Influence of Renal Function on the Pharmacokinetics of Piperacillin/Tazobactam in Intensive Care Unit Patients During Continuous Venovenous Hemofiltration

Abstract

The pharmacokinetics of piperacillin/tazobactam (4 g/0.5 g every 6 or 8 hours, by 20-minute intravenous infusion) were studied in 14 patients with acute renal failure who underwent continuous venovenous hemofiltration with AN69 membranes. Patients were grouped according to severity (CL(CR) < or =10 mL/min, 10 < CL(CR) < or =50 mL/min, and CL(CR) > 50 mL/min). A noncompartmental analysis was performed. The sieving coefficient (0.78 +/- 0.28) was similar to the unbound fraction (0.65 +/- 0.24) for tazobactam, but it was significantly different (0.34 +/- 0.25) from the unbound fraction (0.78 +/- 0.14) for piperacillin. Extracorporeal clearance was 37.0% +/- 28.8%, 12.7% +/- 12.6%, and 2.8% +/- 3.2% for piperacillin in each group and 62.5% +/- 44.9%, 35.4% +/- 17.0%, and 13.1% +/- 8.0% for tazobactam. No patients presented tazobactam accumulation. In patients with CL(CR) < 50 mL/min, t(%)ss >MIC90 values were 100% for a panel of 19 pathogens, but in those with CL(CR) > 50 mL/min, t(%)ss >MIC90 indexes were 55.5% and 16.6% for pathogens with MIC90 values of 32 and 64. The extracorporeal clearance of piperacillin/tazobactam is clinically significant in patients with CL(CR) > 50 mL/min, in which the risk of underdosing and clinical failure is important and extra doses are required.

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

“…Protein binding was lower, volume of distribution was higher, and half-life was longer than described in this prescribing guide (16). Half-lives measured in our study resembled those values measured by Valtonen et al (17) for 2 L/h CVVHDF effluent, but they were shorter than those values reported in the work by Arzuaga et al (3,18). 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).…”

“…Half-lives measured in our study resembled those values measured by Valtonen et al (17) for 2 L/h CVVHDF effluent, but they were shorter than those values reported in the work by Arzuaga et al (3,18). 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 Piperacillin and Ciprofloxacin in Critically Ill Patients Undergoing Continuous Venovenous Haemodialysis or Haemodiafiltration

“…17 patients received both antibiotics as a combination therapy. The sample size of patients is higher than in other published studies [18][19][20][21][22]26,30] and underscores the validity of the study results. Of note the study population is homogenous with regard to antibiotic treatment, renal function, and type and conditions of CRRT.…”

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

“…On the other hand clearance may be unchanged [17] or decreased [4,18] and in the presence of organ dysfunction such acute kidney injury, diminished clearance may lead to massive accumulation and toxicity [25][26][27]. In patients with renal dysfunction, optimization antibiotic dosing is further complicated by the use of renal replacement therapy which provides significant and variable extracorporeal clearance for several -lactams [28][29][30][31][32][33][34]. These pharmacokinetic challenges would mean that empiric fixed dose strategy is unlikely to ensure sufficient antibiotic exposure and as well empiric dose optimization is unrealistic due the little data available to guide clinicians.…”