Daily Sepsis Research Analysis

IMPORTANCE: Pediatric sepsis causes substantial morbidity and mortality, but population surveillance relies on administrative codes with limited and variable accuracy. OBJECTIVE: To estimate US national incidence, mortality, and trends of sepsis in nonneonatal children using a Pediatric Sepsis Event (PSE) definition adapted from the 2024 Phoenix criteria for scalable electronic health record (EHR)-based surveillance using routinely captured clinical data. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 3.9 million hospitalizations (age, >30 days to 17 years) in 2 EHR datasets: Epic Cosmos (245 health care systems, 2016-2023) and HCA Healthcare (146 hospitals, 2018-2023). Secondary datasets were analyzed to assess feasibility of implementation and face validity across heterogeneous settings. The PSE was validated through medical record reviews of 581 high-risk encounters at 3 geographically diverse hospitals. EXPOSURES: A PSE required presumed infection with concurrent organ dysfunction using Phoenix-derived thresholds adapted for routine EHR data. Septic shock was defined as a PSE with cardiovascular dysfunction. MAIN OUTCOMES AND MEASURES: Sepsis incidence, characteristics, and in-hospital mortality were calculated. Sensitivity and specificity of PSE for physician-adjudicated Phoenix sepsis were compared with administrative codes for severe sepsis/septic shock. National sepsis case counts and deaths in 2022 and temporal trends from 2016 to 2022 were estimated using regression models. RESULTS: Among 3 925 809 pediatric hospitalizations from 2016 to 2023, 51 542 sepsis cases (mean age, 6.6 [SD, 6.0] years; 22 840 [44.3%] female) were identified (1.3% incidence); 37 405 (72.6%) were community onset and 31 744 (61.6%) had septic shock. In-hospital mortality was 10.1% and sepsis was present in 17.8% of hospitalizations that culminated in death. Incidence, characteristics, and mortality were broadly consistent across secondary datasets. On medical record review, the PSE definition had 69.9% sensitivity (95% CI, 58.1%-79.8%) and 93.1% specificity (95% CI, 89.6%-95.7%), with higher sensitivity than and comparable specificity with administrative codes. National estimates for 2022 were 18 231 sepsis cases (95% CI, 16 129-20 334) and 1877 deaths(95% CI, 1629-2126). Neither sepsis cases nor deaths changed significantly from 2016 to 2022 (annual change, 0.2% [95% CI, -2.2% to 2.7%] and 0.3% [95% CI, -3.1% to 3.8%], respectively). CONCLUSIONS AND RELEVANCE: An EHR-based definition for pediatric sepsis demonstrated strong validity compared with physician-adjudicated Phoenix sepsis and identified sepsis in 1.3% of pediatric hospitalizations with 10% mortality, corresponding to more than 18 000 cases and more than 1800 deaths annually in the US.

BACKGROUND: Escherichia coli is a common cause of invasive infections such as bloodstream and cerebrospinal fluid infections in neonates. Strains positive for the K1 capsule are considered the most common cause of such neonatal invasive infections. This assumption of K1 dominance, and indeed the population genomics of E coli causing invasive infections in general is largely unstudied. We aimed to provide a comprehensive characterisation of this pathogen population using a longitudinal isolate collection. METHODS: In this analysis we report the findings of the SENTINEL study, a longitudinal genomic analysis of 1790 invasive E coli isolates collected mainly from newborns in the Netherlands between 1975 and 2021 by the Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam University Medical Centre, Amsterdam, Netherlands. The dataset included all bacterial strains cultured from cerebrospinal fluid or blood in cases of (clinical) bacterial meningitis (1976 to 1980). In 1981 the criteria were expanded to include neonates (aged ≤4 weeks) with E coli sepsis, and from July, 2016 all infants younger than 1 year with E coli sepsis were included. All isolates were sequenced using either the HiSeq 2500 or HiSeq 4000 platforms (Illumina, San Diego, CA, USA). We confirmed species and identified sequence types (STs), detected antimicrobial resistance genes, virulence genes, and the presence of K1 capsule, and characterised the dynamics of these factors over time. FINDINGS: Our data show a highly dynamic bacterial population that is entirely unaffected by antimicrobial resistance determinants. Key pathogen population fluctuations include the complete disappearance of the dominant lineage ST567 and the swapping of dominant ST95 clones from a single serotype O18:H7 clone to two distinct serotype O1:H7 clones, with changes in virulence factors including major fimbrial adhesins. These findings, combined with only 58·8% (1053 of 1790) prevalence in K1-expressing isolates in the entire study population, point to host-pathogen interaction and immune selection pressures as key drivers of bacterial population dynamics in this largely antimicrobial-naive population. INTERPRETATION: Our data show the vital need for ongoing genomic surveillance of microbial pathogen populations to guide appropriate intervention strategies. Additionally, genomic insights of a pathogen population from one specific disease syndrome or patient population cannot always be generalised across other cohorts. FUNDING: Wellcome Antimicrobial and Antimicrobial Resistance Doctoral Training Programme and the National Institute for Health and Care Research Birmingham Biomedical Research Centre.

INTRODUCTION: Ceftazidime is a mainstay in the treatment of neonatal sepsis. However, the lack of pharmacokinetic data regarding its blood-cerebrospinal fluid (CSF) penetration in neonates hinders accurate exposure assessment and dose optimization for patients with concomitant central nervous system infections. METHODS: A population pharmacokinetic (PPK) model was established using plasma and CSF samples from 69 neonates using NLME software. Model predictive performance was validated using goodness-of-fit plots, bootstrapping, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were employed to optimize dosing regimens, targeting a probability of target attainment (PTA) ≥90%. RESULTS: A two-compartment plasma-CSF model was developed, with body weight and eGFR identified as significant covariates for ceftazidime clearance. Simulations indicated that a 50 mg/kg q8h regimen (30-minute infusion) achieved ≥ 90% PTAs for bloodstream infections (MIC ≤ 4 mg/L) in neonates weighing 2-5 kg with an eGFR of 15-60 mL/min/1.73m². Achieving similar PTAs in the CSF for MIC = 4 mg/L requires a 4-hour extended infusion. For higher CSF MICs (MIC = 8 mg/L), 150 mg/kg/day or less cannot achieve the desired pharmacodynamic targets (PTAs < 90%), regardless of infusion modality. CONCLUSION: This study developed a PPK model of ceftazidime in plasma and CSF. The dosing regimen of 50 mg/kg q8h (30-minute infusion) is suitable for treating most cases of neonatal sepsis caused by susceptible Enterobacterales in neonates with normal body weight and renal function. For CSF infections with MICs up to 4 mg/L, extended infusion is recommended. Precise dosing should be tailored to the developmental maturity, renal function, and pathogen susceptibility.