title: Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?
abstract: BACKGROUND
  Contemporary vancomycin dosing schemes are designed to achieve an area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio of ≥400. However, scant clinical data exist to support this target and available data relied on pharmacokinetic formulas based on daily vancomycin dose and estimated renal function (demographic pharmacokinetic model) to estimate AUCs.
  
  
  METHODS
  A cohort study of hospitalized, adult, nondialysis patients with methicillin-resistant Staphylococcus aureus bloodstream infections treated with vancomycin was performed to quantitatively evaluate the relationship between vancomycin exposure and outcomes. Bayesian techniques were used to estimate vancomycin exposure profile for day 1 and 2 of therapy for each patient based on their dosing schedule and collected concentrations. Classification and Regression Tree (CART) analysis was used to identify day 1 and 2 exposure thresholds associated with an increased risk of failure. Failure was defined as 30-day mortality, bacteremia was ≥7 days, or recurrence.
  
  
  RESULTS
  During the study period, 123 cases met criteria. Failure was uniformly less pronounced (approximately 20% less in absolute value) in patients who achieved the CART-derived day 1 and 2 thresholds for AUC/MIC by broth microdilution and AUC/MIC by Etest. In the multivariate analyses, all risk ratios were approximately 0.5 for all CART-derived AUC/MIC exposure thresholds, indicating that achievement of CART-derived AUC/MIC exposure thresholds was associated with a 2-fold decrease in failure.
  
  
  CONCLUSIONS
  These findings establish the critical importance of daily AUC/MIC ratios during the first 2 days of therapy. As with all observational studies, these findings should be interpreted cautiously and validated in a multicenter randomized trial before adoption into practice.
authors.affiliation: Albany College of Pharmacy and Health Sciences, New York.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.affiliation: Institute for Therapeutic Innovation, College of Medicine, University of Florida, Lake Nona.
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.affiliation: Albany College of Pharmacy and Health Sciences, New York.
authors.forename: Evan
authors.initials: E
authors.lastname: Zasowski
authors.affiliation: Albany College of Pharmacy and Health Sciences, New York.
authors.forename: Amanda
authors.initials: A
authors.lastname: Dihmess
authors.affiliation: University at Albany, State University of New York.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lazariu
authors.affiliation: Albany College of Pharmacy and Health Sciences, New York.
authors.forename: Leon
authors.initials: L
authors.lastname: Cosler
authors.affiliation: University at Albany, State University of New York.
authors.forename: Louise-Anne
authors.initials: LA
authors.lastname: McNutt
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D019540:Area Under Curve; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology*; D001499:Bayes Theorem; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D017211:Treatment Failure; D014640:Vancomycin / Q000008:administration & dosage*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin
keywords: MRSA; outcomes; pharmacodynamics; pharmacokinetics; vancomycin