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

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 ß-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.

Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT.

BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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.

Management of hemodialysis catheter-related bacteremia with an adjunctive antibiotic lock solution.

BACKGROUND: Tunneled dialysis catheters are complicated by frequent systemic infections. Standard therapy of catheter-associated bacteremia involves both systemic antibiotics and catheter replacement. Recent data suggest that biofilms in the catheter lumen are responsible for the bacteremia, and that instillation of an antibiotic lock (highly concentrated antibiotic solution) into the catheter lumen after dialysis sessions can eradicate the biofilm. METHODS: We analyzed prospectively the efficacy of an antibiotic lock protocol, in conjunction with systemic antibiotics, for treatment of patients with dialysis catheter-associated bacteremia without catheter removal. Protocol success was defined as resolution of fever and negative surveillance cultures one week following completion of the protocol. Protocol failure was defined as persistence of fever or surveillance cultures positive for any pathogen. In addition, infection-free catheter survival was compared to that observed in institutional historical control patients treated with catheter replacement. RESULTS: Blood cultures were positive in 98 of 129 of episodes (76%) in which patients dialyzing with a catheter had fever or chills. Protocol success occurred in 40 of 79 infected patients (51%) treated with the antibiotic lock. Protocol failure occurred in 39 cases (49%): 7 had persistent fever, 15 had positive surveillance cultures (9 for Candida and 6 for bacteria), and 17 required catheter removal due to malfunction. Each of the pathogens in the surveillance cultures was different from the original pathogen in that patient. Eight of the 9 secondary Candida infections and all 6 secondary bacterial infections resolved after catheter exchange and specific antimicrobial treatment. Overall catheter survival with the antibiotic lock protocol was similar to that observed among patients managed with catheter replacement (median survival, 64 vs. 54 days, P = 0.24). CONCLUSIONS: Use of an antibiotic lock, in conjunction with systemic antibiotic therapy, can eradicate catheter-associated bacteremia while salvaging the catheter in about one half of cases. Moreover, this management approach offers clinical advantages over routine catheter exchange.