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.