Weekly Sepsis Research Analysis
This week’s sepsis literature is dominated by high-impact clinical and mechanistic advances: a multicenter randomized trial (CloCeBa) shows cefazolin is non-inferior to cloxacillin for MSSA bacteraemia with substantially less acute kidney injury, offering immediate practice implications. Mechanistic studies identified new immunometabolic and innate-immune drivers — BRD3-mediated upregulation of ACOD1 in myeloid cells and PAD4-driven NET formation in neutrophils — that worsen sepsis outcomes and
Summary
This week’s sepsis literature is dominated by high-impact clinical and mechanistic advances: a multicenter randomized trial (CloCeBa) shows cefazolin is non-inferior to cloxacillin for MSSA bacteraemia with substantially less acute kidney injury, offering immediate practice implications. Mechanistic studies identified new immunometabolic and innate-immune drivers — BRD3-mediated upregulation of ACOD1 in myeloid cells and PAD4-driven NET formation in neutrophils — that worsen sepsis outcomes and represent tractable therapeutic targets. Across the week, multi-omics, single-cell profiling, and rigorous translational validation continue to deliver candidate biomarkers and targets that can enable precision stratification and next-generation adjunctive therapies.
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 (315 randomized, 292 analyzed), cefazolin achieved non-inferior 90-day composite outcomes compared with cloxacillin for MSSA bacteraemia (75% vs 74%) and was associated with significantly fewer serious adverse events and markedly lower rates of acute kidney injury (1% vs 12%). The trial supports cefazolin as an effective and safer parenteral alternative in many non‑device/CNS MSSA bloodstream infections.
Impact: First randomized clinical trial directly comparing cefazolin and cloxacillin for MSSA bacteraemia demonstrating equivalent efficacy with superior renal safety — a finding with immediate antimicrobial stewardship and prescribing implications.
Clinical Implications: Clinicians can consider cefazolin as a first-line parenteral therapy for MSSA bacteraemia in eligible patients (excluding device/CNS infections), potentially reducing AKI incidence and improving tolerability; stewardship protocols should be updated accordingly.
Key Findings
- Primary composite endpoint: 75% (cefazolin) vs 74% (cloxacillin); non-inferiority met (treatment difference −1%; non-inferiority p=0.012).
- Serious adverse events were lower with cefazolin (15% vs 27%, p=0.010).
- Acute kidney injury markedly reduced with cefazolin (1% vs 12%, p=0.0002).
2. A non-canonical immunometabolic function of BRD3 during sepsis.
This mechanistic study uncovers a BRD3–TRIM21–CREBBP–CREB1 axis that transcriptionally upregulates ACOD1 in monocytes and macrophages, amplifying IL‑1β/NLRP3-driven inflammation. Myeloid-specific Brd3 deletion protected mice across four infection models, showing reduced inflammatory responses and improved survival, and positioning BRD3 as a promising immunometabolic target in sepsis.
Impact: Identifies a novel, targetable immunometabolic pathway linking chromatin reader BRD3 to inflammasome activation and worse sepsis outcomes, with robust multi-model in vivo validation that accelerates translational target prioritization.
Clinical Implications: Although preclinical, BRD3 inhibition or modulation of the BRD3–TRIM21–CREBBP–CREB1 axis represents a rational strategy to blunt maladaptive inflammation in sepsis; development of inhibitors and translational biomarkers is warranted.
Key Findings
- BRD3 interacts with TRIM21 to activate CREBBP and acetylate/activate CREB1, driving ACOD1 transcription in myeloid cells.
- Myeloid-specific Brd3 deletion reduced IL‑1β/NLRP3-driven inflammation and improved outcomes across four murine infection models.
- The pathway establishes a non-canonical immunometabolic mechanism amenable to pharmacologic targeting.
3. Multi-omics analysis reveals neutrophil heterogeneity and key molecular drivers in sepsis-associated acute kidney injury.
Integrating single-cell and bulk transcriptomics, machine learning, and experimental models, this study identified four neutrophil subtypes with a marked expansion of pro‑inflammatory neutrophils in sepsis. PAD4 emerged as a hub gene driving NET formation and renal injury; PAD4 knockdown reduced NETs and ameliorated kidney damage in a rat model and hub-gene expression was elevated in human sepsis samples.
Impact: Provides a translational bridge from immune‑cell heterogeneity to organ-specific injury, validating PAD4/NETs as mechanistic drivers and therapeutic targets in sepsis-associated AKI with cross-species evidence.
Clinical Implications: Supports development of PAD4/NET-targeted assays and interventions for sepsis-associated AKI, and suggests neutrophil-subtype monitoring could inform risk-stratified organ-protective strategies.
Key Findings
- Four neutrophil subtypes identified; pro-inflammatory neutrophils expanded markedly in sepsis (≈40.5% vs 4.2% in controls).
- Hub genes (PAD4, CASP4, CR1, MAPK14) implicated in SAKI; PAD4 mediates NET formation and renal injury.
- PAD4 knockdown in rats reduced NETs formation and attenuated kidney injury; human samples confirmed elevated expression.