Daily Sepsis Research Analysis
A mechanistic study demonstrates that paroxetine preserves neutrophil CXCR2 expression and improves survival in murine sepsis, suggesting a repurposable adjunctive therapy. A large EHR-wide association analysis identifies renal/urologic conditions as dominant drivers of E. coli bacteraemia risk. A multicenter cohort of candidemia reveals predictors of echinocandin treatment failure and signals that higher dosing may reduce failure in select high-risk subgroups.
Summary
A mechanistic study demonstrates that paroxetine preserves neutrophil CXCR2 expression and improves survival in murine sepsis, suggesting a repurposable adjunctive therapy. A large EHR-wide association analysis identifies renal/urologic conditions as dominant drivers of E. coli bacteraemia risk. A multicenter cohort of candidemia reveals predictors of echinocandin treatment failure and signals that higher dosing may reduce failure in select high-risk subgroups.
Research Themes
- Neutrophil trafficking and chemokine receptor preservation in sepsis
- EHR-wide risk stratification for E. coli bacteraemia
- Optimizing antifungal dosing to reduce candidemia treatment failure
Selected Articles
1. Paroxetine attenuates sepsis by preserving the expression of the G protein-coupled chemokine receptor CXCR2 on neutrophils.
In murine CLP sepsis, paroxetine (10 mg/kg/day) enhanced neutrophil recruitment, preserved membrane CXCR2 on circulating neutrophils, reduced bacterial load and inflammatory mediators, stabilized blood pressure, and improved survival. In vitro, paroxetine prevented LPS/CXCR2 ligand-induced CXCR2 downregulation in human and murine neutrophils and increased CD11b with stimulation, supporting a neutrophil-targeted immunomodulatory mechanism.
Impact: This study links a clinically available drug to a defined neutrophil trafficking mechanism and shows survival benefit in sepsis models, opening a feasible repurposing path.
Clinical Implications: Paroxetine could be explored as an adjunct to antibiotics in sepsis to restore neutrophil chemotaxis via CXCR2 preservation; early-phase clinical trials should assess safety, dosing, and interaction with standard care.
Key Findings
- Paroxetine increased peritoneal neutrophil recruitment and reduced local bacterial load in moderate CLP sepsis.
- Preserved membrane CXCR2 on circulating neutrophils, lowered plasma CXCL2 and IL-6, and attenuated heart and lung leukocyte infiltration in severe CLP with antibiotics.
- Prevented LPS/CXCR2 ligand-induced CXCR2 downregulation in human and murine neutrophils and HEK293 cells; increased CD11b upon stimulation.
- Improved survival and stabilized blood pressure in sepsis models.
Methodological Strengths
- Use of both moderate and severe CLP models with comprehensive physiologic, histologic, and survival endpoints
- Cross-species validation including human neutrophils, murine neutrophils, and HEK293 cells with flow cytometry assays
Limitations
- Preclinical study in mice and in vitro systems; no human clinical outcomes
- Paroxetine dosing and off-target SSRI effects in septic patients remain untested
Future Directions: Early-phase clinical trials to test safety and pharmacodynamics in sepsis; biomarker-driven studies assessing CXCR2 preservation and neutrophil function as pharmacodynamic endpoints.
2. An electronic health record-wide association study to identify populations at increased risk of E. coli bacteraemia.
Using an EHR-WAS framework on 277,515 hospital-exposed individuals across three two-year periods, renal/urologic/UTI-related factors emerged as dominant drivers of E. coli bacteraemia, with an estimated 47% of cases potentially preventable if minimized. Cancer-related variables (proximity to chemotherapy), gastrointestinal, and infectious disease factors increased risk, whereas cardiac/respiratory variables associated with lower risk; associations were broadly consistent across periods.
Impact: The study operationalizes an EHR-wide framework to quantify modifiable risk domains for E. coli bacteraemia, directly informing targeted prevention strategies at scale.
Clinical Implications: Enhanced surveillance and preventive interventions should prioritize renal/urologic/UTI risk clusters and recent chemotherapy exposure, with integration into EHR alerts and care pathways.
Key Findings
- In FY2022/23–2023/24, 757 cases and 276,758 controls were analyzed using adjusted Poisson regression across 377 features.
- Renal/urologic/UTI-related variables had the largest impact; up to 47% of cases could be theoretically prevented if minimized.
- Cancer-related variables (closer proximity to chemotherapy), gastrointestinal, and infectious disease variables increased risk; cardiac/respiratory variables associated with lower risk.
- Healthcare exposure showed no consistent effect; associated factors varied by period but broad domains were stable.
Methodological Strengths
- Large EHR-based dataset with hospital-exposed controls and case ascertainment across three time periods
- Adjusted Poisson regression and comprehensive feature screening (377 variables) using an established EHR-WAS method
Limitations
- Observational EHR-based design limits causal inference and may retain residual confounding
- Single-region dataset (Oxfordshire, UK); associated factors varied by period, affecting generalizability
Future Directions: External validation in diverse health systems and interventional studies targeting UTI/renal risk clusters to test preventability at scale.
3. Why do echinocandins fail? Identifying key predictors to improve clinical outcomes of candida bloodstream infections: a retrospective multicenter cohort study.
In a multicenter retrospective cohort of 218 candidemia patients treated with echinocandins, 38% met a composite treatment failure endpoint and 90-day mortality was 30% (higher in the TF group). Obesity, septic shock, and elevated echinocandin MICs predicted failure, whereas removable intravascular devices and higher-dose echinocandin (30–50% above standard) were protective, with IPTW analyses suggesting benefit in ICU patients with SOFA<6, BMI>30, or hypoalbuminemia.
Impact: Identifies actionable predictors of antifungal treatment failure and a pragmatic dosing strategy that may reduce failure in defined high-risk candidemia subgroups.
Clinical Implications: Consider early removal of intravascular devices, monitor echinocandin MICs, and evaluate higher-dose echinocandin regimens in obese, hypoalbuminemic, or ICU patients with lower SOFA scores, pending prospective validation.
Key Findings
- Treatment failure occurred in 38% with 90-day all-cause mortality of 30%, higher among those with failure (P<0.001).
- Obesity, septic shock, and increased echinocandin MICs predicted treatment failure in multivariable Cox regression.
- Removable intravascular devices and higher-dose echinocandin (30–50% above standard) were protective; IPTW analyses showed benefit in ICU patients with SOFA<6, BMI>30, or albumin ≤2.5 g/dL.
Methodological Strengths
- Multicenter cohort with predefined composite failure endpoint and 90-day mortality
- Advanced analytics including multivariable Cox regression and IPTW to address treatment assignment bias
Limitations
- Retrospective observational design with potential residual confounding and non-randomized dosing decisions
- Modest sample size and heterogeneity of Candida species and clinical contexts
Future Directions: Prospective, randomized dose-optimization trials stratified by MIC, BMI, albumin, and illness severity to validate higher-dose strategies.