Daily Sepsis Research Analysis

The emergence of multidrug-resistant pathogens presents a major clinical challenge worldwide. The underexplored bacterial genus Aquimarina harbors a large biosynthetic potential for the discovery of new classes of antibiotics with distinctive modes of action, which can be unearthed in a scalable manner using a synthetic bioinformatic natural product approach. Here, the discovery of a pair of linear or cyclic bifunctional cationic lipopeptide antibiotics, aquicidine L and aquicidine C4, with opposite antibacterial spectra, is reported, which are chemically synthesized on the basis of distinct structure prediction of the aquicidine gene cluster from Aquimarina. Aquicidine L mainly targets both anionic lipopolysaccharide and phosphatidylethanolamine in the bacterial membrane and is efficacious against two different meropenem-resistant Gram-negative pathogens in murine peritonitis-sepsis models. In contrast, aquicidine C4 mainly binds to both anionic cardiolipin and phosphatidylglycerol in the membrane and proves effective at treating methicillin- or vancomycin-resistant Gram-positive pathogen infections in vivo. Owing to the dual-mechanism features of aquicidine L or aquicidine C4, both of them are absent in detectable resistance in laboratory tests. These findings provide a pair of naturally inspired and mechanistically interesting therapeutic leads for evading antimicrobial resistance.

INTRODUCTION: Sepsis-associated acute kidney injury (SA-AKI) is a highly lethal condition with a rapid onset, and effective treatments are lacking because the molecular pathogenesis remains unclear. Tubular epithelial cells (TECs) have increasingly been recognized as driving forces in the progression of kidney diseases, partly through the release of extracellular vesicles (EVs) carrying proinflammatory cargos. However, the role of TEC-derived EVs on neutrophil extracellular traps (NETs) formation, which is an established feature of sepsis, and SA-AKI remains unclear. METHODS: EVs isolated from phosphate buffer saline (PBS)/lipopolysaccharide (LPS)-treated TECs were injected intravenously into C57BL/6J wild type mice to determine whether TECs-derived EVs can directly induce NETs formation and kidney injury. Proteomics and single-cell RNA sequencing analysis were used to screen the key molecules that mediate the effects of TECs-derived EVs. EVs secretion from TECs and serum amyloid A1 (SAA1) expression in TECs were specifically inhibited via adeno-associated virus (AAVs). Finally, the association between SAA1 level in plasma EVs and clinical features of septic patients was determined. RESULTS: This study demonstrated that EVs secreted from LPS-stimulated TECs exacerbated AKI by promoting NETs formation. Specifically blocking EVs secretion from TECs via AAVs reduced NETs formation and alleviated LPS-induced AKI. Bioinformatics analysis suggested that LPS increased SAA1 expression in TECs, and then released extracellularly through EVs. Further mechanistic studies revealed that SAA1 packaged in TECs-derived EVs was responsible for NETs formation and AKI via activation of the TLR4/p38 MAPK signaling pathway in neutrophils. Specifically inhibiting SAA1 upregulation in TECs via AAVs also reduced NETs formation and alleviated LPS-induced AKI. Interestingly, modulating EVs release from TECs or SAA1 expression in TECs also alleviated remote lung injury induced by LPS, indicated that TECs-derived EVs may participate in kidney‒lung crosstalk during sepsis. Furthermore, plasma TECs-derived EVs proportion and SAA1 expression in plasma EVs may be promising prognostic indexes for SA-AKI patients. DISCUSSION: Here, we explored a new mode of TECs-neutrophils crosstalk mediated by EVs during SA-AKI, and strategies to modify TECs-derived EVs and the cargo SAA1 could be a new avenue for developing therapeutics against SA-AKI.

OBJECTIVES: Sepsis and septic shock require prompt intervention to improve outcomes. A rapid response team (RRT) system facilitates early recognition and management, including transfer to the ICU, but its impact on clinical outcomes remains unclear. This study assessed the association between RRT activation and clinical outcomes in septic patients initially managed in general wards, in a cohort of predominantly tertiary care hospitals in Japan. DESIGN: Secondary analysis of prospectively collected data from the Japanese Intensive Care PAtient Database (JIPAD) for the fiscal years 2017-2022. SETTING: A multicenter study using the JIPAD, which includes 324,037 patients across 95 ICUs in Japan. PATIENTS: We identified 3883 adult patients admitted to the ICU with sepsis or septic shock after initial management in a general ward. INTERVENTIONS: The patients were divided into those in whom the RRT was activated before ICU admission (the RRT group) and those in whom it was not (the control group). MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. Secondary outcomes included rate of discharge to home, ICU mortality, length of hospital stay, and length of ICU stay. All outcome analyses were performed after stabilized inverse probability of treatment weighting using generalized estimating equations to account for clustering at the hospital level. There was no statistically significant difference in-hospital mortality between the RRT group ( n = 850) and the control group ( n = 3033; 38.6% vs. 37.1%; risk difference, 1.4%; 95% CI, -2.8% to 5.6%; p = 0.51). No significant differences were observed in secondary outcomes. CONCLUSIONS: In this nationwide study of septic patients requiring ICU admission, RRT activation was not associated with improvement of in-hospital mortality or other clinical outcomes. Despite the widespread implementation of RRTs, their impact on outcomes of sepsis in well-resourced healthcare systems such as Japan remains uncertain.