Daily Sepsis Research Analysis
Analyzed 46 papers and selected 3 impactful papers.
Summary
A pragmatic cluster RCT in rural China showed a digitally enabled antibiotic stewardship program reduced antibiotic prescribing for acute respiratory infections from 71% to 26% without increasing 30-day hospitalization for respiratory illness or sepsis. A preclinical study established a timing-dependent therapeutic window for disulfiram targeting the GSDMD–NETs axis in sepsis, improving survival when given 8 h after CLP but harming when given immediately. A rapid culture-free DARQ-LAMP assay delivered Gram typing of six common bloodstream pathogens directly from whole blood within 1.5 hours at 1–5 CFU/μL sensitivity.
Research Themes
- Pragmatic antimicrobial stewardship and patient safety in primary care
- Timing-specific inhibition of GSDMD–NETs axis in sepsis
- Rapid culture-free molecular Gram typing from whole blood
Selected Articles
1. Effects of a comprehensive antibiotic stewardship program on antibiotic prescribing for acute respiratory infections in rural facilities: a cluster randomized trial.
In 34 rural township hospitals, a digitally enabled, multi-component stewardship program reduced antibiotic prescribing for ARIs from 71% to 26% across 97,239 consultations over 12 months (adjusted risk difference −39 percentage points; 95% CI, −47 to −29; P<0.001), with no increase in 30-day hospitalizations for respiratory illness or sepsis. The pragmatic cluster RCT supports scalable stewardship without compromising safety.
Impact: This large, pragmatic cluster RCT demonstrates a substantial and safe reduction in antibiotic overuse in rural primary care, addressing antimicrobial resistance and sepsis safety concerns. It provides actionable evidence for health systems seeking scalable stewardship solutions.
Clinical Implications: Health systems can implement digitally supported stewardship (EMR prompts, peer feedback, training, patient education) to markedly reduce unnecessary antibiotics for ARIs without increasing short-term hospitalizations for respiratory illness or sepsis.
Key Findings
- Antibiotics were prescribed in 26% of intervention vs 71% of control consultations (adjusted risk difference −39 pp; 95% CI −47 to −29; P<0.001).
- No increase in 30-day hospitalization for respiratory illness or sepsis (adjusted risk difference 0.2 pp; 95% CI −0.3 to 0.6).
- A multi-component, digitally enabled program (EMR prompts, training, peer review, patient app) was feasible across 34 rural hospitals over 12 months.
Methodological Strengths
- Pragmatic cluster randomized controlled design with large sample (97,239 consultations) and real-world implementation.
- Pre-specified primary outcome with robust effect size and safety assessment including sepsis-related hospitalization.
Limitations
- Conducted in two rural counties in Guangdong, China; generalizability to other settings may vary.
- Did not assess microbiologic outcomes or long-term resistance patterns.
Future Directions: Evaluate long-term resistance trends, cost-effectiveness, and scalability across diverse health systems; integrate microbiologic surveillance and patient-centered outcomes.
Antimicrobial resistance is driven by inappropriate use of antibiotics for acute respiratory infections (ARIs), which is a major challenge in primary care in low- and middle-income countries. Here we conducted a pragmatic, cluster randomized controlled trial in 34 township hospitals in two rural counties of Guangdong, China, to evaluate whether a digitally enabled stewardship program could reduce antibiotic prescribing. The intervention combined training and guidelines for doctors; concise, evi
2. Delayed disulfiram targeting GSDMD-NETs axis rescues sepsis by limiting bacterial spread and lung injury.
Immediate DSF (0 h) after CLP increased bacterial dissemination, cytokines, and mortality, whereas delayed DSF at 8 h reduced lung and blood bacterial loads, suppressed TNF-α/IL-6, attenuated lung injury, and significantly improved survival. Mechanistically, DSF inhibited GSDMD cleavage and NET formation; only delayed inhibition reduced NET-driven microthrombosis and preserved antibacterial functions.
Impact: This study defines a therapeutic window for targeting the GSDMD–NETs axis in sepsis, reconciling host defense with tissue protection and offering a clinically actionable framework for timing inhibitor therapies.
Clinical Implications: Biomarker-guided, delayed inhibition of GSDMD/NETs may avoid early harm while delivering organ protection later; trial designs should incorporate sepsis staging and time-sensitive dosing.
Key Findings
- Immediate DSF (0 h) increased bacterial dissemination (lung and blood) and inflammatory cytokines, shortening survival.
- Delayed DSF (8 h) reduced lung and blood bacterial load, suppressed TNF-α/IL-6, attenuated lung injury, and markedly improved survival (P<0.0001).
- DSF consistently inhibited GSDMD cleavage and NET formation; only delayed intervention reduced NET-driven microthrombosis while preserving neutrophil antibacterial functions.
Methodological Strengths
- Rigorous CLP sepsis model with prespecified dosing time points (0, 4, 8 h) enabling temporal causal inference.
- Comprehensive multi-dimensional endpoints: survival, bacterial burden, cytokines, histopathology, vascular leakage, and mechanistic assays of GSDMD/NETs.
Limitations
- Preclinical murine model; human translatability and optimal timing windows require validation.
- Single compound and dosing regimen; off-target effects and pharmacokinetics in humans are unknown.
Future Directions: Develop biomarkers to stage sepsis and guide timing of GSDMD/NET inhibitors; test delayed strategies in larger animal models and early-phase clinical trials.
BACKGROUND: Sepsis therapy faces a critical paradox: Gasdermin D (GSDMD)-mediated neutrophil extracellular traps (NETs) exert protective host defense early but drive tissue injury late. Defining the temporal dynamics of intervening in this axis is central to overcoming therapeutic limitations. METHODS: In a cecal ligation and puncture (CLP) model recapitulating human sepsis progression, disulfiram (DSF, 80 mg/kg) or vehicle was administered intraperitoneally at 0 h, 4 h, or 8 h postoperatively.
3. Gram Typing Bacteria Panels in Whole Blood Using a Biphasic Duplex-Loop-Mediated Isothermal Amplification Assay.
A culture-free duplex DARQ-LAMP assay combined with a biphasic sample prep enabled Gram typing of six common bloodstream pathogens directly from 4 μL of whole blood within 1.5 h at 1–5 CFU/μL sensitivity. The assay distinguishes a four-organism Gram-negative panel from two Gram-positive pathogens (including MSSA/MRSA) and could obviate blood culture for early decision-making.
Impact: Introduces a rapid, extraction-free molecular workflow delivering clinically actionable Gram-type information from whole blood, addressing a key bottleneck in early sepsis management.
Clinical Implications: Early Gram typing from whole blood may support earlier targeted therapy and de-escalation, potentially reducing broad-spectrum use and resistance; prospective clinical validation is needed.
Key Findings
- Duplex DARQ-LAMP distinguished Gram-negative (E. coli, S. marcescens, P. mirabilis, K. pneumoniae) from Gram-positive (MSSA/MRSA, S. epidermidis) directly from whole blood.
- Sensitivity of 1–5 CFU/μL and turnaround time of ~1.5 h using a 4 μL sample volume with biphasic prep.
- Eliminates need for culture, extraction, and purification steps to provide early Gram-type information.
Methodological Strengths
- Innovative duplex DARQ-LAMP chemistry with probe-based detection enabling multiplexed Gram typing.
- Biphasic sample preparation minimizes matrix interference and allows ultra-low input volume (4 μL).
Limitations
- Limited organism panel (six targets) and Gram-type output without species-level breadth beyond the panel.
- Clinical validation on real patient samples and comparative performance versus blood culture not reported.
Future Directions: Prospective clinical studies comparing against blood culture; expansion of organism panels and incorporation of resistance markers and semi-quantitation.
Timely identification of bacteria in bloodstream infections is critical for guiding appropriate antibiotic treatment. However, current clinical workflows entail blood culture (1-5 days), followed by Gram staining, PCR, and antibiotic susceptibility testing. These steps delay actionable results, often leading clinicians to prescribe broad-spectrum antibiotics without results from the above tests, contributing to the rising threat of antimicrobial resistance. Specifically, rapid information of even