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Background Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. We conducted a randomized controlled trial (NCT03517007) of an opt-out protocol to decrease unnecessary antibiotics in selected patients with suspected sepsis. Methods We evaluated non-ICU adults remaining on broad-spectrum antibiotics with negative blood cultures at 48-96 hours at ten U.S. hospitals during September 2018-May 2020. A 23-item safety check excluded patients with ongoing signs of infection, concerning or inadequate microbiologic data, or high-risk conditions (Figure 1). Eligible patients were randomized to the opt-out protocol vs. usual care. The primary outcome was 30-day post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted by a pharmacist or physician to encourage antibiotic discontinuation or de-escalation using opt-out language, discuss rationale for continuing antibiotics, working diagnosis, and de-escalation and duration plans. Hurdle models separately compared the odds of antibiotic continuation and DOT distributions among those who continued antibiotics. Components of the De-Escalating Empiric Therapy: Opting-OUt of Rx in Selected patients with Suspected Sepsis (DETOURS) Trial Protocol Results Among 9606 screened, 767 (8%) were enrolled (Figure 2). Common reasons for exclusion were antibiotics given prior to blood culture (35%), positive culture from non-blood sites (26%), and increased oxygen requirement (21%). Intervention patients had 32% lower odds of antibiotic continuation (79% vs. 84%, OR 0.68, 95% confidence interval [0.47, 0.98]). DOT distributions among those who continued antibiotics were similar (ratio of means 1.06 [0.88-1.26], Figure 3). Fewer intervention patients were exposed to extended-spectrum agents (38% vs. 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was not safe (31%). Safety outcomes such as mortality, readmission, sepsis relapse, C. difficile, and length of stay did not differ. DETOURS Trial Flow Diagram Flow of participants through the DETOURS Trial. Observed Days of Antibiotic Therapy Among Intervention and Control Subjects in the DETOURS Trial Post-enrollment days of antibiotic therapy among 767 DETOURS Trial participants in 10 US acute care hospitals within 30 days after enrollment. Dark pink color indicates percent overlap between intervention (purple) and control (light pink) groups. Conclusion In this patient-level randomized trial of a stewardship intervention, the opt-out de-escalation protocol targeting selected patients with suspected sepsis resulted in more antibiotic discontinuations but did not affect safety events. Disclosures Rebekah W. Moehring, MD, MPH, UpToDate, Inc. (Other Financial or Material Support, Author Royalties) Michael Z. David, MD PhD, GSK (Board Member) Michael Klompas, MD, MPH, UpToDate (Other Financial or Material Support, Chapter Author)

Background Recent guidelines recommend a transition from trough-based to area-under the curve-based (AUC) monitoring for vancomycin for serious invasive methicillin-resistant Staphylococcus aureus infections. Due to the challenges of performing AUC monitoring in clinical practice, this study sought to compare the accuracy of an AUC calculated from two points using trapezoidal calculations and from a single steady-state trough combined with population assumptions. Methods This prospective cohort analysis included hospitalized patients with stable renal function from 10.2020 to 12.2020 with two vancomycin concentrations obtained at steady-state during a single dosing interval. For each patient, AUC was calculated via trapezoidal equations utilizing peak and trough concentrations (P/T) and using the trough concentration (T) combined with population volume of distribution. Appropriate concentrations were defined as a peak at least 2 hours after the end of the infusion and a trough within one hour of the next dose. The percent and actual differences were calculated between the P/T and T AUC assessments for each patient. A patient level review was independently conducted by two clinical pharmacists to evaluate if a change in dosing would have been made according to AUC estimation methodology. Results Thirty-one patients had appropriate steady-state P/T obtained. Baseline demographics are shown in Table 1 with the majority of patients being overweight with normal renal function. The mean calculated AUC for both groups was similar, P/T 544.8 and T 549.8. The mean and median percent differences were 1.85% and 0.65%, with a standard deviation of 7.3% and an apparent normal distribution (Figure 1, p = 0.94 by Shapiro’s test). The median absolute difference in AUC was 25.82 mg*h/L between methodologies. Both methods would have resulted in the same modification to the vancomycin regimen based on patient level chart review. Conclusion The single-trough method performed similarly to the more laborious P/T method. No patient would have received a dose adjustment based on the two different AUC estimation methods. The single-trough method may represent a resource and workflow conscious AUC estimation method for patients meeting population assumptions. Disclosures All Authors: No reported disclosures