Daily Sepsis Research Analysis

BACKGROUND: Difficult-to-treat resistant (DTR) Gram-negative infections show resistance to all first-line antibiotics (ie, β-lactams and fluoroquinolones) and have a 40% greater mortality rate than susceptible infections. New antibiotics are now available with improved safety and efficacy and with in-vitro activity against DTR infections; however, their influence on the outcomes of patients with DTR infections remains unclear. We aimed to evaluate whether and why mortality in patients with DTR infections has changed since the introduction of these newer antibiotics in the USA. METHODS: In this retrospective cohort study in the USA, adult patients (aged ≥18 years) with a DTR Gram-negative infection, defined as microbiological evidence of DTR Enterobacterales, Pseudomonas aeruginosa, or Acinetobacter baumannii and receipt of at least 3 consecutive days of any antibiotic therapy, were identified from hospitals reporting microbiology data in the PINC-AI Healthcare Database. We characterised the proportion of inpatient encounters receiving newer DTR-active antibiotics, traditional DTR-active antibiotics, and non-DTR-active antibiotics. We used a generalised linear mixed model with marginal predictions to examine changes in in-hospital mortality, defined as death or discharge to hospice, over the study period when adjusting for patient-related and treatment-related factors (including receipt of a new antibiotic and receipt of in-vitro discordant initial therapy), hospital-related factors (including the availability of newer antibiotics and corresponding susceptibility testing), and COVID-19 pandemic-related factors. A three-way interaction term for time (year), pathogen, and infection site (ie, bloodstream and non-bloodstream) was included given the expected differences in mortality. FINDINGS: Between Jan 1, 2016, and Aug 31, 2023, 8 319 398 adult inpatient encounters with available microbiology data were recorded from 471 hospitals, of which 9384 (0.11%) encounters had microbiological evidence of an eligible DTR organism. 5065 (54·0%) of these 9384 encounters, from 262 hospitals, met the inclusion criteria for DTR Gram-negative infections and were included in the study. Among this cohort, the prescription of newer antibiotics, as well as the availability of newer antibiotics and their corresponding susceptibility tests, increased substantially from 2016 to 2023. Although the proportion of encounters in which the patient received a newer antibiotic as initial therapy increased from 4% (21 of 589) in 2016 to 15% (34 of 234) in 2023, in most cases (196 [84%] of 234) patients continued to receive in-vitro discordant initial antibiotic therapy, even in 2023. We observed no change in the average marginal effect (the average percentage change per year) for adjusted mortality between 2016 and 2023 for Enterobacterales (0.1% [95% CI -1.1 to 1.4]), P aeruginosa (-0.7% [-1.7 to 0.3]), or A baumannii (-0.4% [-1.8 to 0.9]) infections. When dichotomised into bloodstream and non-bloodstream infections, the marginal effect for adjusted mortality remained unchanged over time for most pathogen and site combinations, with the exception of P aeruginosa bloodstream infections, for which a decrease was observed (-4.5% [-8.2 to -0.60]). INTERPRETATION: Despite the availability of newer antibiotic agents, the estimated mortality and ongoing use of in-vitro discordant initial antibiotics remains unacceptably high among patients with DTR infections in US hospitals. Prompt recognition of both the pathogen and resistance phenotype could be a crucial component in reducing mortality. Although notable, the decrease over time in adjusted mortality for P aeruginosa bloodstream infections should be considered hypothesis-generating because the cohort of patients with such infections was small. FUNDING: US National Institutes of Health (NIH) Clinical Center; US National Cancer Institute; the Intramural Research Program of the US National Heart, Lung, and Blood Institute; the US National Institute of Allergy and Infectious Diseases; and the US Food and Drug Administration.

Septic shock (SS), the most severe stage of sepsis, has a high mortality rate. Mitochondria-mediated programmed cell death (MPCD) plays a key role in SS pathogenesis, but its diagnostic value remains unclear. This study integrated the GEO public dataset and used the WGCNA method to identify gene modules significantly associated with SS, and intersected them with MPCD-related genes to obtain the SS-MPCD gene set. LASSO regression and Boruta algorithms screened key genes, with their diagnostic performance verified in an independent queue. Through single-cell transcriptome analysis, immune infiltration score (ssGSEA), and regulatory network construction (TF miRNA, PPI), the immune regulatory characteristics of candidate genes were systematically analyzed. Clinical blood samples were collected, and the expression levels of candidate genes were validated through qRT-PCR. Finally, the CLP-induced SS mouse model was used for ACSL1 intervention, and its functional effects were evaluated by survival analysis, H&E, qRT PCR, WB, and IF. Four diagnostic genes were identified: ACSL1, BLOC1S1, SPTLC2, and TSPO. They were upregulated in SS patients and clinical samples, showed immune cell-specific expression, and were regulated by specific miRNAs/TFs. Immune profiling revealed a neutrophil- and Treg-dominated microenvironment. Inhibiting ACSL1 improved survival, reduced organ damage and inflammation, decreased apoptosis markers, and suppressed neutrophil/Treg infiltration. The study systematically identifies and preliminarily validates four MPCD-related diagnostic genes, offering insights into SS pathogenesis and potential early diagnosis.

Sepsis-induced acute lung injury (ALI) remains a critical factor contributing to mortality in intensive care units, and effective therapeutic strategies are still lacking. The present research explores the defensive impacts and associated mechanisms of Tubuloside A (TA), an active phenanthrenoid glycoside extracted from Cistanche deserticola, in sepsis-induced ALI. Utilizing both a cecal ligation and puncture (CLP) mouse model and LPS-stimulated MLE-12 alveolar epithelial cells, we found that TA markedly attenuated lung injury, as indicated by improved histopathological features, reduced pulmonary edema, and maintenance of alveolar structure. Mechanistically, TA provided multifaceted protection by concurrently inhibiting oxidative stress, ferroptosis, and inflammatory signaling-critical drivers of sepsis-induced ALI. Treatment with TA diminished lipid peroxidation, restored GPX4 expression, and inhibited pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Network pharmacology identified NFKB1 as a therapeutic target of TA against ALI. Molecular docking predicted and SPR analysis verified that TA binds to NF-κB p50. Notably, functional validation via NF-κB p50 overexpression abolished TA-mediated protection and re-sensitized cells to ferroptosis, confirming NF-κB p50 as a central regulatory node. Furthermore, TA activated Nrf2 signaling in an NF-κBp50-dependent manner, as demonstrated by nuclear translocation assays and rescue experiments. Calcein AM imaging and iron chelation studies confirmed that TA's anti-ferroptotic effect requires functional NF-κB/Nrf2/GPX4 crosstalk. Collectively, our findings reveal that TA ameliorates sepsis-ALI by targeting the NF-κBp50-Nrf2/GPX4 axis to coordinately inhibit inflammation, oxidative stress, and ferroptosis, highlighting its potential as a multi-target phytotherapeutic agent for acute respiratory disorders.