Immediate Versus Substantiated Antibiotic Therapy in Suspected Non-Severe Ventilator-Associated Pneumonia
- Conditions
- Ventilator-Associated Pneumonia (VAP)
- Registration Number
- NCT06743529
- Lead Sponsor
- Nantes University Hospital
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 686
- 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
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method Assessment of the risk to the patient of delaying antibiotic therapy until bacteriological results are available From day 0 to day 28 To assess, in intensive care units patients with suspected nonsevere ventilator-associated pneumonia (no septic shock or severe acute respiratory distress syndrome), whether delaying antibiotic therapy until ventilator-associated pneumonia is confirmed by a positive respiratory-sample culture and/or polymerase chain reaction test (conservative strategy) neither increases day-28 mortality nor prolongs invasive mechanical ventilation , compared to antibiotic therapy initiation immediately after sampling (immediate strategy).
- Secondary Outcome Measures
Name Time Method Sequential Organ Failure Assessment (SOFA) score From day 0 to day 7 Daily Sequential Organ Failure Assessment (SOFA)
Modified clinical pulmonary infection score (mCPIS) From day 0 to day 7 Daily mcPIS
Clinical cure day 7 Clinical cure is defined as the combination of resolution of signs and symptoms present at enrollment, and improvement or lack of progression of radiological signs
Invasive mechanical ventilation duration From day 0 to day 28 Days of invasive mechanical ventilation
Ventilator free days From day 0 to day 28 Use of vasopressors From day 0 to day 28 Days on vasopressors
Mortality rates Hospital discharge, an average of 20 days Mortality rates at hospital discharge
ICU stay lenghts From day 0 until the day of discharge from ICU, an average of 10 days ICU stay lenghts (days),
Hospital stay lenghts From day 0 until the day of discharge from Hospital, an average of 20 days Hospital stay lenghts (days)
Incidence of ventilator associated pneumonia related abscess From day 0 until the day of discharge from ICU, an average of 10 days Incidence of ventilator associated pneumonia related bacteria From day 0 until the day of discharge from ICU, an average of 10 days Incidence and timing of subsequent ventilator associated pneumonia during the hospital stay From day 0 until the day of discharge from Hospital, an average of 20 days Incidence and timing of subsequent ventilator associated pneumonia during the hospital stay: relapse, recurrence, superinfection, ventilator associated pneumonia occurrence after a suspected but refuted ventilator associated pneumonia episode; recurrence is defined as improvements in manifestations (fever, secretions, vasopressor needs, inflammatory biomarkers, and chest radiograph infiltrates) after 7 days' treatment with at least ne antibiotic active on all documented bacteria, followed by the return or worsening of these manifestations with a new respiratory sample (culture, with or without PCR) positive for at least one bacterial species in significant concentrations; the same scenario with a respiratory sample positive for at least one of the initial causative bacteria defined relapse; no improvement in manifestations after 7 days' active treatment with a respiratory sample positive for at least one of the initial causative bacteria defined superinfection.
Incidence of noscomial infections between randomisation and hospital discharge From day 0 until the day of discharge from Hospital, an average of 20 days Nosocomial infections including ventilator asssociated pneumonia, nosocomial pneumonia, bacteremia, catheter-related bloodstream infection, urinary-tract infection, soft-tissue infection, C. difficile infection, and other infections
Incidence of in-hospital nosocomial infections by multiresistant bacteria (MRB) From day 0 until the day of discharge from Hospital, an average of 20 days Defined as any of the following: methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant Enterococcus (VRE), extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-e), carbapenemase-producing Enterobacterales (CPE), and imipenem-resistant Acinetobacter baumannii (IRAB).
Incidences of allergies and of diarrhea From day 0 until the day of discharge from Hospital, an average of 20 days Antibiotic-free days day 10 Number of antibotic therapy days by day 28 day 28 computed as days of therapy (DOT), defined as the number of days on AT, with each day multiplied by the number of individual antimicrobial agents given on that day, irrespective of the number of doses given.
Broad-spectrum days of therapy (DOT) by day 28 day 28 (ceftazidime, piperacillin/tazobactam, cefepime, fluoroquinolones, carbapenems, or new AT for multidrug-resistant Gram-negative bacilli) (number of days on broad-spectrum AT multiplied by the number of individual antimicrobial agents given on each of those days, irrespective of the number of doses given)
Carbapenom days of therapy (DOT) by day 28 day 28 Carbapenem DOT by day 28 (number of calendar days during which the patient received at least one carbapenem dose multiplied by the number of individual antimicrobial agents given on each of those days, until day 28, irrespective of the number of doses given).
Ventilator associated pneumonia antibiotic therapy From day 0 to day 28 Descriptive data : dual therapy, median time from respiratory sampling to AT, duration, de-escalation (defined as empirical AT stopped or number of empirical antimicrobials decreased or spectrum of empirical AT narrowed, based on AST results)
Descriptive antibiotic therapy data From day 0 to day 28 Ventilator associated pneumonia antibiotic therapy: antimicrobial(s), dual therapy, median time from respiratory sampling to antibiotic therapy, duration, de-escalation (defined as empirical AT stopped or number of empirical antimicrobials decreased or spectrum of empirical antibiotic therapy narrowed, based on AST results) , antibiotic therapy for reasons other than suspected VAP: antimicrobial, duration, reason
Descriptive bacteriological data From day 0 to day 28 gram stain, organisms recovered (cultured and/or identified by PCR), and antimicrobial resistance profiles
Descriptive clinical, laboratory and radiological data 48 hours before ventilator associated pneumonia suspicion 48 hours before ventilator asociated pneumonia suspicion Proportion of patients with confirmed ventilator associated pneumonia From day 0 to day 28 Number of patients given active/inactive/unnecessary antibiotic therapy on day 0 and on the day of antibiotic therapy initiation Day 0 and on the day of antibiotic therapy initiation, an average of 1 day Number of patients given active/inactive/unnecessary antibiotic therapy on day 0 and on the day of antibiotic therapy initiation (with active defined as at least one antimicrobial agent active against each bacterial species isolated from respiratory samples in concentrations greater than prespecified thresholds, based on AST; inactive defined as not meeting criteria for active AT; and unnecessary defined as antibiotic therapy given before sample results with these being negative)
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 Day 0 and on the day of antibiotic therapy initiation, until discharge from intensive care unit or up to 28 days * Number of patients given substantiated antibotic therapy defined as started upon receipt of positive respiratory-sample culture and/or PCR test results
* Number of patients given rescue antibotic therapy defined as started, in a conservative group patient, after sampling but before culture and/or PCR results, due to the development of ventilator associated pneumonia severity criteria (shock or severe ARDS)
* Number of patients spared antibotic therapy for the suspected ventilator associated pneumonia episode, that is, not given antibotic therapy after sampling and having negative respiratory-sample resultsEQ-5D-5L EuroQol score day 0 Quality of life will be assessed using the EQ5D EuroQol score
Quality of life day 90 Quality of life will be assessed using the EQ5D-5L EuroQol score
Incremental cost-utility ratio (ICUR) day 90 The incremental cost-utility ratio (ICUR, cost per quality-adjusted life year \[QALY\] gained) of the two strategies will be computed from a collective perspective and with a 90-day time horizon then compared between the two groups.
Trial Locations
- Locations (40)
CHU Nice - Hôpital de l'Archet
🇫🇷Nice, France
GHRU de Nîmes
🇫🇷Nîmes, France
CHR d'Orléans
🇫🇷Orléans, France
APHP - Hôpital Cochin
🇫🇷Paris, France
APHP - Hôpital Tenon
🇫🇷Paris, France
CH de Pau
🇫🇷Pau, France
CHU Nice -Hôpital Pasteur
🇫🇷Nice, France
CHU Amiens
🇫🇷Amiens, France
CHU Angers
🇫🇷Angers, France
CH Angoulème
🇫🇷Angoulème, France
CH Argenteuil
🇫🇷Argenteuil, France
CH Avignon
🇫🇷Avignon, France
Hôpital Nord Franche Comté
🇫🇷Belfort, France
CH Béthune
🇫🇷Béthune, France
CH Simone Veil
🇫🇷Cannes, France
CH Public du Cotentin
🇫🇷Cherbourg En Cotentin, France
CH Cholet
🇫🇷Cholet, France
CHU Clermont-Ferrand
🇫🇷Clermont-Ferrand, France
CH Dax
🇫🇷Dax, France
CHU Dijon
🇫🇷Dijon, France
APHP - Hôpital Raymond Poincaré
🇫🇷Garches, France
CHD Vendée
🇫🇷La Roche-sur-Yon, France
CH Versailles
🇫🇷Le Chesnay, France
CH Le Mans
🇫🇷Le Mans, France
CHRU Lille
🇫🇷Lille, France
GHB Sud- Hôpital de Lorient
🇫🇷Lorient, France
CHU de Lyon - Hôpital Edouard Herriot
🇫🇷Lyon, France
CH de Mont de Marsan
🇫🇷Mont-de-Marsan, France
CHU Nantes
🇫🇷Nantes, France
CHU Rennes
🇫🇷Rennes, France
CH de Saint-Nazaire
🇫🇷Saint Nazaire, France
CH de Saint-Malo
🇫🇷Saint-Malo, France
CHRU de Strasbourg - Nouvel Hôpital Civil
🇫🇷Strasbourg, France
CHRU de Strasbourg -Hôpital de Hautepierre
🇫🇷Strasbourg, France
Hôpital Foch
🇫🇷Suresnes, France
CHRU De Tours
🇫🇷Tours, France
CH de Valence
🇫🇷Valence, France
CH de Valenciennes
🇫🇷Valenciennes, France
CH Bretagne Atlantique
🇫🇷Vannes, France
CHU La Guadeloupe
🇹🇫Pointe-à-Pitre, French Southern Territories