Antibiotic stewardship in the context of management of early onset neonatal sepsis-an evolving paradigm shift

Table 1 Grading of evidence for included references using the Oxford Centre for Evidence-Based Medicine 2011 guidance

Ref.	Design	Level
[1]	Guideline	5
[2]	Guideline	5
[3]	Guideline	5
[4]	Cohort (model derivation)	2b
[5]	Narrative review	5
[6]	Cohort (surveillance)	2b
[7]	Cohort	2b
[8]	Implementation study	2b
[9]	Cohort	2b
[10]	Retrospective comparison	2b
[11]	Observational comparison	2b
[12]	Retrospective cohort	2b
[13]	Implementation study	2b
[14]	Multinational cohort	2b
[15]	Narrative article	5
[16]	Cohort	2b
[17]	Cohort	2b
[18]	Cohort	2b
[19]	Cohort	2b
[20]	Cross-sectional	4
[21]	Cohort	2b
[22]	Case control	3b
[23]	Review	5
[24]	Cohort (metagenomics)	2b
[25]	Cohort	2b
[26]	Cohort	2b
[27]	Cross-sectional	4
[28]	Economic model	-
[29]	Guideline	5
[30]	Cohort	2b
[31]	Guideline	5
[32]	Review	5
[33]	Cohort	2b
[34]	Multicentre cohort	2b
[35]	Observational study	2b
[36]	Systematic review + meta-analysis	1a
[37]	Cluster randomised controlled trial	1b
[38]	Systematic review + meta-analysis	1a
[39]	Review	5
[40]	Cohort	2b
[41]	Prospective observational implementation study	2b
[42]	Population cohort	2b
[43]	Population cohort	2b
[44]	Observational study	2b

Table 2 Summary of studies evaluating early onset neonatal sepsis management strategies

Ref.	Design	Population (gestation)	Sample size (n)	Intervention/comparison	Key outcomes	Antibiotic reduction	Safety data	Level of evidence (OCEBM)	Main findings
Berardi et al[40], 2016	Cohort	Term infants	7628	SPE	Antibiotic use	50%	No increase in adverse outcomes	2b	SPE safely reduced unnecessary antibiotic use
Kuzniewicz et al[4], 2017	Cohort	≥ 34 weeks	608014	Development of SRC	EOS prediction, antibiotic use	48%	No increase in missed EOS reported	2b	SRC reduced empirical antibiotic use significantly
Dhudasia et al[8], 2018	Implementation study	≥ 35 weeks	2059	SRC implementation	Antibiotic exposure	42%	No increase in adverse outcomes	2b	Significant reduction in antibiotic use with maintained safety
Achten et al[36], 2019	Systematic review + meta-analysis	≥ 34 weeks	172385	SRC vs standard care	Antibiotic use, safety	44% (pooled)	No increase in mortality or severe morbidity	1a	Strong evidence supporting safety and reduced antibiotic use
Goel et al[10], 2020	Retrospective comparison	≥ 34 weeks	1187	NICE vs projected SRC	Antibiotic use	50% (projected)	Safety not directly assessed	2b	SRC projected to reduce antibiotic use vs NICE
Morris et al[12], 2020	Retrospective cohort	≥ 34 weeks	75 EOS cases	NICE vs SRC	Sensitivity		SRC less sensitive in identifying EOS cases	2b	Potential risk of delayed/missed treatment
Vatne et al[42], 2020	Population cohort	Term infants	20584	SPE	Antibiotic exposure	50%	No increase in infection-related morbidity/mortality	2b	Reduced antibiotic exposure safely
Pettinger et al[38], 2020	Systematic review + meta-analysis	≥ 34 weeks	NR	SRC sensitivity	Sensitivity		Lower sensitivity vs categorical approaches	1a	Highlights potential safety limitation
van Hasselt et al[35], 2021	Observational study	≥ 34 weeks	4000	SRC implementation	Antibiotic use	30%-40%	No safety concerns reported	2b	Reduction in antibiotic prescribing
Kimpton et al[11], 2021	Observational comparison	≥ 34 weeks	502	NICE vs SRC	Antibiotic use, sensitivity	40%	Lower sensitivity vs NICE noted	2b	Reduced antibiotic use but potential sensitivity trade-off
Goel et al[34], 2022	Multicentre implementation	≥ 34 weeks	66362	Adapted SRC	Antibiotic use, safety	40%	No increase in morbidity/mortality	2b	Safe reduction in antibiotic exposure
Cavigioli et al[41], 2022	Prospective implementation	≥ 34 weeks	4363	SRC + SPE	Antibiotic use	45%	No increase in adverse outcomes	2b	Combined approach reduced interventions safely
Bain et al[44], 2022	Observational study	≥ 34 weeks	1209	Clinical monitoring (SPE-like)	Antibiotic use	35%-50%	No increase in adverse outcomes	2b	Monitoring approach reduced antibiotic exposure safely
Yew et al[13], 2024	Implementation study	≥ 34 weeks	8856	SRC implementation	Antibiotic use	45%	No increase in adverse outcomes	2b	Reduced antibiotic exposure in real-world setting
Vatne et al[43], 2025	Population-based study	≥ 34 weeks	54671	SPE	Antibiotic use, safety	50%	No increase in mortality, NICU admission, or readmission	2b	Strong large-scale safety and effectiveness evidence
van der Weijden et al[37], 2025	Cluster RCT	≥ 34 weeks	18479	SRC vs standard care	Antibiotic use, safety	30%-35%	No increase in adverse outcomes	1b	RCT evidence supporting reduced antibiotic use with maintained safety

EOS: Early-onset sepsis; SRC: Sepsis Risk Calculator; SPE: Serial Physical Examination; NICE: National Institute for Health and Care Excellence; RCT: Randomised controlled trial; NICU: Neonatal intensive care unit; OCEBM: Oxford Centre for Evidence-Based Medicine; NR: Not reported.

Table 3 Comparison of early-onset sepsis management strategies

Feature	Categorical risk-based approach (e.g., NICE/CDC)	Sepsis risk calculator	Serial physical examination
Population	Term and late preterm infants (≥ 34 weeks)	Term and late preterm infants (≥ 34 weeks)	Term and late preterm infants (≥ 34 weeks)
Management logic	Static risk factor–based (maternal and perinatal factors)	Multivariate, individualised risk estimation using Bayesian model (maternal + infant clinical status)	Dynamic, repeated clinical assessments over time (evolving clinical signs)
Approach to treatment	Low threshold for investigation and empirical antibiotics based on risk factors	Risk-stratified approach guiding observation, investigation, or antibiotics	Antibiotics reserved for infants with evolving or persistent clinical signs
Antibiotic use	Higher antibiotic exposure; risk of overtreatment	Reduced antibiotic use (commonly 30%-50% reduction)	Reduced antibiotic use (50% reduction demonstrated in observational studies)
Safety data	High sensitivity; widely accepted safety profile	Observational studies show no increase in missed EOS, morbidity, or mortality; lower sensitivity vs categorical approaches reported	Large observational studies show reduced antibiotic use without increase in adverse outcomes
Strengths	Simple, reproducible, widely implemented; aligns with institutional risk tolerance	Individualised risk assessment; supports antibiotic stewardship; widely adopted	Patient-centred; avoids unnecessary treatment; detects evolving illness
Limitations	Poor specificity; high rates of unnecessary antibiotic use	Lower sensitivity in some studies; potential delay in treatment; derived from United States populations; relies on accurate input data	Resource-intensive; requires frequent assessments, experienced clinicians, and robust systems; inter-observer variability
Implementation considerations	Easy to apply across settings; minimal training required	Requires calculator access, local incidence calibration, and audit	Requires adequate staffing, workflow support, escalation systems, and consistent documentation
Generalisability	Widely applicable across different healthcare settings	May require adaptation for different populations and EOS incidence	More feasible in well-resourced settings with adequate staffing and monitoring capacity

EOS: Early onset neonatal sepsis; NICE: National Institute for Health and Care Excellence; CDC: Centers for Disease Control and Prevention.