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.