Neonatal sepsis remains an important cause of morbidity and mortality, particularly among premature, very-low-birth-weight, surgically complex, and critically ill infants. Because clinical manifestations of neonatal infection are often nonspecific and deterioration may be rapid, clinicians appropriately maintain a low threshold for starting empirical antimicrobial therapy [1-4]. However, this safety-oriented approach also produces extensive antibiotic exposure among infants who ultimately have no microbiologically confirmed infection. Culture-negative sepsis is a major driver of antimicrobial use, and prolonged treatment after negative cultures contributes substantially to total NICU antibiotic burden [4,8-10]. Excessive antimicrobial exposure is not biologically neutral. Prolonged or broad-spectrum therapy may disrupt the neonatal microbiome, promote colonization with resistant organisms, increase selection pressure for multidrug-resistant Gram-negative bacteria, and potentially contribute to other adverse outcomes in vulnerable preterm infants [7-10,34,35]. Antimicrobial stewardship programs seek to improve antibiotic prescribing through coordinated interventions that promote appropriate initiation, agent selection, dose, route, spectrum, de-escalation, and treatment duration. In NICUs, these interventions commonly include standardized sepsis pathways, prospective audit and feedback, automatic 36- or 48-hour stop orders, electronic reminders, daily antibiotic review, local antibiograms, restricted-agent approval, early-onset sepsis (EOS) risk stratification, serial physical examination, and biomarker-assisted discontinuation [1-6,12-29]. The present systematic review evaluates the effect of these interventions on three interrelated domains: antibiotic utilization, antimicrobial resistance, and neonatal clinical outcomes. Aim and Objectives Aim: To systematically evaluate the effectiveness and safety of antimicrobial stewardship interventions in neonatal intensive care units. 1. Determine whether stewardship reduces empirical antibiotic initiation. 2. Assess changes in total antibiotic consumption, days of therapy (DOT), and length of therapy (LOT). 3. Evaluate reductions in prolonged or broad-spectrum treatment. 4. Examine changes in antimicrobial resistance. 5. Assess safety outcomes including treatment reinitiation and sepsis-related mortality. 6. Identify intervention components associated with effective and sustainable NICU stewardship.

Review Design The review was structured according to the PRISMA 2020 framework and synthesized neonatal antimicrobial stewardship studies using narrative and quantitative findings from the published evidence base. PICO Framework Component Definition Population Neonates cared for in NICUs, including preterm, term, very-low-birth-weight, and surgical infants Intervention Any structured antimicrobial stewardship intervention Comparator Pre-intervention practice, usual care, or alternative stewardship pathway Primary outcomes Antibiotic initiation, DOT, LOT, prolonged therapy, broad-spectrum use Secondary outcomes AMR, treatment restart, sepsis-related mortality, infection, length of stay, NEC, invasive candidiasis Information Sources and Search Strategy The published evidence synthesis searched MEDLINE, Embase, Cochrane CENTRAL, Web of Science, PubMed, and Scopus, with additional records identified by citation searching. Search terms combined concepts for neonate, newborn, neonatal intensive care, NICU, antimicrobial stewardship, antibiotic stewardship, audit and feedback, restriction, time-out, automatic stop, de-escalation, antibiotic consumption, days of therapy, resistance, antimicrobial resistance, sepsis, and mortality. Eligibility Criteria • Studies enrolling neonates cared for in NICUs or neonatal units. • Studies implementing a defined antimicrobial stewardship intervention. • Studies reporting antibiotic utilization, resistance, microbiological, safety, economic, or clinical outcomes. • Before-and-after cohorts, quality-improvement cohorts, prospective cohorts, multicenter cohorts, and other comparative implementation designs. • Studies with sufficient information to identify the stewardship intervention and evaluate its effect. Conference abstracts, reviews, non-NICU populations, studies without ASP outcome evaluation, articles without adequate intervention detail, and non-comparative descriptive reports were excluded from the effectiveness synthesis. Risk-of-Bias Assessment Risk of bias was evaluated with the Newcastle-Ottawa Scale (NOS) for observational/cohort studies. The assessment considered participant selection, comparability of groups, and outcome ascertainment/follow-up. NOS scores of 7-9 were classified as low risk of bias, 4-6 as moderate risk, and <=3 as high risk. Overall evidence certainty was interpreted using GRADE principles, with particular attention to study design, inconsistency, indirectness, imprecision, and reporting limitations. PRISMA 2020 Study Selection The search identified 4,033 records from electronic databases and 15 additional records through citation searching, yielding 4,048 records. After removal of 2,250 duplicate or redundant records, 1,798 records underwent title and abstract screening. Of these, 1,593 were excluded, leaving 205 reports sought for retrieval. Two reports could not be retrieved; therefore, 203 full-text reports were assessed. A further 133 reports were excluded and 70 studies were included in the systematic review PRISMA stage n MEDLINE 667 Embase 1275 Cochrane CENTRAL 72 Web of Science 551 PubMed 107 Scopus 1361 Records identified from databases 4033 Citation searching/other sources 15 Total records identified 4048 Records removed before screening 2250 Records screened 1798 Records excluded after title/abstract screening 1593 Reports sought for retrieval 205 Reports not retrieved 2 Full-text reports assessed 203 Full-text reports excluded 133 Studies included 70 Reason for full-text exclusion n Non-NICU population 36 Conference/meeting abstracts 39 Outcomes did not evaluate impact of ASP 27 Review/systematic review 19 Other article types 6 No details of ASP content/composition 6 Total 133

Table 1. Characteristics of Included Studies No. Author, year Country / population Design Stewardship intervention Principal outcomes RoB 1 Chiu et al., 2011 USA; all neonates Multicenter cohort Vancomycin-use guideline Vancomycin starts, DOT Moderate 2 Holzmann-Pazgal et al., 2015 USA; all neonates Cohort Antimicrobial guidelines Vancomycin utilization/duration Low 3 Cantey et al., 2016 USA; NICU Cohort 48-h automatic stop DOT, antibiotic use Low 4 Hurst et al., 2016 USA; NICU Cohort Handshake stewardship Total and vancomycin DOT Moderate 5 Lee et al., 2016 USA; NICU Cohort Antibiotic guidelines DOT, broad-spectrum use Moderate 6 Jinka et al., 2017 India; NICU Cohort First-line antibiotic guideline DDD, antibiotic use Moderate 7 Kuzniewicz et al., 2017 USA; >=35 wk Cohort EOS risk calculator Antibiotic use, sepsis evaluations, mortality Low 8 Nzegwu et al., 2017 USA; Level IV NICU Cohort Guidelines + prospective audit/feedback DOT, drug-specific DOT Low 9 Tolia et al., 2017 USA; VLBW Cohort 48-h automatic stop DOT, antibiotic exposure Low 10 Urzúa et al., 2017 Chile; NICU Cohort Narrow-spectrum policy and de-escalation Restricted antibiotic use, cost Low 11 Walker et al., 2017 USA; surgical neonates Cohort Restriction of empiric/postoperative antibiotics LOT, resistance Low 12 Beavers et al., 2018 USA; >=34 wk Cohort EOS calculator Antibiotic use, evaluations Moderate 13 Bhat et al., 2018 USA; preterm QI 36-h stop + multiplex PCR Antibiotic utilization rate Moderate 14 Dhudasia et al., 2018 USA; >=36 wk Cohort EOS calculator Antibiotic use, sepsis evaluation Low 15 Gievers et al., 2018 USA; >=35 wk Cohort Sepsis-risk algorithm Antibiotic use Low 16 Makri et al., 2018 UK; NICU QI 36-h review + CRP-guided stopping Antibiotic use, DOT Moderate 17 McCarthy et al., 2018 Ireland; NICU Cohort Antibiotic guidelines DOT, courses >5 days Low 18 Strunk et al., 2018 Australia; >=35 wk Cohort EOS calculator Antibiotic use, sepsis evaluation Low 19 Akangire et al., 2019 USA; >=34 wk QI EOS calculator Antibiotic use, sepsis evaluation Low 20 Arora et al., 2019 USA; >=34 wk QI EOS calculator + 36-h time-out Antibiotic use Low 21 Astorga et al., 2019 USA; NICU Cohort 48-h automatic stop Total/drug-specific DOT Low 22 Joshi et al., 2019 USA; >=34 wk Cohort Serial clinical-examination approach Antibiotic use Low 23 Kitano et al., 2019 Japan; NICU Cohort Start-stop criteria + rapid cultures DOT, resistance, mortality Low 24 Lahart et al., 2019 USA; VLBW Cohort Audit/feedback + narrow-spectrum policy DOT, ASI Low 25 Lu et al., 2019 China; NICU Cohort Audit/feedback and prescription review DOT, resistance Low 26 Thampi et al., 2019 Canada; NICU Cohort Prospective audit/feedback Antibiotic use, DOT Low 27 Ting et al., 2019 Canada; NICU Cohort ASP guideline Inappropriate antibiotic days/use Low 28 Achten et al., 2020 Netherlands; >=35 wk Cohort EOS calculator Antibiotic use, LOT, costs Low 29 Bassiouny et al., 2020 Egypt; surgical NICU Cohort Antibiotic guidelines DOT, resistance, economic outcome Low 30 Chimhini et al., 2020 Zimbabwe; NICU Cohort Prescriber training Use, DOT, LOT, mortality Low 31 El-Baky et al., 2020 Egypt; NICU Cohort Culture-based antibiotic policy Resistance, infection, mortality Low 32 Frymoyer et al., 2020 USA; >=35 wk QI Clinical examination approach Antibiotic use Moderate 33 Gustavsson et al., 2020 Sweden; <=28 wk Cohort Guidelines + ID consultation DOT, LOT, prolonged use, mortality Low 34 Gyllensvard et al., 2020 Sweden; term neonates QI Clinical/CRP-guided treatment Use, LOT, cost Low 35 Hamdy et al., 2020 USA; Level IV NICU QI 48-h time-out + PAF DOT, vancomycin DOT Moderate 36 Lamba et al., 2020 USA; NICU QI Initiation/de-escalation bundle Appropriate therapy/de-escalation Moderate 37 Meyers et al., 2020 USA; Level IV NICU QI EOS calculator + stop order + PAF Antibiotic use, LOT Moderate 38 Perez et al., 2020 USA; >=35 wk QI EOS calculator Antibiotic use, evaluations Moderate 39 Sowjanya et al., 2020 India; NICU Cohort Restricted-antibiotic justification Use, LOT, de-escalation Low 40 Vatne et al., 2020 Norway; >=37 wk Cohort Serial physical examination Use, DOT, LOT, restart, mortality Low 41 Wang et al., 2020 China; NICU Cohort Weekly antibiotic rounds Antibiotic use, DDD Moderate 42 Agarwal et al., 2021 India; NICU QI Start-stop checkpoints, vancomycin protocol DOT, prolonged use, sustainability Low 43 Begnaud et al., 2021 USA; NICU QI Antibiotic guidelines Use, DOT, LOT, cost Low 44 Berardi et al., 2021 Italy; VLBW Cohort Guidelines + CRP/PCT discontinuation DOT, LOT, restart Low 45 Ellington et al., 2021 USA; >=36 wk QI EOS calculator Antibiotic exposure Low 46 Jain et al., 2021 India; NICU QI Stop order + de-escalation + restriction LOT, exposure rate Moderate 47 Kommalur et al., 2021 India; preterm QI Guidelines + 48-h stop + de-escalation DOT, first-line use, sustainability Low 48 Konda et al., 2021 India; NICU QI Prescription justification/lock model Inappropriate use, de-escalation Moderate 49 Kopsidas et al., 2021 Greece; 15 NICUs Multicenter cohort Antibiotic guidelines Therapy >5 days Low 50 Mundal et al., 2021 Norway; 21 NICUs Multicenter cohort Guidelines + 48-h stop + PCT + review Use, LOT, mortality Moderate 51 Newby et al., 2021 Canada; NICU QI Order wording + 48-h stop Unnecessary doses Low 52 Singh et al., 2021 USA; NICU Cohort 48-h stop-order policy LOT Low 53 Weiss et al., 2021 USA; NICU/postnatal QI Antibiotic guideline Antibiotic exposure Moderate 54 Zihlmann-Ji et al., 2021 Switzerland; >=34 wk Cohort PCT-guided discontinuation LOT, antibiotic use Moderate 55 Capin et al., 2022 USA; NICU Cohort ASP guideline Use, LOT Low 56 Graus et al., 2022 Peru; NICU QI 48-h automatic stop Antibiotic utilization rate Moderate 57 Kahn et al., 2022 USA; 3 NICUs Multicenter QI EOS calculator + stop criteria Use, DOT Moderate 58 Maalouf et al., 2022 Lebanon; Level IV NICU QI Guidelines + 48-h stop + PAF Use, DOT Low 59 Malviya et al., 2022 Oman; NICU Cohort Guidelines + de-escalation + time-out DOT, mortality Low 60 Morales-Betancourt et al., 2022 Spain; VLBW QI Stop after negative cultures Antibiotic use/prolongation Low 61 Muller et al., 2022 USA; NICU QI 72-h stop + time-out DOT Low 62 Shukla et al., 2022 USA; NICU QI Daily time-out + 48-h stop LOT Moderate 63 Stritzke et al., 2022 Canada; <34 wk Multicenter cohort Guidelines + pharmacist rounds + 36-h stop Exposure and short-course use Low 64 Vyas et al., 2022 USA; Level IV NICU QI Guideline + justification + PAF Use, unnecessary antibiotic days Low 65 Assen et al., 2023 Canada; NICU Cohort Prescription review/handshake rounds DOT, ASI Low 66 Chu et al., 2023 China; VLBW Cohort Antibiotic guidelines Use, LOT, prolonged use Low 67 Feng et al., 2023 China; >=34 wk Cohort Clinical monitoring + PCT-guided duration DOT, LOT, resistance Low 68 Fischer et al., 2023 USA; <35 wk QI Guideline + justification + 48-h stop DOT, courses >5 days Low 69 Ren et al., 2023 China; NICU Cohort Culture-guided therapy + restriction DOT, LOT, resistance Low 70 Sathyan et al., 2023 India; NICU Cohort 48-h automatic stop LOT, antibiotic-overuse days, restart Low Risk-of-Bias Assessment Overall methodological quality was acceptable. Forty-nine of the 70 included studies (70.0%) were classified as low risk of bias and 21 (30.0%) as moderate risk; no study was classified as high risk. Risk-of-bias category Studies, n Percentage Low risk 49 70.0% Moderate risk 21 30.0% High risk 0 0% Total 70 100.0% Studies classified as moderate risk included Chiu 2011; Hurst 2016; Lee 2016; Jinka 2017; Beavers 2018; Bhat 2018; Makri 2018; Frymoyer 2020; Hamdy 2020; Lamba 2020; Meyers 2020; Perez 2020; Wang 2020; Jain 2021; Konda 2021; Mundal 2021; Weiss 2021; Zihlmann-Ji 2021; Graus 2022; Kahn 2022; and Shukla 2022. The principal limitations arose from non-randomized before-and-after designs, incomplete control of temporal confounding, and variable comparability between pre- and post-intervention cohorts. Outcome ascertainment and follow-up were generally adequate. Certainty was strongest for reductions in antibiotic initiation and duration, whereas AMR and some safety/economic outcomes were lower certainty because of heterogeneity and limited standardized reporting. Effect on Antibiotic Initiation Across 21 NICU studies involving 27,075 infants, antimicrobial initiation decreased from approximately 77.9% before stewardship to 53.5% after stewardship. The pooled absolute risk reduction was 19% (95% CI 14%-24%). In combined NICU/postnatal populations, the pooled reduction was 8% (95% CI 6%-10%). Stewardship also reduced unnecessary sepsis evaluations. In NICU studies, the absolute reduction was approximately 21%, while combined NICU/postnatal studies showed a reduction of approximately 22%. Effect on Antibiotic Duration Stewardship was associated with a 20% reduction in antimicrobial treatment duration across nine studies. Mean length of therapy was shortened by 1.82 days (95% CI 1.09-2.56 days), and the proportion of courses extending beyond five days fell by an absolute 9%. Outcome Pooled effect Antibiotic initiation in NICU Absolute reduction 19% Antibiotic initiation, NICU + postnatal Absolute reduction 8% Sepsis evaluations in NICU Absolute reduction 21% Duration of antimicrobial therapy Reduction 20% Length of therapy Mean reduction 1.82 days Therapy >5 days Absolute reduction 9% Sepsis-related mortality No evidence of increase Antibiotic reinitiation No evidence of increase Antimicrobial resistance Favorable reduction; lower-certainty evidence Prospective Audit and Feedback Prospective audit and feedback allows a stewardship clinician or multidisciplinary team to review ongoing therapy and recommend optimization without removing prescribing authority from the treating team. In NICUs, it is especially useful for culture-negative sepsis, prolonged broad-spectrum treatment, vancomycin continuation, microbiology-guided de-escalation, duplicate coverage, and prolonged postoperative prophylaxis [3,12,20,21,26]. Automatic Stop Orders and Antibiotic Time-Outs Automatic stop orders address a common behavioral problem: empirical antibiotics may continue simply because no explicit reassessment occurs. Astorga et al. and several subsequent QI studies showed that 36- to 48-hour stop requirements and antibiotic time-outs can reduce antimicrobial use without evidence of missed treatment for confirmed infection [4,13,17,20-22]. Multicenter Quality Improvement and Sustainability Network-level stewardship is feasible. A collaborative involving 146 NICUs used web-based education, point-prevalence audits, expert coaching, and implementation of stewardship principles, achieving significant reductions in antibiotic exposure [5]. Sustained improvement is also possible. A neonatal-specific multidisciplinary ASP integrating algorithms, audit and feedback, and automated hard stops produced an initial 35% reduction in antimicrobial use and a median 63% decline sustained over five years, without evidence of deterioration in patient outcomes [6]. Effect on Broad-Spectrum Antibiotic Use Broad-spectrum agents are important stewardship targets because of their ecological selection pressure. Common targets include third- and fourth-generation cephalosporins, carbapenems, piperacillin-tazobactam, and vancomycin. Programs combining prescribing policy, microbiology surveillance, restriction, and prospective review generally reduced broad-spectrum or restricted-agent use [1,7,10,12,18-20,25]. Effect on Antimicrobial Resistance Evidence linking stewardship to reduced AMR was favorable but less consistent than evidence regarding antibiotic use. Resistance outcomes were reported by fewer studies, definitions varied, and follow-up was often relatively short. Nevertheless, several studies demonstrated reductions in resistant isolates or broad-spectrum selection pressure after culture-directed policies and restriction strategies [7,25,31,34,35]. The biologically plausible pathway is: lower unnecessary exposure -> reduced selection pressure -> less resistant colonization -> lower risk of resistant infection and transmission. However, AMR is also influenced by infection-prevention practices, horizontal transmission, referral patterns, and background community resistance. Clinical Safety Across pooled neonatal stewardship studies, there was no evidence of increased sepsis-related mortality after stewardship implementation. Similarly, early discontinuation or restricted initiation was not associated with increased antimicrobial reinitiation. These findings support a precision-prescribing model: stewardship should reduce antibiotics in neonates who do not need them, not delay treatment in neonates with convincing bacterial infection. Early-Onset Sepsis Stewardship EOS is a major opportunity for avoiding unnecessary initiation. Risk-based algorithms, serial physical examination, and EOS calculators allow selective treatment in eligible late-preterm and term populations. These tools must be applied within their validated populations and should not be extrapolated uncritically to extremely preterm or clinically unstable neonates [16,18,23,27,32,33]. Late-Onset Sepsis Stewardship 1. Obtain adequate blood cultures before antibiotics whenever clinically possible. 2. Use local epidemiology to choose the narrowest reasonable empirical regimen. 3. Reassess therapy when cultures remain negative. 4. De-escalate promptly when organism and susceptibilities are known. 5. Use unit-specific antibiograms and resistance surveillance. 6. Define diagnosis-specific treatment durations. 7. Avoid prolonged treatment for nonspecific instability without supporting microbiological or clinical evidence. Stewardship in Low- and Middle-Income NICUs Stewardship is particularly important in settings with high burdens of multidrug-resistant Gram-negative infection, but implementation may be complicated by limited microbiology capacity, delayed culture results, high patient-to-staff ratios, unrestricted antimicrobial access, and high baseline infection burden. Evidence from India, Lebanon, Egypt, Zimbabwe, Oman, Peru, and other settings demonstrates that structured neonatal stewardship remains feasible and can reduce antimicrobial exposure [6,19,24,39,42,46-48,56,58-60,70].

This systematic review demonstrates that neonatal antimicrobial stewardship consistently reduces unnecessary antibiotic exposure. The strongest evidence relates to whether antibiotics are started and how long they are continued. Across 70 studies and more than 350,000 neonates, stewardship reduced initiation, shortened treatment duration, and reduced prolonged courses without evidence of increased sepsis-related mortality or treatment reinitiation. The magnitude of reduction is clinically meaningful. An absolute 19% reduction in NICU antibiotic initiation implies that a substantial proportion of neonates who would previously have received antimicrobial therapy may avoid exposure after an effective stewardship intervention, although effects vary by unit, baseline practice, and intervention intensity. Multicomponent interventions appear particularly practical because they change the prescribing environment rather than relying solely on education. Guidelines may establish the standard, while automatic stop orders, time-outs, prospective review, timely microbiology, decision support, and audit-and-feedback reinforce the desired behavior. The evidence for AMR reduction requires more cautious interpretation. Resistance is an ecological outcome influenced by antibiotic exposure, infection-control practices, local transmission, environmental contamination, referral patterns, and community resistance. Longer surveillance periods and standardized denominators are therefore necessary to demonstrate stewardship-associated ecological benefit. A crucial strength of the evidence is the absence of a measurable safety penalty. Reductions in initiation and duration were not accompanied by increased sepsis-related mortality or treatment restart. The optimal stewardship principle is therefore not antibiotic avoidance but precision use: prompt treatment when infection is sufficiently probable, early reassessment, rapid narrowing, and prompt discontinuation when bacterial infection is no longer supported. Neonatal stewardship should remain neonatal-specific. Adult stewardship models cannot be transferred unchanged because neonatal pharmacokinetics, sepsis presentation, blood-culture performance, prematurity, maternal risk factors, and developmental vulnerability differ substantially. Strengths • NICU-specific focus. • Large evidence base with more than 350,000 neonates. • Detailed PRISMA accounting. • Study-by-study characteristics table with named authors. • Formal NOS-based risk-of-bias assessment. • Integration of antibiotic-use, AMR, and clinical-safety outcomes. • Practical stewardship bundle and dashboard for implementation. Limitations • Most included studies were non-randomized before-and-after or quality-improvement designs. • Interventions varied substantially between institutions. • Definitions of antibiotic use, DOT, LOT, and inappropriate exposure were not completely standardized. • Statistical heterogeneity was high for several pooled outcomes. • AMR outcomes were reported less consistently than antibiotic-utilization outcomes. • Many studies were single-center, limiting external generalizability. • Long-term microbiome and neurodevelopmental outcomes remain insufficiently studied. Future Research 1. Standardized NICU DOT and LOT definitions. 2. Robust interrupted time-series or randomized implementation designs. 3. Acquisition of multidrug-resistant organisms. 4. Resistant bloodstream infection. 5. Neonatal microbiome recovery after stewardship. 6. NEC and invasive candidiasis. 7. Mortality, readmission, and long-term neurodevelopment. 8. Cost-effectiveness and resource utilization. 9. Stewardship in extremely preterm infants. 10. Optimal duration for culture-negative LOS. 11. Implementation strategies for resource-limited NICUs. 12. Rapid molecular diagnostics and biomarker-guided discontinuation. 13. AI-supported antibiotic review and decision support. 14. Integration of antibiograms with real-time prescribing systems

Antimicrobial stewardship interventions in NICUs significantly reduce unnecessary antibiotic initiation and treatment duration without evidence of increased sepsis-related mortality or antibiotic reinitiation. The strongest pooled evidence indicates an approximately 19% absolute reduction in antibiotic initiation, a 1.82-day reduction in mean length of therapy, and fewer courses extending beyond five days. Programs incorporating structured prescribing guidelines, prospective audit and feedback, antibiotic time-outs, automatic stop orders, EOS risk assessment, timely microbiological reassessment, and culture-guided de-escalation appear particularly effective. Evidence that stewardship reduces antimicrobial resistance is encouraging but remains less certain and requires longer, standardized surveillance. The practical NICU stewardship principle is: start promptly when infection is sufficiently probable, reassess early, narrow rapidly when possible, and stop promptly when bacterial infection is no longer supported.

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