Phage-Antimicrobial combination strategies for management of multidrug-resistant E. coli and K. pneumoniae

Multidrug-resistant (MDR) bacterial infections constitute a major challenge, resulting in significant morbidity and mortality. One of the cornerstones of the management of AMR infections is development of antimicrobials. In recent years several novel antimicrobials have been developed, but the emergence of resistance has already been described, and novel approaches are needed to improve the efficacy of current treatment regimens, while preventing development of resistance. Bacteriophages are viruses that selectively target bacteria, causing lysis of bacterial cells. Phage therapy has emerged as a potential tool to mitigate the effects of AMR. The possibility of using phages in combination with antimicrobials is largely unexplored although our evidence, and that of others, suggests that phages can improve the efficacy of antibiotics. However, there is limited knowledge about how to combine them, how this works in vitro and in vivo including impacts on the immune system. Herein, we describe a project aimed at generating pivotal information on how to optimally combine phages and antimicrobials by using several infection models – in silico, in vitro, ex vivo cell culture, patient-derived organoid models, and murine animal models. We will also investigate the emergence of phage resistance and development of antibodies in animals receiving long-term treatment with phages. This project explores the utility of phage-antimicrobial combinations in various infection models and will direct roadmaps for clinical use.