Daily Sepsis Research Analysis
Analyzed 11 papers and selected 3 impactful papers.
Summary
A multiscale digital twin integrating PBPK, eco-evolutionary pharmacodynamics, and machine learning proposes evolution-aware precision dosing of aminoglycosides in neonates with suspected sepsis. New neonatal molecular epidemiology from East Asia underscores high ceftriaxone resistance and lethal E. coli lineages, while a large ICU cohort shows no outcome benefit for continuous versus intermittent high-dose meropenem infusion.
Research Themes
- Evolution-aware precision dosing via clinical digital twins
- Antimicrobial resistance and clonal lineages in neonatal sepsis
- Optimization of beta-lactam administration strategies in critical care
Selected Articles
1. Evolutionary digital twin framework for optimal aminoglycoside dosing in neonates with suspected sepsis.
A multiscale medical digital twin integrating PBPK, eco-evolutionary pharmacodynamics, and an LSTM-updated GFR was calibrated on 1,634 neonates to optimize aminoglycoside therapy in silico. Nonlinear optimal control achieved bacteriostatic exposure across all digital twins, and model predictive control reduced late bacterial rebound while largely preserving safety at higher MICs.
Impact: Introduces an evolution-aware, control-theory-enabled digital twin for neonatal antibiotic dosing, bridging PBPK/PD modeling and real-world data for precision therapy.
Clinical Implications: Provides a computational foundation for individualized aminoglycoside dosing that accounts for renal function dynamics and resistance evolution; supports design of prospective trials and decision-support tools.
Key Findings
- Integrated PBPK with eco-evolutionary pharmacodynamics and LSTM-updated GFR into a multiscale digital twin calibrated on 1,634 neonates.
- Nonlinear optimal control achieved bacteriostatic exposure across all digital-twin neonates.
- Safety was preserved in most cases even at higher MICs, and model predictive control reduced late bacterial rebound.
Methodological Strengths
- Multiscale integration of PBPK and eco-evolutionary PD with machine learning–updated renal function
- Large real-world calibration cohort (n=1,634) and use of optimal/model predictive control
Limitations
- In silico study without prospective clinical outcome validation
- Generalizability to other antibiotics and non-renally cleared agents is untested
Future Directions: Prospective clinical trials embedding the digital twin for real-time dosing, external validation across centers, and extension to other antibiotic classes.
Aminoglycoside dosing in suspected neonatal sepsis remains difficult due to highly variable pharmacokinetics driven by marked physiological diversity, from extremely preterm to term neonates, and further complicated by acute kidney injury, perinatal asphyxia, and concomitant interventions. We developed multiscale medical digital twins combining a physiologically-based pharmacokinetic model with an eco-evolutionary pharmacodynamic module capturing drug-modulated bacterial growth and resistance. Glomerular filtration rate is continuously updated using a long short-term memory neural network trained on real-world data. Calibrated on 1634 neonates, the framework enables in silico optimization of full-course antibiotic therapy through real and virtual cohorts, balancing efficacy and safety while accounting for resistance-driven changes in the minimum inhibitory concentration (MIC). Nonlinear optimal control achieved bacteriostatic exposure across all digital-twin neonates, with safety preserved in most cases at higher MICs. Model predictive control further reduced bacterial rebound during late therapy. This framework supports evolution-aware precision dosing of renally cleared antibiotics in vulnerable neonatal populations.
2. Molecular epidemiological characterization of invasive extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates from infants less than 3 months old in East Asia.
Across Taiwanese and Korean infants under 90 days, invasive E. coli predominated with broad clonal diversity; high-risk ST1193 and ST131 were associated with higher mortality, while ST95 linked to neonatal meningitis. Ceftriaxone resistance was common—about one-third of isolates in Taiwan and over 60% in Korea—and K. pneumoniae showed marked regional clonal diversity.
Impact: Provides contemporary, region-specific resistance patterns and high-risk clonal lineages in neonatal invasive infections, informing empiric therapy and stewardship.
Clinical Implications: High ceftriaxone resistance rates argue for reconsidering third-generation cephalosporins as empiric monotherapy in East Asian neonates and emphasize ongoing surveillance and tailored empiric strategies.
Key Findings
- Escherichia coli predominated with 29 sequence types across 23 clonal complexes.
- High-risk E. coli ST1193 and ST131 were associated with higher mortality; ST95 was linked to neonatal meningitis.
- Klebsiella pneumoniae showed regional clonal diversity with 15 unique sequence types.
- Ceftriaxone resistance occurred in approximately one-third of isolates in Taiwan and over 60% in Korea.
Methodological Strengths
- Recent, multi-year, bi-regional surveillance with MLST and susceptibility testing
- Clonal lineage analysis linked to clinical phenotypes (mortality, meningitis)
Limitations
- Sample size not reported in the abstract; retrospective design limits causal inference
- Resistance gene details are truncated in the abstract, limiting genotypic specificity
Future Directions: Prospective multicenter neonatal cohorts linking clonal lineages and resistance genotypes to standardized clinical outcomes to refine empiric therapy algorithms.
OBJECTIVES: Neonatal sepsis due to Gram-negative bacteria remains a clinical challenge. This study aimed to characterize the current epidemiology, genetic diversity, and antimicrobial resistance of invasive Escherichia coli and Klebsiella pneumoniae infections in infants under 90 days old in Taiwan and Korea. METHODS: Culture-confirmed clinical isolates collected from 2020-2023 (Taiwan) and 2015-2023 (Korea) were analyzed. Multilocus sequence typing, antimicrobial susceptibility testing, and screening for β-lactamase-encoding genes were performed. RESULTS: E. coli was the predominant pathogen in both regions, encompassing 29 sequence types (STs) across 23 clonal complexes. ST1193 and ST131 were predominant and linked to high mortality, whereas ST95 was linked to neonatal meningitis. K. pneumoniae exhibited regional diversity, with 15 unique STs. Ceftriaxone resistance was common, in approximately one-third of isolates in Taiwan and over 60% in Korea. Key resistance genes included bla CONCLUSIONS: High ceftriaxone resistance rates necessitate urgent, judicious antimicrobial selection for critically ill neonates. The diversity of sequence types and region-specific ESBL patterns highlight the need for continuous surveillance and tailored empiric strategies.
3. Continuous versus intermittent infusion of high-dose meropenem in critically ill patients: an observational cohort study.
In a propensity score–matched ICU cohort (n=3,768 overall; matched 199 continuous vs 597 intermittent), continuous high-dose meropenem infusion did not reduce 90-day mortality compared with intermittent infusion. No significant differences were detected across secondary outcomes including 30-day mortality, carbapenem resistance emergence, ECMO initiation, ARDS (acute respiratory distress syndrome), fever, or hospital length of stay.
Impact: Provides high-quality negative evidence against routine continuous infusion of high-dose meropenem in critically ill patients, informing dosing strategies.
Clinical Implications: Routine continuous infusion of high-dose meropenem may not confer survival or safety advantages over intermittent infusion; emphasizes individualized PK/PD-based dosing and the need for RCTs.
Key Findings
- After 1:3 propensity score matching (199 continuous vs 597 intermittent), adjusted 90-day mortality was 39.5% vs 35.9% (risk difference 3.7%; 95% CI −3.7 to 11.0; p=0.33).
- No significant differences in secondary outcomes: 30-day mortality, carbapenem resistance emergence, ECMO initiation, ARDS, fever, or length of stay.
- Cohort included 3,768 critically ill patients receiving high-dose meropenem (6 g/day; 4 g/day if renal impairment).
Methodological Strengths
- Large single-center dataset with propensity score matching and covariate adjustment
- Comprehensive assessment of mortality and safety-related secondary outcomes
Limitations
- Retrospective observational design with potential unmeasured confounding
- Generalizability limited to high-dose regimens (6 g/day; 4 g/day in renal impairment) at a single center
Future Directions: Randomized controlled trials comparing continuous vs intermittent infusion with therapeutic drug monitoring and PK/PD target attainment as mediators of clinical outcomes.
BACKGROUND: Whether continuous infusion of high-dose meropenem improves outcomes compared with intermittent infusion in critically ill patients remains unclear. METHODS: We conducted a retrospective propensity score-matched cohort study at a tertiary academic hospital in Vienna, Austria, including critically ill patients treated with high-dose meropenem between March 2014 and April 2024. Eligible patients had an ICU stay of ≥3 days and received meropenem 6 g/day (or 4 g/day in renal impairment) as continuous or intermittent infusion. Patients were matched 1:3 using propensity scores with covariate adjustment. The primary outcome was 90-day all-cause mortality. Secondary outcomes included 30-day mortality, emergence of carbapenem resistance, initiation of extracorporeal membrane oxygenation (ECMO), new-onset acute respiratory distress syndrome (ARDS), incidence of fever, and hospital length of stay. RESULTS: Among 3,768 patients receiving high-dose meropenem, 597 intermittent-infusion patients were matched with 199 continuous-infusion patients. Adjusted 90-day mortality was 39.5% (95% CI, 33.1-45.9) with continuous infusion and 35.9% (95% CI, 32.4-39.4) with intermittent infusion (adjusted risk difference, 3.7%; 95% CI, -3.7 to 11.0; p=0.33). No significant differences were observed for secondary outcomes. CONCLUSIONS: Continuous infusion of high-dose meropenem was not associated with improved outcomes compared with intermittent infusion in critically ill patients.