title: Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units.
abstract: OBJECTIVE
  (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.
authors.affiliation: School of Pharmacy, University of Queensland, Brisbane, and Department of Intensive Care Medicine, Royal Brisbane Hospital, Australia. jroos@pharmacy.uq.edu.au
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Roos
authors.forename: Jurgen
authors.initials: J
authors.lastname: Bulitta
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000378:metabolism; D040981:Acinetobacter baumannii / Q000187:drug effects; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D007362:Intensive Care Units; D007710:Klebsiella Infections / Q000188:drug therapy / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime