Effect of renal clearance and continuous renal replacement therapy on appropriateness of recommended meropenem dosing regimens in critically ill patients with susceptible life-threatening infections

J Antimicrob Chemother. 2018 Dec 1;73(12):3413-3422. doi: 10.1093/jac/dky370.


Background: Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.

Objectives: To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.

Methods: A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients.

Results: A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR ≥90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.

Conclusions: Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacokinetics*
  • Bacterial Infections / drug therapy*
  • Computer Simulation
  • Critical Illness*
  • Female
  • Humans
  • Male
  • Meropenem / administration & dosage
  • Meropenem / pharmacokinetics*
  • Metabolic Clearance Rate
  • Middle Aged
  • Plasma / chemistry
  • Prospective Studies
  • Renal Insufficiency / complications*
  • Renal Insufficiency / therapy
  • Renal Replacement Therapy*


  • Anti-Bacterial Agents
  • Meropenem