title: Pharmacokinetics and Pharmacodynamics of Extended Infusion Versus Short Infusion Piperacillin-Tazobactam in Critically Ill Patients Undergoing CRRT.
abstract: Infection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of β-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT.
  
  
  
  We conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 μg/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate.
  
  
  
  Sixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion.
  
  
  
  Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.
authors.affiliation: Departments of Biostatistics.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Shotwell
authors.affiliation: Nephrology and Hypertension, and.
authors.forename: Ross
authors.initials: R
authors.lastname: Nesbitt
authors.affiliation: Nephrology and Hypertension, and.
authors.forename: Phillip N
authors.initials: PN
authors.lastname: Madonia
authors.affiliation: Nephrology and Hypertension, and.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Gould
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, Georgia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Connor
authors.affiliation: Department of Nephrology and Hypertension, King's Daughters Medical Center, Ashland, Kentucky.
authors.forename: Charbel
authors.initials: C
authors.lastname: Salem
authors.affiliation: Department of Internal Medicine, Marion General Hospital, Marion, Ohio.
authors.forename: Olufemi A
authors.initials: OA
authors.lastname: Aduroja
authors.affiliation: Department of Internal Medicine and Nephrology, Veterans Affairs Southern Nevada Healthcare System, Las Vegas, Nevada; and.
authors.forename: Milen
authors.initials: M
authors.lastname: Amde
authors.affiliation: Nephrology and Hypertension, and.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Groszek
authors.affiliation: Departments of Biostatistics.
authors.forename: Peilin
authors.initials: P
authors.lastname: Wei
authors.affiliation: Department of Nephrology and Hypertension, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Taylor
authors.affiliation: Department of Nephrology and Hypertension, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Ashita J
authors.initials: AJ
authors.lastname: Tolwani
authors.affiliation: Nephrology, Hypertension, and Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: William H
authors.initials: WH
authors.lastname: Fissell
mesh_terms: D058186:Acute Kidney Injury / Q000382:microbiology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001424:Bacterial Infections / Q000150:complications / Q000188:drug therapy*; D016638:Critical Illness; D015314:Dialysis Solutions / Q000737:chemistry; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; 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; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D015314:Dialysis Solutions; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin
keywords: Acute Kidney Injury; Anti-Bacterial Agents; Critical Illness; Dialysis Solutions; Humans; Microbial Sensitivity Tests; Renal Replacement Therapy; extended-infusion; pharmacokinetics; piperacillin