title: Antibiotic exposure and resistance development in Pseudomonas aeruginosa and Enterobacter species in intensive care units.
abstract: OBJECTIVE
  We quantified the association between antibiotic exposure and acquisition of antibiotic resistance in Pseudomonas aeruginosa and Enterobacter species in intensive care unit patients.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  In 1,201 patients, respiratory tract colonization was determined through regular screening on admission, twice weekly, and on discharge. Primary outcome was the acquisition of antibiotic resistance in previous antibiotic sensitive P. aeruginosa and Enterobacter species, with acquisition attributable to cross-transmission excluded based on genotyping and epidemiologic linkage. Cox regression analysis, adjusted for covariates, was performed to calculate hazard ratios of patients exposed to antibiotics compared to patients not exposed to antibiotics.
  
  
  RESULTS
  In total, 194 and 171 patients were colonized with P. aeruginosa and Enterobacter species, respectively. Two or more cultures per episode were available for 126 and 108 patients. For P. aeruginosa, ceftazidime exposure was associated with 6.3 acquired antibiotic resistance events per 100 days of exposure, whereas incidence rates were lower for ciprofloxacin, meropenem, and piperacillin-tazobactam. In multivariate analysis, meropenem, ciprofloxacin, and ceftazidime were significantly associated with risk of resistance development in P. aeruginosa (adjusted hazard ratio, 11.1; 95% confidence interval, 2.4-51.5 for meropenem; adjusted hazard ratio, 4.1; 95% confidence interval, 1.1-16.2 for ciprofloxacin; adjusted hazard ratio, 2.5; 95% confidence interval, 1.1-5.5 for ceftazidime). For Enterobacter, ceftriaxone and ciprofloxacin exposure were associated with most antibiotic resistance acquisitions. No significant associations were found in multivariate analysis.
  
  
  CONCLUSIONS
  Meropenem exposure is associated with the highest risk of resistance development in P. aeruginosa. Increasing carbapenem use attributable to emergence of Gram-negative bacteria producing extended-spectrum β-lactamases will enhance antibiotic resistance in P. aeruginosa.
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. d.s.y.ong@umcutrecht.nl
authors.forename: David S Y
authors.initials: DS
authors.lastname: Ong
authors.forename: Irene P
authors.initials: IP
authors.lastname: Jongerden
authors.forename: Anton G
authors.initials: AG
authors.lastname: Buiting
authors.forename: Maurine A
authors.initials: MA
authors.lastname: Leverstein-van Hall
authors.forename: Ben
authors.initials: B
authors.lastname: Speelberg
authors.forename: Jozef
authors.initials: J
authors.lastname: Kesecioglu
authors.forename: Marc J M
authors.initials: MJ
authors.lastname: Bonten
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004754:Enterobacter / Q000187:drug effects* / Q000302:isolation & purification; D005260:Female; D005838:Genotype; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents