Combination of in vivo phage therapy data with in silico model highlights key parameters for pneumonia treatment efficacy
Raphaëlle Delattre,
Jérémy Seurat,
Feyrouz Haddad,
Thu-Thuy Nguyen,
Baptiste Gaborieau,
Rokhaya Kane,
Nicolas Dufour,
Jean-Damien Ricard,
Jérémie Guedj,
Laurent Debarbieux
Affiliations
Raphaëlle Delattre
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium Host, Paris 75015, France; Université Paris Cité, INSERM U1137, IAME, Paris 75006, France
Jérémy Seurat
Université Paris Cité, INSERM U1137, IAME, Paris 75006, France
Feyrouz Haddad
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium Host, Paris 75015, France; Université Paris Cité, INSERM U1137, IAME, Paris 75006, France
Thu-Thuy Nguyen
Université Paris Cité, INSERM U1137, IAME, Paris 75006, France
Baptiste Gaborieau
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium Host, Paris 75015, France; Université Paris Cité, INSERM U1137, IAME, Paris 75006, France; APHP, Hôpital Louis Mourier, DMU ESPRIT, Service de Médecine Intensive Réanimation, Colombes, France
Rokhaya Kane
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium Host, Paris 75015, France
Nicolas Dufour
Centre Hospitalier René Dubos, Médecine Intensive Réanimation, Cergy Pontoise 95503, France
Jean-Damien Ricard
Université Paris Cité, INSERM U1137, IAME, Paris 75006, France; APHP, Hôpital Louis Mourier, DMU ESPRIT, Service de Médecine Intensive Réanimation, Colombes, France
Jérémie Guedj
Université Paris Cité, INSERM U1137, IAME, Paris 75006, France; Corresponding author
Laurent Debarbieux
Institut Pasteur, Université Paris Cité, CNRS UMR6047, Bacteriophage Bacterium Host, Paris 75015, France; Corresponding author
Summary: The clinical (re)development of bacteriophage (phage) therapy to treat antibiotic-resistant infections faces the challenge of understanding the dynamics of phage-bacteria interactions in the in vivo context. Here, we develop a general strategy coupling in vitro and in vivo experiments with a mathematical model to characterize the interplay between phage and bacteria during pneumonia induced by a pathogenic strain of Escherichia coli. The model allows the estimation of several key parameters for phage therapeutic efficacy. In particular, it quantifies the impact of dose and route of phage administration as well as the synergism of phage and the innate immune response on bacterial clearance. Simulations predict a limited impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage-therapy clinical trials.
