title: Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration: A randomised controlled trial of continuous infusion versus intermittent bolus administration.
abstract: Here we describe the pharmacokinetics of piperacillin administered by continuous infusion (CI) versus intermittent bolus (IB) dosing in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and compare the frequency of pharmacodynamic/pharmacokinetic (PK/PD) target attainment with each dosing strategy. This was a prospective pharmacokinetic trial in 16 critically ill patients with severe sepsis or septic shock undergoing CVVH and randomised to receive either CI or IB administration of a standard daily dose of piperacillin/tazobactam (11.25g/day on Day 1 followed by 9g/day). Serial blood samples were measured on two occasions. Piperacillin pharmacokinetics were calculated using a non-compartmental approach. Blood concentrations were compared with established PK/PD targets. On occasion 1 (Days 1-3 of therapy), IB administration resulted in significantly higher piperacillin peak concentrations (169 vs. 89mg/L; P=0.002), whereas significantly higher steady-state concentrations were observed in CI patients (83 vs. 57mg/L; P=0.04). Total clearance and clearance not mediated by CVVH were significantly higher with CI administration [median (interquartile range), 1.0 (0.7-1.1) and 0.8 (0.6-1.0)mL/kg/min; P=0.001 and 0.001, respectively]. The estimated unbound piperacillin concentrations were four times above the target susceptibility breakpoint (16mg/L) for the entire dosing interval (100%fT>4xMIC) in 87.5% of patients receiving CI administration (sampling occasion 1), compared with 62.5% of IB patients achieving the desired target (50%fT>4xMIC). Compared with IB dosing, and despite similar CVVH settings, CI administration of piperacillin results in a pharmacokinetic profile that may optimise outcomes for less susceptible pathogens.
authors.affiliation: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Janattul-Ain
authors.initials: JA
authors.lastname: Jamal
authors.affiliation: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Roberts
authors.affiliation: Department of Hyperbaric and Intensive Care Medicine, The Alfred Hospital, Commercial Road, Prahran, Melbourne, Victoria, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Udy
authors.affiliation: Department of Anaesthesiology and Intensive Care, Kulliyyah of Medicine, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia.
authors.forename: Mohd-Basri
authors.initials: MB
authors.lastname: Mat-Nor
authors.affiliation: Department of Nephrology, Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia.
authors.forename: Fariz-Safhan
authors.initials: FS
authors.lastname: Mohamad-Nor
authors.affiliation: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns, Trauma and Critical Care Research Centre, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Department of Intensive Care Medicine, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Department of Pharmacy, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. Electronic address: j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D061605:Administration, Intravenous / Q000379:methods*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D016638:Critical Illness; D005260:Female; D006440:Hemofiltration; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010878:Piperacillin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D010878:Piperacillin
keywords: CVVH; Continuous infusion; Intensive care; Piperacillin; RRT; Renal replacement therapy