title: Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study.
abstract: BACKGROUND
  The impact of in vitro resistance on initially appropriate antibiotic therapy (IAAT) remains unclear. We elucidated the relationship between non-IAAT and mortality, and between IAAT and multi-drug resistance (MDR) in sepsis due to Gram-negative bacteremia (GNS).
  
  
  METHODS
  We conducted a single-center retrospective cohort study of adult intensive care unit patients with bacteremia and severe sepsis/septic shock caused by a gram-negative (GN) organism. We identified the following MDR pathogens: MDR P. aeruginosa, extended spectrum beta-lactamase and carbapenemase-producing organisms. IAAT was defined as exposure within 24 hours of infection onset to antibiotics active against identified pathogens based on in vitro susceptibility testing. We derived logistic regression models to examine a) predictors of hospital mortality and b) impact of MDR on non-IAAT. Proportions are presented for categorical variables, and median values with interquartile ranges (IQR) for continuous.
  
  
  RESULTS
  Out of 1,064 patients with GNS, 351 (29.2%) did not survive hospitalization. Non-survivors were older (66.5 (55, 73.5) versus 63 (53, 72) years, P = 0.036), sicker (Acute Physiology and Chronic Health Evaluation II (19 (15, 25) versus 16 (12, 19), P < 0.001), and more likely to be on pressors (odds ratio (OR) 2.79, 95% confidence interval (CI) 2.12 to 3.68), mechanically ventilated (OR 3.06, 95% CI 2.29 to 4.10) have MDR (10.0% versus 4.0%, P < 0.001) and receive non-IAAT (43.4% versus 14.6%, P < 0.001). In a logistic regression model, non-IAAT was an independent predictor of hospital mortality (adjusted OR 3.87, 95% CI 2.77 to 5.41). In a separate model, MDR was strongly associated with the receipt of non-IAAT (adjusted OR 13.05, 95% CI 7.00 to 24.31).
  
  
  CONCLUSIONS
  MDR, an important determinant of non-IAAT, is associated with a three-fold increase in the risk of hospital mortality. Given the paucity of therapies to cover GN MDRs, prevention and development of new agents are critical.
authors.affiliation: EviMed Research Group, LLC, PO Box 303, Goshen, MA, 01032, USA. evimedgroup@gmail.com.|University of Massachusetts, PO Box 303, Amherst, MA, USA. evimedgroup@gmail.com.
authors.forename: Marya D
authors.initials: MD
authors.lastname: Zilberberg
authors.affiliation: Washington Hospital Center, 110 Irving St NW, Washington, DC, 20010, USA. andrew.shorr@gmail.com.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Shorr
authors.affiliation: St. Louis College of Pharmacy, 4588 Parkview Place, St. Louis, MO, 63110, USA. Scott.micek@stlcop.edu.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Micek
authors.affiliation: University of New Mexico School of Medicine, Department of Medicine, MSC 10 5550, 1 University of New Mexico, Albuquerque, NM, 87131, USA. c.vazquezguillamet@gmail.com.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vazquez-Guillamet
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, St. Louis, MO, 63110, USA. mkollef@dom.wustl.edu.
authors.forename: Marin H
authors.initials: MH
authors.lastname: Kollef
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D017052:Hospital Mortality / Q000639:trends*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D012772:Shock, Septic / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*
chemical_list: D000900:Anti-Bacterial Agents