PRODISCO: Impact of an Algorithm on the Duration of Antibiotic Therapy in Pediatric Intensive Care Units

Sponsor

University Hospital, Toulouse (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05350813

Collaborator

(none)

296

Enrollment

Location

Arms

Anticipated Duration (Months)

14.1

Patients Per Site Per Month

Study Details

Study Description

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 and until the end of their hospitalization.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Infections	Procedure: Measurement of the PCL plasma levels Procedure: Usual practice based on guidelines	N/A

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 group, 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. 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. An evaluation will be conducted at the end of hospitalization and another at Day 28 (Day 0 = day of randomization), to monitor infection recurrence and antibiotic-related adverse events.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

296 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Impact of Procalcitonin-guided Algorithm on Early Discontinuation of Antibiotic Therapy in Pediatric Intensive Care Units : a Multicenter Randomized Controlled Trial

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PCT-guided arm Group of patients whose duration of antibiotic therapy will depend on the level of procalcitonin (PCT) in plasma on days 0 and 1, then on the plasma PCT level every 48 hours and on the pSOFA (Pediatric Sequential Organ Failure Assessment) score every day until antibiotics are stopped in hospital or until discharge if the patient is discharged with an antibiotic treatment.	Procedure: Measurement of the PCL plasma levels antibiotic treatment duration will be based on PCT plasma levels
Active Comparator: standard-of-care A group of patients whose duration of antibiotic therapy will be determined by the type of infection, microbiological findings and clinical, biological and/or radiological course, according to standard practice based on guidelines.	Procedure: Usual practice based on guidelines antibiotic therapy duration will be determined by the type of infection, microbiological results and clinical, biological and/or radiological evolution, according to the usual practice based on guidelines.

Arm

Intervention/Treatment

Experimental: PCT-guided arm

Group of patients whose duration of antibiotic therapy will depend on the level of procalcitonin (PCT) in plasma on days 0 and 1, then on the plasma PCT level every 48 hours and on the pSOFA (Pediatric Sequential Organ Failure Assessment) score every day until antibiotics are stopped in hospital or until discharge if the patient is discharged with an antibiotic treatment.

Procedure: Measurement of the PCL plasma levels

antibiotic treatment duration will be based on PCT plasma levels

Active Comparator: standard-of-care

A group of patients whose duration of antibiotic therapy will be determined by the type of infection, microbiological findings and clinical, biological and/or radiological course, according to standard practice based on guidelines.

Procedure: Usual practice based on guidelines

antibiotic therapy duration will be determined by the type of infection, microbiological results and clinical, biological and/or radiological evolution, according to the usual practice based on guidelines.

Outcome Measures

Primary Outcome Measures

The duration of antibiotic therapy (in days) for a suspected or proven bacterial infection, including the first episode and any recurrences [month 3 (maximum follow-up period of 3 months)]
The duration of antibiotic therapy (in days) for a suspected or proven bacterial infection, including the first episode and any recurrences

Secondary Outcome Measures

The duration of broad-spectrum antibiotic therapy in days) for a suspected or proven bacterial infection, including the first episode and recurrences [month 3 (maximum follow-up period of 3 months)]
duration of broad-spectrum antibiotic therapy in days) for a suspected or proven bacterial infection, including the first episode and recurrences
Length of Intensive Care Unit stay (in days) from Day 0 [month 3 (maximum follow-up period of 3 months)]
Length of Intensive Care Unit stay (in days) from Day 0
Length of hospital stay from Day 0 (day of randomization) [month 3 (maximum follow-up period of 3 months)]
Length of hospital stay from Day 0 (day of randomization)
Recurrence of bacterial infection within 28 days following the day of randomization [day 28]
Recurrence of bacterial infection within 28 days following the day of randomization
All cause mortality at Day 28 [day 28]
All cause mortality at Day 28
All cause mortality at the end of antibiotic treatment for bacterial infection recurrence (if ending after Day 28) [month 3 (maximum follow-up period of 3 months)]
All cause mortality at the end of antibiotic treatment for bacterial infection recurrence (if ending after Day 28)
Sepsis-related mortality at Day 28 [day 28]
Sepsis-related mortality at Day 28
Sepsis-related mortality at the end of antibiotic treatment for bacterial infection recurrence (if ending after Day 28). [month 3 (maximum follow-up period of 3 months)]
Sepsis-related mortality at the end of antibiotic treatment for bacterial infection recurrence (if ending after Day 28).
Antibiotic-related adverse events [month 3 (maximum follow-up period of 3 months)]
Antibiotic-related adverse events
Adherence to the PCT-guided algorithm [month 3 (maximum follow-up period of 3 months)]
This outcome can be evaluated by a stop of antibiotics within 24 hours after reaching stopping criteria : - Before Day 3: PCT levels at Day 0 and Day 1 less than 0.5 ng/mL.; - Starting Day 3: PCT level less than 0.5 ng/mL or down by ≥80% from the peak value since Day 0 AND favorable patient clinical course (defined by a decrease in pSOFA score compared to maximal value at Day 0 or Day 1, a reduction of fever and an improvement of the infected organ). - Or if the antibiotic duration, as defined by current infectious guidelines, is reached and the patient shows a favorable course, even if PCT is still ≥0.5 ng/mL or >20% of the peak value
Incremental cost-effectiveness ratios [month 3]
This outcome is expressed in terms of hospital costs per number of patients without recurrent bacterial infection at 3 months and hospital costs per number of patients alive at 3 months
unit quantity costs of antibiotic therapy and PCT testing during each inpatient stay [month 3]
unit quantity costs of antibiotic therapy and PCT testing during each inpatient stay

Eligibility Criteria

Criteria

Ages Eligible for Study:

38 Weeks to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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, 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.