Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration

This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3-3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 samples were collected. Median peak plasma concentrations were 210.5 (interquartile range = 161.5-229.0) and 29.4 (27.9-32.0) mg/L and median trough plasma concentrations were 64.3 (49.0-68.9) and 12.3 (7.7-13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6-8.7) and 7.3 (4.6-11.8) h, volume of distribution 0.42 (0.29-0.49) and 0.32 (0.24-0.36) L/kg, total clearance 5.1 (4.2-6.2) and 3.8 (3.3-4.2) L/h and CVVHDF clearance 2.5 (2.3-3.1) and 2.5 (2.3-3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration-time curve of the unbound drug in ISF to plasma (unbound AUCISF/AUCplasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5 g piperacillin/tazobactam administered evry 8 h resulted in piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.