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

Abstract

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 b-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 mg/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.

Piperacillin–tazobactam as alternative to carbapenems for ICU patients

“…Extending the infusion duration to 4 h should allow the attainment of several times the MIC. However, dose requirements seem to importantly depend on the membrane used and the effluent rate that are major aspects of CRRT poorly investigated to date [ 41 , 42 ]. An interesting point is that piperacillin concentration in the dialysate effluent is equal to the free plasma concentration and can therefore be used for the individual adaptation of the dose via therapeutic drug monitoring (TDM) [ 43 ].…”

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“…However, many patients receiving CRRT do not reach target antibiotic concentrations in plasma. In these cases, extended infusion (e.g., 4-h infusion) of piperacillin-tazobactam may be beneficial for achieving the optimal plasma concentration [15].…”

What’s new in pharmacokinetics of antimicrobials in AKI and RRT?

“…Further exploration of the role of changing the method of infusion of beta-lactams was separately performed by Shotwell et al [12] and Jamal et al [13,14]. Shotwell and colleagues analysed piperacillin concentrations in 68 CRRT patients.…”