Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing

Abstract

We hypothesized that dosing vancomycin to achieve trough concentrations >15 mg/L overdoses many adults compared to AUC-guided dosing. We conducted a 3-year, prospective study of vancomycin dosing, plasma concentrations, and outcomes. In year 1, non-study clinicians targeted trough concentrations of 10-20 mg/L (infection dependent) and controlled dosing. In years 2 and 3, the study team controlled vancomycin dosing with the BestDose Bayesian software to achieve a daily, steady-state AUC:MIC≥400, with maximum AUC 800 mg*h/L, regardless of trough concentration. For Bayesian estimation of AUCs, we used trough samples in years 1-2 and optimally timed samples in year 3. We enrolled 252 adults ≥18 years old with ≥1 available vancomycin concentration. Only 19% of all trough concentrations were therapeutic vs. 70% of AUCs (P<0.0001). After enrollment, median trough concentrations by year were 14.4, 9.7, and 10.9 mg/L (P=0.005), with 36%, 7%, and 6% over 15 mg/L (P<0.0001). Bayesian AUC-guided dosing in years 2 and 3 was associated with fewer additional blood samples per subject (3.6, 2.0, 2.4, P=0.003), shorter therapy (8.2, 5.4, 4.7 days, P=0.03), and reduced nephrotoxicity (8%, 0% and 2%, P=0.01). Among nephrotoxic patients, the median inpatient stay was 20 vs. 6 days (P=0.002). There was no difference in efficacy by year, with 42% having microbiologically proven infections. Compared to trough concentration targets, AUC-guided, Bayesian-assisted vancomycin dosing was associated with decreased nephrotoxicity, reduced per-patient blood sampling, and shorter length of therapy, without compromising efficacy. These benefits have the potential for substantial cost savings.