Premium
Inhaled bacteriophage therapy in a porcine model of pneumonia caused by Pseudomonas aeruginosa during mechanical ventilation
Author(s) -
Guillon Antoine,
Pardessus Jeoffrey,
L'Hostis Guillaume,
Fevre Cindy,
Barc Celine,
Dalloneau Emilie,
Jouan Youenn,
BodierMontagutelli Elsa,
Perez Yonatan,
Thorey Camille,
Mereghetti Laurent,
Cabrera Maria,
Riou Mickaël,
Vecellio Laurent,
Le Guellec Sandrine,
HeuzéVourc'h Nathalie
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15526
Subject(s) - pseudomonas aeruginosa , microbiology and biotechnology , phage therapy , lytic cycle , bacteriophage , pneumonia , antimicrobial , antibiotics , in vivo , bacteria , medicine , chemistry , biology , virology , virus , escherichia coli , biochemistry , genetics , gene
Background and Purpose 255 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 pneumonia 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 anaesthetized, 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 < .001). No infective 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 and (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of P. aeruginosa pneumonia with high translational value.