Ventilator Associated Bacterial Pneumonia, Pseudomonas Aeruginosa Infection
Conditions
Keywords
Nebulized Bacteriophages, Ventilator Associated Bacterial Pneumonia
Brief summary
Ventilator-associated pneumonia (VAP) complicates the hospital course of up to 40% of mechanically ventilated patients and is associated with mortality rates approaching 30%, despite appropriate antibiotic therapy (ATB). Gram-negative bacteria account for approximately 60% of VAP episodes, with Pseudomonas aeruginosa (Pa) being one of the most common pathogens. Recurrent Pa-VAP occurs in 19-33% of cases outside the COVID-19 setting, whereas recurrence rates as high as 79% have been reported in patients with COVID-19, most often caused by the same pathogen and frequently occurring despite adequate antibiotic therapy. Several attempts have been made to improve pulmonary antibiotic exposure by combining intravenous therapy with aerosolized antibiotics delivered through conventional nebulizers. However, clinical results have been disappointing, largely because standard jet nebulizers deliver less than 10% of the nominal dose to the lungs owing to high residual volumes, drug deposition within the ventilator circuit and endotracheal tube, and loss through the expiratory limb. Even with more efficient vibrating mesh nebulizers, two recent randomized con-trolled trials failed to demonstrate any clinical benefit of adjunctive nebulized antibiotics in patients with Gram-negative VAP. Bacteriophages are bacteria-specific viruses that have emerged as a promising therapeutic alternative for difficult-to-treat bacterial infections. Their highly specific host range allows selective targeting of pathogenic bacteria while sparing the commensal microbiota and human cells, thereby minimizing toxicity and off-target effects. An increasing body of preclinical evidence and clinical case reports supports the safety and potential efficacy of anti-P. aeruginosa phage therapy. More recently, a porcine model of Pa-VAP demonstrated that high concentrations of bacteriophages can be efficiently delivered to the lungs by nebulization during mechanical ventilation, resulting in rapid control of the pulmonary infection. The use of phages as compassionate treatment has been authorized in September 2021 in this indication using phages produced by Phagenix- ©. The aim of this placebo controlled study is to demonstrate the efficacy and safety of nebulized anti-Pa bacteriophages, delivered to the lung using a vi-brating mesh nebulizer, in addition to conventional IV ATB treatment.
Interventions
BIOLOGICALBacteriophages GMP
Five administrations of phages daily from D1 to D5
Five administrations of saline solution daily from D1 to D5
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Multicenter, 2 parallel arms, double-blind, randomised (1:1) superiority trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients ≥ 18 years old 2. Intubated and mechanically ventilated for at least 48 hours 3. Mechanical ventilation expected to continue for at least 3 days 4. Clinical diagnosis of VAP 5. VAP due to P. aeruginosa (P. aeruginosa recovered at a significant level from lung sample (≥10\^4/ml for BAL or ≥10\^5/ml for tracheal aspirate or ≥10\^3 CFU/ml for plugged telescopic catheter) 6. Signed informed consent from the patient or the patient's legal representative or a family member or a close relative. According to the legal conditions of emergency inclusion, randomization without the family member or the surrogate consent could be performed if the patient is unable to give his/her consent and if no legal representative/family member or close relative is present. Close relative/ legal representative/family member consent will be asked as soon as possible. The patient will be asked to give his/her consent for continuation of the trial when his/her condition will allow. 7. Patient with childbearing potential\* should have reliable contraception for the all duration of the study 8. Affiliation to social security (AME excluded)
Exclusion criteria
1. Severe hypoxemia as defined by PaO2/FiO2 \< 100 mmHg, except if the patient is on ECMO (extracorporeal membrane oxygenation) 2. Impossibility to set a tidal volume of 6 ml/kg of ideal body weight during nebulization without risk of barotrauma 3. Patients with cystic fibrosis, lung cancer, lung resection, known bronchial obstruction, or active tuberculosis 4. Patient not expecting to survive 48 hours after randomization 5. Polymicrobial VAP (presence of pathogens other than P. aeruginosa at a significant level in lung samples (≥10\^4/ml for BAL or ≥10\^5/ml for tracheal aspirate). If the culture retrieves oropharyngeal flora, even at a significant threshold, in addition to Pseudomonas aeruginosa, the patient is eligible. 6. Contraindication to nebulization 7. Participation in another interventional study evaluating drugs for VAP or being in the exclusion period following the end of a previous interventional study evaluating drugs for VAP 8. Pregnancy or breastfeeding 9. Patients under guardianship or curatorship
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients alive and cured at D28 and without any recurrence of Pa-VAP between the initial episode and D28. | Day 28 | Cure is defined as : * Resolution of signs and symptoms of infection * Improvement of PaO2/FiO2 ratio as compared to value the day VAP is diagnosed * No appearance of new signs of sepsis All 3 criteria must be fulfilled 7 to 10 days after antibiotic initiation Recurrence is defined as: -a clinically suspected VAP (fever, radiological opacity, increase in ventilation need) A microbiological confirmation with Pa recovered at a significant level from lung sample (≥10\^4/ml for BAL or ≥10\^5/ml for tracheal aspirate or ≥ 10\^3 CFU/mL for plugged telescopic catheter). |
Secondary
| Measure | Time frame |
|---|---|
| Resolution of ventilator-associated pneumonia symptoms | Day 7 +/- 3 days |
| Incidence of new ventilator-associated pneumonia | Day 7 +/- 3 days and day 14 |
| Clinical improvement, defined by a modified Clinical pulmonary infection score <4 (range 0-12, with higher score indicating worse outcome) and no new Pseudomonas aeruginosa ventilator-associated pneumonia episode | Day 14 |
| Incidence of Pseudomonas aeruginosa detection in respiratory samples | Day 3, Day 5, Day 7, Day 10, Day 14 and Day 28 |
| Number of days alive | Day 28 |
| Number of day without invasive mechanical ventilation | Day 28 |
| Number of day without antibiotics | Day 28 |
| Anti-phage antibody presence and titers, | Day 1, 7, 10, 14 and 28 |
| Phage neutralization titers | Day 1, 7, 10, 14 and 28 |
| Mortality rate | Day 28 and Day 60 |
| Prevalence of ESBL-producing and carbapenem-resistant Gram-negative bacteria in fecal and tracheal aspirate samples | Day 28 |
Countries
France
Contacts
CONTACTAlexandre BLEIBTREU, MD
Outcome results
None listed