Clinical trial NCT06743529: Immediate Versus Substantiated Antibiotic Therapy in Suspected Non-Severe Ventilator-Associated Pneumonia
Official title: Immediate Versus Substantiated Antibiotic Therapy in Suspected Non-Severe Ventilator-Associated Pneumonia: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Ventilator-Associated Pneumonia (VAP)
Keywords: Intensive care medicine
Intensive care
Ventilator-associated pneumonia
antibiotic sparing
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
First posted: 2024-12-20
Enrollment: 686
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Ventilator-associated pneumonia is the leading nosocomial infection in the intensive care units, and is associated with prolonged mechanical ventilation and overuse of antibiotics. Initiating antibiotic therapy immediately after bacteriological sampling (immediate strategy) may expose uninfected patients to unnecessary treatment, while waiting for bacteriological confirmation (conservative strategy) may delay ventilator-associated pneumonia in infected patients.

The decision to start antibiotic therapy for ventilator-associated pneumonia takes three points into account: diagnostic probability, the risks to the patient if Antibiotic Therapy is delayed, and the risk of selection of resistant bacteria. Diagnostic probability is limited, given the subjective and non-specific nature of the diagnostic criteria, and only 30-50% of suspected cases are confirmed bacteriologically (whereas samples are only taken when the pre-test probability is sufficient). The risks associated with delayed antibiotic therapy are unknown, as few observational studies have directly assessed the impact of the timing of Antibiotic Therapy initiation on outcome (frequent confusion between delayed and inappropriate Antibiotic Therapy).

Iregui et al. found that delaying Antibiotic Therapy by more than 24 hours was associated with higher mortality. However, more recent before-and-after studies have shown that the conservative strategy was associated with lower mortality, more frequently appropriate initial Antibiotic Therapy and shorter duration of Antibiotic Therapy. Similarly, in a recent before-and-after study by our team, initiating antibiotic therapy only upon microbiological confirmation of ventilator-associated pneumonia without septic shock or severe acute respiratory distress syndrome was not associated with an increase in ventilation time, length of stay or excess mortality at D28; but was associated with antibiotic therapy that was more often appropriate (DELAVAP, MARTIN et al, Annals of Intensive Care, 2024). Finally, the recent multicenter TARPP pilot study in surgical intensive care suggests that antibiotic therapy initiated on the basis of microbiological data in patients with suspected ventilator-associated pneumonia not requiring vasopressor support is not associated with a poorer outcome than immediate antibiotic therapy without documentation (the only randomized study on this subject).

Antibiotic Therapy for suspected ventilator-associated pneumonia that is not subsequently confirmed is an unnecessary use of antibiotics and carries a risk of selection of resistant bacteria, with adverse effects on public health. It has been reported that a conservative Antibiotic Therapy prescription strategy for intensive care units -acquired infections reduces Antibiotic Therapy use and the incidence of acquired β-lactamase-producing Enterobacteriaceae infections.

Overall, in patients with suspected ventilator-associated pneumonia but no signs of clinical severity, given the uncertainty about attributable mortality and concerns about bacterial resistance, the evaluation of the conservative Antibiotic Therapy strategy is reasonable. Some French intensive care units already delay Antibiotic Therapy until confirmation of ventilator-associated pneumonia, except in patients with severe hypoxemia or the need for vasopressor support.


Eligibility criteria: Inclusion Criteria:

* Invasive mechanical ventilation for longer than 48 hours
* Respiratory sampling (method at the physician's discretion, according to local protocol) for a first episode of suspected ventilator-associated pneumonia (meeting the prespecified criteria)
* Age ≥18 years
* Informed consent from the patient or next of kin to participation in the trial, or emergency procedure if no next of kin is available
* Patients affiliated to a social security system

Non-inclusion Criteria:

* Criteria for severe ventilator-associated pneumonia defined as:

  * Vasopressor therapy for onset of septic shock around the time of ventilator-associated pneumonia suspicion
  * Onset or severe worsening of hypoxemia (PaO2/FiO2\<150 with 60% FiO2 and 10 mm H2O peak expiratory pressure, or patient on veno-venous extracorporeal membrane oxygenation)
* Immunosuppression defined as :

  * leukocytes \<1G/L or neutrophils \<0,5 G/L
  * within the last 3 months
  * hematopoietic stem-cell transplant or organ transplant with chronic immunosuppressant therapy
  * HIV infection with CD4\<50/mm3
  * chronic corticosteroid use (\>0.5 mg/kg day for at least one month within the last three months).
* Patient already on Antibiotic Therapy of predicted duration ≥4 weeks (endocarditis, spondylodiscitis, abscess...)
* Previous ventilator-associated pneumonia suspicion with sampling and/or Antibiotic Therapy for suspected ventilator-associated pneumonia
* Previous inclusion in the trial
* Patient included in an interventional study on ventilator-associated pneumonia management.
* Pregnancy, recent delivery, or breastfeeding
* Correctional facility inmate, adult under guardianship
* Patient under legal protection
* Life expectancy less than 48 hours and/or decision to withhold and/or withdraw life-sustaining therapies
* Organ donor reanimation

Primary outcomes:
measure: Assessment of the risk to the patient of delaying antibiotic therapy until bacteriological results are available
timeFrame: From day 0 to day 28
Secondary outcomes:
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: From day 0 to day 7
measure: Modified clinical pulmonary infection score (mCPIS)
timeFrame: From day 0 to day 7
measure: Clinical cure
timeFrame: day 7
measure: Invasive mechanical ventilation duration
timeFrame: From day 0 to day 28
measure: Ventilator free days
timeFrame: From day 0 to day 28
measure: Use of vasopressors
timeFrame: From day 0 to day 28
measure: Mortality rates
timeFrame: ICU discharge, an average of 10 days
measure: Mortality rates
timeFrame: day 28
measure: Mortality rates
timeFrame: day 90
measure: Mortality rates
timeFrame: Hospital discharge, an average of 20 days
measure: ICU stay lenghts
timeFrame: From day 0 until the day of discharge from ICU, an average of 10 days
measure: Hospital stay lenghts
timeFrame: From day 0 until the day of discharge from Hospital, an average of 20 days
measure: Incidence of ventilator associated pneumonia related abscess
timeFrame: From day 0 until the day of discharge from ICU, an average of 10 days
measure: Incidence of ventilator associated pneumonia related bacteria
timeFrame: From day 0 until the day of discharge from ICU, an average of 10 days
measure: Incidence and timing of subsequent ventilator associated pneumonia during the hospital stay
timeFrame: From day 0 until the day of discharge from Hospital, an average of 20 days
measure: Incidence of noscomial infections between randomisation and hospital discharge
timeFrame: From day 0 until the day of discharge from Hospital, an average of 20 days
measure: Incidence of in-hospital nosocomial infections by multiresistant bacteria (MRB)
timeFrame: From day 0 until the day of discharge from Hospital, an average of 20 days
measure: Incidences of allergies and of diarrhea
timeFrame: From day 0 until the day of discharge from Hospital, an average of 20 days
measure: Antibiotic-free days
timeFrame: day 10
measure: Number of antibotic therapy days by day 28
timeFrame: day 28
measure: Broad-spectrum days of therapy (DOT) by day 28
timeFrame: day 28
measure: Carbapenom days of therapy (DOT) by day 28
timeFrame: day 28
measure: Ventilator associated pneumonia antibiotic therapy
timeFrame: From day 0 to day 28
measure: Descriptive antibiotic therapy data
timeFrame: From day 0 to day 28
measure: Descriptive bacteriological data
timeFrame: From day 0 to day 28
measure: Descriptive clinical, laboratory and radiological data 48 hours before ventilator associated pneumonia suspicion
timeFrame: 48 hours before ventilator asociated pneumonia suspicion
measure: Proportion of patients with confirmed ventilator associated pneumonia
timeFrame: From day 0 to day 28
measure: Number of patients given active/inactive/unnecessary antibiotic therapy on day 0 and on the day of antibiotic therapy initiation
timeFrame: Day 0 and on the day of antibiotic therapy initiation, an average of 1 day
measure: Number of patients with suitable antibotic therapy (defined as active antibiotic therapy or spared antibiotic therapy as defined below) on day 0 and on the day of antibiotic therapy initiation in the conservative strategy arm
timeFrame: Day 0 and on the day of antibiotic therapy initiation, until discharge from intensive care unit or up to 28 days
measure: EQ-5D-5L EuroQol score
timeFrame: day 0
measure: Quality of life
timeFrame: day 28
measure: Quality of life
timeFrame: day 90
measure: Incremental cost-utility ratio (ICUR)
timeFrame: day 90
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU Angers
city: Angoulème
country: France
facility: CH Angoulème
city: Argenteuil
country: France
facility: CH Argenteuil
city: Avignon
country: France
facility: CH Avignon
city: Belfort
country: France
facility: Hôpital Nord Franche Comté
city: Béthune
country: France
facility: CH Béthune
city: Cannes
country: France
facility: CH Simone Veil
city: Cherbourg En Cotentin
country: France
facility: CH Public du Cotentin
city: Cholet
country: France
facility: CH Cholet
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Dax
country: France
facility: CH Dax
city: Dijon
country: France
facility: CHU Dijon
city: Garches
country: France
facility: APHP - Hôpital Raymond Poincaré
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Le Chesnay
country: France
facility: CH Versailles
city: Le Mans
country: France
facility: CH Le Mans
city: Lille
country: France
facility: CHRU Lille
city: Lorient
country: France
facility: GHB Sud- Hôpital de Lorient
city: Lyon
country: France
facility: CHU de Lyon - Hôpital Edouard Herriot
city: Mont-de-Marsan
country: France
facility: CH de Mont de Marsan
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice -Hôpital Pasteur
city: Nice
country: France
facility: CHU Nice - Hôpital de l'Archet
city: Nîmes
country: France
facility: GHRU de Nîmes
city: Orléans
country: France
facility: CHR d'Orléans
city: Paris
country: France
facility: APHP - Hôpital Cochin
city: Paris
country: France
facility: APHP - Hôpital Tenon
city: Pau
country: France
facility: CH de Pau
city: Rennes
country: France
facility: CHU Rennes
city: Saint Nazaire
country: France
facility: CH de Saint-Nazaire
city: Saint-Malo
country: France
facility: CH de Saint-Malo
city: Strasbourg
country: France
facility: CHRU de Strasbourg - Nouvel Hôpital Civil
city: Strasbourg
country: France
facility: CHRU de Strasbourg -Hôpital de Hautepierre
city: Suresnes
country: France
facility: Hôpital Foch
city: Tours
country: France
facility: CHRU De Tours
city: Valence
country: France
facility: CH de Valence
city: Valenciennes
country: France
facility: CH de Valenciennes
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Pointe-à-Pitre
country: French Southern Territories
facility: CHU La Guadeloupe
Study officials:
References: