Pharmacokinetics and Pharmacodynamics of Extended Infusion Versus Short Infusion Piperacillin-Tazobactam in Critically Ill Patients Undergoing CRRT.

Shotwell MS, Nesbitt R, Madonia PN, Gould ER, Connor MJ, Salem C, Aduroja OA, Amde M, Groszek JJ, Wei P, Taylor ME, Tolwani AJ, Fissell WH
Clin J Am Soc Nephrol. 2016 11 (8): 1377-83

PMID: 27197907 · PMCID: PMC4974884 · DOI:10.2215/CJN.10260915

BACKGROUND AND OBJECTIVES - 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.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - 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.

RESULTS - 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.

CONCLUSIONS - Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

Copyright © 2016 by the American Society of Nephrology.

MeSH Terms (17)

Acute Kidney Injury Adult Aged Anti-Bacterial Agents Bacterial Infections Critical Illness Dialysis Solutions Female Hemodiafiltration Humans Infusions, Intravenous Male Middle Aged Penicillanic Acid Piperacillin Piperacillin, Tazobactam Drug Combination Time Factors

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