Sepsis, October 2025 edition

In this multicenter non-inferiority randomized trial, cefazolin was non-inferior to cloxacillin for 90-day outcomes in eligible MSSA bacteremia. Cefazolin was associated with substantially fewer serious adverse events and markedly less acute kidney injury, supporting its use as a safer parenteral option in many non-device and non-CNS infections.

Impact: It is a directly practice-relevant randomized antibiotic comparison showing equivalent efficacy with substantially improved renal safety.

Clinical Implications: Cefazolin can be considered a first-line parenteral option for eligible MSSA bloodstream infections, particularly when renal safety is important. Device-associated, central nervous system, and other excluded infection categories require separate treatment considerations.

This multinational randomized clinical trial enrolled 1,467 patients across 86 centers in 19 countries and compared capillary-refill-time-targeted personalized hemodynamic resuscitation with usual care during early septic shock. The CRT strategy significantly improved a hierarchical 28-day composite outcome, with the benefit driven mainly by shorter duration of vital organ support rather than a clear mortality reduction.

Impact: It provides high-level, pragmatic evidence that a bedside perfusion measure can guide early resuscitation and improve a patient-centered outcome in septic shock.

Clinical Implications: Structured CRT-guided protocols may be incorporated into early septic shock care to reduce exposure to vasopressors and organ support. The absence of a definitive mortality benefit means implementation should include protocol training, appropriate patient selection, and continued outcome monitoring.

A systematic review and trial sequential meta-analysis of 27 randomized trials involving 2,253 patients found that ultrashort-acting beta-blockers were associated with lower 28-day mortality. The signal was strongest in patients with septic tachycardia or septic cardiomyopathy and in studies using esmolol, although standardized indications and safety protocols remain necessary.

Impact: It aggregates randomized evidence suggesting that carefully selected septic patients may benefit from controlling excessive adrenergic cardiac stress with short-acting beta-blockade.

Clinical Implications: Ultrashort-acting beta-blockers may be considered in persistent septic tachycardia or selected septic cardiomyopathy under continuous hemodynamic monitoring. The findings should not be generalized to all septic patients, and pragmatic mortality-focused trials are still desirable.

This mechanistic study identified a BRD3-TRIM21-CREBBP-CREB1 axis that increases ACOD1 transcription in monocytes and macrophages and amplifies IL-1β/NLRP3-mediated inflammation. Myeloid-specific Brd3 deletion protected mice across four infection models, positioning BRD3 as a promising but still preclinical immunometabolic target.

Impact: It defines a previously unrecognized chromatin-immune-metabolic pathway with reproducible in vivo protection across multiple infection models.

Clinical Implications: BRD3 inhibition or modulation of the downstream pathway could become a host-directed strategy to limit maladaptive inflammation. Translation will require selective pharmacologic inhibitors, biomarker development, infection-specific safety assessment, and human validation.

This study developed and externally validated a four-gene blood panel consisting of TBX21, GNLY, PRF1, and IL2RB for immune-status assessment in sepsis. The panel achieved AUROCs of 0.891–0.909, and analysis of a randomized cohort suggested that an identified endotype could experience markedly higher mortality with hydrocortisone or thymosin treatment.

Impact: It offers a relatively compact, externally validated biomarker approach for identifying immune states that may modify the safety of immunomodulatory treatment.

Clinical Implications: The panel could support enrichment of biomarker-stratified trials and help avoid indiscriminate immunotherapy in potentially vulnerable endotypes. The treatment-interaction findings are hypothesis-generating and require prospective confirmation before routine clinical use.