Daily Sepsis Research Analysis
Three impactful sepsis studies span mechanisms, stewardship, and therapeutics. A Circulation Research paper uncovers lactate-driven HADHA lactylation as a causal mechanism for sepsis-induced myocardial depression. A 20-year interrupted time-series shows carbapenem preauthorization sustainably reduces use without worsening mortality and correlates with lower resistance, while a preclinical study demonstrates Salvianolic acid A directly targets STING to blunt inflammation and improve survival in a
Summary
Three impactful sepsis studies span mechanisms, stewardship, and therapeutics. A Circulation Research paper uncovers lactate-driven HADHA lactylation as a causal mechanism for sepsis-induced myocardial depression. A 20-year interrupted time-series shows carbapenem preauthorization sustainably reduces use without worsening mortality and correlates with lower resistance, while a preclinical study demonstrates Salvianolic acid A directly targets STING to blunt inflammation and improve survival in a CLP sepsis model.
Research Themes
- Mechanisms of sepsis-induced organ dysfunction
- Antimicrobial stewardship and resistance mitigation
- Targeted immunomodulation in sepsis
Selected Articles
1. Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.
Using LPS and CLP sepsis models plus in vitro systems, the authors identify lactate-driven lactylation of HADHA at K166 and K728 as a causal mechanism impairing mitochondrial function and cardiomyocyte contractility. SIRT1 and SIRT3 regulate these modifications, positioning lactylation as a therapeutic target for septic cardiomyopathy.
Impact: This is a rigorous mechanistic discovery linking lactate signaling to a specific posttranslational modification that drives septic myocardial depression, opening a tractable axis (HADHA lactylation/SIRT1/3) for intervention.
Clinical Implications: Although preclinical, these findings suggest measuring or modulating cardiac lactylation and targeting SIRT1/3 or HADHA-lactylation could mitigate septic cardiomyopathy. They also reframe lactate as an active modifier, not just a biomarker.
Key Findings
- Identified lactylation at HADHA K166 and K728 in septic myocardium and LPS-treated cells; levels were lactate dependent.
- HADHA lactylation inhibited enzymatic activity, impaired mitochondrial function and ATP production, reducing cardiomyocyte contractility in vitro and in vivo.
- SIRT1 and SIRT3 regulated HADHA lactylation; 1127 lysine lactylation sites were mapped with 83 differentially lactylated in sepsis.
Methodological Strengths
- Integrated proteomics, transcriptomics, and metabolomics with in vivo (CLP/LPS) and in vitro validation.
- Site-directed mutagenesis of HADHA and functional assays linking modification to mitochondrial and contractile phenotypes.
Limitations
- Preclinical rodent and cell models; human validation of HADHA lactylation and therapeutic modulation is lacking.
- Use of H9c2 cell line may not fully recapitulate adult human cardiomyocyte biology.
Future Directions: Validate HADHA lactylation in human septic cardiomyopathy, test pharmacologic modulation (e.g., SIRT1/3 activators/inhibitors) and develop assays to monitor cardiac lactylation in patients.
2. Long-term effect of carbapenem preauthorization: an interrupted time-series study over 20 years.
In a single tertiary hospital over 20 years, carbapenem preauthorization produced significant immediate and sustained reductions in carbapenem use without increasing 28-day mortality from nosocomial bacteremia. Usage intensity correlated positively with MRSA and carbapenem-resistant Gram-negative bacteremia prevalence.
Impact: Provides rare, long-horizon quasi-experimental evidence that formulary restriction can sustainably curb carbapenem exposure without harming patient outcomes and may mitigate resistance.
Clinical Implications: Hospitals can implement and maintain carbapenem preauthorization to reduce use while monitoring resistance and outcomes. ITS metrics (AUD) and resistance surveillance should be integrated into stewardship dashboards.
Key Findings
- Significant level (-0.367/100 patient-days; P=0.002) and trend (-0.014/100 patient-days; P=0.048) reductions in carbapenem AUD after preauthorization.
- No increase in 28-day mortality from nosocomial bacteremia following implementation.
- Carbapenem AUD positively correlated with MRSA (ρ=0.77), meropenem-resistant Pseudomonas aeruginosa (ρ=0.85), and Acinetobacter baumannii (ρ=0.80) bacteremia prevalence.
Methodological Strengths
- Two-decade interrupted time-series with clear pre- and post-intervention phases.
- Use of standardized antimicrobial use density and linkage to resistance and mortality endpoints.
Limitations
- Single-center design; concurrent infection control or stewardship changes may confound associations.
- Correlational analyses do not establish causality between carbapenem use and resistance trends.
Future Directions: Multi-center ITS or stepped-wedge studies to generalize findings; assess patient-level outcomes and microbiome/ecology effects; integrate rapid diagnostics to optimize carbapenem sparing.
3. Salvianolic acid A ameliorates sepsis through inhibiting inflammation via binding STING and modulating TBK1/IRF3 signaling pathway.
In CLP sepsis and LPS-stimulated macrophage models, Salvianolic acid A improved survival, reduced inflammation, and preserved organ function by directly binding STING and inhibiting TBK1/IRF3 signaling. Target engagement was supported by CETSA and in silico docking/dynamics.
Impact: Identifies a small-molecule natural product that directly targets STING to modulate sepsis inflammation, bridging mechanism with a plausible therapeutic candidate.
Clinical Implications: While preclinical, STING pathway inhibition emerges as a tractable strategy; SAA or optimized analogs warrant translational development and safety/pharmacokinetic profiling for potential adjunctive sepsis therapy.
Key Findings
- In CLP mice, high-dose SAA improved survival from 18.75% to 55% and reduced lung neutrophil infiltration and histopathologic injury.
- SAA suppressed STING and TBK1/IRF3 activation in vivo and in vitro, lowering inflammatory cytokines and improving hepatorenal function.
- Target engagement demonstrated via CETSA, molecular docking, and molecular dynamics; SAA directly binds STING.
Methodological Strengths
- Combined in vivo CLP model outcomes with in vitro macrophage assays for mechanistic consistency.
- Direct target engagement assessment (CETSA) complemented by computational binding analyses.
Limitations
- Preclinical models; dosing, toxicity, and pharmacokinetics in humans are unknown.
- Potential off-target effects and species-specific STING biology may limit translation.
Future Directions: Define SAA pharmacology (PK/PD, safety) and optimize STING-binding analogs; evaluate efficacy in diverse sepsis models and consider combinatorial regimens with antibiotics and organ support.