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 ( < 0.0001). After enrollment, median trough concentrations by year were 14.4, 9.7, and 10.9 mg/liter ( = 0.005), with 36%, 7%, and 6% over 15 mg/liter ( < 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; = 0.003), shorter therapy durations (8.2, 5.4, and 4.7 days; = 0.03), and reduced nephrotoxicity (8%, 0%, and 2%; = 0.01). The median inpatient stay was 20 days among nephrotoxic patients versus 6 days ( = 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.).

Review and Validation of Bayesian Dose‐Optimizing Software and Equations for Calculation of the Vancomycin Area Under the Curve in Critically Ill Patients

“…In agreement with other data, a large percentage of patients had adequate AUC with troughs lower than 15 mg/L. Another study evaluated BestDose with collection of a single vancomycin level . AUC‐guided dosing resulted in shorter durations of therapy, less nephrotoxicity, and lower troughs while maintaining similar efficacy.…”

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

“…The authors report that 97% (36 of 37 patients) reached therapeutic goals for sirolimus after 2 to 3 months of therapy. They noted several important lessons from such a study design, which we have also noted in our own work . First, scheduled samples (eg, trough concentrations) are often not obtained at the correct time under routine clinical circumstances, which is why traditional TDM that relies on exact timing and comparison to therapeutic ranges is less robust than model‐based TDM that can handle such deviations from planned sample times.…”

“…They noted several important lessons from such a study design, which we have also noted in our own work. 49 First, scheduled samples (eg, trough concentrations) are often not obtained at the correct time under routine clinical circumstances, which is why traditional TDM that relies on exact timing and comparison to therapeutic ranges is less robust than model-based TDM that can handle such deviations from planned sample times. Second, there is usually greater within-individual variability in clinical patient populations than in study populations.…”

The Importance of Individualized Vancomycin Dosing to Ensure Optimal Exposure Early in Therapy

“…Although approximately half of adult patients may need trough concentrations >15 mg/L to ensure efficacy, the other half do not, and maintaining trough concentrations in this range puts these patients at undue risk of nephrotoxicity . This concept serves as the basis of continuous infusion vancomycin, and recent clinical data demonstrate reduced vancomycin‐associated nephrotoxicity in patients monitored by AUC relative to those monitored by trough concentrations of 15‐20 mg/L …”

“…An alternative approach to the logarithmic trapezoidal rule is the use of Bayesian software programs to estimate vancomycin AUC 24h from a single serum concentration . This approach has been shown to estimate AUC 24h from trough‐only sampling with 97% accuracy and has also been applied clinically, resulting in reduced vancomycin‐associated nephrotoxicity . Although this approach typically requires only a single vancomycin concentration, it should be noted that its accuracy depends on the population pharmacokinetic model used as the Bayesian prior and the patient population to which it is applied .…”