Reduction of Intravenous Antibiotics In Neonates

Study Overview
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Brief Summary
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Randomized controlled open-label non-inferiority trial comparing complete intravenous antibiotic treatment with a short iv. course followed by oral antibiotics in neonates (0-28 days) with probable bacterial infection. Primary outcome: - Bacterial re-infection within 28 days after finishing of antibacterial therapy. Secondary outcome(s): Pharmacokinetic profile of oral amoxicillin/clavulanic acid Quality of life Cost-effectiveness Alterations in gut microbiome Use of molecular techniques for better detection of bacterial pathogens

Detailed Description
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Neonates have a high antibiotic consumption because of their susceptibility for bacterial infections. Since the early diagnosis of bacterial infection in neonates is difficult, intravenous broad-spectrum antimicrobial therapy is usually started promptly after subtle symptoms. The majority of neonates become asymptomatic shortly after initiation; when infection is probable or proven by elevated inflammatory markers and/or a positive blood culture, intravenous antibiotics are administered for at least 7 days. However, for neonates blood culture has a limited sensitivity. Therefore, the majority of neonates with probable infection are treated for a prolonged time with intravenous broad-spectrum antimicrobial therapy. In older children, intravenous antibiotics are often changed to oral antibiotics after cessation of symptoms and decreasing inflammatory parameters. This is not yet widely practised in neonates because of uncertainties in pharmacokinetics. Two explorative small studies from France and Italy into neonatal antibiotic switch therapy suggest that follow-up treatment with an oral antibiotic is promising; but the non-inferiority and safety was not yet properly addressed. Neonatal switch therapy, if proven to be safe and efficacious, would have a major impact on neonatal well-being, mother-to-child bonding and moreover costs.

Official Title
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Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness

Conditions
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Neonatal Infection, Neonatal SEPSIS

Intervention / Treatment
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* Drug: Amoxicillin Clavulanate
* Drug: Antibiotics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates (≥ 35+0 weeks, 0-28 days old, ≥ 2 kg) Probable bacterial infection defined as clinical symptoms and/or maternal risk factors and elevated inflammatory markers for which empiric broad-spectrum antibiotic treatment was initiated and needs to be continued for > 48 hours Clinically well Toleration of oral feeding without overt vomiting Signed informed consent Exclusion Criteria: Proven bloodstream infection Absence of blood culture Severe localized infection (meningitis, osteomyelitis, necrotizing enterocolitis) Severe clinical sepsis (compromised circulation, need for mechanical ventilation) Continuous need for a central venous line Severe hyperbilirubinemia exceeding the exchange level Parents inability to administer medication Major congenital or syndromic anomalies

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 28 Days

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: Multicenter prospective randomized controlled non-inferiority trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral group<br>After 48 hours of intravenous antibiotics eligible neonates will switch to amoxicillin/clavulanic acid suspension for the remaining 5 days. When the oral suspension is well tolerated neonates can be discharged from hospital. In order to investigate the pharmacokinetic profile of oral amoxicillin/clavulanic acid serum levels will be measured. | Drug: Amoxicillin Clavulanate<br>* Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1<br>|
| Active Comparator: Intravenous group<br>Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol. | Drug: Antibiotics<br>* Intravenous antibiotic therapy following local protocol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation) |  | 0-35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospitalization |  | 0-35 days after birth | 
| Percentage of re-admission |  | 0-35 days after birth | 
| Total costs and cost-effectiveness | Cost-effectiveness of intravenous to oral switch compared to a full course of antibiotics + possible extra costs due to early antibiotic switch | 0-35 days after birth | 
| Difference in Quality of Life between oral and intravenous antibiotic treatment | Two questionnaires on day 7 and 21 after admission, filled in by both parents. Data will be provided in a descriptive manner as no validated QoL questionnaires exist for neonates. | 0-35 days after birth | 
| Time above MIC (T>MIC) of oral amoxicillin. | 2 blood samples after administration of antibiotic suspension at different time points will be taken. Time above MIC (T>MIC) will be defined. Target MIC is 8 mg/liter. | 0-7 days | 
| Time above MIC (T>MIC) of oral clavulanic acid. | 2 blood samples after administration of antibiotic suspension at different time points will be taken. Time above MIC (T>MIC) will be defined. Target MIC is 8 mg/liter. | 0-7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibiotic switch therapy, Amoxicillin/clavulanic acid