Daily Sepsis Research Analysis
Three studies stand out today in sepsis research: a systematic review shows that biomarker-based predictive enrichment can enhance success signals in sepsis RCTs; a multicenter ICU cohort finds higher treatment failure with daptomycin versus alternatives for Enterococcus faecium bloodstream infections; and an observational multicenter analysis links enoxaparin use to lower 28-day ICU mortality in ventilated sepsis patients with adequate platelet counts.
Summary
Three studies stand out today in sepsis research: a systematic review shows that biomarker-based predictive enrichment can enhance success signals in sepsis RCTs; a multicenter ICU cohort finds higher treatment failure with daptomycin versus alternatives for Enterococcus faecium bloodstream infections; and an observational multicenter analysis links enoxaparin use to lower 28-day ICU mortality in ventilated sepsis patients with adequate platelet counts.
Research Themes
- Predictive enrichment and biomarker-guided trial design in sepsis
- Antibiotic effectiveness for E. faecium bloodstream infections in ICU
- Anticoagulation and outcomes in mechanically ventilated sepsis patients
Selected Articles
1. Predictive enrichment using biomarkers in studies of critically-ill patients with sepsis: a systematic review.
This systematic review of 12 RCTs found that biomarker-based predictive enrichment (e.g., suPAR, antithrombin, mHLA-DR, IL-6, EAA) can identify subgroups with improved outcomes to immune, antimicrobial, or coagulation-modulating therapies. The findings support embedding biologically-driven enrichment strategies to increase trial efficiency in sepsis.
Impact: Addresses a central reason for repeated negative sepsis RCTs by proposing and summarizing evidence for predictive enrichment strategies.
Clinical Implications: Encourages biomarker-guided enrollment (e.g., suPAR, mHLA-DR) in future sepsis trials, potentially leading to targeted therapies with demonstrable benefit.
Key Findings
- Twelve RCTs used biomarkers for predictive enrichment; 42% showed significant effects on primary outcomes.
- Three enriched trials demonstrated patient-important benefits (reduced mortality or disease severity).
- Beneficial interventions targeted immune, antimicrobial, or coagulation pathways using suPAR, AT, mHLA-DR, IL-6, or EAA for enrichment.
Methodological Strengths
- PRISMA-ScR methodology with comprehensive multi-database search and risk-of-bias assessment.
- Focus on biologically driven enrichment strategies across RCTs.
Limitations
- Heterogeneous trial designs and biomarkers precluded quantitative meta-analysis.
- Limited number of eligible RCTs reduces generalizability.
Future Directions: Prospective validation of biomarker thresholds and integration into adaptive/platform sepsis trials to test targeted therapies.
2. Daptomycin is associated with higher treatment failure rates than alternatives for Enterococcus faecium bloodstream infections in critically ill patients: a multicentric retrospective cohort.
Among 166 ICU patients with monomicrobial E. faecium bloodstream infection, definitive daptomycin therapy was associated with increased treatment failure versus vancomycin/linezolid-based regimens (adjusted SHR 2.53; propensity-weighted HR 2.48). Groups had similar time to adequate therapy and source control rates; all isolates were vancomycin-susceptible with median daptomycin MIC 3 mg/L.
Impact: Provides comparative-effectiveness evidence in a high-risk ICU population, challenging the use of daptomycin as definitive therapy for E. faecium BSI.
Clinical Implications: For vancomycin-susceptible E. faecium BSI in ICU, consider vancomycin or linezolid over daptomycin as definitive therapy; if daptomycin is used, ensure optimized dosing and close monitoring, especially with higher MICs.
Key Findings
- Definitive daptomycin therapy associated with higher treatment failure vs comparators (Fine–Gray aSHR 2.53, 95% CI 1.14–5.62; p=0.022).
- Propensity score overlap weighting confirmed increased failure risk (HR 2.48, 95% CI 1.05–5.86; p=0.038).
- All isolates were vancomycin-susceptible; median daptomycin MIC 3 mg/L; similar time to adequate therapy and source control rates across groups.
Methodological Strengths
- Multicenter ICU cohort with competing-risks modeling and propensity score-based sensitivity analyses.
- Clear, patient-important composite primary endpoint within 30 days.
Limitations
- Retrospective design with potential residual confounding and selection bias.
- Small daptomycin group (n=26) limits precision; dosing/exposure-response not fully explored.
Future Directions: Prospective trials comparing optimized daptomycin regimens versus vancomycin/linezolid, incorporating MIC-guided dosing and source control stratification.
3. Association between enoxaparin administration and ICU 28-day mortality in sepsis patients: A comparative study.
In a multicenter retrospective cohort from the eICU database including 2,078 ventilated sepsis patients with platelets ≥150×10^9/L, enoxaparin administration was associated with reduced ICU 28-day mortality using propensity score IPTW Cox modeling.
Impact: Suggests a survival benefit of pharmacologic thromboprophylaxis with enoxaparin in a clearly defined sepsis subgroup, informing risk–benefit considerations.
Clinical Implications: Supports consideration of enoxaparin for thromboprophylaxis in ventilated sepsis patients with adequate platelet counts, while individualizing for bleeding risk.
Key Findings
- Among 2,078 ventilated sepsis patients with platelets ≥150×10^9/L, enoxaparin use correlated with lower ICU 28-day mortality.
- Association persisted after adjustment using propensity score-based inverse probability weighting in Cox models.
- Study focuses on a pragmatic, clinically relevant subgroup to balance thrombosis and bleeding risk.
Methodological Strengths
- Large multicenter cohort with propensity score IPTW adjustment.
- Clear inclusion criteria (mechanical ventilation, platelet threshold) enhancing internal validity.
Limitations
- Retrospective design prone to residual confounding and confounding by indication.
- Lack of detailed dosing/timing and bleeding outcomes limits safety interpretation.
Future Directions: Randomized trials to test enoxaparin versus standard care in ventilated sepsis with platelet stratification and bleeding outcomes.