Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator

NCT05274776 | Unknown DMC

• 1 other identifier: NL78203.018.21
• Study Type: interventional
• Target: 1,830
• Locations: 1 country
• Sites: 10

Brief Summary

Newborns are at risk for early-onset sepsis (EOS), which occurs within 72 hours after birth. The incidence of proven EOS is 0.5-2.0 per 1000 live births. The annual birth rate in the Netherlands is around 170.000, consequently the number of EOS cases varies between 85 to 340. However, about 5%, thus 8500, of late preterm and term newborns receive empiric antibiotic therapy in compliance with the current Dutch guideline. An alternative is the CE certified EOS calculator application, which calculates an individual EOS risk with treatment advice. In this prospective cluster-randomized multicenter trial the current Dutch guideline will be compared with the EOS calculator in newborns at risk for EOS. The primary objectives of this study are:

1. 1.To investigate whether the use of the EOS calculator reduces antibiotic exposure in newborns with suspected EOS in the first 24 hours after birth.
2. 2.To investigate the presence of one or more of the following four predefined safety criteria, namely 1) the need for any respiratory support, and/or 2) the need for an intravascular fluid bolus for hemodynamic instability due to sepsis, and/or 3) referral to a Neonatal Intensive Care Unit for sepsis treatment, and/or 4) proven EOS.
3. 3.To investigate if the use of the EOS calculator decreases the total duration of antibiotic therapy in newborns with suspected EOS.
4. 4.To investigate if the use of the EOS calculator decreases the percentage of antibiotic therapy started for suspected and, or proven EOS if symptoms started between 24-72 hours after birth.
5. 5.To study the impact of (suspected) EOS on parents/guardians.

Conditions

Early-Onset Sepsis, Neonatal; EOS

Keywords

early-onset sepsis; neonatal; EOS calculator

Outcome Measures

Primary Outcomes (5)

• Co-primary superiority outcome: antibiotic therapy started within 24 hours after birth

  The proportion of patients that started antibiotic therapy for suspected and, or proven EOS in the first 24 hours after birth.

  0-24 hours after birth

• First co-primary non-inferiority outcome (safety): proportion of patients with respiratory support

  A composite non-inferiority outcome regarding the presence of one or more of the following four predefined safety criteria, namely 1) the need for any respiratory support, and/or 2) the need for an intravascular fluid bolus for hemodynamic instability due to sepsis, and/or 3) referral to a Neonatal Intensive Care Unit (NICU) for sepsis treatment, and/or 4) proven EOS. \- Respiratory support is defined as any form of respiratory support (invasive ventilation, continuous positive airway pressure (CPAP), high flow nasal cannula (HFNC), low flow oxygen) during the first week of life.

  0-14 days after birth

• Second co-primary non-inferiority outcome (safety): proportion of patients with hemodynamic support

  \- Intravascular fluid bolus is defined as the intravenous administration of a fluid bolus of 10ml/kg within 15-30 minutes. It is the first step in the treatment of hemodynamically unstable newborns due to sepsis.

  0-14 days after birth

• Third co-primary non-inferiority outcome (safety): proportion of patients referred to a NICU for sepsis treatment

  0-14 days after birth

• Fourth co-primary non-inferiority outcome (safety): proportion of patients with proven EOS

  \- Proven EOS is defined as a blood or cerebrospinal fluid (CSF) culture obtained within 72 hours after birth growing a pathogenic bacterial species.

  0-14 days after birth

Secondary Outcomes (3)

• Duration of antibiotic therapy

  0-14 days after birth

• Antibiotic therapy started between 24-72 hours after birth

  24-72 hours after birth

• Questionnaire: quality of life

  14-28 days after birth

Study Arms (2)

NVK Guidelines

NO INTERVENTION

The NVK guidelines use 8 maternal and 15 neonatal risk factors, each categorized as either red flag or non-red flag. These criteria guide clinicians on the management in case of suspected EOS. Briefly, antibiotic treatment is recommended if at least one red flag and, or, two or more non-red flags are present. An observation period of at least 12 hours is recommended if one non-red flag is present. Antibiotics are recommended when an infection is suspected during this observation. Newborns without EOS risk factors, with a good clinical condition, and a gestational age of more than 36 weeks will be discharged. If the guidelines recommend an observation period, the newborn with a good clinical condition is discharged after repeating physical examination. In case antibiotic treatment is started, discharge depends on the duration of treatment and the clinical course. At discharge, parents are instructed to call the hospital in case of signs of infection within the first 14 days of life.

EOS Calculator

EXPERIMENTAL

Using the EOS calculator application between 0-24 hours after birth, maternal EOS risk factors combined with the physical examination of the newborn are used to assign a risk category and accompanying clinical recommendation based on estimated EOS incidence for each newborn at-risk for an infection. The EOS calculator results are used to guide clinical management on performing either a diagnostic work-up and start of antibiotics for (suspected) EOS, or a conservative approach with routine controls of vital parameters every 3 hours. In case of routine controls, re-evaluation of physical appearance by a pediatric resident or pediatrician will take place within 24 hours postpartum. Newborns will be observed for at least 24 hours. In case antibiotics are started, the need for further treatment is depending on blood culture results, infection parameters, and clinical condition of the newborn. Discontinuation of antibiotics and discharge is at the discretion of the treating physician.

Device: EOS calculator

Interventions

EOS calculator DEVICE

For this study the EOS calculator was developed as a mobile application (by everywhereIM), including CE marking. It is concerned a medical device for health care professionals.

Also known as: early-onset sepsis calculator, neonatal early-onset sepsis calculator, sepsis risk calculator (SRC), newborn sepsis calculator, neonatal EOS calculator

EOS Calculator

Eligibility Criteria

• Age: Up to 24 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• postmenstrual age of 34 weeks or more;
• age between 0-24 hours;
• at least one EOS risk factor or clinical sign of infection (suspected of EOS) present within the first 24 hours of life;
• parental/guardian consent.

You may not qualify if:

• major congenital anomalies;
• language barrier (lack of effective communication or whenever it hinders understanding).

Sponsors & Collaborators

• prof. dr. Frans B. Plötz: lead
• Dutch Society of Pediatrics: collaborator
• Zorgevaluatie Nederland: collaborator
• Care4Neo: collaborator
• everywhereIM: collaborator

Study Sites (10)

Northwest Clinics

Alkmaar, Netherlands

RECRUITING

FlevoHospital

Almere Stad, Netherlands

RECRUITING

Amstelland Hospital

Amstelveen, Netherlands

RECRUITING

OLVG

Amsterdam, Netherlands

RECRUITING

Martini Hospital

Groningen, Netherlands

RECRUITING

Spaarne Hospital

Haarlem, Netherlands

RECRUITING

Dijklander Hospital

Hoorn, Netherlands

RECRUITING

Canisius-Wilhelmina Hospital

Nijmegen, Netherlands

RECRUITING

Máxima Medical Center

Veldhoven, Netherlands

RECRUITING

Zaans Medical Centre

Zaandam, Netherlands

RECRUITING

Related Publications (35)

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• Sagori Mukhopadhyay, Karen M. Puopolo; Neonatal Early-Onset Sepsis: Epidemiology and Risk Assessment. Neoreviews April 2015; 16 (4): e221-e230.

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• Puopolo KM, Draper D, Wi S, Newman TB, Zupancic J, Lieberman E, Smith M, Escobar GJ. Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics. 2011 Nov;128(5):e1155-63. doi: 10.1542/peds.2010-3464. Epub 2011 Oct 24.

  PMID: 22025590 BACKGROUND

• Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, Kipnis P, Escobar GJ. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr. 2017 Apr 1;171(4):365-371. doi: 10.1001/jamapediatrics.2016.4678.

  PMID: 28241253 BACKGROUND

• Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, Giannoni E, Bokelaar R, Driessen GJA, Brodin P, Uthaya S, van Rossum AMC, Plotz FB. Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019 Nov 1;173(11):1032-1040. doi: 10.1001/jamapediatrics.2019.2825.

  PMID: 31479103 BACKGROUND

• Achten NB, Dorigo-Zetsma JW, van der Linden PD, van Brakel M, Plotz FB. Sepsis calculator implementation reduces empiric antibiotics for suspected early-onset sepsis. Eur J Pediatr. 2018 May;177(5):741-746. doi: 10.1007/s00431-018-3113-2. Epub 2018 Feb 18.

  PMID: 29455368 BACKGROUND

• van der Weijden BM, Achten NB, Bekhof J, Evers EE, van Dongen O, Rijpert M, Kamps AWA, Ten Tusscher GW, van Houten MA, Plotz FB. Neonatal early-onset sepsis calculator recommended significantly less empiric antibiotic treatment than national guidelines. Acta Paediatr. 2020 Dec;109(12):2549-2551. doi: 10.1111/apa.15391. Epub 2020 Jun 17. No abstract available.

  PMID: 32497338 BACKGROUND

• Achten NB, Klingenberg C, Plotz FB. Neonatal Early-Onset Sepsis Calculator and Antibiotic Therapy-Reply. JAMA Pediatr. 2020 May 1;174(5):508-509. doi: 10.1001/jamapediatrics.2019.6269. No abstract available.

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• Kerste M, Corver J, Sonnevelt MC, van Brakel M, van der Linden PD, M Braams-Lisman BA, Plotz FB. Application of sepsis calculator in newborns with suspected infection. J Matern Fetal Neonatal Med. 2016 Dec;29(23):3860-5. doi: 10.3109/14767058.2016.1149563. Epub 2016 Mar 7.

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• Achten, N. B., Zonneveld, R., Tromp, E., & Plotz, F. B. (2017). Association between sepsis calculator and infection parameters for newborns with suspected early onset sepsis. Journal of clinical neonatology, 6(3), 159-162.

  BACKGROUND

• Achten NB, Visser DH, Tromp E, Groot W, van Goudoever JB, Plotz FB. Early onset sepsis calculator implementation is associated with reduced healthcare utilization and financial costs in late preterm and term newborns. Eur J Pediatr. 2020 May;179(5):727-734. doi: 10.1007/s00431-019-03510-9. Epub 2020 Jan 2.

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• Achten NB, Dorigo-Zetsma JW, van Rossum AMC, Oostenbrink R, Plotz FB. Risk-based maternal group B Streptococcus screening strategy is compatible with the implementation of neonatal early-onset sepsis calculator. Clin Exp Pediatr. 2020 Oct;63(10):406-410. doi: 10.3345/cep.2020.00094. Epub 2020 Apr 16.

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• Benitz WE, Achten NB. Finding a role for the neonatal early-onset sepsis risk calculator. EClinicalMedicine. 2020 Jan 26;19:100255. doi: 10.1016/j.eclinm.2019.100255. eCollection 2020 Feb. No abstract available.

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• Benitz WE, Achten NB. Technical assessment of the neonatal early-onset sepsis risk calculator. Lancet Infect Dis. 2021 May;21(5):e134-e140. doi: 10.1016/S1473-3099(20)30490-4. Epub 2020 Oct 29.

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• Achten NB, Plotz FB, Klingenberg C, Stocker M, Bokelaar R, Bijlsma M, Giannoni E, van Rossum AMC, Benitz WE. Stratification of Culture-Proven Early-Onset Sepsis Cases by the Neonatal Early-Onset Sepsis Calculator: An Individual Patient Data Meta-Analysis. J Pediatr. 2021 Jul;234:77-84.e8. doi: 10.1016/j.jpeds.2021.01.065. Epub 2021 Feb 3.

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• Ferrand A, Gorgos A, Ali N, Payot A. Resilience Rather than Medical Factors: How Parents Predict Quality of Life of Their Sick Newborn. J Pediatr. 2018 Sep;200:64-70.e5. doi: 10.1016/j.jpeds.2018.05.025. Epub 2018 Jun 27.

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• NFU (Dutch Federation of University Medical Centers). Richtlijn Kwaliteitsborging Mensgebonden Onderzoek 2020. 2020.

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• Cotten CM. Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016 Apr;28(2):141-9. doi: 10.1097/MOP.0000000000000338.

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• Zven SE, Susi A, Mitre E, Nylund CM. Association Between Use of Multiple Classes of Antibiotic in Infancy and Allergic Disease in Childhood. JAMA Pediatr. 2020 Feb 1;174(2):199-200. doi: 10.1001/jamapediatrics.2019.4794.

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• van Herk W, Stocker M, van Rossum AM. Recognising early onset neonatal sepsis: an essential step in appropriate antimicrobial use. J Infect. 2016 Jul 5;72 Suppl:S77-82. doi: 10.1016/j.jinf.2016.04.026. Epub 2016 May 21.

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• National Institute for Health and Care Excellence. Neonatal infection (early onset): Antibiotics for prevention and treatment. Clinical Guideline. 2012

  BACKGROUND

• van der Weijden BM, Janssen SWCM, van der Weide MC, Cornelisse-van Vugt RJPM, Ten Tusscher GW, Lutterman CAM, Kamps AWA, Lorente Flores CM, Hol J, van Laerhoven H, Rijpert M, Oeij NA, Schiering IAM, Obermann-Borst SA, Visser DH, van Leeuwen LM, Kornelisse RF, van Rossum AMC, Bijlsma MW, Plotz FB, Achten NB. Safety and effectiveness of the early-onset sepsis calculator to reduce antibiotic exposure in at-risk newborns: a cluster-randomised controlled trial. EClinicalMedicine. 2025 Aug 12;87:103419. doi: 10.1016/j.eclinm.2025.103419. eCollection 2025 Sep.

  PMID: 40831464 DERIVED

• van der Weijden BM, van der Weide MC, Plotz FB, Achten NB. Evaluating safety and effectiveness of the early-onset sepsis calculator to reduce antibiotic exposure in Dutch at-risk newborns: a protocol for a cluster randomised controlled trial. BMJ Open. 2023 Feb 14;13(2):e069253. doi: 10.1136/bmjopen-2022-069253.

  PMID: 36787971 DERIVED

Related Links

• Webpage of Zorgevaluatie Nederland, where everybody can find all study-related information, documents and progress.

MeSH Terms

Conditions

Neonatal Sepsis

Condition Hierarchy (Ancestors)

Sepsis; Infections; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Frans B. Plötz, MD, PhD

  Amsterdam UMC, Tergooi Ziekenhuizen

  PRINCIPAL INVESTIGATOR

• Niek B. Achten, MD, PhD

  Erasmus Medical Center

  STUDY DIRECTOR

• Bo M. van der Weijden, MD

  Amsterdam UMC, Tergooi Ziekenhuizen

  STUDY DIRECTOR

Central Study Contacts

Prof. Frans B. Plötz, MD, PhD

CONTACT

+31(0)887531753; fbplotz@tergooi.nl

Bo M. van der Weijden, MD

CONTACT

b.m.vanderweijden@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Hospitals nor physicians are blinded for the assigned study protocol. Since the assigned protocol is considered standard care for newborns with suspected EOS within 0-24 hours after birth during the study period in that hospital, independent of study participation, parents of participants are not blinded as well.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pediatric Health Care Evaluation

Model Details: A prospective, cluster-randomized trial will be conducted; five hospitals will be randomized to NVK guidelines use, five hospitals will be randomized to EOS calculator use. After randomization, the assigned protocol is considered standard care for newborns with suspected EOS within 0-24 hours after birth during the study period in that hospital. This means that the NVK guidelines or the EOS calculator (depending on randomization) will be used for all newborns at risk for EOS (within 0-24 hours after birth) in the assigned hospital, independent of study participation. It is noteworthy that attending physicians have the option to choose for clinical management according to another protocol instead of the assigned protocol.

Study Record Dates

• First Submitted: February 28, 2022
• First Posted: March 10, 2022
• Study Start: April 12, 2022
• Primary Completion: April 1, 2024
• Study Completion: October 1, 2024
• Last Updated: February 1, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share

Locations

NL (10)