Video Abstract

Video Abstract

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BACKGROUND AND OBJECTIVES

Neonatal sepsis is a significant contributor to mortality and morbidity; however, the uncontrolled use of antimicrobials is associated with significant adverse effects. Our objective with this article is to review the components of neonatal antimicrobial stewardship programs (ASP) and their effects on clinical outcomes, cost-effectiveness, and antimicrobial resistance.

METHODS

We selected randomized and nonrandomized trials and observational and quality improvement studies evaluating the impact of ASP with a cutoff date of May 22, 2023. The data sources for these studies included PubMed, Medline, Embase, Cochrane CENTRAL, Web of Science, and SCOPUS. Details of the ASP components and clinical outcomes were extracted into a predefined form.

RESULTS

Of the 4048 studies retrieved, 70 studies (44 cohort and 26 observational studies) of >350 000 neonates met the inclusion criteria. Moderate-certainty evidence reveals a significant reduction in antimicrobial initiation in NICU (pooled risk difference [RD] 19%; 95% confidence interval [CI] 14% to 24%; 21 studies, 27 075 infants) and combined NICU and postnatal ward settings (pooled RD 8%; 95% CI 6% to 10%; 12 studies, 358 317 infants), duration of antimicrobial agents therapy (pooled RD 20%; 95% CI 10% to 30%; 9 studies, 303 604 infants), length of therapy (pooled RD 1.82 days; 95% CI 1.09 to 2.56 days; 10 studies, 157 553 infants), and use of antimicrobial agents >5 days (pooled RD 9%; 95% CI 3% to 15%; 5 studies, 9412 infants). Low-certainty evidence reveals a reduction in economic burden and drug resistance, favorable sustainability metrices, without an increase in sepsis-related mortality or the reinitiation of antimicrobial agents. Studies had heterogeneity with significant variations in ASP interventions, population settings, and outcome definitions.

CONCLUSIONS

Moderate- to low-certainty evidence reveals that neonatal ASP interventions are associated with reduction in the initiation and duration of antimicrobial use, without an increase in adverse events.

Neonatal sepsis is a major contributor to morbidity and mortality worldwide.1 ,2  Empirical treatment with broad-spectrum antibiotics is a common practice for neonates to prevent infection or halt the progression to overwhelming and fulminant sepsis. Antimicrobials are the most frequently administrated drugs in NICUs,3 ,4  possibly playing a role in the emergence of antimicrobial resistant organisms.5 ,6  Excessive antibiotic exposure has been linked to increased neonatal mortality and morbidity, as well as adverse neurodevelopmental outcomes.7 10 

Antimicrobial stewardship program (ASP) refers to interventions to improve the appropriate use of antimicrobials, enhance patient outcomes, reduce costs, and prevent antimicrobial resistance.11  Components of ASP include accountability, expertise, action, tracking, reporting, and education.12  Descriptions of ASP in neonates have been emerging recently. Gustavsson et al reported a reduction in antibiotic days from 287 to 197 days per 1000 patient days (PD) in extremely preterm neonates.13  Cantey et al reported a decrease from 343 at baseline to 252 of 1000 days of therapy (DOT) after electronic medical record programming to discontinue antibiotics after predefined period.14  On the other hand, no difference in length of therapy (LOT) was reported by Lamba et al after ASP.15  High vulnerability to infection, unique infection risks, reduced treatment options, limited clinical data, and long-term effects of infection makes neonatal population a hard target for ASP.

Rajar et al16  and Da-silva et al17  have reviewed ASP in neonates previously; however, the number of studies included in these reviews is small, and several new studies have been published recently. Therefore, we aimed to systematically review the effectiveness, balancing measures, and sustainability of ASP interventions in neonates.

We searched the electronic databases PubMed, Medline, Embase, Cochrane CENTRAL, Web of Science, and SCOPUS from inception until May 22, 2023, without language restrictions, with help of an information specialist. We also conducted manual searches. Only published data were included (search strategy in Supplemental Tables 2–7). We included studies of neonates admitted in NICU or postnatal wards who were studied along with introduction of ASP. Randomized and nonrandomized trials, observational studies, and quality improvement (QI) studies evaluating the effectiveness of ASP were included. Studies in which the authors described antimicrobial use without detailing the ASP content, studies lacking patient outcomes, and studies in which the intervention targeted a specific organism were excluded. Narrative reviews, abstracts, opinions, letters, editorials, commentaries, preprints, unpublished articles, and systematic reviews were excluded. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement for reporting.18 

Two authors (DM and MH) independently reviewed the citation lists and abstracts to assess potential eligibility, reviewed the full texts of potential articles to determine inclusion, and collected data on a predetermined data extraction form. Discrepancies were resolved through discussions and by senior reviewers (JT and PS). Outcomes were categorized on the basis of the intended target of the intervention into 3 groups, including Groups A, B, and C.

Group A included the initiation of antimicrobial agents (A.1: percentage of neonates receiving antimicrobial therapy; A.2: percentage of neonates who underwent evaluation for sepsis). Group B included the duration of antimicrobial agents (B.1: proportion of DOT defined as the proportion of days each antimicrobial was administered out of total number of PD [eg, 2 antimicrobial agents each given concurrently for 3 days would count as 6 DOT]; B.2: LOT defined as the proportion of days any antimicrobial was administered out of total number of PD, irrespective of the number of antimicrobial agents given on the same day [eg, 2 antimicrobial agents each given concurrently for 3 days would count as 3 LOT]; B.3: percentage of neonates receiving antimicrobial therapy for >5 days). Group C included the appropriateness of antimicrobial agents (C.1: Antimicrobial Spectrum Index [ASI]). ASI is used to describe the spectrum of an antimicrobial agent, with 1 point assigned for each clinically relevant pathogen that the antimicrobial covers. The aggregate ASI for a patient on any given day is the summation of the ASI of all antimicrobial agents prescribed for that day.19  Other outcomes included DOT of individual antimicrobial, rate of drug resistance, economic benefits, and sustainability of ASP. Balancing measures included the need for the reinitiation of antimicrobial agents after early discontinuation and sepsis-related mortality.

Studies in which clinical (similar population and setting) or methodological (similar programs) homogeneity was identified, random effects meta-analysis was conducted by using Review Manager version 5.4.1 3 (Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark). The effect measures were expressed as risk difference (RD) for categorical variables and mean difference (MD) for continuous variables, along with 95% confidence intervals (CI). The statistical heterogeneity of studies was quantified by using extent of heterogeneity (I2) values with assigned values of low, moderate, and high heterogeneity to I2 values of 25%, 50%, and 75%. Studies not eligible for meta-analysis were included in the systematic review. Two authors (DM, MH) independently conducted a risk of bias assessment for all included studies. The risk of bias in observational studies was evaluated by using the Newcastle-Ottawa scale,20  and a score of 7 to 9 was deemed as low risk, as score of 4 to 6 was deemed as moderate risk, and a score ≤3 was deemed as a high risk of bias. Certainty of evidence was reported according to the Grades of Recommendation, Assessment, Development and Evaluation guidelines.21  Subgroup analyses were planned for different settings (NICU and NICU with postnatal ward), very low birth weight (VLBW; <1500 g birth weight), extremely low birth weight (<1000 g birth weight), very preterm infants (<33 weeks gestational age), culture-negative sepsis, and infants receiving surgery. The protocol was registered in the PROSPERO registry (CRD42023428258). There was no funding source for the study.

Of a total of 4048 potential studies identified in the search, 70 studies met the inclusion criteria (Fig 1; Table 1). A total of 44 were cohort studies,13 ,14 ,22 32 ,34 ,35 ,37 ,38 ,41 51 ,57 59 ,62 ,67 ,68 ,70 ,72 ,73 ,77 ,81 ,83 85 ,87 ,88  and 26 were QI studies with a cohort design.15 ,33 ,36 ,39 ,40 ,52 56 ,60 ,61 ,63 66 ,69 ,71 ,74 76 ,78 80 ,82 ,86  Five studies were multicenter,22 ,67 ,68 ,75 ,81  and 65 were single-center studies. A total of 40 studies included all neonates, 18 enrolled late preterm and term,27 ,32 ,34 ,35 ,38 40 ,42 ,48 ,52 ,53 ,56 ,58 ,63 ,67 ,68 ,72 ,85  5 included preterm,13 ,33 ,65 ,81 ,86  5 included VLBW,29 ,44 ,62 ,78 ,84  and 2 included surgical neonates.31 ,49  A total of 52 (74%) studies were published between 2019 and 2023. The risk of bias of the included studies is presented in Supplemental Table 8. A total of 49 (70%) studies had low risk of bias,13 ,14 ,23 ,27 31 ,34 ,35 ,37 51 ,53 ,57 ,58 ,60 63 ,65 ,67 ,69 ,70 ,73 ,76 79 ,81 88  and 21 (30%) studies had moderate risk of bias.15 ,22 ,24 26 ,32 ,33 ,36 ,52 ,54 56 ,59 ,64 ,66 ,68 ,71 ,72 ,74 ,75 ,80  Some studies addressed multiple ASP strategies. The publication bias for outcomes have been depicted in Supplemental Fig 5. The findings and certainty of evidence are summarized in Supplemental Table 9 and Supplemental Fig 4.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-analysis flow diagram.

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TABLE 1

Study Characteristics

Author, yPopulation (Gestational Age)LocationType of StudyInterventionsOutcomes GroupOutcomes of InterestRisk of Bias Assessment
Chiu et al,22  2011 All Level III B + Level III C NICU, USA Multicenter cohort Guidelines for vancomycin use A, B Vancomycin starts, DOT (vancomycin) Moderate 
Holzmann-Pazgal et al,23  2015 All Level II – IV NICU, USA Single-center cohort AM guidelines A, B Vancomycin utilization, Vancomycin duration Low 
Cantey et al,14  2016 All Level III C NICU, USA Single-center cohort Auto-stop order at 48 h DOT, % use Low 
Hurst et al,24  2016 All NICU, USA Single-center cohort Handshake stewardship DOT, DOT (vancomycin) Moderate 
Lee et al,25  2016 All NICU, USA Single-center cohort AM guidelines DOT, DOT (broad-spectrum AM) Moderate 
Jinka et al,26  2017 All NICU, India Single-center cohort AM guidelines to improve use of first line AM DDD, % use Moderate 
Kuzniewicz et al,27  2017 ≥35 wk NICU + postnatal ward, USA Single-center cohort Risk estimator (calculator) % use, sepsis evaluation, AUR, sepsis-related mortality Low 
Nzegwu et al,28  2017 All Level IV NICU, USA Single-center cohort AM guidelines, PAF DOT, DOT (vancomycin, cefotaxime, gentamicin/tobramycin, clindamycin) Low 
Tolia et al,29  2017 VLBW NICU, USA Single-center cohort Auto-stop order at 48 h DOT, % use, sepsis evaluation Low 
Urzúa et al,30  2017 All NICU, Chile Single-center cohort Change in AM policy to narrow-spectrum first line AM, culture-based de-escalation, limited use of restricted AMs % use of Vancomycin & Cefotaxime, economic impact Low 
Walker et al,31  2017 Surgical neonates Level IV NICU, USA Single-center cohort No empirical AMs,
post-op AM duration limit to 72 h 
A, B % use, LOT, % resistance Low 
Beavers et al,32  2018 ≥34 wk Level III NICU, USA Single-center cohort EOS calculator % use, sepsis evaluation Moderate 
Bhat et al,33  2018 Preterm Level III B NICU, USA Single-center QI Auto-stop order at 36 h, use of multiplex polymerase chain reaction panel for septicemia/ meningitis B, C AUR Moderate 
Dhudasia et al,34  2018 ≥36 wk Well-baby nursery (WBN) + Level III NICU, USA Single-center cohort EOS calculator % use, sepsis evaluation Low 
Gievers et al,35  2018 ≥35 wk Mother baby unit (MBU) + NICU, USA Single-center cohort Sepsis risk score algorithm % use Low 
Makri et al,36  2018 All Level III NICU, UK Single-center QI Review at 36 h, policy change to not initiate AM >34 wk without risk factors, CRP to stop AM A, B % use, DOT Moderate 
McCarthy et al,37  2018 All Level III NICU, Ireland Single-center cohort AM guidelines DOT, % use >5 d Low 
Strunk et al,38  2018 ≥35 wk NICU + postnatal ward, Australia Single-center cohort EOS calculator % use, sepsis evaluation Low 
Akangire et al,39  2019 ≥34 wk Level III NICU, USA Single-center QI EOS calculator % use, sepsis evaluation Low 
Arora et al,40  2019 ≥34 wk Level III NICU, USA Single-center QI EOS calculator, 36-h time-out % use Low 
Astorga et al,41  2019 All Level III NICU, USA Single-center cohort Auto-stop order at 48 h DOT (ampicillin, cefotaxime, gentamicin, metronidazole, vancomycin), total doses per patient, total doses per PD, % use Low 
Joshi et al,42  2019 ≥34 wk Nursery + Level II – IV NICU, USA Single-center cohort Clinical examination-based approach % use Low 
Kitano et al,43  2019 All Level III NICU, Japan Single-center cohort AM guidelines with start and stop criteria, timely release of blood culture report including on weekends A, B % use, DOT, % resistance, sepsis-related mortality Low 
Lahart et al,44  2019 VLBW NICU, USA Single-center cohort PAF, change in AM policy to narrow-spectrum first line AM, policy for AM duration A, B, C % use, DOT, ASI Low 
Lu et al,45  2019 All Level III-IV NICU, China Single-center cohort PAF, prescription review DOT, % resistance Low 
Thampi et al,46  2019 All Level II and III NICU, Canada Single-center cohort PAF A, B % use, DOT Low 
Ting et al,47  2019 All Level III-IV NICU, Canada Single-center cohort ASP guidelines B, C Inappropriate AM days, inappropriate AM use Low 
Achten et al,48  2020 ≥35 wk Level II neonatal ward + mother–child unit, Netherlands Single-center cohort EOS calculator % use, LOT, economic impact Low 
Bassiouny et al,49  2020 Surgical neonates Surgical NICU, Egypt Single-center cohort AM guidelines DOT (amoxicillin-clavulanate, ampicillin sulbactam, gentamicin, imipenem, vancomycin), % resistance, economic impact Low 
Chimhini et al,50  2020 All NICU, Zimbabwe Single-center cohort Training program for interns in antibiotic use A, B % use, DOT, LOT, sepsis-related mortality Low 
El-Baky et al,51  2020 All NICU, Egypt Single-center cohort Culture-based antibiotic policy Surveillance swab culture positivity, % resistance (AM-specific), sepsis-related mortality Low 
Frymoyer et al,52  2020 ≥35 wk Level II-IV NICU + postpartum unit, USA Single-center QI Clinical examination-based approach % use Moderate 
Gustavsson et al,13  2020 ≤28 wk Level III NICU, Sweden Single-center cohort AM guidelines
outlining drug choice and duration, infectious disease consult access 
A, B % use, DOT, LOT, % use >5 d, AM reinitiation, sepsis-related mortality Low 
Gyllensvard et al,53  2020 Term Level II NICU + postnatal, ward
Sweden 
Single-center QI Clinical symptoms- and CRP- based decision-making for initiation and duration of AM A, B % use, LOT, economic impact Low 
Hamdy et al,54  2020 All Level IV NICU, USA Single-center QI 48-h time-out, AM guidelines, PAF DOT, DOT (vancomycin) Moderate 
Lamba et al,15  2020 All Level III B NICU, USA Single-center QI ASP bundle for AM initiation and de-escalation A, C Appropriate AM use, appropriate AM de-escalation, bundle compliance Moderate 
Meyers et al,55  2020 All Level IV NICU, USA Single-center QI Sepsis calculator, guidelines for EOS evaluation in <35 wk, auto-stop order at 36 h, PAF A, B % use, LOT Moderate 
Perez et al,56  2020 ≥35 wk NICU + postnatal ward, USA Single-center QI EOS calculator % use, sepsis evaluation Moderate 
Sowjanya et al,57  2020 All Level III NICU, India Single-center cohort Antibiotics justification form for restricted antibiotics, culture-based discontinuation A, B, C % use, LOT, % of neonates de-escalated from high-end AMs Low 
Vatne et al,58  2020 ≥37 wk Level III NICU + postnatal ward, Norway Single-center cohort Serial physical examinations A, B % use, DOT, LOT, AM reinitiation, sepsis-related mortality Low 
Wang et al,59  2020 All Level III NICU, China Single-center cohort Weekly antibiotic round in NICU (WARN) A, B % use, DDD Moderate 
Agarwal et al,60  2021 All Level III NICU, India Single-center QI AM guidelines with checkpoints for starting and early stoppage of AM, specific Vancomycin protocol A, B % use, DOT, DOT (vancomycin), % use >5 d, sustainability Low 
Begnaud et al,61  2021 All Level III NICU, USA Single-center QI AM guidelines A, B % use, sepsis evaluation, DOT, LOT, economic impacts Low 
Berardi et al,62  2021 VLBW Level III NICU, Italy Single-center cohort AM guidelines, culture-based discontinuation, CRP and procalcitonin to reduce AM duration A, B % use, DOT, DOT (ampicillin, penicillin, gentamicin, teicoplanin, oxacillin, piperacillin, tazobactam), LOT, AM reinitiation Low 
Ellington et al,63  2021 ≥36 wk Level III NICU + postnatal ward, USA Single-center QI EOS calculator % use Low 
Jain et al,64  2021 All NICU, India Single-center QI AM guidelines including auto-stop order at 72 h, culture-based discontinuation, AM de-escalation, justification of restricted antimicrobial use B, C LOT, mean AM exposure rate Moderate 
Kommalur et al,65  2021 Preterm Level III NICU, India Single-center QI AM guidelines, auto-stop order at 48 h, AM de-escalation A, B, C % use, DOT, % use of first line AM, sustainability Low 
Konda et al,66  2021 All Level III NICU, India Single-center QI AM guidelines, prescription justification, lock model for upgrading antibiotics, AM de-escalation Unindicated AM use, de-escalation rate Moderate 
Kopsidas et al,67  2021 ≥37 wk 15 public NICUs, Greece Multicenter cohort AM guidelines % use >5 d Low 
Mundal et al,68  2021 ≥34 wk 21 NICUs + postnatal ward, Norway Multicenter cohort AM guidelines,
auto-stop order at 48 h, procalcitonin to reduce AM duration, daily prescription review 
A, B % use, LOT, sepsis-related mortality Moderate 
Newby et al,69  2021 All Level III NICU, Canada Single-center QI Change in the wording in AM duration order, auto-stop order at 48 h No. of unnecessary doses Low 
Singh et al,70  2021 All Level III NICU, USA Single-center cohort Auto-stop order at 48 h, no CRP level to stop AM LOT Low 
Weiss et al,71  2021 All Level III NICU + postnatal ward, USA Single-center QI AM guidelines % use Moderate 
Zihlmann-Ji et al,72  2021 ≥34 wk Level III NICU, Switzerland Single-center cohort Procalcitonin level-based guidelines to stop AMs LOT, % use Moderate 
Capin et al,73  2022 All NICU, USA Single-center cohort ASP guidelines % use, LOT Low 
Graus et al,74  2022 All Level III NICU, Peru Single-center QI Auto-stop order at 48 h AUR Moderate 
Kahn et al,75  2022 All 3 NICUs (Level II – III), USA Multicenter QI Implementation of EOS calculator for ≥34 wk, clinical decision-making for <34 wk, AM guideline for initiation and discontinuation, culture-based discontinuation A, B % use, DOT Moderate 
Maalouf et al,76  2022 All Level IV NICU, Lebanon Single-center QI AM guidelines, auto-stop order at 48 h, PAF A, B % use, DOT, DOT (ampicillin, gentamicin, meropenem, vancomycin) Low 
Malviya et al,77  2022 All Level III NICU, Oman Single-center cohort AM guidelines, culture-based discontinuation, AM time-out at 48 h A, B % use, DOT, DOT (ampicillin), sepsis-related mortality Low 
Morales-Betancourt et al,78  2022 VLBW Level III NICU, Spain Single-center QI AM guidelines, stop AM if negative cultures at 72 h A, B % use, % use >3 d, % use on days 1–2 of life Low 
Muller et al,79  2022 All NICU, USA Single-center QI Auto-stop order at 72 h, AM time-out DOT Low 
Shukla et al,80  2022 All Level III NICU, USA Single-center QI Daily time-out, auto-stop order at 48 h LOT Moderate 
Stritzke et al,81  2022 Preterm
<34 wk 
4 NICUs (Level II-III), Canada Multicenter cohort AM guidelines, auto-stop order at 5 d, daily pharmacist rounds,
culture-based discontinuation at 36 h 
A, B % use, % use <48 h Low 
Vyas et al,82  2022 All Level IV NICU, USA Single-center QI AM guidelines, provider justification, auto-stop order at 48 h, daily time-out, PAF A, B % use, unnecessary AM days Low 
Assen et al,83  2023 All Level III – IV NICU, Canada Single-center cohort Prescription review,
handshake rounds 
B, C DOT, DOT (ampicillin, aminoglycosides, linezolid, cloxacillin), ASI Low 
Chu et al,84  2023 VLBW NICU, China Single-center cohort AM guidelines A, B % use, LOT, % use >5 d, sustainability Low 
Feng et al,85  2023 ≥34 wk NICU + postnatal ward, China Single-center cohort Clinical monitoring (observership) form,
AMs stop as per guideline duration, procalcitonin to reduce AM duration 
A, B % use, DOT, LOT, % use >5 d, % resistance Low 
Fischer et al,86  2023 Preterm
<35 wk 
Level IV NICU, USA Single-center QI AM guidelines, Prescriber justification, auto-stop order at 48 h DOT, % use >5 d Low 
Ren et al,87  2023 All Level IV NICU, China Single-center cohort AMs stop as per guideline duration, culture-based choice of AMs, justification of restricted antimicrobial use B, C DOT, LOT, % use, % resistance Low 
Sathyan et al,88  2023 All Level III B NICU, India Single-center cohort Auto-stop order at 48 h LOT, AM overuse days, AM reinitiation Low 
Author, yPopulation (Gestational Age)LocationType of StudyInterventionsOutcomes GroupOutcomes of InterestRisk of Bias Assessment
Chiu et al,22  2011 All Level III B + Level III C NICU, USA Multicenter cohort Guidelines for vancomycin use A, B Vancomycin starts, DOT (vancomycin) Moderate 
Holzmann-Pazgal et al,23  2015 All Level II – IV NICU, USA Single-center cohort AM guidelines A, B Vancomycin utilization, Vancomycin duration Low 
Cantey et al,14  2016 All Level III C NICU, USA Single-center cohort Auto-stop order at 48 h DOT, % use Low 
Hurst et al,24  2016 All NICU, USA Single-center cohort Handshake stewardship DOT, DOT (vancomycin) Moderate 
Lee et al,25  2016 All NICU, USA Single-center cohort AM guidelines DOT, DOT (broad-spectrum AM) Moderate 
Jinka et al,26  2017 All NICU, India Single-center cohort AM guidelines to improve use of first line AM DDD, % use Moderate 
Kuzniewicz et al,27  2017 ≥35 wk NICU + postnatal ward, USA Single-center cohort Risk estimator (calculator) % use, sepsis evaluation, AUR, sepsis-related mortality Low 
Nzegwu et al,28  2017 All Level IV NICU, USA Single-center cohort AM guidelines, PAF DOT, DOT (vancomycin, cefotaxime, gentamicin/tobramycin, clindamycin) Low 
Tolia et al,29  2017 VLBW NICU, USA Single-center cohort Auto-stop order at 48 h DOT, % use, sepsis evaluation Low 
Urzúa et al,30  2017 All NICU, Chile Single-center cohort Change in AM policy to narrow-spectrum first line AM, culture-based de-escalation, limited use of restricted AMs % use of Vancomycin & Cefotaxime, economic impact Low 
Walker et al,31  2017 Surgical neonates Level IV NICU, USA Single-center cohort No empirical AMs,
post-op AM duration limit to 72 h 
A, B % use, LOT, % resistance Low 
Beavers et al,32  2018 ≥34 wk Level III NICU, USA Single-center cohort EOS calculator % use, sepsis evaluation Moderate 
Bhat et al,33  2018 Preterm Level III B NICU, USA Single-center QI Auto-stop order at 36 h, use of multiplex polymerase chain reaction panel for septicemia/ meningitis B, C AUR Moderate 
Dhudasia et al,34  2018 ≥36 wk Well-baby nursery (WBN) + Level III NICU, USA Single-center cohort EOS calculator % use, sepsis evaluation Low 
Gievers et al,35  2018 ≥35 wk Mother baby unit (MBU) + NICU, USA Single-center cohort Sepsis risk score algorithm % use Low 
Makri et al,36  2018 All Level III NICU, UK Single-center QI Review at 36 h, policy change to not initiate AM >34 wk without risk factors, CRP to stop AM A, B % use, DOT Moderate 
McCarthy et al,37  2018 All Level III NICU, Ireland Single-center cohort AM guidelines DOT, % use >5 d Low 
Strunk et al,38  2018 ≥35 wk NICU + postnatal ward, Australia Single-center cohort EOS calculator % use, sepsis evaluation Low 
Akangire et al,39  2019 ≥34 wk Level III NICU, USA Single-center QI EOS calculator % use, sepsis evaluation Low 
Arora et al,40  2019 ≥34 wk Level III NICU, USA Single-center QI EOS calculator, 36-h time-out % use Low 
Astorga et al,41  2019 All Level III NICU, USA Single-center cohort Auto-stop order at 48 h DOT (ampicillin, cefotaxime, gentamicin, metronidazole, vancomycin), total doses per patient, total doses per PD, % use Low 
Joshi et al,42  2019 ≥34 wk Nursery + Level II – IV NICU, USA Single-center cohort Clinical examination-based approach % use Low 
Kitano et al,43  2019 All Level III NICU, Japan Single-center cohort AM guidelines with start and stop criteria, timely release of blood culture report including on weekends A, B % use, DOT, % resistance, sepsis-related mortality Low 
Lahart et al,44  2019 VLBW NICU, USA Single-center cohort PAF, change in AM policy to narrow-spectrum first line AM, policy for AM duration A, B, C % use, DOT, ASI Low 
Lu et al,45  2019 All Level III-IV NICU, China Single-center cohort PAF, prescription review DOT, % resistance Low 
Thampi et al,46  2019 All Level II and III NICU, Canada Single-center cohort PAF A, B % use, DOT Low 
Ting et al,47  2019 All Level III-IV NICU, Canada Single-center cohort ASP guidelines B, C Inappropriate AM days, inappropriate AM use Low 
Achten et al,48  2020 ≥35 wk Level II neonatal ward + mother–child unit, Netherlands Single-center cohort EOS calculator % use, LOT, economic impact Low 
Bassiouny et al,49  2020 Surgical neonates Surgical NICU, Egypt Single-center cohort AM guidelines DOT (amoxicillin-clavulanate, ampicillin sulbactam, gentamicin, imipenem, vancomycin), % resistance, economic impact Low 
Chimhini et al,50  2020 All NICU, Zimbabwe Single-center cohort Training program for interns in antibiotic use A, B % use, DOT, LOT, sepsis-related mortality Low 
El-Baky et al,51  2020 All NICU, Egypt Single-center cohort Culture-based antibiotic policy Surveillance swab culture positivity, % resistance (AM-specific), sepsis-related mortality Low 
Frymoyer et al,52  2020 ≥35 wk Level II-IV NICU + postpartum unit, USA Single-center QI Clinical examination-based approach % use Moderate 
Gustavsson et al,13  2020 ≤28 wk Level III NICU, Sweden Single-center cohort AM guidelines
outlining drug choice and duration, infectious disease consult access 
A, B % use, DOT, LOT, % use >5 d, AM reinitiation, sepsis-related mortality Low 
Gyllensvard et al,53  2020 Term Level II NICU + postnatal, ward
Sweden 
Single-center QI Clinical symptoms- and CRP- based decision-making for initiation and duration of AM A, B % use, LOT, economic impact Low 
Hamdy et al,54  2020 All Level IV NICU, USA Single-center QI 48-h time-out, AM guidelines, PAF DOT, DOT (vancomycin) Moderate 
Lamba et al,15  2020 All Level III B NICU, USA Single-center QI ASP bundle for AM initiation and de-escalation A, C Appropriate AM use, appropriate AM de-escalation, bundle compliance Moderate 
Meyers et al,55  2020 All Level IV NICU, USA Single-center QI Sepsis calculator, guidelines for EOS evaluation in <35 wk, auto-stop order at 36 h, PAF A, B % use, LOT Moderate 
Perez et al,56  2020 ≥35 wk NICU + postnatal ward, USA Single-center QI EOS calculator % use, sepsis evaluation Moderate 
Sowjanya et al,57  2020 All Level III NICU, India Single-center cohort Antibiotics justification form for restricted antibiotics, culture-based discontinuation A, B, C % use, LOT, % of neonates de-escalated from high-end AMs Low 
Vatne et al,58  2020 ≥37 wk Level III NICU + postnatal ward, Norway Single-center cohort Serial physical examinations A, B % use, DOT, LOT, AM reinitiation, sepsis-related mortality Low 
Wang et al,59  2020 All Level III NICU, China Single-center cohort Weekly antibiotic round in NICU (WARN) A, B % use, DDD Moderate 
Agarwal et al,60  2021 All Level III NICU, India Single-center QI AM guidelines with checkpoints for starting and early stoppage of AM, specific Vancomycin protocol A, B % use, DOT, DOT (vancomycin), % use >5 d, sustainability Low 
Begnaud et al,61  2021 All Level III NICU, USA Single-center QI AM guidelines A, B % use, sepsis evaluation, DOT, LOT, economic impacts Low 
Berardi et al,62  2021 VLBW Level III NICU, Italy Single-center cohort AM guidelines, culture-based discontinuation, CRP and procalcitonin to reduce AM duration A, B % use, DOT, DOT (ampicillin, penicillin, gentamicin, teicoplanin, oxacillin, piperacillin, tazobactam), LOT, AM reinitiation Low 
Ellington et al,63  2021 ≥36 wk Level III NICU + postnatal ward, USA Single-center QI EOS calculator % use Low 
Jain et al,64  2021 All NICU, India Single-center QI AM guidelines including auto-stop order at 72 h, culture-based discontinuation, AM de-escalation, justification of restricted antimicrobial use B, C LOT, mean AM exposure rate Moderate 
Kommalur et al,65  2021 Preterm Level III NICU, India Single-center QI AM guidelines, auto-stop order at 48 h, AM de-escalation A, B, C % use, DOT, % use of first line AM, sustainability Low 
Konda et al,66  2021 All Level III NICU, India Single-center QI AM guidelines, prescription justification, lock model for upgrading antibiotics, AM de-escalation Unindicated AM use, de-escalation rate Moderate 
Kopsidas et al,67  2021 ≥37 wk 15 public NICUs, Greece Multicenter cohort AM guidelines % use >5 d Low 
Mundal et al,68  2021 ≥34 wk 21 NICUs + postnatal ward, Norway Multicenter cohort AM guidelines,
auto-stop order at 48 h, procalcitonin to reduce AM duration, daily prescription review 
A, B % use, LOT, sepsis-related mortality Moderate 
Newby et al,69  2021 All Level III NICU, Canada Single-center QI Change in the wording in AM duration order, auto-stop order at 48 h No. of unnecessary doses Low 
Singh et al,70  2021 All Level III NICU, USA Single-center cohort Auto-stop order at 48 h, no CRP level to stop AM LOT Low 
Weiss et al,71  2021 All Level III NICU + postnatal ward, USA Single-center QI AM guidelines % use Moderate 
Zihlmann-Ji et al,72  2021 ≥34 wk Level III NICU, Switzerland Single-center cohort Procalcitonin level-based guidelines to stop AMs LOT, % use Moderate 
Capin et al,73  2022 All NICU, USA Single-center cohort ASP guidelines % use, LOT Low 
Graus et al,74  2022 All Level III NICU, Peru Single-center QI Auto-stop order at 48 h AUR Moderate 
Kahn et al,75  2022 All 3 NICUs (Level II – III), USA Multicenter QI Implementation of EOS calculator for ≥34 wk, clinical decision-making for <34 wk, AM guideline for initiation and discontinuation, culture-based discontinuation A, B % use, DOT Moderate 
Maalouf et al,76  2022 All Level IV NICU, Lebanon Single-center QI AM guidelines, auto-stop order at 48 h, PAF A, B % use, DOT, DOT (ampicillin, gentamicin, meropenem, vancomycin) Low 
Malviya et al,77  2022 All Level III NICU, Oman Single-center cohort AM guidelines, culture-based discontinuation, AM time-out at 48 h A, B % use, DOT, DOT (ampicillin), sepsis-related mortality Low 
Morales-Betancourt et al,78  2022 VLBW Level III NICU, Spain Single-center QI AM guidelines, stop AM if negative cultures at 72 h A, B % use, % use >3 d, % use on days 1–2 of life Low 
Muller et al,79  2022 All NICU, USA Single-center QI Auto-stop order at 72 h, AM time-out DOT Low 
Shukla et al,80  2022 All Level III NICU, USA Single-center QI Daily time-out, auto-stop order at 48 h LOT Moderate 
Stritzke et al,81  2022 Preterm
<34 wk 
4 NICUs (Level II-III), Canada Multicenter cohort AM guidelines, auto-stop order at 5 d, daily pharmacist rounds,
culture-based discontinuation at 36 h 
A, B % use, % use <48 h Low 
Vyas et al,82  2022 All Level IV NICU, USA Single-center QI AM guidelines, provider justification, auto-stop order at 48 h, daily time-out, PAF A, B % use, unnecessary AM days Low 
Assen et al,83  2023 All Level III – IV NICU, Canada Single-center cohort Prescription review,
handshake rounds 
B, C DOT, DOT (ampicillin, aminoglycosides, linezolid, cloxacillin), ASI Low 
Chu et al,84  2023 VLBW NICU, China Single-center cohort AM guidelines A, B % use, LOT, % use >5 d, sustainability Low 
Feng et al,85  2023 ≥34 wk NICU + postnatal ward, China Single-center cohort Clinical monitoring (observership) form,
AMs stop as per guideline duration, procalcitonin to reduce AM duration 
A, B % use, DOT, LOT, % use >5 d, % resistance Low 
Fischer et al,86  2023 Preterm
<35 wk 
Level IV NICU, USA Single-center QI AM guidelines, Prescriber justification, auto-stop order at 48 h DOT, % use >5 d Low 
Ren et al,87  2023 All Level IV NICU, China Single-center cohort AMs stop as per guideline duration, culture-based choice of AMs, justification of restricted antimicrobial use B, C DOT, LOT, % use, % resistance Low 
Sathyan et al,88  2023 All Level III B NICU, India Single-center cohort Auto-stop order at 48 h LOT, AM overuse days, AM reinitiation Low 

% use, percentage of neonates receiving antimicrobial agents; % use >5 d, percentage of neonates receiving antimicrobial agents >5 d; % resistance, percentage of drug-resistant organisms; AM, antimicrobial; DDD, defined daily dose; LOS, late-onset sepsis; Sepsis evaluation, number of sepsis evaluations performed.

Outcome group (based on focus of interventions): Group A, initiation of antimicrobial agents; Group B, duration of antimicrobial agents; Group C, Appropriateness of antimicrobial agents.

The authors of 42 studies reported on the outcome of the initiation of antimicrobial agents (Fig 2).13 ,15 ,22 ,23 ,27 ,31 ,32 ,34 36 ,38 40 ,42 44 ,46 ,48 ,50 ,52 ,53 ,55 63 ,65 ,68 ,71 ,73 ,75 78 ,81 ,82 ,84 ,85  The interventions included implementing guidelines or unit policies with explicit criteria for antimicrobial initiation (23 studies [54.8%]),13 ,15 ,22 ,23 ,31 ,36 ,43 ,50 ,55 ,60 62 ,65 ,68 ,71 ,73 ,75 78 ,81 ,82 ,84  employing early-onset sepsis calculators (12 studies [28.6%]),27 ,32 ,34 ,35 ,38 40 ,48 ,55 ,56 ,63 ,75  the use of serial clinical examinations and monitoring (5 studies [11.9%]),42 ,52 ,53 ,58 ,85  audit with feedback (4 studies [9.5%]),44 ,46 ,59 ,76  and the use of justification forms at the time of initiation (1 study [2.4%]).57  A total of 28 studies enrolled neonates in the NICU, whereas 14 enrolled neonates in both the NICU and postnatal wards. There was a significant reduction in the initiation of antimicrobial agents after ASP, both in the NICU setting (77.9% [pre] vs 53.5% [post]; pooled RD 19%; 95% CI 14% to 24%; 21 studies, 27 075 infants; I2 = 94%; moderate-certainty evidence) and in the NICU+ postnatal ward setting (6.2% [pre] vs 3.5% [post]; pooled RD 8%; 95% CI 6% to 10%; 12 studies, 358 317 infants; I2 = 99%; moderate-certainty evidence). Neonates in the post-ASP group were also less likely to undergo sepsis evaluations in the NICU (74.5% [pre] vs 51.8% [post]; pooled RD 21%; 95% CI 8% to 34%; 4 studies, 1245 infants; I2 = 87%; moderate-certainty evidence) and NICU+ postnatal setting (20.5% [pre] vs 10.4% [post]; pooled RD 22%; 95% CI 15% to 29%; 6 studies, 208 967 infants; I2 = 100%; moderate-certainty evidence).

FIGURE 2

Forest plot of pairwise meta-analysis between pre-ASP and post-ASP group (using random effects model). A, Initiation of antimicrobial agents. B, Sepsis evaluation.

FIGURE 2

Forest plot of pairwise meta-analysis between pre-ASP and post-ASP group (using random effects model). A, Initiation of antimicrobial agents. B, Sepsis evaluation.

Close modal

Of the 9 studies not included in the meta-analysis, the authors of 2 studies reported decreased use of Vancomycin after the guideline implementation.22 ,23  Makri et al reported a 43% reduction in the DOT/1000 PD after a policy change to not initiate antimicrobial agents in infants without risk factors.36  Joshi et al adopted a clinical examination-based approach and reported low rates of sepsis evaluations and antimicrobial use without adverse events, as well as reduced mother–infant separation.42  Capin et al reported a reduction from 95% to 41% in the empirical use of antimicrobial agents without missing any cases of early-onset sepsis (EOS) for infants born with respiratory distress.73  Lamba et al, using a QI model, reported an improvement in “appropriate antimicrobial use.”15  The authors of 3 studies reported a significant reduction in antimicrobial initiation, sepsis evaluations, or both after using EOS calculators.55 ,56 ,75 

The authors of 51 studies reported on the outcome of duration of antimicrobial agents (Fig 3).13 ,14 ,22 25 ,28 ,29 ,31 ,33 ,36 ,37 ,41 ,43 47 ,49 ,50 ,53 55 ,57 62 ,64 ,65 ,67 70 ,72 ,74 88  The authors of 29 studies (56.9%) used protocols for the duration of antimicrobial agents,13 ,22 ,23 ,25 ,28 ,31 ,37 ,43 ,44 ,47 ,49 ,50 ,53 ,58 ,60 62 ,64 ,65 ,67 ,68 ,75 77 ,82 ,84 87  the authors of 18 (35.3%) implemented a hard stop for antimicrobial prescriptions,14 ,29 ,33 ,41 ,55 ,64 ,65 ,68 70 ,74 ,76 ,79 82 ,86 ,88  the authors of 12 (23.5%) conducted prospective audits and providing feedback,24 ,28 ,44 46 ,54 ,55 ,59 ,76 ,81 83  the authors of 9 (17.7%) used culture reports to discontinue antimicrobial use at 36 to 48 hours,43 ,57 ,62 ,64 ,75 ,77 ,78 ,81 ,87  the authors of 7 (13.7%) reported the use of antibiotic timeouts/prescription reviews,36 ,54 ,68 ,77 ,79 ,80 ,82  and the authors of 6 (11.8%) used C-reactive protein (CRP) or procalcitonin to limit the duration of antimicrobial agents.36 ,53 ,62 ,68 ,72 ,85  A significant reduction was noted in the post-ASP group in the proportion of DOT, decreasing from 571 to 367 per 1000 PD (pooled RD 20%; 95% CI 10% to 30%; 9 studies, 303 604 infants; I2 = 100%; moderate-certainty evidence), and the LOT (pooled MD 1.82 days; 95% CI 1.09 to 2.56 days; 10 studies, 157 553 infants; I2 = 100%; moderate-certainty evidence). A significantly lower proportion of infants were exposed to >5 days of antimicrobial agents in the absence of culture-proven sepsis (58.9% [pre] vs 48.4% [post]; pooled RD 9%; 95% CI 3% to 15%; 5 studies, 9412 infants; I2 = 74%; moderate-certainty evidence).

FIGURE 3

Forest plot of pairwise meta-analysis between pre-ASP and post-ASP group (using random effects model). A, Proportion of DOT. B, LOT. C, Antimicrobial use <5 days.

FIGURE 3

Forest plot of pairwise meta-analysis between pre-ASP and post-ASP group (using random effects model). A, Proportion of DOT. B, LOT. C, Antimicrobial use <5 days.

Close modal

The authors of 13 studies reported techniques aimed at enhancing the appropriateness of antibiotics.15 ,26 ,30 ,33 ,44 ,47 ,51 ,57 ,64 66 ,83 ,87  The authors of 6 studies (46.2%) reported modifications to antimicrobial protocols to narrow spectrum antimicrobial agents.26 ,30 ,44 ,47 ,65 ,66  Jinka et al reported a significant increase in the proportion of patients on first-line antimicrobial agents (ampicillin and gentamicin; 66% vs 84%) and a decrease in the use of third-generation cephalosporins (1.45 vs 0.45 DDD/100 PD).26  Lahart et al reported a significant reduction in ASI per antibiotic day in each of the subgroup analyses, including culture proven LOS, necrotizing enterocolitis stage ≥2 or spontaneous intestinal perforation, and total infections.44  The use of a lock model or justification forms for upgrading antimicrobial agents or restricted antimicrobial use was reported in 6 studies (46.2%).30 ,57 ,64 ,66 ,83 ,87  Konda et al described the use of a lock model needing senior approval to initiate second- and third-line antimicrobial agents and reported a 4% reduction in the misuse of “reserve drugs.”66  Sowjanya et al implemented a justification form for the use of restricted antimicrobial agents and reported a significant decrease in the usage of restricted antimicrobial agents.57  The implementation of a strict policy for antimicrobial de-escalation was described in 4 (30.8%) studies.15 ,64 66  Similar benefits were reported in 2 studies by Kommalur et al and Konda et al.65 ,66  El-Baky et al implemented a culture-based antimicrobial policy and reported a change in the type of microorganisms isolated with a reduction in antibiotic resistance.51  Bhat et al described the use of a multiplex polymerase chain reaction panel for septicemia and meningitis and reported a 10.6% decrease in overall antibiotic utilization rate (AUR).33  Lahart et al described a change in the antimicrobial policy to a narrow-spectrum first-line agent, resulting in a significant reduction in ASI from 7.64 to 5.97.44  Assen et al assessed the influence of prescription review and handshake rounds but reported no significant change in ASI.83 

The authors of 5 studies described the economic impact of ASP, reporting a reduction in costs ranging from 4% to 82% (low-certainty evidence). Urzua et al focused on the appropriateness of antimicrobial agents and reported a cost reduction from an estimated $280 to $50.30  Achten et al, using an EOS calculator, reported a reduction in the mean costs incurred for EOS-related laboratory evaluations (from €36.8 to €24.9) and the mean combined cost of EOS-related care (from €2248 vs to €2041).48  Bassoiuny et al reported 1185.97 Egyptian Pounds-lower drug cost, and Begnaud et al reported a 62% reduction in the total cost of EOS evaluations from $486 504 to $185 476.49 ,61  Gyllensvard reported a savings of €159 000 during the study period, corresponding to a savings of ∼€122 000 per year using clinical symptoms- and CRP- based decision-making for the initiation and duration of antimicrobial agents.53  The authors of 7 studies reported a reduction of between 11% and 66% in drug resistant organisms in the post-ASP group (low-certainty evidence).31 ,43 ,45 ,49 ,51 ,85 ,87  The authors of 3 studies reported on the sustainability of the interventions and documented a persistent effect of the ASP, even after completing the study interventions (low-certainty evidence). Chu et al reported sustainability after 5 years,84  and Agarwal et al and Kommalur et al demonstrated sustained reduction after 8 months and 2 months, respectively.60 ,65  The authors of 4 studies reported no increase in the reinitiation of antimicrobial agents for sepsis within 3 to 14 days of their discontinuation (low-certainty evidence).13 ,58 ,62 ,88  The authors of 8 studies reported no increase in sepsis-related mortality in the post-ASP group (low-certainty evidence).13 ,27 ,43 ,50 ,51 ,58 ,68 ,77 

In 5 studies of VLBW infants,29 ,44 ,62 ,78 ,84  a significant reduction in the initiation of antimicrobial agents in the post-ASP group compared with the pre-ASP group was noted (91.9% [pre] vs 80.5% [post]; pooled RD 11%; 95% CI 3% to 18%; 4 studies, 880 infants; I2 = 75%, low-certainty evidence).44 ,62 ,78 ,84  The authors of 3 studies reported a reduction in DOT per 1000 PD,29 ,44 ,62  and the authors of 2 studies reported a reduction in LOT62 ,84  in the VLBW cohort; however, these data could not be meta-analyzed. Gustavsson et al described a reduction in overall antimicrobial use from 534 to 466 days per 1000 PD, a reduction in antibiotic treatment days from 287 to 197 days per 1000 PD, and a decrease in the use of meropenem from 69% to 44%, with no increase in mortality or the reinitiation of antimicrobial agents.13  The authors of no studies reported on ASP interventions in extremely low birth weight infants, very preterm infants, or culture-negative sepsis. The authors of 2 studies reported on surgical infants.31 ,49  Walker et al reported a significant reduction in use of antimicrobial agents after policy change against the routine use of empirical antimicrobial agents and LOT without any change in rates of surgical site infections, antimicrobial resistance, or hospital-acquired infections.31  Bassiouny et al reported a significant reduction in the DOT per 1000 PD of Ampicillin-Sulbactam, Imipenem, and Vancomycin, along with a reduction in resistant strains and drug costs using antimicrobial use guidelines.49 

Our systematic review and meta-analysis of 70 studies of preterm and term neonates in the NICU and postnatal ward settings revealed variations in the ASP components across diverse settings. The majority of studies were focused on interventions aimed at reducing antimicrobial initiation and duration. Moderate-certainty evidence suggests reductions in sepsis evaluations and antimicrobial initiation. Moderate-certainty evidence suggests a reduction in antimicrobial duration, as evidenced by decreased DOT per 1000 PD, shorter LOT, and the reduced use of antimicrobial agents for >5 days. Low-certainty evidence suggests a reduction in drug resistance prevalence, a reduction in cost, the sustainability of ASP, and no increase in the rates of reinitiation of antimicrobial agents or sepsis-related mortality.

Da Silva et al, in a review of 6 studies, reported a reduction in antibiotic consumption,17  whereas Rajar et al reviewed 12 studies and reported an overall reduction in antibiotic use.16  However, the data in both studies were deemed non-meta-analyzable. We were able to meta-analyze data from 33 studies, including 385 392 neonates for whom antibiotic initiation was targeted. Nevertheless, we identified some clinical heterogeneity in the level of care and population, some methodological heterogeneity in study design, types of interventions, outcome measures, and definitions, and high statistical heterogeneity in all meta-analyses. Similar to Rajar et al, we identified that ASPs that focused on >1 domain revealed a higher decrease in DOT compared with those selectively focused on 1 domain.

In contrast to older children, neonates display significant differences that impede the direct extrapolation of results from published pediatric ASPs. Neonates, especially preterm neonates, are often born with exposure to peripartum risk factors, such a preterm–prelabor rupture of membranes, spontaneous onset of preterm labor, or maternal Group-B Streptococcus colonization. In addition, neonates are immunocompromised and tend to deteriorate rapidly compared with older children. The death toll due to neonatal sepsis worldwide is estimated to be 400 000 annually, with survivors experiencing significant neurodevelopmental implications.89 ,90  The fear of delaying the treatment leads to the early use of potent broad-spectrum empirical antibiotics.91  Moreover, the definition of certain neonatal infections, like ventilator-associated pneumonia and urinary tract infection, are inconsistent, and there is no standardized treatment regimen defined in the literature. The use of EOS calculators can provide a more objective basis for antimicrobial initiation, potentially limiting their widespread use. Rohsiswatmo et al reviewed 5 studies of 18 352 neonates and demonstrated a 54% reduction in the inappropriate use of antimicrobial agents without an increase in safety issues through the use of EOS calculators.92  However, such calculators are limited to those born at ≥34 weeks’ gestation, but not the preterm populations. Other interventions that could help include clear indications for antimicrobial initiation and the use of serial clinical assessments for neonates in the hospital. Our finding of a 19% reduction in the NICU and an 8% reduction in the combined NICU and postnatal ward settings are expected outcomes, given the differing likelihood of exposure to antimicrobial agents in these 2 populations. However, more work needs to be conducted.

The prolonged use of antimicrobial agents is associated with dysbiosis and an increased risk of mortality, severe morbidity, severe bronchopulmonary dysplasia, and necrotizing enterocolitis, as well as long-term adverse health consequences like celiac diseases, diabetes, and asthma.93 96  Hou et al demonstrated that an increased incidence of invasive fungal infections was associated with a 10% increase in AUR, each additional day of DOT and LOT, and each additional day of third-generation cephalosporins and carbapenems.97  Auto-stop orders, antibiotic stewardship rounds with prospective audit and feedback, have revealed considerable benefit in reducing the period of antimicrobial exposure and ensuring appropriateness of antibiotics (both choice and duration). Our findings of a 20% reduction in DOT and nearly a 2-day reduction in LOT are encouraging, and further efforts to identify biomarkers of true sepsis may help even greater reductions. The Neonatal Procalcitonin Intervention Study revealed the advantages of procalcitonin levels in curtailing the length of antimicrobial administration;98  however, further refinement in armamentarium of sepsis markers is needed.

Given the fact that antibiotics are the most common medication used in the NICU, there is great potential for ASP interventions to advocate the use of narrower-spectrum antibiotics, which can be quantified by the use of ASI.44 ,83  A cohort study from China revealed that early antibiotic use was associated with an increase in bronchopulmonary dysplasia, with more pronounced association when broad-spectrum antibiotics were employed.99  Broad-spectrum antibiotics are particularly harmful because of an increase in extended spectrum β-lactamase organisms, carbapenem-resistant enterobacteriaceae, and glucose non-fermenter types of antimicrobial-resistant organisms. Culture-based antibiograms were effective in reducing antimicrobial resistance.100  The utilization of unit-specific antibiogram-guided antimicrobial protocols would play a pivotal role in narrowing the spectrum of antimicrobial agents.

Outcomes such as economic impact, sustainability of interventions, and drug resistance were reported in only a handful of studies. These data are extremely important when analyzing the broader benefits of ASPs on overall health care provision. Differences in units and definitions for recording antimicrobial use make direct comparisons extremely challenging. Despite this, there was an encouraging trend in results; however, further studies are warranted. Standardizing the reporting of outcomes is urgently needed to facilitate better understanding of the consequences of various interventions in ASP.

Our study represents the largest systematic review of ASPs in neonates, employing a pragmatic approach to classifying interventions on the basis of their target intervention or outcomes. Moreover, our review is the first to include meta-analysis to quantify the impact. Although limited, we assessed the influence on other vital clinical outcomes, as well as balancing measures of reinitiation of antimicrobial agents and sepsis-related mortality. We also evaluated evidence using the Grades of Recommendation, Assessment, Development and Evaluation framework. However, our review has its limitations. First, owing to the wide variety of terminologies used to describe ASP interventions, there may be studies that were missed, despite a rigorous search strategy and thorough manual searches. Second, there was marked variation in the reporting units of antimicrobial usage across the studies. Third, although a large number of studies were included in the review, some of them could not be included in the meta-analysis. Fourth, ASP often consisted of multiple interventions. It was difficult, if not impossible, to determine the effectiveness of a single specific intervention. Fifth, there was high heterogeneity in the studies included in the meta-analysis, which should be kept in mind when interpreting these results. Sixth, none of studies included outcomes based on infant sex.

Our review highlights the overall positive impact of ASP interventions in restricting the initiation and duration of antimicrobial use in neonates, with quantifiable measures. The success of ASP in neonates can serve as a blueprint for promoting its use in other populations in the form of responsible antimicrobial use, data-guided decision algorithms, and cross-discipline collaboration and may contribute to attempts to curb antimicrobial resistance globally. However, achieving a uniform and standardized approach to reporting outcomes is paramount. We suggest that the authors of future studies meticulously report interventions of ASP within the specified domains in this review and report on balancing measures. Clear definitions of the study population, explicit highlighting of interventions targeted by the ASP domain, and alignment of outcomes with standard definitions are crucial aspects that should be emphasized. The substantial gap in the domains of economic benefit and drug resistance should be a focal point in future studies.

In conclusion, moderate- to low-certainty evidence suggests that ASP interventions in neonates are associated with either limiting initiation or curtailing duration of antimicrobial exposure, both in the NICU and postnatal settings, without increasing adverse events. Future prospective studies are warranted to evaluate drug resistance and economic burden.

The authors wish to thank Eleni Philippopoulos (information specialist) for her expertise and assistance in designing and executing the literature strategy. During the preparation of this work, the authors used GPT-3.5 for text refinement. After using this tool and service, the authors reviewed and edited the content, as needed, and take full responsibility for the content of the publication.

Dr Mascarenhas conceptualized and designed the study, designed the data collection instruments, collected data, conducted the initial analyses, and drafted the initial manuscript; Dr Ho designed the data collection instruments and collected data; Dr Ting designed the data collection instruments and coordinated and supervised data collection; Dr Shah conceptualized and designed the study, designed the data collection instruments, coordinated and supervised data collection, and conducted the initial analyses; and all authors critically reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

This trial has been registered with the PROSPERO Registry (https://www.crd.york.ac.uk/prospero/) (identifier CRD42023428258).

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2024-065735.

FUNDING: No external funding.

CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

ASI

Antimicrobial Spectrum Index

ASP

Antimicrobial Stewardship Program

AUR

antibiotic utilization rate

CI

confidence interval

CRP

C-reactive protein

DOT

days of therapy

EOS

early-onset sepsis

I2

extent of heterogeneity

LOT

length of therapy

MD

mean difference

PD

patient days

QI

quality improvement

RD

risk difference

VLBW

very low birth weight

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Supplementary data