title: Elevated β-lactam concentrations associated with neurological deterioration in ICU septic patients.
abstract: BACKGROUND
  Although β-lactams are considered to have a safe therapeutic profile, neurotoxicity has been reported. The aim of this study was to assess the association between β-lactam concentrations and neurological alterations in septic ICU patients.
  
  
  METHODS
  Retrospective study on all ICU patients who were treated with meropenem (MEM), piperacillin-tazobactam (TZP) or ceftazidime/cefepime (CEF) and in whom at least one β-lactam trough concentration (C min) was determined. Drug levels were measured using high-performance liquid chromatography; C min was normalized to the clinical breakpoint of Pseudomonas aeruginosa (as determined by EUCAST) for each drug (C min/MIC). Changes in neurological status were evaluated using changes in the neurological sequential organ failure assessment score (ΔnSOFA) using the formula: ΔnSOFA = nSOFA(day of TDM) - nSOFA(ICU admission). Worsening neurological status (NWS) was defined as a ΔnSOFA ≥ 1 for an nSOFA on admission of 0-2.
  
  
  RESULTS
  We collected 262 C min in 199 patients (130 MEM, 85 TZP, 47 CEF). Median APACHE II score and GCS on admission were 17 and 15, respectively. Overall ICU mortality was 27 %. There were no differences in the occurrence of NWS between antibiotics (39% for MEM, 32% for TZP and 35% for CEF). The occurrence of NWS increased with increasing C min/MIC ranges (P = 0.008); this correlation was found for TZP (P = 0.05) and MEM (P = 0.01), but not for CEF. C min/MIC was an independent predictive factor for NWS (OR 1.12 [1.04-1.20]).
  
  
  CONCLUSIONS
  We found a correlation between high β-lactam trough concentrations and increased occurrence of neurological deterioration in septic ICU patients. Although our data cannot determine causality, monitoring of β-lactam levels should be considered when deterioration of neurological status occurs during critical illness.
authors.affiliation: Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium - ftaccone@ulb.ac.be.
authors.forename: M
authors.initials: M
authors.lastname: Beumier
authors.forename: G S
authors.initials: GS
authors.lastname: Casu
authors.forename: M
authors.initials: M
authors.lastname: Hites
authors.forename: F
authors.initials: F
authors.lastname: Wolff
authors.forename: F
authors.initials: F
authors.lastname: Cotton
authors.forename: J L
authors.initials: JL
authors.lastname: Vincent
authors.forename: F
authors.initials: F
authors.lastname: Jacobs
authors.forename: F S
authors.initials: FS
authors.lastname: Taccone
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003422:Critical Care; D016638:Critical Illness; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009422:Nervous System Diseases / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012189:Retrospective Studies; D018805:Sepsis / Q000097:blood* / Q000150:complications* / Q000503:physiopathology; D047090:beta-Lactams / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams