title: Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration.
abstract: 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 (4g/0.5g) was administered every 8h and CVVHDF was performed as a 3-3.5L/h exchange using a polyacrylonitrile filter with a surface area of 1.05m(2). 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 4.5g piperacillin/tazobactam administered evry 8h resulted in piperacillin concentrations in plasma and ISF >32mg/L throughout most of the dosing interval.
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia. Electronic address: j.varghese1@uq.edu.au.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Varghese
authors.affiliation: Department of Intensive Care Medicine, Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Boots
authors.affiliation: Centre for Medicine Use and Safety, Monash University, 381 Royal Parade, Melbourne, VIC 3052, Australia.
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns, Trauma & Critical Care Research Centre, The University of Queensland, Level 7, Block 6, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Department of Intensive Care Medicine, Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Pharmacy Department, Level 1, Ned Hanlon Building, Royal Brisbane & Women's Hospital, Brisbane, QLD 4029, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D058186:Acute Kidney Injury / Q000401:mortality / Q000628:therapy; D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D016638:Critical Illness; D045604:Extracellular Fluid / Q000737:chemistry; D005260:Female; D006207:Half-Life; D006440:Hemofiltration / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000652:urine; D010878:Piperacillin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy*; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin
keywords: CRRT; Microdialysis; Pharmacodynamics; Pharmacokinetics; Target site; β-Lactam