title: The association between colonization with carbapenemase-producing enterobacteriaceae and overall ICU mortality: an observational cohort study.
abstract: OBJECTIVE
  Infections caused by carbapenemase-producing Enterobacteriaceae are increasing worldwide, especially in ICUs, and have been associated with high mortality rates. However, unequivocally demonstrating causality of such infections to death is difficult in critically ill patients because of potential confounding and competing events. Here, we quantified the effects of carbapenemase-producing Enterobacteriaceae carriage on patient outcome in two Greek ICUs with carbapenemase-producing Enterobacteriaceae endemicity.
  
  
  METHODS
  Observational cohort study.
  
  
  METHODS
  Two ICUs with carbapenemase-producing Enterobacteriaceae endemicity.
  
  
  METHODS
  Patients admitted to the ICU with an expected length of ICU stay of at least 3 days were included.
  
  
  METHODS
  None.
  
  
  RESULTS
  Carbapenemase-producing Enterobacteriaceae colonization was established through screening in perineum swabs obtained at admission and twice weekly and inoculated on chromogenic plates. Detection of carbapenemases was performed phenotypically, with confirmation by polymerase chain reaction. Risk factors for ICU mortality were evaluated using cause-specific hazard ratios and subdistribution hazard ratios, with carbapenemase-producing Enterobacteriaceae colonization as time-varying covariate. One thousand seven patients were included, 36 (3.6%) were colonized at admission, and 96 (9.5%) acquired carbapenemase-producing Enterobacteriaceae colonization during ICU stay, and 301 (29.9%) died in ICU. Of 132 carbapenemase-producing Enterobacteriaceae isolates, 125 (94.7%) were Klebsiella pneumoniae and 74 harbored K. pneumoniae carbapenemase (56.1%), 54 metallo-β-lactamase (40.9%), and four both (3.0%). Carbapenemase-producing Enterobacteriaceae colonization was associated with a statistically significant increase of the subdistribution hazard ratio for ICU mortality (subdistribution hazard ratio=1.79; 95% CI, 1.31-2.43), not explained by an increased daily hazard of dying (cause-specific hazard ratio for death=1.02; 95% CI, 0.74-1.41), but by an increased length of stay (cause-specific hazard ratio for discharge alive=0.73; 95% CI, 0.51-0.94). Other risk factors in the subdistribution hazard model were Acute Physiology and Chronic Health Evaluation II score (subdistribution hazard ratio=1.13; 95% CI, 1.11-1.15), female gender (subdistribution hazard ratio=1.29; 95% CI, 1.02-1.62), presence of solid tumor (subdistribution hazard ratio=1.54; 95% CI, 1.15-2.06), hematopoietic malignancy (subdistribution hazard ratio=1.61; 95% CI, 1.04-2.51), and immunodeficiency (subdistribution hazard ratio=1.59; 95% CI, 1.11-2.27).
  
  
  CONCLUSIONS
  Patients colonized with carbapenemase-producing Enterobacteriaceae have on average a 1.79 times higher hazard of dying in ICU than noncolonized patients, primarily because of an increased length of stay.
authors.affiliation: 1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 3Department of Molecular Microbiology, National Medicines Institute, Warsaw, Poland. 44th Department of Internal Medicine, Athens University Medical School, University General Hospital Attikon, Athens, Greece. 56th Department of Internal Medicine, Hygeia General Hospital, Athens University Medical School, Athens, Greece. 6Infectious Diseases Unit, Laikon General Hospital, University of Athens, Athens, Greece. 7Service de Reanimation Médicale and INSERM U657, Institut Pasteur, APHP GH Henri Mondor, Université Paris Est-Créteil, Creteil, France. 8Department of Intensive Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mirjam J D
authors.initials: MJ
authors.lastname: Dautzenberg
authors.forename: Ann N
authors.initials: AN
authors.lastname: Wekesa
authors.forename: Marek
authors.initials: M
authors.lastname: Gniadkowski
authors.forename: Anastasia
authors.initials: A
authors.lastname: Antoniadou
authors.forename: Helen
authors.initials: H
authors.lastname: Giamarellou
authors.forename: George L
authors.initials: GL
authors.lastname: Petrikkos
authors.forename: Anna
authors.initials: A
authors.lastname: Skiada
authors.forename: Christian
authors.initials: C
authors.lastname: Brun-Buisson
authors.forename: Marc J M
authors.initials: MJ
authors.lastname: Bonten
authors.forename: Lennie P G
authors.initials: LP
authors.lastname: Derde
mesh_terms: D018806:APACHE; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001426:Bacterial Proteins / Q000302:isolation & purification*; D002353:Carrier State / Q000175:diagnosis; D015331:Cohort Studies; D016638:Critical Illness; D003428:Cross Infection / Q000401:mortality*; D004755:Enterobacteriaceae / Q000302:isolation & purification*; D004756:Enterobacteriaceae Infections / Q000401:mortality*; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data*; D008297:Male; D008875:Middle Aged; D010502:Perineum / Q000382:microbiology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D012737:Sex Factors; D001618:beta-Lactamases / Q000302:isolation & purification*
chemical_list: D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase