Quality-Controlled Small-Scale Production of a Well-Defined Bacteriophage Cocktail for Use in Human Clinical Trials

We describe the small-scale, laboratory-based, production and quality control of a cocktail, consisting of exclusively lytic bacteriophages, designed for the treatment of Pseudomonas aeruginosa and Staphylococcus aureus infections in burn wound patients. Based on succesive selection rounds three bacteriophages were retained from an initial pool of 82 P. aeruginosa and 8 S. aureus bacteriophages, specific for prevalent P. aeruginosa and S. aureus strains in the Burn Centre of the Queen Astrid Military Hospital in Brussels, Belgium. This cocktail, consisting of P. aeruginosa phages 14/1 (Myoviridae) and PNM (Podoviridae) and S. aureus phage ISP (Myoviridae) was produced and purified of endotoxin. Quality control included Stability (shelf life), determination of pyrogenicity, sterility and cytotoxicity, confirmation of the absence of temperate bacteriophages and transmission electron microscopy-based confirmation of the presence of the expected virion morphologic particles as well as of their specific interaction with the target bacteria. Bacteriophage genome and proteome analysis confirmed the lytic nature of the bacteriophages, the absence of toxin-coding genes and showed that the selected phages 14/1, PNM and ISP are close relatives of respectively F8, φKMV and phage G1. The bacteriophage cocktail is currently being evaluated in a pilot clinical study cleared by a leading Medical Ethical Committee

Phagetherapy: Clinical Applications – Critical Appraisal of Randomized Controlled Trials

Phagotherapy, defined as the use of bacteriophage to treat bacterial infections, was initially proposed by Felix d’Herelle, a French-Canadian who did a lot of research on this topic in Paris, but also travelled the world to treat patients in different settings and conditions. While the literature on this topic is quite extensive, the number of randomized controlled trials is rather limited. Large studies were performed and published in the former USSR republics more than 50 years ago. Since then, there were few trials performed, enrolling a limited number of patients and assessing potential phage efficacy in different settings such as chronic otitis or infected burn wounds. In this chapter, we review and discuss these different randomized trials. While the results might look disappointing at first sight, they all confirm safety of phage used for treatment of difficult clinical situations. Those trials should help define further studies in order to obtain the best possible results and hopefully confirm that phages could be used as an alternative to treat difficult to treat multi-drug-resistant bacterial infections

Phage treatment of human infections

Phages as bactericidal agents have been employed for 90 years as a means of treating bacterial infections in humans as well as other species, a process known as phage therapy. In this review we explore both the early historical and more modern use of phages to treat human infections. We discuss in particular the little-reviewed French early work, along with the Polish, US, Georgian and Russian historical experiences. We also cover other, more modern examples of phage therapy of humans as differentiated in terms of disease. In addition, we provide discussions of phage safety, other aspects of phage therapy pharmacology, and the idea of phage use as probiotics