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

January 31, 2024 updated by: prof. dr. Frans B. Plötz

Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator: a Cluster Randomized Study (EOS Calculator RCT)

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. 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. 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.

Secondary objectives of the study are:

  1. To investigate if the use of the EOS calculator decreases the total duration of antibiotic therapy in newborns with suspected EOS.
  2. 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.
  3. To study the impact of (suspected) EOS on parents/guardians.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Suspicion of EOS is often based on risk factors and nonspecific clinical symptoms, such as maternal fever during labor or rapid breathing in the newborn. The combination of the difficulty to recognize EOS in time and the risk of serious consequences of EOS not treated timely has resulted in a low threshold for the start of empirical antibiotic therapy. This has led to significant overtreatment.

The current standard of care in the Netherlands is the Dutch Society of the Nederlands (NVK) guideline "Prevention and treatment of early-onset neonatal infections", which is an adaptation of the 2012 version of the National Institute for Health and Care Excellence (NICE) guideline "Antibiotics for early-onset neonatal infection: antibiotics for the prevention and treatment of early-onset neonatal infection". The NVK guideline uses risk factors and symptoms to categorically indicate which newborns need antibiotic therapy. Evaluating its use in 9 Dutch hospitals, limited adherence was found, especially when antibiotics were recommended by the guideline but withheld by the clinicians. This limited adherence indicates that it is desirable to amend the current guideline or to investigate the use of an alternative method.

A new method for determining which newborns need antibiotic therapy is the "EOS calculator". Developed in the United States, this method uses a combination of detailed information about 5 maternal risk factors and the presence of clinical neonatal symptoms to calculate an individual EOS risk and treatment advice.

For the Dutch situation, equipoise between the current NVK guideline and the EOS calculator can be established given balance of risk for both over- and undertreatment of EOS for both strategies. A large body of evidence now supports the safety of the EOS calculator approach, but validation outside of the North-American setting is limited, especially for safety outcomes.

A prospective cluster-randomized Dutch validation study of the EOS calculator is needed before implementation because of the following reasons:

  1. Multicenter validation of actual EOS calculator use has not been performed in the Netherlands.
  2. To date, no randomized prospective study of EOS calculator use with safety as an outcome measure has been performed. Specifically, there are no studies that take into account the potential effects of a treatment delay due to EOS calculator use. This especially holds true for cases that are clinically suspect for EOS, but not culture-confirmed.

Study Type

Interventional

Enrollment (Estimated)

1830

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Prof. Frans B. Plötz, MD, PhD
  • Phone Number: +31(0)887531753
  • Email: fbplotz@tergooi.nl

Study Contact Backup

Study Locations

  • Netherlands
      • Alkmaar, Netherlands
        • Recruiting
        • Northwest Clinics
      • Almere, Netherlands
        • Recruiting
        • FlevoHospital
      • Amstelveen, Netherlands
        • Recruiting
        • Amstelland Hospital
      • Amsterdam, Netherlands
        • Recruiting
        • OLVG
      • Groningen, Netherlands
        • Recruiting
        • Martini Hospital
      • Haarlem, Netherlands
        • Recruiting
        • Spaarne Hospital
      • Hoorn, Netherlands
        • Recruiting
        • Dijklander Hospital
      • Nijmegen, Netherlands
        • Recruiting
        • Canisius-Wilhelmina Hospital
      • Veldhoven, Netherlands
        • Recruiting
        • Maxima Medical Center
      • Zaandam, Netherlands
        • Recruiting
        • Zaans Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 day (Child)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: NVK Guidelines
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.
Experimental: EOS Calculator
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
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.
Other Names:
  • early-onset sepsis calculator
  • neonatal early-onset sepsis calculator
  • sepsis risk calculator (SRC)
  • newborn sepsis calculator
  • neonatal EOS calculator

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Co-primary superiority outcome: antibiotic therapy started within 24 hours after birth
Time Frame: 0-24 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
Time Frame: 0-14 days after birth

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
Time Frame: 0-14 days after birth
- 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
Time Frame: 0-14 days after birth
0-14 days after birth
Fourth co-primary non-inferiority outcome (safety): proportion of patients with proven EOS
Time Frame: 0-14 days after birth
- 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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of antibiotic therapy
Time Frame: 0-14 days after birth
The total duration of antibiotic therapy: date and time of first administration of intravenous antibiotic therapy, and date and time of the last administration of intravenous antibiotic therapy.
0-14 days after birth
Antibiotic therapy started between 24-72 hours after birth
Time Frame: 24-72 hours after birth
The proportion of antibiotic therapy started for suspected and, or proven EOS if symptoms started between 24-72 hours after birth.
24-72 hours after birth
Questionnaire: quality of life
Time Frame: 14-28 days after birth
To get an impression of the impact of (suspected) early-onset sepsis on the quality of life (QoL) of both parents/guardians and their child, parents/guardians will be asked to fill in a questionnaire on day 14 after birth. The first part collects information on medical factors after hospitalization (side effects, number of medical visits, readmission, and medication use) and basic needs of the newborn (sleep quality of the patient, (breast)feeding success rate). The second part addresses the subjective parental/guardian evaluation of the impact of newborns' admission, and parental/guardian projection of future QoL of their newborn. Statements with six possible answers will be used: 'not at all, a little, on average, more than average, a lot, not applicable' or 'poor, fair, good, very good, excellent, not applicable'. Participants will not score on a numbered scale but tick the answer (in text) that apply best. The last part of the questionnaire collects demographic data.
14-28 days after birth

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

prof. dr. Frans B. Plötz

Collaborators

Dutch Society of Pediatrics
Zorgevaluatie Nederland
Care4Neo
everywhereIM

Investigators

  • Principal Investigator: Frans B. Plötz, MD, PhD, Amsterdam UMC, Tergooi Ziekenhuizen
  • Study Director: Bo M. van der Weijden, MD, Amsterdam UMC, Tergooi Ziekenhuizen
  • Study Director: Niek B. Achten, MD, PhD, Erasmus Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 12, 2022

Primary Completion (Estimated)

April 1, 2024

Study Completion (Estimated)

October 1, 2024

Study Registration Dates

First Submitted

February 28, 2022

First Submitted That Met QC Criteria

March 9, 2022

First Posted (Actual)

March 10, 2022

Study Record Updates

Last Update Posted (Actual)

February 1, 2024

Last Update Submitted That Met QC Criteria

January 31, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL78203.018.21

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be made available on request through a repository and shared after consent of the principal investigator.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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