Clinical trial NCT03247920: Reduction of Intravenous Antibiotics In Neonates
Official title: Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Neonatal Infection
Neonatal SEPSIS
Keywords: Antibiotic switch therapy
Amoxicillin/clavulanic acid
Lead sponsor: Franciscus Gasthuis
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
First posted: 2017-08-14
Enrollment: 510
Sex: ALL
Minimum age (years): 1
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter prospective randomized controlled non-inferiority trial
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
timeFrame: 0-35 days
Secondary outcomes:
measure: Duration of hospitalization
timeFrame: 0-35 days after birth
measure: Percentage of re-admission
timeFrame: 0-35 days after birth
measure: Total costs and cost-effectiveness
timeFrame: 0-35 days after birth
measure: Difference in Quality of Life between oral and intravenous antibiotic treatment
timeFrame: 0-35 days after birth
measure: Time above MIC (T>MIC) of oral amoxicillin.
timeFrame: 0-7 days
measure: Time above MIC (T>MIC) of oral clavulanic acid.
timeFrame: 0-7 days
Other outcomes:
Locations:
city: Amersfoort
country: Netherlands
facility: Meander Medical Center
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Capelle Aan Den IJssel
country: Netherlands
facility: IJsselland Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medical Center
city: Den Haag
country: Netherlands
facility: Juliana Kinderziekenhuis-Haga Hospital
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC-Sophia Children's Hospital
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Maasstad Hospital
city: Schiedam
country: Netherlands
facility: Franciscus Vlietland
city: Veldhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Zwolle
country: Netherlands
facility: Isala
Study officials:
affiliation: Franciscus Gasthuis & Vlietland
name: Gerdien Tramper
role: PRINCIPAL_INVESTIGATOR
References:
citation: Keij FM, Kornelisse RF, Hartwig NG, van der Sluijs-Bens J, van Beek RHT, van Driel A, van Rooij LGM, van Dalen-Vink I, Driessen GJA, Kenter S, von Lindern JS, Eijkemans M, Stam-Stigter GM, Qi H, van den Berg MM, Baartmans MGA, van der Meer-Kappelle LH, Meijssen CB, Norbruis OF, Heidema J, van Rossem MC, den Butter PCP, Allegaert K, Reiss IKM, Tramper-Stranders GA. Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial. Lancet Child Adolesc Health. 2022 Nov;6(11):799-809. doi: 10.1016/S2352-4642(22)00245-0. Epub 2022 Sep 9.
citation: Keij FM, Kornelisse RF, Hartwig NG, Mauff K, Poley MJ, Allegaert K, Reiss IKM, Tramper-Stranders GA. RAIN study: a protocol for a randomised controlled trial evaluating efficacy, safety and cost-effectiveness of intravenous-to-oral antibiotic switch therapy in neonates with a probable bacterial infection. BMJ Open. 2019 Jul 9;9(7):e026688. doi: 10.1136/bmjopen-2018-026688.