Impact of renal replacement modalities on the clearance of piperacillin-tazobactam administered via continuous infusion in critically ill patients

Abstract

This prospective pharmacokinetic study aimed to compare the clearance of piperacillin-tazobactam administered as a 24-h continuous infusion between continuous venovenous haemodiafiltration (CVVHDF) and continuous venovenous haemofiltration (CVVH) applied at equal dose in critically ill patients.A loading dose of 4.5 g of piperacillin-tazobactam followed by a continuous infusion (500 mg/h) was administered to patients randomized to receive CVVHDF or CVVH. Serial pre- and postfilter blood samples were drawn during an 8-h sampling interval. Piperacillin plasma concentrations were measured using a validated chromatography method. Piperacillin pharmacokinetics were calculated using a non-compartmental approach.In total, 212 piperacillin plasma concentrations were determined. Median [interquartile range (IQR)] total piperacillin clearance was 7.5 (5.9–11.2) L/h in the CVVHDF group and 4.7 (4.5–9.6) L/h in the CVVH group (P = 0.21). Median (IQR) piperacillin clearance related to continuous renal replacement therapy (CRRT) was 3.0 (2.7–3.2) L/h in the CVVHDF group and 2.6 (1.9–3.0) L/h in the CVVH group (P = 0.29). Mean (standard deviation) steady state concentrations were 68.4 (25.8) mg/L in the CVVHDF group and 89.1 (35.6) mg/L in the CVVH group (P = 0.16). The estimated unbound concentrations resulting from piperacillin continuous infusion were above the target susceptibility breakpoint (16 mg/L) for the entire dosing interval (100% fT>MIC) in all study patients.In the present study, higher (but not significantly) piperacillin clearance and lower piperacillin exposure were observed in patients receiving CVVHDF compared with CVVH. In patients receiving CRRT, the use of piperacillin continuous infusion should be considered to ensure optimal exposure for less susceptible pathogens.