Phagothérapie et pneumonies acquises sous ventilation mécanique à Escherichia coli : une approche thérapeutique possible ? Aspects fondamentaux et éléments de faisabilité.

Abstract : Year after year, multi-drug resistant bacteria expand over the world. As a real public health concern, bacterial resistance is particularly significant within healthcare-associated infections. Among alternative therapy to antibiotics, phage therapy appears as one of the most promising approach and is now reappraised in western countries. This work is dedicated to a feasibility approach in order to evaluate phage therapy potential in the most frequent and severe complication in the intensive care unit context: the ventilator-associated pneumonia. We focused on a commonly involved bacterium which is also highly affected by antibiotic resistance: Escherichia coli. Starting from a large multicenter collection of strains isolated from airways of mechanically ventilated patients, we showed that there was no practical impediment to get a bacteriophage collection able to target efficiently a large range of strains. By selecting the best host range combination, we observed that 5 bacteriophages were able to cover 70% of the collection. We then experimentally demonstrated that two bacteriophages were able to rescue deadly infected mice in a murine pneumonia model. By using the bioluminescence imaging tool, we also observed that the kinetic of bacterial load decrease obtained with the bacteriophage treatment was as fast as the one obtained with a reference antibiotic. Finally, we concentrated on a highly specialized bacteriophage (LM33-P1) that turned out to be only able to infect O25b strains, a particularly worrisome serotype in terms of antibiotic resistance and pathogenicity. LM33-P1 was able to lyse 74% of O25b strains and its specificity was shown to be LPS-dependent. We also demonstrated that this bacteriophage was biologically active in vivo. These results provide new knowledge allowing the consideration of phage therapy development in the field of respiratory infections due to E. coli, in the context of mechanical ventilation but not only. Given the pathophysiology of such infection, a preventive approach seems promising.
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Nicolas Dufour. Phagothérapie et pneumonies acquises sous ventilation mécanique à Escherichia coli : une approche thérapeutique possible ? Aspects fondamentaux et éléments de faisabilité. . Bactériologie. Université Paris Diderot Paris 7, 2015. Français. ⟨tel-01330223⟩

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