Daily Sepsis Research Analysis
Analyzed 12 papers and selected 3 impactful papers.
Summary
Three studies span mechanistic and clinical advances in sepsis. Ferrostatin-1 mitigates early sepsis-induced lung injury by interrupting a lipid peroxidation–NINJ1–DAMP release axis and dampening neutrophil responses. Clinically, culture discordance between preoperative urine and intraoperative samples strongly predicts post-PCNL sepsis, and prolonged antibiotics in culture-negative very preterm infants are associated with worse outcomes, underscoring targeted stewardship.
Research Themes
- Ferroptosis and DAMP signaling in sepsis-induced lung injury
- Microbiologic culture discordance predicting postoperative sepsis risk
- Antibiotic stewardship and outcomes in culture-negative preterm infants
Selected Articles
1. Ferrostatin-1 protects against early sepsis-induced acute lung injury by suppressing lipid peroxidation-driven NINJ1-mediated DAMP release and neutrophil activation.
In murine sepsis (CLP), Ferrostatin-1 improved survival and reduced lung injury while dampening inflammatory transcriptional programs and neutrophil infiltration. Mechanistically, Fer-1 curtailed lipid peroxidation, acted upstream of NINJ1 to reduce large DAMP release, and suppressed LPS-induced cytokine production in neutrophils.
Impact: Identifies a tractable lipid peroxidation–NINJ1–DAMP axis and demonstrates a dual-action pharmacologic strategy to blunt early septic lung injury. Offers a mechanistic foundation for ferroptosis-targeted interventions in sepsis.
Clinical Implications: While preclinical, the data support testing ferroptosis inhibition or NINJ1-pathway modulation as adjuncts to standard sepsis care to prevent early lung injury.
Key Findings
- Ferrostatin-1 increased survival and reduced histologic lung injury and inflammatory cytokine expression in CLP-induced sepsis.
- RNA-seq showed attenuation of inflammatory/chemotaxis programs and reduced neutrophil infiltration in lungs after Fer-1.
- Fer-1 limited lipid peroxidation–induced lytic cell death and reduced large DAMP release by acting upstream of NINJ1.
- Fer-1 suppressed LPS-induced IL-1β and IL-6 in neutrophils; effects were reversed by JNK/p38 activation.
Methodological Strengths
- Integrated in vivo CLP sepsis model with survival, histology, and lung transcriptomics.
- Mechanistic in vitro validation including pathway reversal with pharmacologic JNK/p38 activation.
Limitations
- Preclinical mouse and cell-based data without human validation.
- Pharmacokinetics, dosing optimization, and off-target effects of Fer-1 were not addressed.
Future Directions: Evaluate ferroptosis/NINJ1-targeting strategies in large-animal sepsis models and early-phase clinical trials; define dosing, timing, and combinatorial regimens with antimicrobials and organ support.
Sepsis-induced acute lung injury (ALI) is a critical condition driven by neutrophil-dominated inflammation, lytic cell death and the subsequent DAMP release, etc. We tested whether the radical-trapping antioxidant Ferrostatin-1 (Fer-1) interrupts lipid peroxidation induced DAMP release and limits early lung injury in sepsis. We found that Fer-1 improved survival, preserved alveolar architecture, reduced lung-injury scores, and suppressed pulmonary inflammatory cytokine expression in a murine cecal ligation and puncture (CLP) model. Lung tissue RNA-sequencing showed that Fer-1 attenuated the CLP-induced inflammatory and chemotaxis transcriptome and significantly reduced neutrophil infiltration. In vitro, Fer-1 protected cells from lipid peroxidation-induced lytic death and impaired the release of large DAMPs associated with NINJ1 pathway, indicated Fer-1 acts upstream of NINJ1 to preserve membrane integrity. Fer-1 also directly lowered lipid peroxidation and reduced lipopolysaccharide (LPS)-induced IL-1β and IL-6 transcription and secretion in neutrophils, an effect reversed by pharmacological JNK/p38 activation. Together, our results indicate that Fer-1 functions as a dual-action modulator that prevents DAMP release and blunts neutrophil-driven inflammation escalation, thereby interrupting the lipid peroxidation-NINJ1-DAMP release axis, and mitigating early septic ALI.
2. Discordance between preoperative urine culture and intraoperative stone/pelvis culture as a predictor of post-PCNL sepsis: a single-center retrospective analysis for targeted antibiotic stewardship.
In 250 PCNL patients, preoperative urine culture missed upper-tract colonization frequently (48% sensitivity). Discordance between preoperative and intraoperative cultures independently predicted post-PCNL sepsis (adjusted OR 6.23), suggesting routine intraoperative cultures can guide targeted antibiotics and reduce septic complications.
Impact: Establishes culture discordance as a strong, actionable predictor of post-PCNL sepsis and challenges reliance on preoperative urine cultures alone. Supports procedural changes to reduce preventable septic events.
Clinical Implications: Adopt routine intraoperative stone and pelvic urine cultures to detect occult colonization/biofilm and tailor perioperative antibiotics, particularly when preoperative cultures are sterile.
Key Findings
- Culture discordance occurred in 30% of PCNL patients; PMUC sensitivity for upper-tract colonization was 48%.
- Post-PCNL sepsis was more frequent in discordant cases (17.3% vs 2.3%, p<0.0001).
- Discordance independently predicted sepsis (adjusted OR 6.23, 95% CI 2.20–17.62), outperforming stone burden and operative time.
- Sterile preoperative urine with positive intraoperative cultures accounted for 92.3% of sepsis events within the discordant group.
Methodological Strengths
- Use of multivariable logistic regression, LASSO penalization, and propensity-score matching to address confounding.
- Clear, Sepsis-3-defined primary outcome and concurrent preoperative/intraoperative cultures.
Limitations
- Single-center retrospective design may limit generalizability.
- No randomized antibiotic protocol; potential residual confounding remains.
Future Directions: Prospective multicenter validation of culture discordance as a risk stratifier, and trials testing intraoperative culture-guided antibiotic strategies to prevent sepsis.
PURPOSE: To evaluate the diagnostic accuracy of preoperative midstream urine culture (PMUC) against intraoperative stone and pelvic urine cultures, and to determine if culture discordance independently predicts sepsis following percutaneous nephrolithotomy (PCNL). METHODS: This retrospective cohort study analyzed 250 adult patients undergoing PCNL between January 2023 and October 2025. All participants had both PMUC and intraoperative stone/pelvic urine cultures. The primary outcome was post-PCNL sepsis defined by Sepsis-3 criteria. Diagnostic performance metrics were calculated, and the association between discordance and sepsis was assessed using multivariable logistic regression, LASSO penalization, and propensity-score matching to adjust for confounders. RESULTS: Culture discordance was observed in 30% (75/250) of patients. The sensitivity of PMUC for detecting upper urinary tract colonization was only 48%. Sepsis occurred in 6.8% of the total cohort but was significantly more frequent in the discordant group (17.3 vs 2.3%, p < 0.0001). In multivariable analysis, discordance remained the strongest independent predictor of sepsis (adjusted OR 6.23, 95% CI 2.20-17.62, p < 0.001), displacing stone burden and operative time. Notably, patients with sterile preoperative urine but positive intraoperative cultures accounted for 92.3% of sepsis events within the discordant group. CONCLUSION: PMUC is an unreliable surrogate for the upper tract microbiome, failing to detect colonization in over half of cases. Culture discordance is a robust predictor of post-PCNL sepsis, driven by untreated bacterial biofilms within stones. Routine intraoperative culturing is essential for targeted antibiotic stewardship to mitigate septic complications.
3. Antibiotic exposure in culture-negative preterm infants: a 10-year single-centre study.
In a 10-year single-center cohort of 3,235 culture-negative very preterm infants, higher antibiotic utilization and prolonged exposure were associated with increased mortality and major morbidities (LOS, NEC, CLD, severe ROP, severe brain injury). DOT and AUR decreased over time, but prolonged courses remained common.
Impact: Provides large-scale evidence linking prolonged antibiotics in culture-negative preterm infants to worse outcomes, reinforcing stewardship to minimize harm.
Clinical Implications: Implement strict antibiotic timeouts and criteria for discontinuation in culture-negative preterm infants, leveraging DOT/AUR monitoring and rapid diagnostics to reduce unnecessary exposure.
Key Findings
- Among 3,235 culture-negative infants <32 weeks, 26.0% received antibiotics for ≥5 days; 8.2% received none.
- Higher AUR and prolonged antibiotic exposure were associated with increased mortality and morbidities (LOS, NEC, CLD, severe ROP, severe brain injury).
- Over 2012–2022, DOT decreased from 78.0 to 61.9 per 1000 and AUR from 0.07 to 0.05, indicating improving stewardship but persistent overuse in some cases.
Methodological Strengths
- Large sample size over a decade with standardized electronic data extraction.
- Use of DOT and AUR metrics enables longitudinal stewardship assessment.
Limitations
- Single-center retrospective design; causality cannot be inferred.
- Potential residual confounding (illness severity, indication bias) despite large N.
Future Directions: Prospective, protocolized antibiotic stewardship interventions (e.g., early stop rules) with patient-level severity adjustment and integration of rapid diagnostics.
BACKGROUND: Antibiotic exposure in neonatal intensive care units (NICU) is high. This study describes antibiotic use in very preterm infants and examines the association between duration of exposure and outcomes in blood culture negative (CN) infants. METHODS: Infants <32 weeks' gestation admitted between January 2012 and June 2022 were included in this retrospective cohort study. Data were extracted from electronic databases. Antibiotic exposure was calculated as duration of treatment (DOT) and antibiotic utilisation rate (AUR) and compared with neonatal outcomes including mortality, late onset sepsis (LOS), necrotising enterocolitis (NEC), chronic lung disease (CLD), severe retinopathy of prematurity (ROP) and/or severe brain injury. RESULTS: There were 3235 CN infants included in the study; 1601 (49.5%) received antibiotics for ≤ 2 days of which 266 (8.2%) received no antibiotics; 841 (26.0%) received antibiotics for ≥ 5 days. DOT decreased from 78.0 to 61.9 per 1000 and AUR from 0.07 (IQR 0.04-0.11) to 0.05 (IQR 0.03-0.10) from 2012 to 2022. Higher AUR and/or prolonged antibiotic exposure was associated with increased mortality, brain injury, NEC, ROP, LOS, and CLD. CONCLUSION: Antibiotics are critical for infants with sepsis but can cause harm in those without. Strategies to reduce antibiotic exposure are needed to improve preterm infant outcomes. IMPACT: Prolonged antibiotic exposure is common in culture-negative, very preterm infants. Although antibiotics are critical for infants with culture-positive sepsis, they can cause harm in those who are culture-negative. This study adds to the small pool of evidence examining antibiotic use and its association with increased morbidity and mortality in very preterm infants. The study findings will impact antibiotic prescribing practices significantly and result in strategies to reduce antibiotic exposure in these at-risk infants.