title: Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.
abstract: BACKGROUND
  β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets.
  
  
  METHODS
  Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR).
  
  
  RESULTS
  Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis.
  
  
  CONCLUSIONS
  Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.
authors.affiliation: Department of Intensive Care Medicine, Herston, Brisbane, QLD, Australia; Burns, Trauma, and Critical Care Research Center, University of Queensland, Herston, Brisbane, QLD, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Udy
authors.affiliation: Department of Intensive Care Medicine, Herston, Brisbane, QLD, Australia; Pharmacy Department, Herston, Brisbane, QLD, Australia; Burns, Trauma, and Critical Care Research Center, University of Queensland, Herston, Brisbane, QLD, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Varghese
authors.affiliation: Department of Intensive Care Medicine, Herston, Brisbane, QLD, Australia.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Altukroni
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Briscoe
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia.
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Ungerer
authors.affiliation: Department of Intensive Care Medicine, Herston, Brisbane, QLD, Australia; Burns, Trauma, and Critical Care Research Center, University of Queensland, Herston, Brisbane, QLD, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Department of Intensive Care Medicine, Herston, Brisbane, QLD, Australia; Pharmacy Department, Herston, Brisbane, QLD, Australia; Burns, Trauma, and Critical Care Research Center, University of Queensland, Herston, Brisbane, QLD, Australia. Electronic address: j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D016638:Critical Illness / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015999:Multivariate Analysis; D012372:ROC Curve; D012189:Retrospective Studies; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome; D047090:beta-Lactams / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D003404:Creatinine