Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Enrollment
- 510
- Locations
- 18
- Primary Endpoint
- Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 1 Day to 28 Days (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Oral group
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.
Intervention: Amoxicillin Clavulanate (Drug)
Intravenous group
Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol.
Intervention: Antibiotics (Drug)
Outcomes
Primary Outcomes
Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
Time Frame: 0-35 days
Secondary Outcomes
- Difference in Quality of Life between oral and intravenous antibiotic treatment(0-35 days after birth)
- Duration of hospitalization(0-35 days after birth)
- Percentage of re-admission(0-35 days after birth)
- Time above MIC (T>MIC) of oral amoxicillin.(0-7 days)
- Time above MIC (T>MIC) of oral clavulanic acid.(0-7 days)
- Total costs and cost-effectiveness(0-35 days after birth)
Investigators
Gerdien Tramper
Principal investigator, MD, PhD
Franciscus Gasthuis