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 of >15 mg/liter overdoses many adults compared to area under the concentration-time curve (AUC)-guided dosing. We conducted a 3-year, prospective study of vancomycin dosing, plasma concentrations, and outcomes. In year 1, nonstudy clinicians targeted trough concentrations of 10 to 20 mg/liter (infection dependent) and controlled dosing. In years 2 and 3, the study team controlled vancomycin dosing with BestDose Bayesian software to achieve a daily, steady-state AUC/MIC ratio of ≥400, with a maximum AUC value of 800 mg · h/liter, regardless of trough concentration. For Bayesian estimation of AUCs, we used trough samples in years 1 and 2 and optimally timed samples in year 3. We enrolled 252 adults who were ≥18 years old with ≥1 available vancomycin concentration. Only 19% of all trough concentrations were therapeutic versus 70% of AUCs (P < 0.0001). After enrollment, median trough concentrations by year were 14.4, 9.7, and 10.9 mg/liter (P = 0.005), with 36%, 7%, and 6% over 15 mg/liter (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, and 2.4; P = 0.003), shorter therapy durations (8.2, 5.4, and 4.7 days; P = 0.03), and reduced nephrotoxicity (8%, 0%, and 2%; P = 0.01). The median inpatient stay was 20 days among nephrotoxic patients versus 6 days (P = 0.002). There was no difference in efficacy by year, with 42% of patients having microbiologically proven infections. Compared to trough concentration targets, AUC-guided, Bayesian estimation-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. (This study has been registered at ClinicalTrials.gov under registration no. NCT01932034.).

Keywords: Bayesian; clinical study; prospective; therapeutic drug monitoring; vancomycin.

FIG 1

Distribution of optimal sample times in year 3. (A) Actual sample times and measured concentrations are shown as open circles. The dark line shows the median simulated steady-state time-concentration profile for vancomycin administered at 1,000 mg every 12 h to a 75-kg adult with normal renal function. The gray box shows the recommended sampling trough window at 10 to 12 h after a dose at the steady state. One can easily see that optimal sampling times are frequently outside this window and that there is tremendous variability in vancomycin concentrations within a population of adult patients. (B) Categories of optimal sample times relative to the previous dose. Only 43 (21.5%) of the 200 optimally timed samples were trough concentrations.

FIG 2

(A) Violin plots by year showing the distribution of AUCs with the second vancomycin concentration and after, which reflects the effect of the method of controlling vancomycin exposure, since enrollment occurred after the first vancomycin concentration was measured. While the distributions are not statistically significantly different from each other (P = 0.29, analysis of variance), the tighter control (less variation) of vancomycin AUC is readily seen with Bayesian control in year 2 and even more so with Bayesian control and optimal sampling in year 3 (P = 0.0001 versus year 1, F-test). The solid horizontal line represents the target AUC of 400 mg · h/liter for experiments in which the MIC was 1 mg/liter or was unknown or for an organism other than S. aureus. The dashed line represents the efficacy target of 300 mg · h/liter for documented clinical response (and unknown MIC) before evaluation with BestDose. The dotted line represents the target toxicity cap of 800 mg · h/liter. These targets were used to control dosing only in years 2 and 3. (B) AUC/MIC ratios by year among subjects with documented MRSA infections and known MICs. The ratios were significantly higher and more varied using trough concentrations to dose vancomycin in year 1 than by Bayesian adaptive control of AUC in years 2 and 3 (P < 0.0001, analysis of variance). The solid horizontal line represents the usual efficacy target of 400, and the dashed line represents the acceptable target of 300 for those subjects who had an established clinical response before evaluation with BestDose. The increased exposures in year 1 were not associated with improved outcomes and were associated with increased trough concentrations and more nephrotoxicity, as described in Results.