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.).

Acute kidney injury (AKI) associated with high-dose vancomycin (VAN) therapy is a clinical concern, but no uniform diagnostic criteria exist. The AKI Network (AKIN) proposed new criteria to diagnose AKI based on abrupt changes in serum creatinine or urine output. We conducted a prospective observational study to determine the incidence and severity of AKI and associated outcomes using the AKIN criteria versus traditional definitions. Eligible patients (n ‫؍‬ 227) were elderly (median, 70 years) and received VAN therapy for 8 days (median). AKI occurred in 43 patients (19%) using AKIN criteria at an onset of 6 days. AKI incidence was similar for patients with a trough level of >15 (24%; 17/72) versus <15 (17%; 26/155) g/ml. ; P ‫؍‬ 0.04). Seventeen of the AKI patients met traditional criteria, of whom more patients had stage 2 and 3 AKI (76% versus 8%; P ‫؍‬ 0.0001), dosage adjustment (41% versus 15%) and renal consultation (35% versus 12%), prolonged length of stay after AKI (11 versus 7.5 days) and died (29% versus 12%) than those diagnosed by AKIN criteria (P value not significant). Use of AKIN criteria for AKI has the potential to improve care of VAN-treated patients by facilitating early detection of AKI and warrants confirmation in large prospective trials.

Sustained elevation of interleukin-10/tissue necrosis factor ratio at 72 hours suggests a dysregulated immune response and may be used to guide management to improve outcomes.