title: A pharmacodynamic analysis of resistance trends in pathogens from patients with infection in intensive care units in the United States between 1993 and 2004.
abstract: BACKGROUND
  Increasing nosocomial pathogen resistance to available antimicrobial agents is of growing concern. While higher MICs can diminish antimicrobial effectiveness, dose adjustments often mitigate this effect. This study's objective was to ascertain whether MICs among major pathogens in the ICU to several commonly used agents have increased enough to significantly impact their ability to achieve bactericidal effect.
  
  
  METHODS
  Cefepime, ceftriaxone, imipenem and piperacillin-tazobactam MICs were determined with 74,394 Gram-negative bacilli obtained from ICU patients with various infections in the US between 1993 and 2004. Results were grouped into four 3-year periods. The predicted cumulative fraction of response (CFR) was estimated based on patient-derived pharmacokinetic values and Monte Carlo simulation. Trends in CFR over the four study periods were assessed using the Cochran-Armitage test. The primary analysis included all organisms combined; Pseudomonas aeruginosa and Acinetobacter species were also evaluated individually.
  
  
  RESULTS
  In the primary analysis, imipenem 500 mg q6h showed CFRs from 87% to 90% across all four study periods, with a trend toward slightly improved bactericidal target attainment (p < 0.01). CFRs for cefepime 2 g q12h and piperacillin-tazobactam 4.5 g q6h both declined by 2% (p < 0.01 and p < 0.05, respectively), reflecting upward shifts in the underlying MIC distributions. Ceftriaxone had <52% CFR for all regimens in all periods, with no significant trend. Against P. aeruginosa, significant declines in CFR were seen for (range, p-value): imipenem 1 g q8h (82%-79%, p < 0.01), cefepime 1 g q12h (70%-67%, p < 0.01), cefepime 2 g q12h (84%-82%, p < 0.05), piperacillin-tazobactam 3.375 g q6h (76%-73%, p < 0.01), piperacillin-tazobactam 4.5 g q8h (71%-68%, p < 0.01), and piperacillin-tazobactam 4.5 g q6h (80%-77%, p < .01). Against Acinetobacter spp., all regimens of imipenem, cefepime and piperacillin-tazobactam showed significant declines in CFR over time (p < 0.01).
  
  
  CONCLUSIONS
  Our observations suggest that as a result of increasing antimicrobial resistance among ICU pathogens in the US, drug effectiveness, assessed as a function of individual agents' ability to attain pharmacodynamic targets, has declined, especially with P. aeruginosa and Acinetobacter spp. Cefepime 2 g q8h and imipenem were the most potent agents against these species, respectively. More aggressive dosing of all of the agents characterized could preserve their clinical utility, but this must be balanced with safety and tolerability issues by the physician.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA. keagye@harthosp.org
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Eagye
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Lockhart
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
authors.forename: Gary V
authors.initials: GV
authors.lastname: Doern
authors.forename: Gale
authors.initials: G
authors.lastname: Gallagher
authors.forename: Murray A
authors.initials: MA
authors.lastname: Abramson
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003428:Cross Infection / Q000382:microbiology*; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology*; D006801:Humans; D007362:Intensive Care Units; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D014481:United States; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams