title: Pharmacodynamic Characteristics of Nephrotoxicity Associated With Vancomycin Use in Children.
abstract: BACKGROUND
  Limited studies incorporating population-based pharmacokinetic modeling have been conducted to determine pharmacodynamic indices associated with nephrotoxicity during vancomycin exposure in children.
  
  
  METHODS
  A retrospective cohort analysis was conducted from September 2003 to December 2011 at 2 hospitals. Nephrotoxicity was defined as an increase in serum creatinine concentration (SCr) by ≥0.5 mg/dL, or ≥50% increase in baseline SCr, either persisting for ≥2 consecutive days. A 1-compartment model with first-order kinetics was used in NONMEM 7.2 to estimate trough concentrations (Cmin) and area under the curve over 24 hours (AUC). Univariate, classification and regression tree (CART), and multivariate analyses were conducted to identify factors contributing to nephrotoxicity.
  
  
  RESULTS
  The analyses included 680 pediatric subjects with 1576 vancomycin serum concentrations. Based on univariate analysis, median Cmin (14.2 [interquartile range, IQR, 7.1-25.4] vs 8.4 [IQR, 5.5-12.4] mcg/mL; P = .001) and AUC (544 [IQR, 359-801] vs 378 [IQR, 304-494]; P < .001) were significantly higher in the nephrotoxic group compared with the non-nephrotoxic group. Using CART, we discovered that subjects with doses ≥60 mg/kg per day and AUC >1063 mg-h/L had a significantly higher occurrence of nephrotoxicity (P = .005). Adjusting for intensive care unit stay and concomitant nephrotoxic drugs, steady-state vancomycin Cmin ≥15 mcg/mL (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 1.1-5.8; P = .028) and AUC ≥800 mg-h/L (aOR, 3.7; 95% CI, 1.2-11.0; P = .018) were associated with increased risk of nephrotoxicity.
  
  
  CONCLUSIONS
  Our study describes the pediatric exposure-nephrotoxicity relationships for vancomycin. Vancomycin Cmin ≥15 mcg/mL and AUC ≥800 mg-h/L in children are independently associated with a > 2.5-fold increased risk of nephrotoxicity and may provide justification for use of alternative antibiotics in selected situations.
authors.affiliation: University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences Miller Children's Hospital of Long Beach, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Le
authors.affiliation: Miller Children's Hospital of Long Beach, California.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ny
authors.affiliation: University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences San Diego School of Medicine, La Jolla.
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.affiliation: Department of Pharmacy, University of California, San Diego Health System.
authors.forename: James
authors.initials: J
authors.lastname: Lane
authors.affiliation: Miller Children's Hospital of Long Beach, California.
authors.forename: Becky
authors.initials: B
authors.lastname: Ngu
authors.affiliation: University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences Rady Children's Hospital San Diego, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Muus
authors.affiliation: Rady Children's Hospital San Diego, California.
authors.forename: Gale
authors.initials: G
authors.lastname: Romanowski
authors.affiliation: Miller Children's Hospital of Long Beach, California.
authors.forename: Tiana
authors.initials: T
authors.lastname: Vo
authors.affiliation: San Diego School of Medicine, La Jolla Rady Children's Hospital San Diego, California.
authors.forename: John
authors.initials: J
authors.lastname: Bradley
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D012189:Retrospective Studies; D014640:Vancomycin / Q000009:adverse effects*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D003404:Creatinine
keywords: nephrotoxicity; pediatrics; pharmacodynamic; pharmacokinetics; vancomycin