Daily Sepsis Research Analysis
Analyzed 10 papers and selected 3 impactful papers.
Summary
Three papers advance sepsis care across dosing precision, neonatal epidemiology, and host-pathway modulation. PK/PD-guided piperacillin/tazobactam dosing with TDM improved target attainment and linked exposure to 28-day mortality; a nationwide Taiwanese cohort quantified the heavy burden and risk factors of early-onset sepsis in very-low-birth-weight infants; and translational work suggests nafamostat may rebalance complement/coagulation and improve organ function.
Research Themes
- Precision dosing and PK/PD-guided therapy in sepsis
- Neonatal early-onset sepsis epidemiology and outcomes
- Host-pathway modulation (complement/coagulation) as sepsis therapy
Selected Articles
1. Nafamostat mesilate improves sepsis outcomes by modulating complement and coagulation pathways.
Using proteomics, target prediction, animal models, and a pilot clinical cohort, the study shows nafamostat intersects complement/coagulation cascades, reduces KNG1 cleavage, improves organ injury in septic mice, and may benefit septic patients receiving CRRT compared with unfractionated heparin. Findings support host-pathway modulation as a therapeutic strategy in sepsis.
Impact: It integrates systems proteomics with mechanistic and translational evidence to propose a multi-pathway host-directed therapy for sepsis. Such pathway-level modulation could complement antimicrobials where conventional anti-inflammatory trials have failed.
Clinical Implications: For septic patients requiring CRRT, nafamostat as an anticoagulant may improve organ function metrics (SOFA) and reduce platelet consumption while prolonging APTT; however, controlled trials are needed before routine adoption.
Key Findings
- Identified 107 differentially expressed proteins across sepsis prognostic groups; 16 overlapped genes linked NM targets with complement/coagulation cascades.
- Nafamostat reduced plasma KNG1 cleavage and downstream products, alleviating organ damage in septic mice.
- In a pilot retrospective cohort, nafamostat (as CRRT anticoagulant) reduced SOFA scores and platelet consumption and prolonged APTT compared with unfractionated heparin.
Methodological Strengths
- Multi-omics and in silico target prediction integrated with in vivo validation
- Bench-to-bedside design including a clinical comparator (UFH) in a pilot cohort
Limitations
- Pilot clinical cohort was small and retrospective with unspecified sample size
- Target prediction is computational; direct binding/target engagement not fully established in humans
Future Directions: Conduct randomized or well-matched comparative trials of nafamostat in septic patients (including CRRT and non-CRRT populations), and map pharmacodynamics to proteomic pathway changes to validate mechanism in humans.
INTRODUCTION: Sepsis is a leading cause of mortality in critically ill patients, characterized by dysregulation of multiple biological systems, including the complement, coagulation and contact pathways Nafamostat (NM), a serine protease inhibitor, has shown potential in modulating these systems. OBJECTIVES: We investigated the potential therapeutic role of NM in sepsis and its mechanism. METHODS: High-throughput mass spectrometry proteomics analysis was conducted to investigate changes in protein levels among sepsis patients. Leveraging the chemical structure of NM, multiple drug-target prediction databases were employed to forecast potential targets. In septic mice, evaluation of complement, coagulation, and contact system activation were conducted after NM administration. Plasma Kininogen 1 (KNG1) was overexpressed to validate roles in the occurrence and development of sepsis. A retrospective study was conducted to evaluate the impact of NM as an anticoagulant for continuous renal replacement therapy (CRRT) on the prognosis of septic patients. RESULTS: 107 differentially expressed proteins (DEPs) were identified in sepsis patients with varying prognosis. 622 predicted targets for NM and 184 DEPs in sepsis were identified, with 16 overlapped genes enriching in complement and coagulation cascades. NM reduced plasma KNG1 cleavage and downstream products, alleviating organ damage in septic mice. In a small pilot cohort, NM reduced SOFA scores and platelet consumption while prolonging APTT compared to unfractionated heparin. CONCLUSION: NM may offer a novel therapeutic approach by modulating dysregulated pathways, thus improving organ function and clinical outcomes in sepsis.
2. Early-onset sepsis in preterm-very-low-birth-weight neonates in Taiwan: A nationwide cohort study of incidence, outcomes, and risk factors.
In a nationwide Taiwanese registry of 7,349 very-low-birth-weight preterm infants, culture-confirmed early-onset sepsis occurred in 2.83% with 29.3% mortality. Maternal chorioamnionitis, male sex, and lower 1-minute Apgar were independent risk factors, and EOS was associated with markedly higher rates of major morbidities.
Impact: This is the first nationwide epidemiologic quantification of EOS burden in VLBW infants in Taiwan, providing precise risk estimates to inform prevention and early management strategies.
Clinical Implications: Risk stratification at birth (chorioamnionitis exposure, male sex, low 1-min Apgar) can inform heightened surveillance, early empiric therapy, and parental counseling; the high morbidity profile underscores the need for pathogen-specific strategies.
Key Findings
- EOS incidence 2.83% (208/7349) among PVLBW infants; EOS mortality 29.3% (61/208).
- Independent risk factors: maternal chorioamnionitis (AOR 4.10), male sex (AOR 1.38), lower 1-min Apgar (AOR 0.83 per point).
- EOS associated with higher severe outcomes: severe IVH 25.26% vs 8.05%, PVL 8.25% vs 3.42%, chronic lung disease 48.94% vs 31.43%, severe ROP 23.13% vs 12.81%, NEC 8.33% vs 4.69%, and late-onset sepsis 31.58% vs 8.96%.
Methodological Strengths
- Nationwide registry with large sample size and culture-confirmed EOS definition
- Multivariable adjustment for perinatal confounders to derive adjusted odds ratios
Limitations
- Observational design limits causal inference despite adjustment
- Pathogen-specific analyses were not detailed; generalizability outside Taiwan requires caution
Future Directions: Link pathogen profiles and antimicrobial resistance to outcomes to refine empiric protocols and develop predictive tools for EOS in VLBW infants.
BACKGROUND: This cohort study aimed to investigate the impact of early onset sepsis (EOS) on preterm-very-low-birth-weight neonates (PVLBW) before discharge. METHODS: This study utilized data from the Taiwan Neonatal Network (TNN) and focused on neonates weighing less than 1500 g at a gestational age between 22 and 32 + 6 weeks, from 2016 to 2021. EOS was defined as a culture-confirmed bacterial infection of the blood or cerebrospinal fluid within three days of birth. Multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (AOR) to identify independent risk factors for EOS while controlling for factors present at birth. RESULTS: Out of the 7349 eligible PVLBW neonates, 208 (2.83%) experienced EOS, with a mortality rate of 29.3% (61/208). The independent risk factors for EOS included maternal chorioamnionitis (AOR: 4.10), male sex (AOR: 1.38), and a lower 1-min Apgar score (AOR: 0.83). Neonates with EOS exhibited significantly higher rates of severe outcomes, including severe intraventricular hemorrhage (25.26% vs. 8.05%), periventricular leukomalacia (8.25% vs. 3.42%), chronic lung disease (48.94% vs. 31.43%), severe retinopathy of prematurity (23.13% vs. 12.81%), necrotizing enterocolitis (8.33% vs. 4.69%), and late-onset sepsis (31.58% vs. 8.96%) compared to the non-EOS group. CONCLUSION: This study provides the first nationwide epidemiological data on early onset sepsis in neonates with PVLBW. Our findings indicate that EOS in neonates with PVLBW significantly increases the risk of mortality and severe adverse outcomes. Further investigations of the pathogens involved are warranted to develop strategies and predictive tools to improve patient outcomes.
3. Pharmacokinetics, target attainment and outcomes of piperacillin/tazobactam in critically ill patients receiving continuous infusion with therapeutic drug monitoring: a retrospective analysis.
In 1,538 critically ill patients with severe infections including sepsis, individualized continuous infusion plus TDM increased piperacillin target attainment from 45.7% to 62.4%. Exposure strata correlated with 28-day mortality, and women had higher odds of supratherapeutic levels, supporting PK/PD-guided dosing in routine care.
Impact: This is one of the largest real-world cohorts linking beta-lactam exposure distributions to outcomes under a TDM-guided continuous infusion strategy, informing actionable dosing policies.
Clinical Implications: Adopt individualized dosing software with early TDM to achieve therapeutic piperacillin levels, avoid supratherapeutic exposure associated with higher mortality, and consider sex-specific monitoring.
Key Findings
- Individualized empiric dosing achieved 45.7% therapeutic range at first TDM; after TDM adjustment, target attainment rose to 62.4%.
- Subtherapeutic (<32 mg/L) 12.8% and supratherapeutic (>96 mg/L) 11% among all TDM samples during individualized dosing.
- 28-day mortality gradient: 18.2% (therapeutic), 27.0% (extended), 40.9% (supratherapeutic), p=0.05.
- Women had 1.74-fold higher odds of supratherapeutic concentrations (OR 1.74, 95% CI 1.38-2.19).
Methodological Strengths
- Large cohort with 1,538 patients and 3,089 concentration measurements
- PK/PD-guided individualized dosing with iterative TDM adjustments
Limitations
- Retrospective observational design with potential residual confounding
- Therapeutic range thresholds were not validated in randomized trials
Future Directions: Prospective trials to test TDM-driven targets on patient-centered outcomes and to refine sex-specific dosing algorithms.
OBJECTIVES: To provide real-world evidence on piperacillin exposure and outcomes in critically ill patients following the implementation of pharmacokinetic (PK)/pharmacodynamic (PD)-guided dosing in routine care. METHODS: This retrospective observational study included critically ill adults who received continuous piperacillin/tazobactam infusion between 2011 and 2019. Empiric doses were individualized using dosing software based on renal function and subsequently adjusted according to therapeutic drug monitoring (TDM) results. Drug exposure was defined as subtherapeutic (<32 mg/L), therapeutic (32-64 mg/L), extended (64-96 mg/L), or supratherapeutic (>96 mg/L). RESULTS: A total of 1538 critically ill patients with severe infections and sepsis of varying severity were included, and 3,089 piperacillin serum concentrations were analysed. Median daily piperacillin dose was 8 g (6-12 g; IQR), median steady-state concentration 55 mg/L (38-73 mg/L; IQR), and median clearance 6.25 L/h (4.0-9.8 L/h; IQR). At the first measurement, individualized empiric dosing resulted in 45.7% (704/1538)of patients being within the therapeutic range; after TDM-guided adjustment, target attainment increased to 62.4% (968/1551). Subtherapeutic and supratherapeutic concentrations were uncommon among all TDM samples collected during individualized dosing (<32 mg/L: 12.8%, 395/3089; <16 mg/L: 0.8%, 26/3089; >96 mg/L: 11%, 340/3089). 28-day mortality was 18.2% (131/718) in patients within the therapeutic range, 27.0% (107/396) in those within the extended range, and 40.9% (101/247) in those with supratherapeutic concentrations (p=0.05). Women were associated with 1.74-fold higher odds of supratherapeutic concentrations (OR 1.74, 95% CI 1.38-2.19, p<0.001; 176/2022 male vs 152/1067 female with concentrations >96 mg/L). CONCLUSIONS: A multimodal approach combining individualized empiric dosing, TDM, and continuous infusion ensured target attainment while reducing drug consumption. These findings support the integration of individualized, PK/PD-guided dosing into routine care for critically ill patients and warrant further exploration of sex-related differences in exposure.