Reduction of Intravenous Antibiotics In Neonates (RAIN)

Franciscus Gasthuis

Status and phase: Completed; Phase 4

Conditions: Neonatal Infection; Neonatal SEPSIS

Treatments: Drug: Amoxicillin Clavulanate; Drug: Antibiotics

Study type: Interventional

Funder types: Other

Identifiers

NCT03247920

RAIN

Details and patient eligibility

About

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

Full 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.

Enrollment: 510 patients

Sex: All

Ages: 1 to 28 days old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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510 participants in 2 patient groups

Oral group

Active Comparator group

Description:

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.

Treatment:

Drug: Amoxicillin Clavulanate

Intravenous group

Active Comparator group

Description:

Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol.

Treatment:

Drug: Antibiotics