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 firstorder kinetics was used in NONMEM 7.2 to estimate trough concentrations (C min ) 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. [IQR,; 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 C min 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 C min 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.

Background Optimal monitoring of vancomycin in children needs evaluation using the exposure target with area-under-the-curve of the serum concentrations vs. time over 24 hours (AUC). Our study objectives were to: (1) compare the accuracy and precision of vancomycin AUC estimations using two sampling strategies – one serum concentration sample (1S, near trough) versus two samples (2S, near peak and trough) against the rich sample (RS) method; and (2) determine the performance of these strategies in predicting future AUC against an internal validation sample (VS). Methods This was an retrospective cohort study using population-based pharmacokinetic modeling with Bayesian post-hoc individual estimations in NONMEM 7.2. Pediatric subjects 3 months to 21 years of age who received vancomycin ≥ 48 hours and had ≥ 3 drug samples within the first ≤ 96 hours of therapy were enrolled. Outcome measures were the accuracy, precision and internal predictive performance of AUC estimations using two monitoring strategies (i.e., 1S vs 2S) against the RS (which was derived from modeling all serum vancomycin concentrations obtained anytime during therapy), and VS (from serum concentrations obtained after 96 hours of therapy). Results Analysis included 138 subjects with 712 vancomycin serum concentrations. Median age was 6.1 (interquartile range [IQR] 2.2-12.2) yr, weight 22 (13-38) kg, and baseline serum creatinine 0.37 (0.30-0.50) mg/dL. Both accuracy and precision were improved with the 2S, compared to 1S, for AUC estimations (-2.0% vs -7.6 % and 10.3% vs 12.8%, respectively) against the RS. Improved accuracy and precision were also observed for 2S when evaluated against VS in predicting future AUC. Conclusion Compared to 1S, the 2S sampling strategy for vancomycin monitoring improved accuracy and precision in estimating and predicting future AUC. Evaluating two drug concentrations in children may be prudent to ensure adequate drug exposure.

Patients' self-reported personal medication lists are often incomplete and have discrepancies with clinic medication lists. Interventions are needed to improve medication information transfer between patients, providers and healthcare systems.