an Old Drug to Treat Superbugs

The specific aims addressed in this proposal are: 1. To characterize the disposition of polymyxin B in critically-ill patients, including those on renal replacement therapy; and to develop the population pharmacokinetic model for polymyxin B and identify the patient characteristics (i.e. covariates) influencing its disposition. 2. To establish the relationships between polymyxin B pharmacokinetic exposure, bacterial susceptibility and patient characteristics (e.g. infection site), with the probability of attaining and time to achieving clinical and bacteriological outcomes, including emergence of resistance; and to develop the population pharmacodynamic model for polymyxin B, including the influ¬enc¬ing covariates and potential effects of other antibiotics. 3. To investigate associations between the pharmacokinetics of polymyxin B, duration of therapy and patient characteristics, with the development and timing of nephrotoxicity; to use next-generation proteomics to identify the most predictive biomarker(s) of polymyxin B associated nephrotox¬i¬ci¬ty; and to develop the population toxicodynamic model for polymyxin B, including the influ¬enc¬ing covariates. 4. To employ the models from Aims 1, 2 and 3 and Monte Carlo simulation to develop scientifically-based dosage regimens of polymyxin B for various categories of critically-ill patients and to develop an adaptive feedback control (aka, TDM) algorithm for optimizing regimens in individual patients.