title: Integrating pharmacokinetics, pharmacodynamics and MIC distributions to assess changing antimicrobial activity against clinical isolates of Pseudomonas aeruginosa causing infections in Canadian hospitals (CANWARD).
abstract: OBJECTIVE
  To study antimicrobial pharmacodynamic (PD) activity over time against clinical isolates of Pseudomonas aeruginosa in Canadian hospitals.
  
  
  METHODS
  Integrated pharmacokinetic (PK)/PD analyses with Monte Carlo simulations were used to study cefepime, meropenem, piperacillin/tazobactam, ciprofloxacin, amikacin, gentamicin and colistin. Profiles of P. aeruginosa infections were modelled using CANWARD data from January 2007 to June 2012 inclusive. The probability of target attainment (PTA) was the proportion of cases achieving a %ƒT>MIC ≥ 50% for cefepime, meropenem and piperacillin/tazobactam, an ƒAUC/MIC ≥ 90 for ciprofloxacin and the aminoglycosides, and a total AUC/MIC ≥ 60 for colistin.
  
  
  RESULTS
  Some 2126 P. aeruginosa isolates were identified. There were no significant trends over time in the PTA for cefepime (0.93-1.0), meropenem (0.89-0.92) or piperacillin/tazobactam (0.74-0.79) (data shown for the highest recommended doses). The PD activity for ciprofloxacin (PTA 0.48-0.64) was variable. There were notable improvements in the PTA for amikacin (from 0.21 to 0.55, P = 0.027), gentamicin (from 0.10 to 0.51, P = 0.035) and colistin (from 0.04 to ~0.20, P = 0.05), which were not reliably detected by MIC indices. There was a decline over time in the PTA for piperacillin/tazobactam from 0.73 to 0.61 against P. aeruginosa isolated from intensive care units (ICUs) (Pearson correlation coefficient -0.99, P = 0.003). Neither MIC50 nor MIC90 detected this reduction in PD activity.
  
  
  CONCLUSIONS
  The overall PD activity against P. aeruginosa was stable from 2007 to 2012 for cefepime, meropenem and piperacillin/tazobactam, was variable and unreliable for ciprofloxacin, and improved significantly but remained relatively low for the aminoglycosides and colistin. There was a progressive reduction over time in the PD activity of piperacillin/tazobactam against ICU isolates, which was not detected by simply assessing MIC indices.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0T5. zelenits@ms.umanitoba.ca
authors.forename: Sheryl A
authors.initials: SA
authors.lastname: Zelenitsky
authors.forename: Ethan
authors.initials: E
authors.lastname: Rubinstein
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ariano
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002170:Canada / Q000453:epidemiology; D003428:Cross Infection; D006801:Humans; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000453:epidemiology* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000890:Anti-Infective Agents