Establishment of an AUC0-24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia

Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of > 0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC(0-24). All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC(0-24) threshold for AKI of > 563 mg . h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC(0-24). These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.