Daily Sepsis Research Analysis
Three papers stand out today: an international PK study shows subtherapeutic antifungal exposures are common in ICU patients, a prospective cohort demonstrates that combining plasma and blood-cell metagenomic sequencing improves sepsis pathogen detection and severity stratification, and a population-based cohort links higher baseline omega-3 status with lower long-term risk of sepsis hospitalization.
Summary
Three papers stand out today: an international PK study shows subtherapeutic antifungal exposures are common in ICU patients, a prospective cohort demonstrates that combining plasma and blood-cell metagenomic sequencing improves sepsis pathogen detection and severity stratification, and a population-based cohort links higher baseline omega-3 status with lower long-term risk of sepsis hospitalization.
Research Themes
- Precision dosing and pharmacokinetics of antifungals in critical care
- Genomic diagnostics and immune transcriptomics for sepsis
- Nutritional biomarkers and primary prevention of sepsis
Selected Articles
1. Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units-the SAFE-ICU study.
In an international prospective PK study across 30 ICUs (n=339), antifungal target attainment during treatment was suboptimal for several agents (e.g., voriconazole 57.1%, amphotericin B 41.7%) with wide variability, whereas prophylaxis generally achieved >80% targets. The findings support therapeutic drug monitoring and dose optimization in critically ill patients.
Impact: Antifungal underexposure is common in the ICU and may contribute to excess mortality in sepsis with invasive fungal disease; this large, multicenter PK study provides actionable evidence for precision dosing.
Clinical Implications: Implement routine or selective TDM for azoles and consider PK-guided dose adjustments, ensure MIC testing when feasible, and differentiate dosing strategies for prophylaxis versus treatment in critically ill patients.
Key Findings
- Prospective multicenter PK study in 339 ICU patients across 12 countries and 30 ICUs
- During treatment, target attainment was low for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%), and amphotericin B (41.7%)
- Prophylaxis achieved >80% target attainment for most antifungals
- Only 26% of pathogen-positive cases had MIC data available, limiting individualized PK/PD targeting
Methodological Strengths
- Prospective, multicenter design with centralized, validated bioanalysis
- Predefined PK/PD targets and repeated sampling to characterize variability
Limitations
- Observational PK study without standardized dosing or direct clinical outcome endpoints
- MIC data were available in only 26% of pathogen-positive cases
Future Directions: Randomized or adaptive dosing trials comparing PK-guided versus standard dosing, integration of real-time MIC data, and population PK modeling to refine dosing in diverse ICU phenotypes.
2. Role of plasma and blood-cell co-metagenomic sequencing in precise diagnosis and severity evaluation of sepsis, a prospective cohort study in sepsis patients.
In 147 sepsis samples, plasma mNGS achieved 100% sensitivity for bacteria/fungi and 97% for viruses, outperforming blood-cell mNGS, while bc-mNGS aligned better with culture. Dual positivity (p-mNGS+ & bc-mNGS+) correlated with heightened immune activation signatures, worse SOFA/PCT/CRP, and lower survival. Co-mNGS was less affected by prior antibiotics than blood culture.
Impact: This study provides a practical, complementary sequencing strategy that enhances pathogen detection and offers prognostic stratification, addressing two critical gaps in sepsis care.
Clinical Implications: Incorporate co-mNGS (plasma plus blood-cell) for diagnostic workups when cultures are negative or prior antibiotics were given, and consider dual-positivity as a red flag for severity and closer monitoring.
Key Findings
- Plasma mNGS sensitivity: 100% for bacteria/fungi and 97% for viruses; bc-mNGS: 88% and 71%, respectively
- bc-mNGS showed higher concordance with blood culture, suggesting viability inference
- Dual positivity (p-mNGS+ & bc-mNGS+) associated with higher SOFA, higher PCT/CRP, immune activation (low IFN-induced genes, high JAK-STAT), and lower survival
- Broad-spectrum antibiotics reduced culture yield more than p/bc-mNGS performance
Methodological Strengths
- Prospective design with head-to-head comparison against culture/qPCR
- Integration of blood transcriptomics linking test positivity to biological severity
Limitations
- Moderate sample size and potential single-center bias
- Reference standards imperfect and mNGS contamination/interpretation challenges remain
Future Directions: Multicenter diagnostic-impact trials assessing time-to-appropriate therapy and outcomes, standardized reporting thresholds, and cost-effectiveness analyses for co-mNGS in sepsis pathways.
3. Association of Omega-3 Status With Long-Term Risk of Hospitalization for Sepsis.
Using 273,325 UK Biobank participants over a mean 13-year follow-up, higher baseline estimated omega-3 index was associated with progressively lower risk of subsequent sepsis hospitalization (HRs 0.88, 0.80, 0.75 across quartiles Q2–Q4 vs Q1). Findings suggest exploring omega-3 supplementation as a primary prevention strategy.
Impact: This is one of the largest studies to link a modifiable nutritional biomarker with long-term sepsis risk, potentially opening a new prevention avenue beyond acute care.
Clinical Implications: Consider assessing omega-3 status in at-risk populations and testing supplementation in randomized trials to evaluate sepsis prevention; meanwhile, counsel on dietary omega-3 as part of risk reduction.
Key Findings
- Population-based cohort of 273,325 adults with mean 13-year follow-up and 9,241 sepsis hospitalizations
- Higher baseline eO3I associated with lower sepsis risk: HR 0.88 (Q2), 0.80 (Q3), 0.75 (Q4) vs Q1 (all p<0.001)
- Continuous modeling with restricted cubic splines confirmed a graded inverse association
- Outcome defined using ICD-10 codes; exposure was estimated omega-3 index
Methodological Strengths
- Very large sample size with long-term follow-up and multivariable adjustment
- Use of both categorical quartiles and continuous spline modeling
Limitations
- Observational design with potential residual confounding and outcome misclassification via administrative codes
- Exposure based on estimated omega-3 index rather than direct RBC measurement
Future Directions: Randomized supplementation trials targeting omega-3 status with sepsis incidence as a prespecified outcome; validation in diverse populations and mechanistic studies on host-response modulation.