piperacillin--tazobactam-drug-combination and Renal-Insufficiency

This prospective pharmacokinetic study aimed to compare the clearance of piperacillin-tazobactam administered as a 24-h continuous infusion between continuous venovenous haemodiafiltration (CVVHDF) and continuous venovenous haemofiltration (CVVH) applied at equal dose in critically ill patients. A loading dose of 4.5 g of piperacillin-tazobactam followed by a continuous infusion (500 mg/h) was administered to patients randomized to receive CVVHDF or CVVH. Serial pre- and postfilter blood samples were drawn during an 8-h sampling interval. Piperacillin plasma concentrations were measured using a validated chromatography method. Piperacillin pharmacokinetics were calculated using a non-compartmental approach. In total, 212 piperacillin plasma concentrations were determined. Median [interquartile range (IQR)] total piperacillin clearance was 7.5 (5.9-11.2) L/h in the CVVHDF group and 4.7 (4.5-9.6) L/h in the CVVH group (P = 0.21). Median (IQR) piperacillin clearance related to continuous renal replacement therapy (CRRT) was 3.0 (2.7-3.2) L/h in the CVVHDF group and 2.6 (1.9-3.0) L/h in the CVVH group (P = 0.29). Mean (standard deviation) steady state concentrations were 68.4 (25.8) mg/L in the CVVHDF group and 89.1 (35.6) mg/L in the CVVH group (P = 0.16). The estimated unbound concentrations resulting from piperacillin continuous infusion were above the target susceptibility breakpoint (16 mg/L) for the entire dosing interval (100% fT

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Chromatography; Critical Illness; Female; Hemofiltration; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Plasma; Prospective Studies; Renal Insufficiency; Time Factors

To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens.. A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration ( fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs ≤ 16 μg/mL was compared between proposed and standard regimens.. At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in ≥95% PTA versus ≥76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (≥98%) versus standard regimens (≥93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (≥93%) was comparable with those of standard regimens (≥91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens.. Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs ≤ 16 μg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing.

Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Enterobacteriaceae; Humans; Infusions, Intravenous; Kidney; Microbial Sensitivity Tests; Monte Carlo Method; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Renal Insufficiency

Vancomycin and piperacillin-tazobactam are commonly used first guns in the empiric management of critically ill patients. Current studies suggest an increased prevalence of acute kidney injury with concomitant use, however, these studies are few and limited by small sample size. The purpose of this study was to compare the prevalence of nephrotoxicity after treatment with vancomycin alone and concomitant vancomycin and piperacillin-tazobactam treatment at our institution.. Concomitant vancomycin and piperacillin-tazobactam-treated patients will experience greater prevalence of nephrotoxicity compared with vancomycin-only treated patients.. This was a retrospective cohort of patients treated with vancomycin for gram-positive or mixed infections in our facility from 2005 to 2009 who were not receiving hemodialysis at the time of admission. Included patients were stratified by treatment with vancomycin, vancomycin/piperacillin-tazobactam, or vancomycin/an alternative gram-negative rod (GNR) antibiotic. p values for categorical variables were computed using χ(2) while continuous variables were computed using Kruskal-Wallis. Variables deemed statistically significant (< 0.05) were included in the multivariable, log-binomial regression model. Relative risk (RR) and 95% confidence intervals (CI), and p values were computed using a generalized estimating equation (GEE) approach with robust standard errors (i.e., Huber White "sandwich variance" estimates) to accommodate a correlated data structure corresponding to multiple episodes of infection per individual.. A total of 530 patients with 1,007 episodes of infection, were treated with vancomycin (150 patients/302 episodes of infection), vancomycin/piperacillin-tazobactam (213 patients/372 episodes of infection), or vancomycin/GNR alternative (167 patients/333 episodes of infection). Patient demographics, comorbidities, sites of infection, and organisms of infection were compared among groups. After adjusting for statistically significant variables, neither vancomycin/piperacillin-tazobactam (RR = 1.1, 95% CI = 0.99-1.2; p = 0.073) nor vancomycin/GNR alternative (RR = 1.1, 95% CI = 0.98-1.2; p = 0.097) were found to be associated with an increased risk for nephrotoxicity compared with vancomycin alone.. A difference in nephrotoxicity was not observed between vancomycin and vancomycin/piperacillin-tazobactam-treated patients at our institution. Concomitant use as empiric therapy is appropriate, although larger sample sizes are needed to analyze closely this relation among at-risk subsets of this population.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; Bacterial Infections; Critical Illness; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Renal Insufficiency; Retrospective Studies; Risk Assessment; Vancomycin

Tazobactam is a new derivative of penicillinic acid sulfone, which functions as an irreversible inhibitor of many beta-lactamases. The disposition of tazobactam M1 metabolite after intravenous (i.v.) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects with various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (ClCR) ranging from 7.4-41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dialysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluated and were similar to previous reports. Tazobactam M1 metabolite maximum plasma concentration increased as renal function declined. The terminal elimination half-life and area under the plasma concentration-time curve of the tazobactam M1 metabolite increased as renal function declined. The mean rate of recovery of the tazobactam M1 metabolite in hemodialysate during a 3- to 4.2-hour HD session 1 hour after the i.v. infusion of piperacillin/tazobactam was 25.3%. However, when HD was performed at 36-48 hours after the i.v. infusion, 57.6% of the tazobactam dose was recovered as M1 metabolite, suggesting further conversion of tazobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n = 2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of piperacillin/0.375 g of tazobactam, the predicted maximum steady-state plasma concentrations of the tazobactam M1 metabolite are 14.6 micrograms/mL, 34.8 micrograms/mL, and 48.8 micrograms/mL for subjects with ClCR 20-40 mL/min (every 6 hour dosing), ClCR < 20 mL/min (every 8 hour dosing), and on CAPD (every 12 hour dosing), respectively.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Penicillanic Acid; Peritoneal Dialysis, Continuous Ambulatory; Piperacillin; Piperacillin, Tazobactam Drug Combination; Renal Dialysis; Renal Insufficiency; Tazobactam