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Inhaled bacteriophage therapy in a porcine model of ventilator-associated pneumonia caused by pseudomonas aeruginosa.
  • +13
  • Antoine Guillon,
  • Jeoffrey Pardessus,
  • Guillaume L’Hostis ,
  • Cindy Fevre,
  • Celine Barc,
  • Emilie Dalloneau,
  • Youenn Jouan,
  • Elsa Bodier,
  • Yonatan Perez,
  • Camille Thorey,
  • Laurent Mereghetti ,
  • Maria Cabrera,
  • Mickael Riou,
  • Laurent Vecellio,
  • Sandrine Leguellec,
  • Nathalie Heuzé-Vourc’h
Antoine Guillon
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Jeoffrey Pardessus
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Guillaume L’Hostis
Pherecydes Pharma, Research and Development
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Cindy Fevre
Pherecydes Pharma, Research and Development
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Celine Barc
INRAE, UE-1277 Plateforme d'infectiologie expérimentale (PFIE), Centre Val de Loire
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Emilie Dalloneau
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Youenn Jouan
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Elsa Bodier
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Yonatan Perez
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Camille Thorey
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Laurent Mereghetti
INRAE, UMR1282 Infectiologie et Santé Publique, Centre Val de Loire
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Maria Cabrera
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Mickael Riou
INRAE, UE-1277 Plateforme d'infectiologie expérimentale (PFIE), Centre Val de Loire
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Laurent Vecellio
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Sandrine Leguellec
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Nathalie Heuzé-Vourc’h
INSERM, Centre d'Etude des Pathologies Respiratoires, U1100
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Abstract

Background and Purpose. Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of VAP caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy. Experimental Approach. (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa. Key Results. By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p<0.001). No phage was detected in the sera and urines throughout the experiment. Conclusion and Implications. Our findings demonstrated: (i) the feasibility of delivering large amounts of active phages by nebulization during mechanical ventilation, (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of VAP with high translational value.

Peer review status:ACCEPTED

11 Jan 2021Submitted to British Journal of Pharmacology
11 Jan 2021Submission Checks Completed
11 Jan 2021Assigned to Editor
20 Jan 2021Reviewer(s) Assigned
09 Feb 2021Review(s) Completed, Editorial Evaluation Pending
12 Feb 2021Editorial Decision: Revise Minor
12 Mar 20211st Revision Received
22 Mar 2021Assigned to Editor
22 Mar 2021Submission Checks Completed
25 Mar 2021Reviewer(s) Assigned
06 Apr 2021Review(s) Completed, Editorial Evaluation Pending
08 Apr 2021Editorial Decision: Revise Minor
19 Apr 20212nd Revision Received
19 Apr 2021Submission Checks Completed
19 Apr 2021Assigned to Editor
23 Apr 2021Reviewer(s) Assigned
24 Apr 2021Review(s) Completed, Editorial Evaluation Pending
26 Apr 2021Editorial Decision: Accept