Daily Sepsis Research Analysis

Staphylococcus aureus is a leading cause of lethal bacteremia and pneumonia, which are driven by potent virulence factors such as T-cell superantigens and alpha hemolysin. S. aureus has among the highest rates of antibiotic resistance, yet no vaccines or alternative therapies are available. Here, we developed a repertoire of potent, high-affinity nanobodies (Nbs) targeting key toxins in S. aureus infection, including Hla and superantigens SEB, SEC, and TSST-1. Comprehensive cryo-EM and AlphaFold3 analyses of these Nbs, which were elicited with clinical cocktail vaccines, revealed diverse neutralizing epitopes and mechanisms that provide insights for immunotherapy and vaccine strategies. Guided by these findings, we engineered stable, multivalent, and multifunctional Nb constructs. These constructs included an aerosolizable trimeric Nb with enhanced neutralization activity against Hla and SEC, and a decameric Nb-IgG-Fc fusion construct with pM or better potencies against a wide range of major toxins in S. aureus sepsis (SEB, SEC, TSST-1, and Hla). These multifunctional Nbs demonstrated protective activity in murine models of pneumonia and sepsis, underscoring their potential as versatile immunotherapies that address the complex virulence of S. aureus. Our work lays a foundation for precision immunotherapies beyond current treatment options to combat complex bacterial infections with multiple virulence mechanisms.

OBJECTIVES: Timely administration of appropriate antimicrobial therapy is critical for sepsis management, yet conventional antimicrobial susceptibility testing (AST) methods typically provide results within 24-48 hours after positivity. We evaluated the performance and workflow impact of a novel rapid AST system that delivers actionable results within 2-4 hours, compared to standard in-house laboratory methods used across multiple European centers. METHODS: A prospective, multicenter study was conducted at 12 hospitals in the United Kingdom, Germany, Sweden, Italy, and Portugal. Positive blood culture samples were analysed in parallel using the QuickMIC rapid AST system and the local reference AST method (broth microdilution, automated systems, rapid AST, or disk diffusion, depending on site). Essential agreement, categorical agreement, and error rates were calculated as compared to the local method. In addition, workflow analysis quantified the time saved in delivering actionable AST results, defined as the availability of clinically interpretable susceptibility categories. RESULTS: For a total of 306 evaluable isolates (from 309 collected) across all hospitals, QuickMIC demonstrated high concordance with reference methods, with categorical agreement exceeding 90% for the majority of tested antibiotic-pathogen combinations. Workflow analysis revealed a potential reduction in turnaround time of 17-45 hours compared with standard methods. For 88% of all tests, this allowed actionable AST results to be available within the same clinical shift rather than on subsequent days. This acceleration was consistent across both northern and southern European sites despite heterogeneity in reference methods and local laboratory workflows. CONCLUSIONS: The novel rapid AST system reliably provides susceptibility results in 2-4 hours directly from positive blood cultures, with performance comparable to established in-house methods. Implementation of this approach can substantially shorten the time to actionable results, offering clinicians the ability to optimize antimicrobial therapy significantly earlier during sepsis management. These findings support the adoption of rapid AST as a valuable tool to improve patient care and stewardship outcomes across diverse European hospital settings.

BACKGROUND: Intra-abdominal infection (IAI) is the leading cause of sepsis and is often complicated by disseminated intravascular coagulation (DIC), leading to increased mortality. Antithrombin Ⅲ (AT Ⅲ), a crucial endogenous anticoagulant, becomes significantly depleted during sepsis due to increased consumption and reduced synthesis. Its levels are closely associated with disease severity and clinical outcomes. Currently, there is a lack of evidence on the dynamic changes of AT Ⅲ and their relationship with the severity and prognosis of sepsis caused by IAI. METHODS: This was a prospective observational study. The patients with IAI-induced sepsis admitted to the intensive care unit (ICU) of the First Affiliated Hospital of China Medical University between April 20, 2017, and December 31, 2024, constituted the development cohort. Latent class trajectory modeling (LCTM) was applied to classify patients into different subclasses based on the AT Ⅲ level trajectories over the first 7 days after sepsis diagnosis. Clinical characteristics and outcomes were compared among these subclasses. Additionally, the AT Ⅲ trajectory patterns were validated in an external cohort of IAI patients derived from the China Multicenter Sepsis dataset. RESULTS: Four dynamic AT Ⅲ trajectory subclasses were identified and further validated by data from the development cohort ( CONCLUSIONS: This prospective cohort study uncovers heterogeneity in AT Ⅲ trajectories among IAI-induced sepsis, which were closely associated with the disease severity over time. Incorporating Class 1 (initial low AT followed by rapid decline) improves the predictive value for sepsis prognosis.