Daily Sepsis Research Analysis
Three papers stand out today: a multicenter validation of the eQUANT system enabling same-day disk diffusion AST directly from positive blood cultures, a new mouse model recapitulating persistent inflammation, immunosuppression, and catabolism syndrome (PICS) driven by gut dysbiosis and bacterial translocation, and a preclinical study showing that eliminating myeloid-derived suppressor cells reverses sepsis-induced immune paralysis and reduces secondary infections. Together they advance rapid di
Summary
Three papers stand out today: a multicenter validation of the eQUANT system enabling same-day disk diffusion AST directly from positive blood cultures, a new mouse model recapitulating persistent inflammation, immunosuppression, and catabolism syndrome (PICS) driven by gut dysbiosis and bacterial translocation, and a preclinical study showing that eliminating myeloid-derived suppressor cells reverses sepsis-induced immune paralysis and reduces secondary infections. Together they advance rapid diagnostics and mechanistic immunomodulation in sepsis.
Research Themes
- Rapid diagnostics and antimicrobial stewardship in sepsis
- Mechanisms of chronic critical illness: PICS, microbiome, and barrier failure
- Targeted immunomodulation to reverse sepsis-induced immunosuppression
Selected Articles
1. Multicenter evaluation of the eQUANT system for use with disk diffusion AST of gram-negative bacteria directly from positive blood cultures.
In a multicenter evaluation, the eQUANT system produced standardized inocula directly from positive blood cultures, enabling same-day disk diffusion AST. Across 2,679 result pairs for gram-negative rods against 12 antibiotics, categorical agreement was 95.0% with very major errors at 0.15%. This workflow can save up to 24 hours by eliminating subculture.
Impact: Direct-from-blood AST can materially shorten time to targeted therapy in sepsis without compromising accuracy. This platform-level advance supports real-world antimicrobial stewardship.
Clinical Implications: Clinical laboratories can adopt eQUANT to report disk diffusion AST results up to 24 hours earlier, potentially enabling faster de-escalation/escalation and improving outcomes in sepsis and bacteremia.
Key Findings
- Overall categorical agreement of 95.0% across 2,679 AST result pairs compared with standard workflow
- Very major error 0.15%, major error 0.60%, minor error 4.48%
- Eliminates overnight subculture step, saving up to 24 hours
- Validated across 13 gram-negative species and 12 antibiotics using both clinical (n=42) and contrived (n=525) blood cultures
Methodological Strengths
- Multicenter clinical evaluation with a large number of AST result pairs
- Direct head-to-head comparison with standard plate-subculture-based disk diffusion
Limitations
- Included contrived blood culture specimens; limited assessment of patient-centered outcomes
- Focused on gram-negative rods and disk diffusion; performance with other taxonomic groups or methods not reported
Future Directions: Prospective clinical impact studies linking reduced AST turnaround to time-to-effective therapy and patient outcomes; expansion to gram-positive organisms and automated workflows.
2. Eliminating myeloid-derived suppressor cells alleviates immunosuppression and reduces susceptibility to secondary infections in a two-hit sepsis model.
In a two-hit sepsis model, MDSCs accumulated during the late phase, correlating with immune paralysis and susceptibility to secondary infections. Late administration of the LXR agonist GW3965 eliminated MDSCs, restored immune function, improved bacterial clearance, and improved prognosis, highlighting MDSCs as a therapeutic target.
Impact: Provides causal preclinical evidence that targeting MDSCs can reverse sepsis-induced immunosuppression and reduce secondary infections, a key unmet need in chronic critical illness.
Clinical Implications: Supports development of MDSC-directed immunotherapies (e.g., LXR agonists or other MDSC-depleting strategies) to prevent late sepsis complications; requires careful translation and safety assessment.
Key Findings
- MDSCs accumulate and exhibit enhanced activity in late survivors of CLP, correlating with immune paralysis and impaired bacterial clearance
- Late administration of LXR agonist GW3965 eliminated MDSCs and restored immune function
- GW3965 decreased susceptibility to secondary infections and improved prognosis in the two-hit model
Methodological Strengths
- Clinically relevant two-hit sepsis model capturing late immunosuppression
- Intervention applied in the late phase with multi-endpoint assessment (immune function, bacterial clearance, prognosis)
Limitations
- Preclinical mouse study without human validation; safety and dosing of LXR agonists in sepsis remain unknown
- Mechanistic pathways beyond MDSC depletion not fully delineated
Future Directions: Translational studies to profile MDSCs in human sepsis survivors, and early-phase trials of MDSC-modulating agents with infection and immune endpoints.
3. Establishment and evaluation of a new type of animal model of persistent inflammation, immunosuppression, and catabolism syndrome based on gut microbiota dysbiosis and bacterial translocation.
A CLP+dexamethasone mouse model reproduced core PICS features: massive cytokine elevation, expansion of MDSCs with reduced CD4+ T cells, muscle wasting gene upregulation, and gut barrier failure with microbiota dysbiosis and bacterial translocation. The work positions bacterial translocation as central to PICS pathogenesis and points to tryptophan derivatives as potential therapeutics.
Impact: Establishes a reproducible preclinical model of PICS that links microbiome dysbiosis, barrier failure, and immunosuppression, creating a platform to test targeted interventions.
Clinical Implications: Supports gut-targeted strategies (e.g., barrier protection, microbiome modulation, tryptophan pathway therapeutics) for chronic critical illness after sepsis; guides endpoint selection for future trials.
Key Findings
- CLP + dexamethasone mice showed ~3000% (IL-6), 400% (TNF-α), and 300% (IL-1β) increases vs. CLP alone at day 14
- MDSCs increased to ~31.2% and CD4+ T cells decreased to ~5.7% vs. 22.97% and 8.03% in CLP alone
- Body weight and muscle mass decreased (~3.6 g and 135 mg), with Atrogin-1 and MuRF-1 upregulated >500%
- Tight junction proteins (ZO-1, Occludin) decreased; 16S rRNA and blood plating confirmed dysbiosis and bacterial translocation
Methodological Strengths
- Defined four-group design with standardized CLP and controlled DEXA to sustain inflammation
- Comprehensive phenotyping across inflammation, immunity, catabolism, and gut barrier with multi-omics/multiparametric assays
Limitations
- Mouse model with relatively small per-group size (n=10); generalizability to humans uncertain
- Glucocorticoid (DEXA) exposure may confound immune and metabolic phenotypes
Future Directions: Interventional testing of gut barrier protectants, microbiome therapies, and tryptophan-derivative agents; validation of PICS biomarkers and endpoints for translational studies.