title: Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT.
abstract: OBJECTIVE
  Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions.
  
  
  METHODS
  A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters.
  
  
  RESULTS
  Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h(-1), intraquartile range=0.052 h(-1)) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered.
  
  
  CONCLUSIONS
  There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.
authors.affiliation: Departments of Pharmacy, Cleveland Clinic, Ohio, USA.
authors.forename: Seth R
authors.initials: SR
authors.lastname: Bauer
authors.forename: Charbel
authors.initials: C
authors.lastname: Salem
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Connor
authors.forename: Joseph
authors.initials: J
authors.lastname: Groszek
authors.forename: Maria E
authors.initials: ME
authors.lastname: Taylor
authors.forename: Peilin
authors.initials: P
authors.lastname: Wei
authors.forename: Ashita J
authors.initials: AJ
authors.lastname: Tolwani
authors.forename: William H
authors.initials: WH
authors.lastname: Fissell
mesh_terms: D000046:Academic Medical Centers; D058186:Acute Kidney Injury / Q000097:blood / Q000378:metabolism / Q000628:therapy*; D000328:Adult; D000368:Aged; D000407:Alabama; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000378:metabolism / Q000628:therapy*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009820:Ohio; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination; D011446:Prospective Studies; D006435:Renal Dialysis
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin