Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units

J Antimicrob Chemother. 2006 Nov;58(5):987-93. doi: 10.1093/jac/dkl349. Epub 2006 Aug 30.


Objectives: (i) To develop a population pharmacokinetics (PK) model for cefepime in patients in intensive care units (ICUs). (ii) To assess the pharmacokinetic-pharmacodynamic profile of various cefepime dosing regimens and to assess their expected probability of target attainment (=PTA expectation value) against common ICU pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii.

Methods: Thirteen ICU patients received cefepime 2 g 12 hourly intravenous (3 min). Twelve blood samples were taken on two occasions: (i) immediately after initial dose; and (ii) between days 3 and 6 after starting therapy. Population PK models were developed using NONMEM. Based on the final covariate model, Monte Carlo simulations were undertaken (n=1000) to simulate free-drug concentrations of cefepime for two administration methods: (i) intermittent bolus administration (IBA); and (ii) continuous infusion (CI). Concentration-time profiles were evaluated by the probability of achieving free-drug concentration above the MIC for >65% of the dosing interval. Finally, using local MIC distributions of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii the PTA expectation values for each dosing administration method were evaluated.

Results: A three-compartment model with zero-order input best described the concentration-time data. The PTA expectation values for E. coli and K. pneumoniae were >90% in all CI doses but only when administered as 1 g every 6 h and higher daily doses for IBA. For the current treatment protocol, 2 g every 12 h, P. aeruginosa and A. baumannii achieved target concentrations of only 54% and 28%, respectively. For P. aeruginosa, a CI of at least 4 g/day was required to achieve a PTA expectation value>90% while for A. baumannii a 6 g/day CI only achieved a PTA expectation value of 75%.

Conclusions: When given as IBA or CI for E. coli and K. pneumoniae, cefepime should be successful in achieving the bactericidal target. For P. aeruginosa higher doses of cefepime (>4 g/day) are required to achieve the required PTA expectation value. Cefepime fails to achieve the bactericidal target even when administered at high doses, e.g. 6 g/day, for A. baumannii.

MeSH terms

  • Acinetobacter Infections / drug therapy
  • Acinetobacter Infections / metabolism
  • Acinetobacter baumannii / drug effects
  • Adult
  • Aged
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacokinetics*
  • Cefepime
  • Cephalosporins / administration & dosage*
  • Cephalosporins / pharmacokinetics*
  • Drug Administration Schedule
  • Escherichia coli / drug effects
  • Escherichia coli Infections / drug therapy
  • Escherichia coli Infections / metabolism
  • Female
  • Gram-Negative Bacterial Infections / drug therapy*
  • Gram-Negative Bacterial Infections / metabolism*
  • Gram-Negative Bacterial Infections / microbiology
  • Humans
  • Intensive Care Units
  • Klebsiella Infections / drug therapy
  • Klebsiella Infections / metabolism
  • Klebsiella pneumoniae / drug effects
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Models, Biological*
  • Pseudomonas Infections / drug therapy
  • Pseudomonas Infections / metabolism
  • Pseudomonas aeruginosa / drug effects


  • Anti-Bacterial Agents
  • Cephalosporins
  • Cefepime