Pharmacokinetics of Piperacillin-Tazobactam in Anuric Intensive Care Patients during Continuous Venovenous Hemodialysis

Abstract

The pharmacokinetics of piperacillin-tazobactam were investigated in eight anuric intensive care patients treated by continuous venovenous hemodialysis (CVVHD). The elimination half-life of piperacillin was 4.3 ؎ 1.2 h, and that of tazobactam was 5.6 ؎ 1.3 h. The contribution of CVVHD to the overall elimination was relevant (>25%) for both drugs.Piperacillin-tazobactam is a ␤-lactam-␤-lactamase inhibitor combination with a broad spectrum of antibacterial activity against gram-positive as well as gram-negative pathogens. It is frequently used for the empirical treatment of infection in intensive care patients (2, 15). The aim of this investigation was to determine the pharmacokinetics of piperacillin-tazobactam in critically ill patients with acute anuric renal failure treated by continuous venovenous hemodialysis (CVVHD).Eight critically ill patients were included in the investigation (Table 1). Inclusion criteria were an age of Ͼ18 years, acute renal failure treated by CVVHD, anuria (Ͻ100 ml of urine/day), and treatment with piperacillin-tazobactam. Patients with severe liver failure or cholestasis were excluded. The protocol of the study was approved by the local ethical committee, and informed consent was obtained from a first-degree relative. CVVHD was performed with an AN69 hollow-fiber dialyzer (Multiflow 60; Hospal, Nuremberg, Germany) under the following conditions: a blood flow rate of 150 ml/min, a dialysate flow rate of 1.5 liters/h, and an ultrafiltrate flow rate of 80 to 200 ml/h. Doses of piperacillin-tazobactam (4.5 g of Tazobac; Wyeth-Lederle) and dosing schedules were chosen empirically by the attending physicians (Table 2). Piperacillin-tazobactam was administered intravenously over 15 min. Corresponding predialyzer blood samples and dialyzer-outlet dialysate samples were taken before drug administration, at 10 and 30 min after infusion, and at 1, 2, 4,6,8,12,20, 22, and 24 h after infusion. Sampling was performed in the first dosage interval after the dialyzer membrane was changed. Blood samples were centrifuged immediately after they were taken, and plasma and dialysate samples were frozen at Ϫ80°C until analysis. The concentrations of piperacillin and tazobactam were determined by reversed-phase high-performance liquid chromatography with UV detection, with modification of the methods reported previously (13, 16). Plasma specimens were deproteinated, and dialysate was used without pretreatment. The presence of piperacillin was determined from the water layer extracted with dichloromethane; tazobactam samples were derivatized with 1,2,3-triazole and injected without extraction. The chromatographic conditions for piperacillin were as follows: a guarded Nucleosil C 18 100-5/250 ϫ 4 column, an eluent of methanol-KH 2 PO 4 (1:1, vol/vol; 67 mM; pH 3), ambient temperature, a flow rate of 0.5 ml/min, a of 214 nm, and a retention time of ϳ20 min. The chromatographic conditions for tazobactam were as follows: a Superspher C 18 100-5/250 ϫ 4 column; an eluent of acetonitrile-Na 2 HPO 4 (1:3, vol/vol; ...

Pharmacokinetics of Piperacillin and Ciprofloxacin in Critically Ill Patients Undergoing Continuous Venovenous Haemodialysis or Haemodiafiltration

“…This is due to the larger membrane surface of the polysulfone filter [18,20,26]. This explanation is confirmed by the finding that the calculated volume of distribution of 0.28 l/kg is similar to those already reported [21][22][23]. Acute renal failure can alter pharmacokinetics of critical ill patients [9].…”

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

“…Total and extracorporeal clearance was higher in our study (75 versus 50 ml/min; 29.7 versus 11.45 ml/min, respectively) than reported in the work by Arzuaga et al (3,18) for patients with severe renal failure on predilution CVVH with much lower effluent rates than used here (3). Compared with the measurements in the work by Mueller et al (4), our patients had lower elimination rate constants for both piperacillin and tazobactam.…”

“…Patients with severe infections often have multisystem organ failure requiring renal replacement therapy, and continuous therapies are frequently preferred over intermittent hemodialysis in intensive care patients to avoid the development or exacerbation of hypotension and maximize fluid removal. Current dosing recommendations for piperacillin-tazobactam in patients receiving continuous renal replacement therapy (CRRT) (1,2) originate from either pharmacokinetic estimates or studies with relatively few patients and lower doses of CRRT than are used today (3,4). We designed this multicenter prospective observational study to evaluate the pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in patients receiving CRRT with contemporary dialysis equipment and prescriptions.…”

Pharmacokinetics of Intravenous Piperacillin Administration in Patients Undergoing On-Line Hemodiafiltration

“…The pharmacokinetics of intravenously administered piperacillin have been described in healthy patients (3,5,11); patients with decreased renal function (8,19); patients undergoing hemodialysis (6,8); and patients experiencing continuous venovenous hemofiltration (17), continuous venovenous hemodialysis (12), and continuous venovenous hemodiafiltration (16). However, they have not been investigated in patients undergoing on-line HDF, which has been adopted in many dialysis centers around the globe.…”