Clinical trial NCT05350813: Impact of Procalcitonin-guided Algorithm on Early Discontinuation of Antibiotic Therapy
Official title: Impact of Procalcitonin-guided Algorithm on Early Discontinuation of Antibiotic Therapy in Pediatric Intensive Care Units : a Multicenter Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Bacterial Infections
Keywords: procalcitonin
Children
Pediatric Intensive Care Unit
Procalcitonin-guided antibiotic therapy
Algorithm
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2022-04-28
Enrollment: 296
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: In this randomized controlled open-label trial, conducted in 7 French Pediatric and Neonatal Intensive Care Units (ICUs), investigator team hypothesize that the use of a procalcitonin (PCT)-guided algorithm to discontinue antibiotic treatment will decrease antibiotic duration in critically ill children treated for a suspected or proven bacterial infection. Two hundred and ninety-six eligible patients will be randomly assigned in two groups: either PCT-guided or standard-of-care antibiotic discontinuation, and monitored over 28 days, until the end of their hospitalization, or up to the end of antibiotic treatment for bacterial infection recurrence occurring up to 28 days after the day of randomization.

Detailed description: Infections are widespread in Pediatric and Neonatal ICU, and antibiotic treatments widely used. Long courses of antibiotic treatment increase the duration of hospitalization and are associated with changes in the microbiome, emergence of multidrug resistant organisms, and antibiotic-associated adverse events. In Pediatric and Neonatal ICU, PCT has a high negative predictive value to rule out bacterial infection. Thus, in sepsis patients and patients who initially appear to have sepsis but whose final diagnosis of bacterial infection is not retained, the use of a PCT-guided algorithm may be of value to shorten antibiotic duration without increasing infection recurrences. The algorithm has provided strong evidence of efficacy and safety among critically ill adults, excluding immunocompromised patients, patients with cystic fibrosis, and infections requiring prolonged antibiotic therapy. Similar data in critically ill children are lacking. A Spanish team from Sant Joan de Déu published three prospective non-randomized studies in Pediatric ICU (PICU), with encouraging results. Only one American randomized controlled trial (RCT) has been published in PICU with mixed results. One RCT is ongoing in India. Thus, our study will be the first French RCT to study the use of a PCT-guided algorithm to de-escalate antibiotic therapy in PICU, in order to provide evidence of efficacy and safety of such an algorithm in critically ill children with a suspected or proven bacterial infection. In addition, investigator team will also study the economic impact of a PCT-guided algorithm which has never been done before.

In the PCT-guided arm, PCT dosage will be done at Day 0 (day of randomization) and Day 1, and then every 48 hours until cessation of antibiotics in hospital or discharge from hospital if the patient is discharged with an antibiotic treatment. Antibiotic treatment will be stopped according to PCT value and patient clinical evolution. In the control group, antibiotic duration will be determined by usual practices based on guidelines. Inpatient evaluations will be conducted every day so long as patients receives antibiotics in hospital and usual clinical, biological and/or radiological monitoring will be conducted in both groups. To monitor infection recurrence occurring up to 28 days after the day of randomization and antibiotic-related adverse events, an evaluation will be conducted at the end of hospitalization, another at Day 28 (Day 0 = day of randomization), and a last at the end of antibiotic treatment bacterial infection recurrence, if the patient is discharged from hospital on or before Day 28 and is still treated with antibiotics for a bacterial infection recurrence at Day 28, or if the patient is discharged from hospital after Day 28 and is still treated for recurrence on the last day of hospitalization with antibiotics for a bacterial infection recurrence.

Eligibility criteria: Inclusion Criteria:

* Neonates, infants and children hospitalized in Pediatric and Neonatal ICU and receiving intravenous antibiotics for less than 24 hours for an episode of suspected or proven community-acquired or nosocomial bacterial infection.
* Written informed consent signed by both parents or legal guardians.
* Affiliated to a social security scheme.
* Parents French-speaking.

Exclusion Criteria:

* Newborns \<72 hours old.
* Neonates \<37 weeks postmenstrual age.
* Age ≥18 years.
* Pregnant or breastfeeding women.
* Patients with cystic fibrosis.
* Immunocompromised patients including patients with hereditary immunodeficiency, agranulocytosis (neutrophils count \<500/mm3), HIV infection with CD4 count \<200/mm3, sickle cell disease, those who have undergone splenectomy, those who have a history of solid organ or hematopoietic stem cell transplant, those with hemopathy or solid organ tumor treated with chemotherapy, and those on immunosuppressive drugs including systemic corticosteroids taken daily for at least 15 days prior to Day 0.
* Inflammatory situations increasing PCT plasma concentrations in the absence of infection: burns, extracorporeal membrane oxygenation (ECMO), first 48 hours following an open-heart cardiac surgery with cardiopulmonary bypass.
* Infections requiring prolonged antibiotic therapy: infected thrombophlebitis, infective endocarditis, mediastinitis, abscess or empyema (e.g. peritonsillar abscess, retropharyngeal abscess, adenophlegmon, retroauricular abscess, retroorbital abscess, pulmonary abscess, pleural empyema, liver abscess, splenic abscess, brain abscess, subdural empyema, extradural empyema, epidural abscess, intramuscular abscess), necrotizing dermohypodermitis or necrotizing fasciitis, osteomyelitis, osteitis, arthritis, spondylodiscitis, prostatitis, tuberculosis, meningitis except those caused by Haemophilus and Meningococcus, infection on a device excluding intravascular catheter, endotracheal tube, tracheostomy, and urinary catheter.
* Antibiotic for prophylaxis.
* Children previously included in an interventional study in progress.

Primary outcomes:
measure: Total duration of antibiotic therapy (in days) for a suspected or proven bacterial infection, including the first episode and recurrences occurring within 28 days following the day of randomization
timeFrame: month 3 (maximum follow-up period of 3 months)
Secondary outcomes:
measure: Total duration of broad-spectrum antibiotic therapy in days) for a suspected or proven bacterial infection, including the first episode and recurrences
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Length of Intensive Care Unit stay (in days) from Day 0 (day of randomization)
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Length of hospital stay from Day 0 (day of randomization)
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Recurrence of bacterial infection within 28 days following the day of randomization
timeFrame: day 28
measure: All cause mortality at Day 28 (Day 0 = day of randomization)
timeFrame: day 28
measure: All cause mortality at the end of antibiotic treatment for bacterial infection recurrence (if ending after Day 28)
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Sepsis-related mortality at Day 28 (Day 0 = day of randomization)
timeFrame: day 28
measure: Sepsis-related mortality at the end of antibiotic treatment for bacterial infection recurrence (if ending after Day 28).
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Antibiotic-related adverse events
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Adherence to the PCT-guided algorithm
timeFrame: month 3 (maximum follow-up period of 3 months)
measure: Incremental cost-effectiveness ratios
timeFrame: month 3
measure: Costs of antibiotic therapy and PCT testing during each inpatient stay
timeFrame: month 3
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens Picardie
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Clermont-Ferrand
country: France
facility: CHU de Clermont Ferrand
city: Nantes
country: France
facility: CHU de NANTES
city: Paris
country: France
facility: APHP
city: Saint-Denis
country: France
facility: CHU La Réunion
city: Toulouse
country: France
facility: University Hospital of Toulouse
Study officials:
affiliation: University Hospital of Toulouse
name: Romain AMADIEU, MD
role: PRINCIPAL_INVESTIGATOR
References: