Antibiotics are among the most frequently administered medications in NICUs. Their timely use is essential when neonatal bacterial infection is suspected, yet substantial antimicrobial exposure occurs in the absence of confirmed bacterial disease. The traditional way of evaluating antimicrobial stewardship is to ask whether antibiotic use decreased. Although important, this is incomplete. A clinically effective NICU ASP should ideally influence prescribing behavior, microbiological ecology, diagnostic quality, and patient outcomes. Prolonged exposure to broad-spectrum antibiotics can select MDROs and alter unit-level susceptibility patterns. Antibiotic overuse has also been associated with disruption of the developing microbiome, invasive candidiasis, NEC, and late-onset sepsis. NICU bloodstream infections demonstrate substantial microbiological heterogeneity, including Klebsiella pneumoniae, Escherichia coli, coagulase-negative staphylococci, Staphylococcus aureus, Acinetobacter spp., Serratia marcescens, Enterobacter cloacae, and Group B Streptococcus. The present systematic review was designed around clinical and microbiological endpoints, making it distinct from previous NICU stewardship reviews focused principally on antibiotic utilization or neonatal-sepsis decision-making. Aim and Objectives Aim: To systematically evaluate the clinical and microbiological consequences of antimicrobial stewardship implementation in neonatal intensive care units. 1. Evaluate changes in broad-spectrum antibiotic consumption. 2. Determine the effect of ASPs on MDRO prevalence and antimicrobial susceptibility. 3. Evaluate vancomycin and carbapenem stewardship. 4. Assess effects on blood-culture utilization and contamination. 5. Examine culture-positive sepsis and bloodstream-infection patterns. 6. Assess mortality and treatment failure. 7. Evaluate NEC, invasive candidiasis, recurrent infection, and length of stay where reported. 8. Propose a combined clinical-microbiological monitoring framework for NICU ASPs.

Study Design This systematic review was structured according to PRISMA 2020 principles. The review was deliberately limited to studies reporting clinical or microbiological effects of stewardship rather than studies reporting only the number of antibiotic prescriptions. PICO Framework Component Definition Population Neonates admitted to NICUs Intervention Structured antimicrobial stewardship or diagnostic-stewardship intervention Comparator Pre-intervention practice, usual care, or comparator NICU Microbiological outcomes MDRO prevalence, susceptibility, resistant isolates, blood-culture contamination, pathogen distribution Clinical outcomes Culture-positive sepsis, mortality, NEC, candidiasis, treatment failure, recurrence, length of stay Information Sources and Search Strategy The review framework included MEDLINE/PubMed, Embase, Scopus, Web of Science, Cochrane CENTRAL, and citation searching. Search terms combined neonatal intensive care, NICU, antimicrobial stewardship, antibiotic stewardship, antimicrobial resistance, multidrug resistant, MDRO, antibiogram, blood culture, contamination, bloodstream infection, candidiasis, necrotizing enterocolitis, mortality, and clinical outcome. Eligibility Criteria • Defined NICU antimicrobial or diagnostic stewardship intervention. • Neonatal population. • Comparative, interrupted time-series, prospective, cohort, or quality-improvement design. • At least one clinical or microbiological outcome. • Extractable pre-post or comparator data. Studies reporting only educational satisfaction or antibiotic expenditure without microbiological or clinical information were excluded from the principal synthesis. PRISMA 2020 Study Selection Records identified from databases included MEDLINE/PubMed (n=336), Embase (n=402), Scopus (n=257), Web of Science (n=213), and Cochrane CENTRAL (n=64), for 1,272 database records. Fourteen additional records were identified through citation searching, giving 1,286 total records. After removal of 347 duplicates, 939 records were screened and 758 were excluded. Full texts were sought for 181 reports; four could not be retrieved. Of 177 full-text reports assessed, 136 were excluded, leaving 41 studies in the qualitative synthesis. PRISMA stage n MEDLINE/PubMed 336 Embase 402 Scopus 257 Web of Science 213 Cochrane CENTRAL 64 Database records 1272 Citation searching 14 Total records 1286 Duplicates removed 347 Records screened 939 Records excluded 758 Reports sought 181 Reports not retrieved 4 Full texts assessed 177 Full texts excluded 136 Studies included 41 Reason for full-text exclusion n No clinical or microbiological outcome 37 No defined antimicrobial stewardship intervention 29 Antibiotic-utilization-only report 21 Non-neonatal population 15 Review/editorial/commentary 13 Duplicate or overlapping dataset 9 No comparator/pre-post data 7 Insufficient extractable results 5 Total 136 Characteristics of Included Evidence Study emphasis n % AMR / resistant organism outcomes 11 26.8 Broad-spectrum or restricted-agent microbiological impact 8 19.5 Blood culture / diagnostic stewardship 6 14.6 Sepsis and mortality outcomes 7 17.1 NEC / surgical infection stewardship 4 9.8 Multidomain clinical + microbiological outcome 5 12.2 Total 41 100 Risk-of-Bias Assessment The evidence base consisted largely of quality-improvement and before-after cohort studies. The most frequent methodological concern was temporal confounding: resistance, infection rates, and mortality can change because of infection-prevention initiatives, staffing, patient acuity, outbreaks, or referral patterns independent of stewardship. Risk category n % Low risk 25 61.0 Moderate / some concerns 15 36.6 High risk 1 2.4 Total 41 100

Total Antibiotic Exposure and Microbiological Selection Pressure One of the clearest microbiological stewardship studies was conducted in a Level IV NICU in southern China. Total antimicrobial consumption decreased from 791.1 to 466.3 DOT/1,000 patient-days, an approximate 41% reduction. At the same time, the prevalence of multidrug-resistant bacteria decreased from 67.2% to 48.9%. This provides a plausible link between lower antimicrobial pressure and improved resistance ecology. 2. Multidrug-Resistant Organisms AMR is often described as a theoretical benefit of stewardship, but relatively few NICU studies directly quantify resistance outcomes. The southern China intervention demonstrated an absolute MDRO reduction of 18.3 percentage points, from 67.2% to 48.9%, while restricting high-impact agents including meropenem and vancomycin. 3. Vancomycin as a Microbiological Stewardship Target A two-center guideline reduced vancomycin initiation by approximately 35% at one NICU and 62% at a second NICU without significant increases in duration of bacteremia, infection-related complications, or infection-attributable death. Another Level IV NICU initiative reduced vancomycin consumption from 112 to 38 DOT/1,000 patient-days, an approximate 66% reduction. 4. Carbapenem Stewardship Carbapenems exert substantial Gram-negative selection pressure. In the southern China program, combined meropenem/vancomycin use decreased from 7.6% to 1.8%, alongside lower MDRO prevalence. This supports active monitoring of carbapenem DOT as a core NICU microbiological stewardship metric. 5. Blood-Culture Diagnostic Stewardship False-positive blood cultures can trigger unnecessary vancomycin, repeat cultures, lumbar puncture, prolonged hospitalization, and additional investigations. A neonatal blood-culture quality-improvement bundle reduced contamination from 2.0% to 1.0% while 94% of cultures achieved at least 1 mL of blood, illustrating that diagnostic stewardship is antimicrobial stewardship. 6. Blood-Culture Yield and Pathogen Ecology NICU bloodstream infection is microbiologically diverse. Common pathogens include Klebsiella pneumoniae, Escherichia coli, coagulase-negative staphylococci, Staphylococcus aureus, Acinetobacter spp., Serratia marcescens, Enterobacter cloacae, and Group B Streptococcus. Stewardship should therefore be anchored to local susceptibility data rather than universal narrowing. 7. Culture-Positive Sepsis A rural central Indian NICU quality-improvement program reduced antibiotic exposure from 75% to 41%. During the same period, culture-positive sepsis decreased from 18% to 11.56%. Although causality cannot be assumed in a before-after study, reduced antibiotic use was not followed by an increase in confirmed sepsis. 8. Mortality In the same Indian program, all-cause NICU mortality fell from 25% to 16%. A more recent prospective quasi-experimental ASP study reported late-onset sepsis 14-day mortality decreasing from 33.3% to 20.9% and 28-day mortality from 46.4% to 32.1%. These findings are promising but remain susceptible to confounding. 9. Length of Stay Available data generally do not indicate that stewardship prolongs hospitalization. In a recent quasi-experimental study, median length of stay remained 9 days before and after ASP implementation in EOS, while LOS cases showed a change from 13 to 12 days. 10. Necrotizing Enterocolitis A multidisciplinary NEC stewardship pathway reduced overall antibiotic exposure from 119.19 to 80.65 DOT/1,000 patient-days. Piperacillin-tazobactam exposure fell from 68.78 to 7.97 DOT/1,000 patient-days, with no significant increases in progression to surgical NEC, recurrence, bacteremia/fungemia, resistance, or mortality. 11. Invasive Candidiasis Although few stewardship studies report invasive candidiasis as a primary endpoint, prolonged broad-spectrum antibiotic exposure is a recognized ecological risk factor. Invasive candidiasis should therefore be treated as a balancing microbiological outcome, especially in extremely preterm infants. 12. Bloodstream Infection and Resistance Must Be Interpreted Together A reduction in antibiotic use accompanied by increasing resistant bloodstream infection would represent incomplete stewardship success. A comprehensive NICU microbiological dashboard should simultaneously track culture positivity, contamination, Gram-positive and Gram-negative distribution, MDRO prevalence, carbapenem resistance, MRSA, VRE, invasive candidiasis, and antibiotic consumption. Characteristics, antimicrobial stewardship interventions, clinical and microbiological outcomes, and risk-of-bias assessment of studies included in the systematic review. No. Author, Year Country / Population Study Design Main Stewardship Intervention Main Clinical / Microbiological Outcomes Risk of Bias 1 Chiu et al., 2011 USA; NICU neonates Multicenter cohort Vancomycin-use guideline Vancomycin starts; exposure; bacteremia-related safety outcomes Moderate 2 Holzmann-Pazgal et al., 2015 USA; Level II-IV NICU Cohort Antimicrobial guidelines Vancomycin utilization and duration Low 3 Cantey et al., 2016 USA; NICU Cohort 48-h automatic antibiotic stop DOT; unnecessary exposure; clinical safety Low 4 Hurst et al., 2016 USA; NICU Cohort Handshake stewardship Total DOT; vancomycin DOT Moderate 5 Lee et al., 2016 USA; NICU Cohort Antimicrobial prescribing guidelines Total DOT; broad-spectrum antimicrobial use Moderate 6 Jinka et al., 2017 India; NICU Cohort First-line antimicrobial policy Antibiotic consumption; spectrum of therapy Moderate 7 Kuzniewicz et al., 2017 USA; ≥35 weeks Cohort EOS risk calculator Antibiotic exposure; sepsis evaluation; sepsis-related mortality Low 8 Nzegwu et al., 2017 USA; Level IV NICU Cohort Guidelines + prospective audit and feedback DOT; vancomycin, cefotaxime and aminoglycoside use Low 9 Tolia et al., 2017 USA; VLBW infants Cohort 48-h automatic stop DOT; antibiotic exposure; sepsis evaluations Low 10 Urzúa et al., 2017 Chile; NICU Cohort Narrow-spectrum policy + culture-guided de-escalation Vancomycin/cefotaxime use; restricted agents; cost Low 11 Walker et al., 2017 USA; surgical neonates Cohort Restriction of empirical/postoperative antibiotics LOT; resistant organisms; postoperative infection Low 12 Beavers et al., 2018 USA; ≥34 weeks Cohort EOS calculator Antibiotic exposure; sepsis evaluations; clinical safety Moderate 13 Bhat et al., 2018 USA; preterm infants QI cohort 36-h stop + multiplex PCR Antibiotic utilization; diagnostic stewardship Moderate 14 Dhudasia et al., 2018 USA; ≥36 weeks Cohort EOS calculator Antibiotic use; blood cultures; sepsis evaluation Low 15 Strunk et al., 2018 Australia; ≥35 weeks Cohort EOS calculator Antibiotic initiation; sepsis work-up; missed infection Low 16 McCarthy et al., 2018 Ireland; NICU Cohort NICU antimicrobial guideline DOT; prolonged therapy; safety outcomes Low 17 Astorga et al., 2019 USA; NICU Cohort Automatic 48-h antibiotic stop order Total DOT; drug-specific DOT; unintended continuation Low 18 Kitano et al., 2019 Japan; NICU Cohort Start/stop criteria + rapid blood cultures DOT; antimicrobial resistance; mortality Low 19 Lahart et al., 2019 USA; VLBW infants Cohort Audit-feedback + narrow-spectrum policy DOT; antibiotic spectrum index Low 20 Lu et al., 2019 China; NICU Cohort Prescription audit and feedback DOT; antimicrobial consumption; resistance patterns Low 21 Thampi et al., 2019 Canada; NICU Cohort Prospective audit and feedback Antibiotic utilization; DOT; clinical outcomes Low 22 Ting et al., 2019 Canada; tertiary NICU Cohort Antimicrobial stewardship care bundle Inappropriate antibiotic days; DOT; safety Low 23 Bassiouny et al., 2020 Egypt; surgical NICU Cohort Antibiotic guideline DOT; bacterial resistance; economic impact Low 24 Chimhini et al., 2020 Zimbabwe; NICU Cohort Prescriber education + antimicrobial policy Antibiotic consumption; LOT; mortality Low 25 El-Baky et al., 2020 Egypt; NICU Cohort Culture-based antimicrobial policy Resistance patterns; infection; mortality Low 26 Gustavsson et al., 2020 Sweden; extremely preterm infants Cohort Guidelines + infectious-disease consultation DOT; LOT; prolonged treatment; mortality Low 27 Hamdy et al., 2020 USA; Level IV NICU QI cohort 48-h time-out + prospective audit DOT; vancomycin exposure; clinical safety Moderate 28 Sowjanya et al., 2020 India; NICU Cohort Restricted-antibiotic justification + de-escalation LOT; broad-spectrum exposure; de-escalation Low 29 Vatne et al., 2020 Norway; term neonates Cohort Serial physical examination Antibiotic exposure; restart; sepsis; mortality Low 30 Wang et al., 2020 China; NICU Cohort Weekly antibiotic stewardship rounds Antibiotic utilization; DDD; spectrum Moderate 31 Mundal et al., 2021 Norway; 21 NICUs Multicenter cohort Guidelines + 48-h stop + PCT + review LOT; antimicrobial exposure; mortality Moderate 32 Berardi et al., 2021 Italy; VLBW infants Cohort CRP/PCT-guided discontinuation DOT; LOT; treatment restart Low 33 Kopsidas et al., 2021 Greece; 15 NICUs Multicenter cohort Antimicrobial guidelines Prolonged antibiotic use; stewardship adherence Low 34 Maalouf et al., 2022 Lebanon; Level IV NICU QI cohort Guidelines + 48-h hard stop + PAF DOT; meropenem and vancomycin use; sustainability Low 35 Malviya et al., 2022 Oman; NICU Cohort Guideline + de-escalation + antibiotic time-out DOT; mortality; clinical safety Low 36 Stritzke et al., 2022 Canada; preterm infants, 4 NICUs Multicenter cohort Guidelines + pharmacist rounds + culture-based stopping Antibiotic exposure; short-course therapy Low 37 Ren et al., 2022/2023 China; Level IV NICU Cohort Restriction of broad-spectrum therapy + culture-guided treatment Antibiotic consumption 791.1→466.3 DOT/1,000 PD; MDRO 67.2%→48.9% Low 38 Assen et al., 2023 Canada; Level III-IV NICU Cohort Prescription review + handshake rounds DOT; drug-specific DOT; antibiotic spectrum index Low 39 Feng et al., 2023 China; ≥34-week neonates Cohort Clinical monitoring + PCT-guided discontinuation DOT; LOT; prolonged exposure; resistance Low 40 Allen et al., 2021 USA; NICU Quality-improvement study Blood-culture collection bundle Culture contamination 2.0%→1.0%; adequate culture volume improved Low 41 NEC stewardship pathway study, 2023 USA; neonates with NEC QI cohort Bell-stage-specific antibiotic pathway Total DOT 119.19→80.65; piperacillin-tazobactam 68.78→7.97 DOT/1,000 PD; NEC recurrence, bacteremia/fungemia, mortality Low The 41 included studies represented a heterogeneous body of evidence encompassing general NICU antimicrobial stewardship, restricted-agent programs, vancomycin and carbapenem stewardship, diagnostic stewardship, neonatal sepsis management, and disease-specific protocols. The predominant study designs were prospective or retrospective cohorts and quality-improvement before-and-after studies, reflecting the practical implementation nature of NICU stewardship research. The larger neonatal ASP evidence base similarly consists predominantly of cohort and QI designs, with relatively few randomized studies. Microbiological outcomes were reported less consistently than antimicrobial-consumption outcomes. Studies evaluating resistance generally assessed MDRO prevalence, organism-specific susceptibility, broad-spectrum antimicrobial pressure, or resistant bloodstream infections. Diagnostic-stewardship studies focused principally on blood-culture quality and contamination, while clinical balancing outcomes included sepsis-related mortality, treatment restart, NEC recurrence, bacteremia/fungemia, and length of stay. Major Clinical and Microbiological Effects of NICU Stewardship Domain Representative finding Interpretation Total antimicrobial consumption 791.1 -> 466.3 DOT/1,000 patient-days Strong reduction MDRO prevalence 67.2% -> 48.9% Favorable microbiological shift Meropenem/vancomycin use 7.6% -> 1.8% Reduced high-impact antibiotic pressure Vancomycin DOT 112 -> 38/1,000 patient-days Major glycopeptide reduction Blood-culture contamination 2.0% -> 1.0% Improved diagnostic quality Culture-positive sepsis 18% -> 11.56% No evidence of infection rebound NICU mortality 25% -> 16% Favorable clinical trend LOS 28-day mortality 46.4% -> 32.1% Significant improvement NEC piperacillin-tazobactam DOT 68.78 -> 7.97/1,000 patient-days Marked spectrum reduction Length of stay Generally unchanged Stewardship did not prolong admission Microbiological Stewardship Index To complement conventional antibiotic-use metrics, this review proposes a Microbiological Stewardship Index (MSI) incorporating five domains:

This systematic review takes a different perspective from conventional neonatal ASP reviews. The most consistent conclusion is that stewardship has measurable consequences for microbial ecology, not merely prescribing volume. The southern China NICU study provides one of the strongest examples: a reduction of approximately 41% in antibiotic consumption occurred alongside a decline in MDRO prevalence from 67.2% to 48.9%. This is biologically plausible because the same intervention substantially restricted meropenem and vancomycin. Vancomycin stewardship represents another reproducible example. Both guideline-based work and newer QI initiatives show substantial reductions in exposure without increased bacteremia complications or infection-attributable mortality. Another major conclusion is that diagnostics themselves are part of stewardship. A contaminated neonatal blood culture can initiate days of unnecessary antimicrobial therapy. Reducing contamination may have a greater impact than trying to reverse downstream overtreatment. Clinical safety data are broadly reassuring. Reductions in antimicrobial initiation and duration have generally not been accompanied by increased sepsis-related mortality or treatment reinitiation, although the certainty of evidence for resistance remains lower because fewer studies report standardized ecological outcomes. The NEC evidence illustrates why disease-specific stewardship matters. Dramatic reductions in piperacillin-tazobactam exposure occurred without increased recurrence, progression to surgery, bacteremia, fungemia, or mortality. A stewardship program should therefore not be considered successful based on DOT reduction alone. Strong stewardship success requires reduced unnecessary exposure, reduced broad-spectrum pressure, stable or improved resistance ecology, and preserved or improved clinical outcomes. Strengths • Prioritizes microbiological rather than prescription-only outcomes. • Separately evaluates resistance, diagnostic quality, and bloodstream infection. • Incorporates clinical balancing outcomes. • Examines disease-specific stewardship in NEC. • Distinguishes vancomycin and carbapenem pressure. • Proposes a microbiological stewardship index. • Introduces a combined clinical-microbiological dashboard. Limitations • Most included interventions are non-randomized. • Resistance outcomes are vulnerable to secular trends and outbreaks. • Some programs simultaneously introduced infection-prevention measures. • Microbiological outcome definitions differ between studies. • Few studies report long-term antibiogram changes. • Invasive candidiasis and NEC are uncommon outcomes requiring large populations. Future Research 1. Total and class-specific DOT. 2. Unit antibiograms. 3. MDRO colonization and infection. 4. Carbapenem-resistant Enterobacterales. 5. MRSA and VRE. 6. Blood-culture contamination. 7. Adequate blood-culture volume. 8. Culture-positive LOS. 9. CLABSI. 10. Invasive candidiasis. 11. NEC. 12. Sepsis-related mortality. 13. Readmission or treatment failure. 14. Duration of hospitalization. 15. Microbiome outcomes.

Antimicrobial stewardship in NICUs has important clinical and microbiological effects that extend beyond simple reductions in antibiotic use. The available evidence demonstrates that stewardship can substantially reduce broad-spectrum exposure, vancomycin and carbapenem pressure, decrease MDRO prevalence in some settings, improve blood-culture quality, reduce contamination, and preserve or improve clinical outcomes. Particularly compelling findings include a reduction in MDRO prevalence from 67.2% to 48.9%, a reduction in vancomycin utilization from 112 to 38 DOT/1,000 patient-days, and reduction of blood-culture contamination from 2.0% to 1.0%. The optimal measure of NICU stewardship success should therefore be: less unnecessary antimicrobial pressure + better diagnostic quality + preserved antimicrobial susceptibility + stable or improved neonatal outcomes.

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