Reduction of Intravenous Antibiotics In Neonates

Conditions

Neonatal Infection, Neonatal SEPSIS

Keywords

Antibiotic switch therapy, Amoxicillin/clavulanic acid

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.

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.

2022-09-0925 citations

10.1016/s2352-4642(22)00245-0

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

Fleur M. Keij, René F. Kornelisse, Nico G. Hartwig, Katya Mauff, Marten J. Poley et al. (8 authors)

BMJ Open2019-07-0111 citations

10.1136/bmjopen-2018-026688

P49 A pharmacokinetic evaluation of oral clavulanic acid in term newborns

FM Keij, RF Kornelisse, NG Hartwig, J van der Sluijs, Arianne van Driel et al. (12 authors)

Archives of Disease in Childhood2019-05-17

10.1136/archdischild-2019-esdppp.87

Interventions

DRUGAmoxicillin Clavulanate

Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1

DRUGAntibiotics

Intravenous antibiotic therapy following local protocol

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Outcomes Assessor)

Intervention model description

Multicenter prospective randomized controlled non-inferiority trial

Eligibility

Sex/Gender

ALL

Age

1 Days to 28 Days

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

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Percentage of re-admission	0-35 days after birth	—
Total costs and cost-effectiveness	0-35 days after birth	Cost-effectiveness of intravenous to oral switch compared to a full course of antibiotics + possible extra costs due to early antibiotic switch
Duration of hospitalization	0-35 days after birth	—
Time above MIC (T>MIC) of oral amoxicillin.	0-7 days	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.
Time above MIC (T>MIC) of oral clavulanic acid.	0-7 days	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.
Difference in Quality of Life between oral and intravenous antibiotic treatment	0-35 days after birth	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.

Countries

Netherlands

Outcome results

None listed