Daily Sepsis Research Analysis
A multicentre randomized trial shows cefazolin is non-inferior to cloxacillin for MSSA bacteraemia with markedly less acute kidney injury. Two mechanistic studies advance sepsis therapeutics: a microRNA-gated CRISPR-dCas9 platform that mitigates sepsis-induced liver injury in mice via NRF2 activation, and BLP-trained macrophages that protect against S. aureus sepsis through NRF2-driven antioxidative reprogramming.
Summary
A multicentre randomized trial shows cefazolin is non-inferior to cloxacillin for MSSA bacteraemia with markedly less acute kidney injury. Two mechanistic studies advance sepsis therapeutics: a microRNA-gated CRISPR-dCas9 platform that mitigates sepsis-induced liver injury in mice via NRF2 activation, and BLP-trained macrophages that protect against S. aureus sepsis through NRF2-driven antioxidative reprogramming.
Research Themes
- Optimization of antimicrobial therapy in MSSA bacteraemia
- Synthetic biology and gene therapy for organ protection in sepsis
- Innate immune training and NRF2-mediated tolerance in sepsis
Selected Articles
1. Cloxacillin versus cefazolin for meticillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): a prospective, open-label, multicentre, non-inferiority, randomised clinical trial.
In a multicentre open-label non-inferiority RCT (n=315 randomized; 292 analyzed), cefazolin achieved the 90-day composite primary endpoint at a similar rate to cloxacillin (75% vs 74%; non-inferiority p=0.012). Serious adverse events and acute kidney injury were significantly less frequent with cefazolin.
Impact: This is the first randomized clinical trial directly comparing cefazolin and cloxacillin for MSSA bacteraemia, demonstrating non-inferior efficacy with superior renal safety.
Clinical Implications: Cefazolin can be adopted as a first-line parenteral therapy for MSSA bacteraemia (excluding CNS/device infections), offering comparable efficacy with reduced risk of acute kidney injury and better tolerability.
Key Findings
- Primary composite endpoint met in 75% (cefazolin) vs 74% (cloxacillin); treatment difference −1% (95% CI −11 to 9); non-inferiority p=0.012.
- Serious adverse events: 15% with cefazolin vs 27% with cloxacillin (p=0.010).
- Acute kidney injury: 1% with cefazolin (1/134) vs 12% with cloxacillin (15/128) (p=0.0002).
- Randomization stratified by vascular-access-associated bacteraemia and center; total treatment ≥14 days.
Methodological Strengths
- Multicentre randomized non-inferiority design with pre-registration (NCT03248063).
- Stratified randomization and intention-to-treat assessment of the primary endpoint.
Limitations
- Open-label design may introduce performance and detection bias.
- Excluded patients with intravascular implants or suspected CNS infection, limiting generalizability.
- Conducted in France; antimicrobial practices may vary internationally.
Future Directions: Evaluate cefazolin in endocarditis and device-related infections, assess outpatient parenteral therapy feasibility, and perform cost-effectiveness and stewardship impact analyses.
2. Exploring Functionally Enhanced BLP-Trained Macrophage Subpopulations in S. Aureus Infection: Underlying Mechanisms and Therapeutic Significance.
Single-cell profiling identified 13 BMDM subpopulations; BLP training induced novel C5/C7 subsets with enhanced antibacterial, anti-inflammatory, and antioxidative programs. NRF2 activation and metabolic reprogramming underpinned protection, and adoptive transfer of BLP-trained BMDMs reduced lethality, inflammation, and organ damage in S. aureus sepsis.
Impact: This study maps trained macrophage heterogeneity at single-cell resolution and links NRF2-driven antioxidative stress responses to survival benefits in sepsis, suggesting immunometabolic and cell therapy avenues.
Clinical Implications: Findings support development of NRF2-targeted agents and trained immunity-based strategies, including potential adoptive myeloid cell therapies, to reduce sepsis mortality and organ injury.
Key Findings
- scRNA-seq identified 13 BMDM subpopulations; BLP training induced two novel subsets (C5 and C7).
- BLP-trained BMDMs showed activation of NRF2 signaling with enhanced antioxidative responses and reduced ferroptosis.
- Metabolic reprogramming featured increased glycolysis and oxidative phosphorylation with anti-inflammatory metabolites.
- Adoptive transfer of BLP-trained BMDMs protected mice from sepsis lethality by attenuating systemic inflammation, accelerating bacterial clearance, and alleviating organ damage.
Methodological Strengths
- Integrated single-cell transcriptomics with in vivo adoptive transfer models.
- Mechanistic linkage to NRF2 signaling and ferroptosis mitigation with functional readouts (inflammation, bacterial clearance, organ injury).
Limitations
- Preclinical mouse models may not fully recapitulate human sepsis heterogeneity.
- Focused on S. aureus infection and BLP as training stimulus; generalizability to polymicrobial sepsis is uncertain.
Future Directions: Validate NRF2-centric mechanisms in human macrophages, assess safety and durability of trained immunity, and test pharmacologic or cell-based interventions in diverse sepsis models.
3. MiR-ON-CRISPR: a microRNA-activated CRISPR-dCas9 system for precise gene therapy in living cells and mouse models of sepsis.
A miRNA-gated CRISPR-dCas9 platform (miR-ON-CRISPR) enables endogenous miRNA to control both dCas9 and sgRNA, supporting AND/OR logic. It visualizes miRNA activity, enables cell type-specific killing, and in sepsis mouse models, activation of NRF2 alleviated liver injury, oxidative stress, and ER stress.
Impact: Introduces a logic-gated, cell context-aware CRISPR control system with demonstrated therapeutic benefit in sepsis models, opening a path for precision gene therapy in inflammatory organ injury.
Clinical Implications: Potential for organ- and cell-specific gene therapies to mitigate sepsis-induced organ damage via NRF2 activation; translation will require optimized delivery, safety profiling, and durability studies.
Key Findings
- miR-ON-CRISPR uses endogenous miRNAs to regulate both dCas9 and sgRNA, enabling AND/OR logic control.
- System faithfully visualized miRNA activity and neural cell differentiation status via luciferase reporter.
- Enabled cell type-specific killing by activating exogenous DTA or endogenous BAX genes.
- In mouse sepsis models, NRF2 activation via miR-ON-CRISPR reduced liver injury, oxidative stress, and ER stress.
Methodological Strengths
- Demonstrated multi-layered control (miRNA gating and logic) with in vitro and in vivo validation.
- Showed therapeutic impact in disease-relevant mouse sepsis models targeting NRF2.
Limitations
- Proof-of-concept with limited survival and long-term outcome data in sepsis models.
- Translational challenges include delivery, off-target effects, immunogenicity, and context-specific miRNA expression.
Future Directions: Optimize vectors and dosing for organ-selective delivery, assess survival and multi-organ endpoints, and evaluate safety in larger animal models before first-in-human studies.