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\begin{document}

\title{Inhaled bacteriophage therapy in a porcine model of
ventilator-associated pneumonia caused by pseudomonas aeruginosa.}



\author[1]{Antoine Guillon}%
\author[1]{Jeoffrey Pardessus}%
\author[2]{Guillaume  L’Hostis }%
\author[2]{Cindy Fevre}%
\author[3]{Celine Barc}%
\author[1]{Emilie Dalloneau}%
\author[1]{Youenn Jouan}%
\author[1]{Elsa Bodier}%
\author[1]{Yonatan Perez}%
\author[1]{Camille Thorey}%
\author[4]{Laurent  Mereghetti }%
\author[1]{Maria Cabrera}%
\author[3]{Mickael Riou}%
\author[1]{Laurent Vecellio}%
\author[1]{Sandrine Leguellec}%
\author[1]{Nathalie Heuzé-Vourc’h}%
\affil[1]{INSERM, Centre d'Etude des Pathologies Respiratoires, U1100}%
\affil[2]{Pherecydes Pharma, Research and Development}%
\affil[3]{INRAE, UE-1277 Plateforme d'infectiologie expérimentale (PFIE), Centre Val de Loire}%
\affil[4]{INRAE, UMR1282 Infectiologie et Santé Publique, Centre Val de Loire}%


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  \date{June 10, 2024}


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\begin{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\textless{}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.%
\end{abstract}%



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