The objectives of this study were (i) to compare the plasma concentration-time profiles for first-dose and steady-state
piperacillin administered by intermittent or continuous dosing to
critically ill patients with
sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different
piperacillin dosing regimens against bacterial pathogens commonly encountered in
critical care units. Plasma samples were collected on Days 1 and 2 of
therapy in 16
critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of
piperacillin (administered with
tazobactam). A population pharmacokinetic model was developed using NONMEM, which found that a two-compartment population pharmacokinetic model best described the data. Total
body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000
critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f(T>MIC))] and it was found that continuous infusion maintained superior free
piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16g/day by continuous infusion vs. bolus dosing (4g every 6h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of
piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.