Abstract
Background: Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking. Objective: To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations. Methods: This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses. Results: From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC 16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC 32 mg/L. Conclusions and Relevance: In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen.