FROM MICE MODELS TO PHAGE THERAPY OF HUMAN INFECTIONS IN ISRAEL

Daniel Gelman ¹ Shaul Beyth ² Vanda Lerrer ¹ Shunit Coppenhagen-Glazer ¹ Leron Khalifa ¹ Sivan Alkalai-Oren ¹ Yoram A. Weil ² Allon E. Moses ³ Ran Nir Paz ³ Ronen Hazan ¹

¹Institute of Dental Sciences, Faculty of Dental Medicine,, The Hebrew University of Jerusalem, Jerusalem, Israel
²Orthopedic Surgery Department, Hadassah Medical Center, Jerusalem, Israel
³Department of Clinical Microbiology and Infectious Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Introduction: Clinical applications of phage therapy against the alarming emergence of multidrug resistant bacterial infections have been recently got significant attention worldwide. The clinical applications of phage therapy are currently being explored and in most given as a rescue therapy, in cases of near-fatal antibiotic failure. Thus, clinically relevant in-vivo models presenting the applications of phage therapy as a rescue treatment are of highest importance.

Methods: In this study, mice were infected with intraperitoneal injections containing high inoculum (10*LD₅₀) of Vancomycin-Resistant Enterococcus faecalis. The mice were divided into several groups and treated with a novel bacteriophage cocktail, containing two lytic bacteriophages, both individually or in combination with standard antibiotic regimen of ampicillin. The mice were evaluated by clinical and laboratory parameters, including evaluation of the bacterial- and the bacteriophage- spread, immune response and alterations in the mice microbiome.

Results: A single intraperitoneal injection of the presented bacteriophage cocktail was sufficient to rescue up to 100% cases of severe septic peritonitis, in mice that otherwise reached their humane end point within only 24 hours. The administration of bacteriophages led to a significant improvement in both the mice clinical state and the laboratory test results, without harmful effects on the microbiome. The combination of the bacteriophages with suboptimal antibiotic regimen, mimicking highly resistant bacterial strains, imparts an additional beneficial effect on the treatment success.

Conclusions: Our model supports the ability of combined antibiotics and personal phage therapy, tested specifically against the target bacteria to clear invasive bacterial infections even in cases of highly resistant bacteria.

Update: These in-vivo results, in addition to the recent reports from the US on successful bacteriophages treatment of Human infections, have prompted us to apply the first intravenous phage therapy treatment in Israel, which will be described.