A Double-Blind, Placebo-Controlled Study of Nebulized Bacteriophages in Patients With Ventilator-Associated Pneumonia Due to Pseudomonas Aeruginosa

Condition(s) studied

Investigational drug(s) / intervention(s)

Bacteriophages GMP: Five administrations of phages daily from D1 to D5

saline solution (placebo): Five administrations of saline solution daily from D1 to D5

Study 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.

Eligibility

Primary outcome measure(s)

• 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).

Trial sites (16)

More Assistance Publique - Hôpitaux de Paris trials in France

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