PRIMARY* To demonstrate the non-inferiority of intravenous-to-oral antibiotic switch therapy in clinically stable neonates with probable bacterial infection compared to a complete course of intravenous antibiotic therapySECONDARY* To describe the…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Bacterial (re)-infection within 28 days after finishing of antimicrobial
therapy ((defined as clinical signs and symptoms of bacterial infection and
fever (> 38.0 deg C) or undertemperature (< 36.0 deg C) and elevated
inflammatory parameters (CRP, PCT) and need for prolonged (> 48 h) antibiotic
treatment)).
Secondary outcome
* duration of hospitalization
* percentage re-admission
* total costs and cost-effectiveness
* clinical side effects of antibiotics
* pharmacokinetic profile of oral amoxicillin
* pharmacokinetic profile of oral clavulanic acid
* quality of life (painful procedures; breastfeeding; sleep quality;
gastro-intestinal symptoms; parental satisfaction)
* nosocomial infections
* gut microbial flora profile and antimicrobial resistance genes
Background summary
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 objective
PRIMARY
* To demonstrate the non-inferiority of intravenous-to-oral antibiotic switch
therapy in clinically stable neonates with probable bacterial infection
compared to a complete course of intravenous antibiotic therapy
SECONDARY
* To describe the pharmacokinetics of oral amoxicillin/clavulanic acid in
neonates
* To quantify the cost-effectiveness of oral antimicrobial switch therapy in
neonates
* To study antimicrobial resistance and modification of the gut microbiome in
relation to type and delivery of antibiotics.
Study design
Multicenter prospective randomized controlled non-inferiority trial.
Intervention
After informed consent has been obtained, the neonate will be allocated by a
web-based randomisation tool to:
1. continue intravenous antimicrobial therapy (broad-spectrum, preferably
according to the national protocol)
or
2. oral switch therapy to amoxicillin/clavulanic acid 4:1 suspension 25 mg/kg
t.i.d..
Study burden and risks
If oral switch therapy in neonates is effective and safe, the implementation
will have huge effects neonatal well-being (iv-drip cannulas do not need to be
replaced), mother to child binding, and will finally also have huge effects on
costs (saving 3-6 admission days per neonate). Safety is important; the risks
will be minimalized by identification of subjects without risk factors and
close follow-up. Moreover, serum levels of antibiotics will be measured.
Painful procedures in the experimental group will be prevented as much as
possible and do in general not exceed the number of painful procedures in the
control group (1-2 x serum level of antibiotics vs. regular need for new
iv-cannula*s).
Kleiweg 500
Rotterdam 3045 PM
NL
Kleiweg 500
Rotterdam 3045 PM
NL
Listed location countries
Age
Inclusion criteria
Neonates, * 35+0 weeks of gestation, 0-28 days old, * 2.0 kg. ;* probable bacterial infection (clinical symptoms and/or maternal risk factors and elevated inflammatory parameters (elevated CRP and/or elevated PCT according to age-related normogram7) for which empiric broad-spectrum antimicrobial treatment was initiated and needs to be continued for > 48 hours at the discretion of the treating physician
* reassuring level and trends of inflammatory parameters 48-72 hours after initiation of antimicrobial treatment
* clinically stable
* tolerates oral feeding and/or liquids without overt vomiting
* written informed consent of parents or legal representatives;For the specific PK-study, neonates also can participate when they fulfill the inclusion criteria and are given oral amoxicillin/clavulanic acid not for this specific trial but for another reason.
Exclusion criteria
* proven bloodstream infection
* absence of blood culture (i.e. no blood culture taken)
* severe localized infection such as meningitis, osteomyelitis, necrotizing enterocolitis (except pneumonia and urinary tract infection)
* severe clinical sepsis on admission (compromised circulation; need for mechanical ventilation)
* known (maternal) colonization with resistant bacteria such as MRSA, ESBL-producing bacteria
* continuous need for central venous line (umbilical venous catheter, PICC)
* severe hyperbilirubinaemia with need for phototherapy
* clinicians* decision to continue with intravenous antibiotics because of other reasons
* parents* inability to administer medication because of social reasons or language difficulties
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004447-36-NL |
| ClinicalTrials.gov | NCT03247920 |
| CCMO | NL51888.078.16 |