Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin-tazobactam administered by continuous infusion

J Crit Care. 2018 Dec:48:66-71. doi: 10.1016/j.jcrc.2018.08.026. Epub 2018 Aug 23.


Purpose: To determine whether augmented renal clearance (ARC) impacts negatively on piperacillin-tazobactam unbound concentrations in critically ill patients receiving 16 g/2 g/day administered continuously.

Material and methods: Fifty nine critically ill patients without renal impairment underwent 24-h creatinine clearance (CrCL) measurement and therapeutic drug monitoring during the first three days of antimicrobial therapy by piperacillin-tazobactam. The main outcome was the rate of piperacillin underexposure, defined by at least one of three samples under 16 mg/L. Monte Carlo simulation was performed to predict the distribution of piperacillin concentrations for various CrCL and minimal inhibitory concentration (MIC) values.

Results: The rate of piperacillin underexposure was 19%, significantly higher in ARC patients (0 vs. 31%, p = .003). A threshold of CrCL ≥ 170 mL/min had a sensitivity and specificity of 1 (95%CI: 0.79-1) and 0.69 (95%CI: 0.61-0.76) to predict piperacillin underexposure. In ARC patients, a 20 g/2.5 g/24 h PTZ dosing regimen was associated with the highest probability to reach the 16 mg/L empirical target, without risk of excessive dosing.

Conclusions: When targeting a theoretical MIC at the upper limit of the susceptibility range, the desirable target (100%fT>16) may not be achieved in patients with CrCL ≥ 170 mL/min receiving PTZ 16 g/2 g/day administered continuously.

Keywords: Augmented renal clearance; Critical illness; Pharmacokinetics; Piperacillin – Tazobactam; Β-Lactams.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacology
  • Critical Illness / therapy
  • Dose-Response Relationship, Drug
  • Drug Monitoring
  • Female
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Piperacillin, Tazobactam Drug Combination / administration & dosage*
  • Piperacillin, Tazobactam Drug Combination / pharmacology
  • Retrospective Studies
  • Sepsis / drug therapy*


  • Anti-Bacterial Agents
  • Piperacillin, Tazobactam Drug Combination