Daily Sepsis Research Analysis
Analyzed 42 papers and selected 3 impactful papers.
Summary
Three papers stood out today: a 130,938-infant multinational cohort quantifying the high mortality and morbidity burden of early-onset sepsis in extremely preterm neonates; a large, propensity-matched real-world analysis showing that hyperferritinemia-defined macrophage activation-like syndrome in sepsis strongly predicts mortality and organ support needs; and a prospective multicenter PK/PD study recommending continuous infusion strategies to optimize piperacillin/tazobactam exposures in sepsis. Together they advance neonatal epidemiology, risk stratification using ferritin, and precision antibiotic dosing.
Research Themes
- Neonatal early-onset sepsis epidemiology and outcomes
- Ferritin-driven risk stratification in macrophage activation-like syndrome
- Precision dosing of beta-lactams via PK/PD optimization in sepsis
Selected Articles
1. Early-Onset Sepsis in Preterm Neonates of 22-28 Weeks' Gestation: An International Cohort Study.
In an 11-country registry including 130,938 extremely preterm neonates, EOS occurred in 3.3% with substantial inter-country variation and a 35.5% mortality. EOS independently increased the odds of death (AOR 2.49) and serious morbidity, with severe neurological injury most prominent.
Impact: This is one of the largest multinational analyses delineating EOS burden in the most vulnerable neonates, quantifying risk and cross-country variability to inform quality improvement and policy.
Clinical Implications: Prioritize rigorous perinatal infection prevention, standardized EOS definitions and screening, and early aggressive management in extremely preterm infants; benchmark national practices to reduce variation.
Key Findings
- EOS incidence was 3.3% among 130,938 extremely preterm neonates, varying 1.6–6.6% across countries.
- Mortality in EOS infants was 35.5%; mortality or morbidity occurred in 78.2%.
- After adjustment, EOS increased odds of death (AOR 2.49; 95% CI 2.27–2.74) and death or morbidity (AOR 1.89; 95% CI 1.70–2.10).
- Severe neurological injury was the leading complication (AOR 2.34; 95% CI 2.11–2.59).
Methodological Strengths
- Very large multinational cohort across 11 registries with standardized data collection windows (2007–2023).
- Adjusted analyses for mortality and morbidity with clear EOS case definitions (culture-positive within first days of life).
Limitations
- Retrospective design with heterogeneity in EOS time window definitions (<2 to <7 days).
- Potential residual confounding and inter-country practice variation not fully captured.
Future Directions: Harmonize EOS definitions and data elements across countries; evaluate targeted prevention bundles and early therapy pathways to reduce mortality and neurological injury.
OBJECTIVE: Early-onset sepsis (EOS) is associated with increased mortality and morbidity in preterm neonates. We aim to study the epidemiology of EOS among extremely preterm neonates across a multinational neonatal registry. STUDY DESIGN: A retrospective cohort study (2007-2023) of neonates born under 28 weeks' gestation from the International Network for Evaluation of Outcomes in Neonates collaboration, involving 11 national neonatal registries. The definition of EOS was blood or cerebrospinal fluid culture-positive sepsis within the first days after birth (ranging from <2 to <7 days of life). Primary outcome was mortality. Secondary outcome was major morbidities (severe neurological injury, severe retinopathy of prematurity, necrotizing enterocolitis, late-onset sepsis, or bronchopulmonary dysplasia). Univariate and multivariate analyses were performed. RESULTS: Four thousand three hundred fifty-four of 130,938 (3.3%) neonates with mean (±SD) gestational age 26.1 (±1.7) weeks and birthweight 874 (±241) grams developed EOS. Rates of EOS ranged from 1.6% to 6.6% across International Network for Evaluation of Outcomes in Neonates countries. Pregnancy associated hypertension and caesarean delivery were not associated with EOS. For EOS infants the mortality rate was 35.5% and mortality or morbidity rate was 78.2%. Odds of mortality remained higher after adjustment (AOR, 2.49; 95% CI: 2.27, 2.74) along with mortality or morbidity (AOR, 1.89; 95% CI, 1.70-2.10). Severe neurological injury was the leading complications (AOR, 2.34; 95% CI, 2.11-2.59). Variations in incidence, morbidity, and mortality were also noted between countries. CONCLUSION: EOS is common in extremely preterm neonates, varying across countries and associated with higher odds of mortality and morbidity.
2. Real-world clinical outcomes of macrophage activation-like syndrome and hyperferritinemia in sepsis: a retrospective database analysis.
In a propensity-matched real-world cohort (n=20,336), sepsis patients meeting MALS criteria (ferritin ≥4420 ng/mL) had significantly higher 28- and 90-day mortality and greater need for organ support. Mortality rose stepwise with higher ferritin thresholds, while anakinra showed no survival benefit.
Impact: It establishes ferritin as a robust, gradient biomarker for risk stratification in sepsis and challenges off-label anakinra use in hyperferritinemic phenotypes.
Clinical Implications: Incorporate early ferritin testing for sepsis risk stratification; prioritize supportive care and trial enrollment over empiric anakinra pending randomized evidence.
Key Findings
- After 1:1 propensity matching (n=10,168 per group), MALS was associated with higher 28-day (HR 2.73) and 90-day (HR 2.49) mortality.
- MALS increased needs for intubation, ICU admission, CRRT, and vasopressors at 28 and 90 days.
- Mortality rose stepwise with higher ferritin thresholds (e.g., day-28 HRs: 2000 ng/mL 2.44; 3000 2.57; 6000 2.94; 10,000 3.05).
- Anakinra treatment among MALS patients was not associated with improved 14- or 28-day survival.
Methodological Strengths
- Large multicenter EHR-based cohort with propensity score matching and extensive subgroup analyses.
- Evaluation of multiple ferritin thresholds enabling gradient risk modeling.
Limitations
- Retrospective design with potential misclassification and residual confounding.
- Anakinra analysis is observational and susceptible to confounding by indication.
Future Directions: Prospective validation of ferritin-based risk stratification and randomized trials testing immunomodulators in biomarker-enriched sepsis phenotypes.
BACKGROUND: Macrophage activation-like syndrome (MALS) is characterized by hyperferritinemia, yet its clinical course in real-world practice and the prognostic and clinical significance of varying ferritin levels have not been fully defined. The aim of this study was to characterize the epidemiology and clinical outcomes associated with sepsis and MALS. METHODS: We performed a retrospective analysis of the TriNetX database, identifying sepsis patients with MALS and ferritin level ≥4420 ng/mL within 3 days of diagnosis; patients with sepsis and ferritin <4420 ng/mL were classified as no-MALS. Primary outcomes were 28-day and 90-day all-cause mortality, and secondary outcomes included need for endotracheal intubation, intensive care unit (ICU) admission, continuous renal replacement therapy (CRRT), and vasopressors. We performed subgroup analyses according to age, immune suppression status, and bacteremia and assessed varying ferritin cutoff values (2000, 3000, 4420, 6000, and 10,000 ng/mL) for MALS diagnosis against study outcomes. We also performed an exploratory analysis assessing survival among patients with MALS treated with anakinra. We performed propensity score matching using nearest-neighbor matching and used hazard ratios (HRs) with 95% confidence intervals (CIs) to report results. FINDINGS: From January 2017 to January 2025, 10,169 patients met criteria for MALS and 214,338 were classified as no-MALS. After 1:1 propensity score matching, both cohorts included 10,168 matched patients. MALS was associated with higher 28-day (HR: 2.73) and 90-day (HR: 2.49) mortality and increased need for intubation (Day 28: HR: 2.04; Day 90: HR: 2.00), ICU admission (Day 28: HR: 1.86; Day 90: HR: 1.78), CRRT (Day 28: HR: 2.19; Day 90: HR: 2.16), and vasopressors (Day 28: HR: 1.80; Day 90: HR: 1.73). In subgroup analyses, patients aged ≥65 years, those with bacteremia, and immunocompromised patients had worse 28-day and 90-day outcomes. Mortality increased with higher ferritin cutoff values at day 28 (thresholds [ng/mL]: 2000 [HR: 2.44]; 3000 [HR: 2.57]; 6000 [HR: 2.94]; 10,000 [HR: 3.05]) and day 90 (thresholds [ng/mL]: 2000 [HR: 2.21]; 3000 [HR: 2.36]; 6000 [HR: 2.60]; 10,000 [HR: 2.67]), with similar trends for secondary outcomes. Anakinra was not associated with improved survival at day 14 or day 28. INTERPRETATION: In patients with sepsis, MALS was associated with worse 28- and 90-day outcomes compared to patients with no-MALS. Increasing ferritin cutoff values, even below the current diagnostic threshold for MALS diagnosis, were associated with worse primary and secondary outcomes. These findings support the need for systematic ferritin measurement in patients with sepsis for earlier risk stratification and clinical decision-making. FUNDING: None.
3. A multicentre evaluation of pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam and the association with clinical outcomes in critically ill patients with sepsis and septic shock.
In a prospective multicenter PK/PD study (n=45), creatinine clearance was the key determinant of piperacillin/tazobactam clearance, with target attainment in 54% (day 1) and 44% (day 3). Simulations recommend a 4.5 g loading dose followed by 4.5 g q6h as continuous infusion to achieve effective and safe exposures across common renal function ranges.
Impact: It directly informs dose optimization of a frontline antipseudomonal beta-lactam in sepsis, supporting continuous infusion strategies linked to renal function.
Clinical Implications: Adopt continuous infusion with an initial loading dose and adjust by creatinine clearance; integrate PK/PD targets and consider TDM to improve early target attainment.
Key Findings
- One-compartment, first-order elimination best described both drugs; creatinine clearance significantly influenced clearance.
- PK/PD targets were achieved in 54% (day 1) and 44% (day 3); attainment associated with older age and lower CLcr.
- Monte Carlo simulations support a 4.5 g loading dose then 4.5 g every 6 h as continuous infusion to meet efficacy and safety targets (CLcr 50–130 mL/min).
Methodological Strengths
- Prospective multicenter sampling with validated bioanalytical assays and population PK modeling.
- Use of explicit PK/PD targets with Monte Carlo simulations to generate actionable dosing recommendations.
Limitations
- Small sample size and limited to Malaysian ICUs; external generalizability may be constrained.
- Total (not unbound) plasma concentrations measured; clinical outcome associations were exploratory and non-significant.
Future Directions: Validate continuous infusion regimens in larger, diverse ICUs with TDM-guided adjustments; test outcome impact in pragmatic trials.
OBJECTIVES: To characterize the population pharmacokinetics and pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam in critically ill patients with sepsis or septic shock in Malaysian intensive care units and to use the population pharmacokinetic model to estimate individual target attainment and explore associations with clinical outcomes. METHODS: Serial blood samples were collected on days 1 and 3 of therapy in this prospective multicentre study. Total plasma piperacillin and tazobactam concentrations were quantified using a validated chromatographic assay. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Monolix. Therapeutic exposure was defined as achieving 100% fT>16 mg/L for piperacillin and 85% fT>2 mg/L for tazobactam while remaining below the piperacillin toxicity threshold (<160 mg/L). RESULTS: Forty-five critically ill adults with sepsis or septic shock were recruited (median age, 61 years [range: 18-88]; median creatinine clearance (CLcr) 70 mL/min [range: 30-161]; 20 females). A one-compartment model with first-order elimination best described the pharmacokinetics for both drugs. Estimated CLcr significantly influenced drug clearance. Pre-defined therapeutic exposures were achieved in 54% and 44% on days 1 and 3, respectively. Patients attaining exposures were older and had lower CLcr. Clinical cure and ICU survival were numerically different across exposure groups, although these exploratory comparisons were not statistically significant. Simulations indicated that a 4.5 g loading dose followed by 4.5 g every 6 h as a continuous infusion achieved effective and safe exposures in patients with CLcr 50 to 130 mL/min. CONCLUSION: Continuous infusion is the most reliable strategy for achieving early piperacillin/tazobactam therapeutic exposures in patients with sepsis or septic shock.