Daily Sepsis Research Analysis

BACKGROUND: Sepsis remains one of the most prevalent conditions necessitating admission to intensive care units and is associated with high mortality. Unfortunately, randomized trials examining therapeutics for critically-ill patients with sepsis have been disproportionately negative, failing to identify effective interventions, likely due to the dilution of treatment effects across highly diverse populations. Designing trials to identify patients that are most likely to benefit from an intervention based on biologic mechanism, known as predictive enrichment, may be an effective strategy for enhancing clinical trial efficacy. We conducted a systematic review to summarize the use of biological markers (biomarkers) used for predictive enrichment in randomized controlled trials (RCTs) including patients with sepsis. METHODS: We conducted this review following PRISMA-ScR guidelines. We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials databases. We included RCTs that enrolled adult patients with sepsis that used molecular biomarkers for predictive enrichment in their study design. We summarize study characteristics, biomarkers used, predictive enrichment strategies, and trial outcomes narratively without statistical pooling. Risk of bias of individual studies was assessed using the Cochrane Risk of Bias tool. RESULTS: Of the 1,718 citations found with the search, we included 12 eligible studies. All studies used either blood-based circulating proteins or lipopolysaccharide markers for predictive enrichment. Five studies (42%) reported statistically significant impacts on the primary outcome, with three showing patient-important benefit (reduced mortality or disease severity) and two demonstrating improvements in surrogate outcomes related to biomarkers. Interventions that demonstrated benefit included immune, antimicrobial or coagulation modulating therapies. These five trials that showed benefit used suPAR, AT, mHLA-DR, IL-6 and EAA as biomarkers for predictive enrichment. CONCLUSIONS: This review characterizes the use of biomarkers for predictive enrichment in randomized trials of critically-ill patients with sepsis. Although the studies were heterogeneous in design and limited in number, those that employed biomarker-based enrichment strategies demonstrate a promising signal for enhanced clinical trial efficiency. The use of biomarkers for predictive enrichment in critical care trial design requires further exploration, investigation and validation.

BACKGROUND: Enterococcal infections represent 10% of intensive care unit (ICU)-acquired infections and are associated with adverse outcomes, particularly in the case of E. faecium infections. Some studies focusing on non-critically ill patients have cast doubt on the non-inferiority of daptomycin compared to other antibiotics for these infections. We aimed to describe antibiotic treatment practices for monomicrobial E. faecium bloodstream infections (BSI) in patients admitted to the ICU, and to identify factors associated with treatment failure. METHODS: This retrospective multicenter study included adult patients presenting with a monomicrobial E. faecium BSI during their stay in one of 11 ICUs of Paris University hospitals between 2017 and 2022. Patients receiving daptomycin as a definitive antibiotic regimen were compared to those receiving another molecule using competing-risks models and propensity score-based analyses. The primary outcome was a composite criterion of treatment failure including: (1) prolonged bacteremia (≥3days) under treatment and/or (2) relapse within 30 days after the end of treatment and/or (3) the need for salvage therapy within 30 days. RESULTS: Of the 166 included patients, 26 received daptomycin as a definitive antibiotic regimen, at a median dose of 10 [10-10] mg/kg/day and 140 patients received non-daptomycin-based regimens (vancomycin (69%), linezolid (19%) or a beta-lactam (11%)). Source of BSI was predominantly unknown (38%), digestive (37%) or an intravascular device (16%). All isolates were vancomycin-susceptible. Median daptomycin MIC was 3 [2-3.25] mg/L. Time to adequate antibiotic regimen (1 [0-2] vs 1 [0-2] days, p=0.22) and rates of source control (63% vs 43%, p=0.17) were not different between groups. Regarding primary outcome, daptomycin as a definitive antibiotic regimen was associated with a higher rate of treatment failure in the multivariate adjusted analysis using a Fine and Gray model (aSHR 2.53 [1.14-5.62], p=0.022). Sensitivity analyses using propensity score overlap weighting (HR 2.48 [1.05-5.86], p=0.038) or with only patients treated by vancomycin as comparators (aSHR 2.26 [1.00-5.10], p=0.051) yielded similar results. CONCLUSIONS: In this multicenter retrospective cohort of critically ill patients with monomicrobial E. faecium bloodstream infections, use of daptomycin as the definitive antibiotic regimen was associated with a higher rate of treatment failure. Further prospective studies are needed.

BACKGROUND: Limited data are available on enoxaparin use in sepsis patients requiring mechanical ventilation (MV) with platelet counts ≥150 × 10 METHODS: This was a retrospective multicenter cohort study that utilized data from the eICU Collaborative Research Database. The relationship between enoxaparin administration and ICU 28-day mortality was primarily investigated using a multivariable Cox regression model with inverse probability weighting (IPTW) based on the propensity score. RESULTS: A total of 2078 sepsis patients requiring MV with platelet counts ≥150 × 10 CONCLUSIONS: Enoxaparin administration was associated with a lower risk of ICU 28-day mortality among sepsis patients requiring MV with platelet counts ≥150 × 10