Daily Sepsis Research Analysis
Three impactful studies span mechanisms, prevention, and stewardship in sepsis. A mechanistic paper identifies Annexin A3 as a key stabilizer of endothelial barriers during sepsis. Complementing this, an international cohort quantifies pandemic-era antimicrobial use shifts, and a meta-analysis confirms chlorhexidine–alcohol superiority over povidone-iodine in preventing catheter-related bloodstream infection and catheter-related sepsis.
Summary
Three impactful studies span mechanisms, prevention, and stewardship in sepsis. A mechanistic paper identifies Annexin A3 as a key stabilizer of endothelial barriers during sepsis. Complementing this, an international cohort quantifies pandemic-era antimicrobial use shifts, and a meta-analysis confirms chlorhexidine–alcohol superiority over povidone-iodine in preventing catheter-related bloodstream infection and catheter-related sepsis.
Research Themes
- Endothelial barrier biology and sepsis pathophysiology
- Antimicrobial stewardship during pandemics
- Prevention of catheter-related bloodstream infections and sepsis
Selected Articles
1. Annexin A3 Represses Endothelial Permeability and Inflammation During Sepsis via Actin Cytoskeleton Modulation.
Using ANXA3 knockout mice and HUVECs, the study shows that loss of ANXA3 worsens sepsis outcomes by increasing endothelial permeability through actin stress fiber formation and loss of junctional proteins. ANXA3 suppresses E-selectin via ATF2 signaling; actin polymerization inhibitors reverse barrier dysfunction, positioning ANXA3 as a protective regulator of endothelial integrity in sepsis.
Impact: Identifies ANXA3 as a mechanistic gatekeeper of endothelial barrier function in sepsis with in vivo and in vitro validation, opening a tractable target pathway (actin dynamics) for therapy.
Clinical Implications: While preclinical, the work suggests potential biomarker and therapeutic avenues—e.g., enhancing ANXA3 function or modulating actin dynamics—to reduce vascular leak and inflammation in sepsis.
Key Findings
- ANXA3 deficiency increased mortality, lung injury, leukocyte infiltration, and vascular permeability in sepsis models.
- Loss of ANXA3 induced actin stress fibers and reduced junction proteins (ZO-1, VE-cadherin, claudin-5), compromising barrier integrity.
- ANXA3 knockdown upregulated E-selectin via ATF2 phosphorylation, increasing monocyte adhesion; actin polymerization inhibitors reversed these effects.
Methodological Strengths
- Convergent evidence from ANXA3 knockout mice and primary HUVECs strengthens causal inference.
- Mechanistic rescue by actin polymerization inhibition links phenotype to cytoskeletal dynamics.
Limitations
- Preclinical models (LPS/HUVEC) may not fully capture human sepsis heterogeneity.
- Sample size and blinding/randomization details are not specified in the abstract.
Future Directions: Validate ANXA3 as a prognostic/therapeutic target in clinical cohorts; develop small molecules or biologics to enhance ANXA3-mediated cytoskeletal stabilization.
Increased endothelial permeability and a dysregulated inflammatory response play key roles in organ damage in sepsis. The role of annexin A3 (ANXA3) in regulating endothelial permeability and inflammation during sepsis is explored using ANXA3 knockout mice and primary human umbilical vein endothelial cells (HUVECs). The absence of ANXA3 exacerbated sepsis outcomes, including increased mortality, lung injury, leukocyte infiltration, and vascular permeability. ANXA3 is highly expressed in endothelial cells and its loss results in the formation of cytoskeletal stress fibers and a decrease in the expression of the junction proteins zonula occludens (Zo)-1, vascular endothelial (VE)-cadherin, and claudin 5, leading to increase permeability. ANXA3 knockdown also upregulates E-selectin (CD62E) expression through the phosphorylation of activating transcription factor 2 (ATF2), which increases monocyte adhesion in HUVECs after LPS stimulation. Inhibiting actin polymerization reverse these effects. Thus, ANXA3 stabilizes the actin cytoskeleton, playing a protective role in endothelial dysfunction during sepsis.
2. The impact of the COVID-19 pandemic on antimicrobial usage: an international patient-level cohort study.
Across nine countries, broad-spectrum antibiotic use often increased during the first 18 months of COVID-19 among patients with pneumonia/ARDS/sepsis, with policy- and variant-sensitive shifts. Azithromycin prescribing declined after WHO guidance in India and South Korea, while meropenem and others rose in specific settings, underscoring the need for resilient stewardship.
Impact: Provides multi-country, patient-level evidence quantifying antimicrobial prescribing shifts linked to guidance and variant waves, informing stewardship strategies relevant to sepsis care.
Clinical Implications: Hospitals should reinforce stewardship dashboards and rapid feedback, de-implement non-beneficial macrolide use, and monitor carbapenem and antipseudomonal beta-lactam consumption during respiratory infection surges.
Key Findings
- Meropenem prescriptions rose during the pandemic in Bangladesh (OR 1.94–4.07; PDD 1.17–1.58) and Turkey (OR 1.09–1.58).
- Piperacillin/tazobactam increased in Italy (OR 1.07–1.48) with higher DOT (1.01–1.25) and PDD (1.05–1.21).
- Azithromycin increased in Bangladesh (OR 3.36–21.77) and Brazil (OR 2.33–8.42), then dropped in India and South Korea after WHO v1 guidance (e.g., −8.38 to −3.49 g/100 patients in India).
- ITS showed drug-specific surges aligned with the Delta variant (e.g., meropenem +93.40–126.48 g/100 patients in Bangladesh).
Methodological Strengths
- Multi-country, patient-level analysis enhances external validity.
- Interrupted time series captures policy and variant-related temporal shifts beyond simple pre/post comparisons.
Limitations
- Observational design with residual confounding and heterogeneity across sites.
- Microbiological confirmation and appropriateness of prescriptions not uniformly available.
Future Directions: Link prescribing patterns to patient outcomes and resistance trajectories; test targeted stewardship interventions during surge periods in ICU/COVID wards.
BACKGROUND: This study aimed to evaluate the trends in antimicrobial prescription during the first 1.5 years of COVID-19 pandemic. METHODS: This was an observational, retrospective cohort study using patient-level data from Bangladesh, Brazil, India, Italy, Malawi, Nigeria, South Korea, Switzerland and Turkey from patients with pneumonia and/or acute respiratory distress syndrome and/or sepsis, regardless of COVID-19 positivity, who were admitted to critical care units or COVID-19 specialized wards. The changes of antimicrobial prescription between pre-pandemic and pandemic were estimated using logistic or linear regression. Pandemic effects on month-wise antimicrobial usage were evaluated using interrupted time series analyses (ITSAs). RESULTS: Antimicrobials for which prescriptions significantly increased during the pandemic were as follows: meropenem in Bangladesh (95% CI: 1.94-4.07) with increased prescribed daily dose (PDD) (95% CI: 1.17-1.58) and Turkey (95% CI: 1.09-1.58), moxifloxacin in Bangladesh (95% CI: 4.11-11.87) with increased days of therapy (DOT) (95% CI: 1.14-2.56), piperacillin/tazobactam in Italy (95% CI: 1.07-1.48) with increased DOT (95% CI: 1.01-1.25) and PDD (95% CI: 1.05-1.21) and azithromycin in Bangladesh (95% CI: 3.36-21.77) and Brazil (95% CI: 2.33-8.42). ITSA showed a significant drop in azithromycin usage in India (95% CI: -8.38 to -3.49 g/100 patients) and South Korea (95% CI: -2.83 to -1.89 g/100 patients) after WHO guidelines v1 release and increased meropenem usage (95% CI: 93.40-126.48 g/100 patients) and moxifloxacin (95% CI: 5.40-13.98 g/100 patients) in Bangladesh and sulfamethoxazole/trimethoprim in India (95% CI: 0.92-9.32 g/100 patients) following the Delta variant emergence. CONCLUSIONS: This study reinforces the importance of developing antimicrobial stewardship in the clinical settings during inter-pandemic periods.
3. Chlorhexidine solutions are more effective than povidone-iodine solutions as skin disinfectants for the prevention of intravascular catheter-related infections: A meta-analysis.
Across 10 RCTs (9,689 catheters), chlorhexidine-containing skin antisepsis halved CRBSI and reduced catheter-related sepsis versus povidone-iodine. Effectiveness held across CHG concentrations, with CHG–70% alcohol performing best.
Impact: Provides high-level comparative evidence to standardize skin antisepsis, a cornerstone for preventing catheter-related bloodstream infection and secondary sepsis in critical care.
Clinical Implications: Adopt chlorhexidine–alcohol (preferably CHG–70% alcohol) for catheter insertion site antisepsis across ICUs; update bundles and training; monitor for CHG intolerance.
Key Findings
- CHG reduced CRBSI versus PVI (RR 0.460, 95% CI 0.323–0.654; P<0.001).
- CHG reduced catheter-related sepsis (RR 0.419, 95% CI 0.206–0.853; P=0.016).
- Benefits persisted across CHG concentrations (≤1% or >1%); CHG–70% alcohol was most effective.
Methodological Strengths
- Meta-analysis restricted to RCTs with RoB 2.0 quality assessment and PROSPERO registration.
- Subgroup analyses by CHG concentration and solvent (alcohol) increase applicability.
Limitations
- Heterogeneity in protocols (prep techniques, concentrations, co-interventions) across trials.
- Limited reporting on patient-centered outcomes beyond infection rates and on adverse skin reactions.
Future Directions: Head-to-head pragmatic RCTs of CHG–alcohol versus PVI in high-risk populations (e.g., ECMO, hematology) with cost-effectiveness and safety endpoints.
Catheter-related infections pose a significant risk to critically ill patients, making it crucial to select an appropriate sterilization solution. However, there is currently no consensus on the use of chlorhexidine-containing solutions or povidone-iodine (PVI) and the auxiliary ingredients in solutions. Meta-analysis. PubMed, EMBASE, OVID, Web of Science, and Cochrane Library databases. Two reviewers independently performed study screening and data extraction and used the Cochrane risk-of-bias tool 2.0 (RoB 2.0) for quality assessment. We included 10 fully published RCTs with 12 pairs of comparisons, which included a total of 9,689 catheters. The analysis revealed that chlorhexidine gluconate (CHG)-containing solutions were significantly more effective than PVI in preventing CRBSI (RR = 0.460, 95% CI 0.323-0.654, P < 0.001), catheter-related sepsis (RR = 0.419, 95% CI 0.206-0.853, P = 0.016), and catheter colonization (RR = 0.409, 95% CI 0.266-0.630, P < 0.001). Further subgroup analysis demonstrated that, regardless of the concentration of CHG (≤ 1% or > 1%), it was superior to PVI in preventing CRBSI and catheter colonization (RR = 0.271 ~ 0.585, 95% CI 0.110 ~ 0.400‒0.590‒0.926). CHG-alcohol is most effective at preventing catheter-related infections, especially those caused by 70% alcohol. Compared to PVI, CHG-70% alcohol is the most effective disinfectant for preventing catheter-related infections, as it combines the rapid disinfection and evaporation properties of alcohol with the prolonged antimicrobial effects of chlorhexidine.PROSPERO registration number: CRD42024507163.