Individualized Duration of Antibiotic Treatment in Early Onset Infection in Newborns.

Study Overview
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Brief Summary
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A nationwide multicenter open label randomized controlled non-inferiority trial, including 18 departments. The study aims to compare an individualized antibiotic treatment duration with standard seven days of antibiotic treatment for culture negative early-onset infection in term newborns.

Detailed Description
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There is a documented antibiotic overuse in newborns, and a lack of evidence for the optimal duration of antibiotic therapy in culture-negative infection. The study aims to evaluate the effect of individualized treatment duration in early-onset infection. The study aims to compare an individualized treatment duration with seven days of treatment for culture negative early-onset infection. The investigators hypothesize that the individualized treatment duration, based on structured clinical assessment of symptoms and level of CRP is non-inferior to the standard care being seven days of treatment. In the experimental treatment arm, antibiotics will be stopped when the participant had 24 hours without symptoms and at same time point have decreasing level of CRP, with an absolute threshold of CRP ≤ 30 mg/l. The investigators hypothesize that individualized treatment will shorten the duration of antibiotic therapy in newborns with early onset infection with very little risk of relapse. Newborns who fulfill criteria to stop antibiotics within 48 hours will not be eligible for inclusion.

Official Title
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Individualized Duration of Antibiotic Treatment in Culture Negative Early Onset Infection in Term Born Newborns: A Nationwide Randomized Controlled Non-inferiority Trial.

Conditions
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Early-Onset Neonatal Sepsis, Antibiotic Side Effect

Intervention / Treatment
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* Other: Individualized treatment duration strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age ≥ 35 weeks Birth weight ≥ 2000 Probable or possible infection according to the structured infection risk assessment Sufficient size blood culture, preferably 0.5-1 ml, but at least 0.2 ml, drawn after onset of symptoms but before start of antibiotic treatment Negative blood culture after 48 hours Exclusion Criteria: Infants with positive blood culture Blood culture volume prior to antibiotics of < 0.2 ml Site-specific infection as for example, meningitis or osteomyelitis Infant fulfill current recommendation to stop antibiotic treatment at 36-48 hours; Low suspicion of sepsis initially including few and vague symptoms, CRP maximum 35-50 mg/l, negative blood culture and no symptoms after 48 hours of treatment

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 72 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a nationwide multicenter open label non-inferiority pragmatic randomized controlled trial. Patients will be randomized 1:1 to experimental treatment duration or standard care. Patients will be stratified based on if maximum CRP level is above or below 90 mg/l.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized treatment duration<br>Antibiotic treatment will be discontinued when both of the following two criteria are fulfilled: The infant has had 24 hours without clinical symptoms of infection, after systematic clinical evaluation by a neonatologist. Clinical symptoms specified in Table 1. CRP is < 30 mg/l. If CRP is > 30 at the time when the infant has been symptom-free for 24 hours, CRP will be assessed once every 24 -48 hours and antibiotics will be stopped when CRP < 30. | Other: Individualized treatment duration strategy<br>* As listed under arm description.<br>|
| No Intervention: Standard treatment duration<br>Standard treatment duration is seven days. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Readmission due to infection. | Readmission due to infection, defined as symptoms, affected biomarkers and antibiotic treatment > 72 hours | From 1-21 days after end of first course of antibiotic treatment. | 
| Death | Death of any cause | From 1-21 days after end of first course of antibiotic treatment. | 
| Total use of antibiotics | Use of antibiotics (in hours) | From initiation of antibiotics and the next 28 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-reactive protein (CRP) | CRP (mg/l) levels at follow-up | CRP measured at follow-up 2 days after initial antibiotic treatment ended | 
| Readmission due to infection within 3 months | Readmission due to infection, defined as symptoms, affected biomarkers and antibiotic treatment > 72 hours | From 1-100 days after first course of antibiotics ended. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neonatal, early-onset, infection, antibiotic