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Observational Study
. 2017 Apr 24;61(5):e02535-16.
doi: 10.1128/AAC.02535-16. Print 2017 May.

Establishment of an AUC 0-24 Threshold for Nephrotoxicity Is a Step Towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus Aureus Bacteremia

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Free PMC article
Observational Study

Establishment of an AUC 0-24 Threshold for Nephrotoxicity Is a Step Towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus Aureus Bacteremia

R Chavada et al. Antimicrob Agents Chemother. .
Free PMC article

Abstract

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 (AUC0-24), 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 AUC0-24 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 AUC0-24 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 AUC0-24 These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.

Keywords: AUC0–24; Bayesian estimation; MRSA; acute kidney injury; nephrotoxicity; pharmacodynamics; pharmacokinetic; trough concentrations; vancomycin.

Figures

FIG 1
FIG 1
Scatterplot of vancomycin measured trough concentrations and AUC0–24. Vertical and horizontal lines represent current recommended vancomycin trough and AUC24 targets (Spearman rho, 0.923) for clinical efficacy. Shapes represent whether patients achieved AUC0–24 and/or appropriate trough thresholds (i.e., open squares represent patient measurements which achieved AUC0–24 targets but not trough targets).
FIG 2
FIG 2
Box plots of vancomycin AUC0–24 and trough concentrations. Vancomycin AUC0–24 (light gray boxes) on y axis and trough concentrations (dark gray boxes) on the secondary axis are stratified by risk of acute kidney injury. Median and interquartile ranges are represented by horizontal lines within boxes and whiskers (representing minimum and maximum values), respectively. Circles represent outliers.
FIG 3
FIG 3
Vancomycin exposure-toxicity curve. Relationship between risk of acute kidney injury (AKI) and vancomycin AUC0–24 is represented by best-fit curve (open circles represented raw data at various AUC0–24 strata). The CART threshold is reflected by the vertical dashed lines and translates into a therapeutic vancomycin AUC0–24 range of 400 to 563.

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