title: DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?
abstract: BACKGROUND
  Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome.
  
  
  METHODS
  This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome.
  
  
  RESULTS
  We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status.
  
  
  CONCLUSIONS
  Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.
authors.affiliation: Burns Trauma and Critical Care Research Centre, University of Queensland.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Paul
authors.forename: Murat
authors.initials: M
authors.lastname: Akova
authors.forename: Matteo
authors.initials: M
authors.lastname: Bassetti
authors.forename: Jan J
authors.initials: JJ
authors.lastname: De Waele
authors.forename: George
authors.initials: G
authors.lastname: Dimopoulos
authors.forename: Kirsi-Maija
authors.initials: KM
authors.lastname: Kaukonen
authors.forename: Despoina
authors.initials: D
authors.lastname: Koulenti
authors.forename: Claude
authors.initials: C
authors.lastname: Martin
authors.forename: Philippe
authors.initials: P
authors.lastname: Montravers
authors.forename: Jordi
authors.initials: J
authors.lastname: Rello
authors.forename: Andrew
authors.initials: A
authors.lastname: Rhodes
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D001774:Blood Chemical Analysis; D016638:Critical Illness; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D007391:International Cooperation; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D011446:Prospective Studies; D016896:Treatment Outcome; D047090:beta-Lactams / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams
keywords: adverse events; continuous infusion; extended infusion; pharmacodynamics; pharmacokinetics