Insights into Current Phage Therapeutics: Identification and Safety Evaluation of an Existing Phage Therapy

As I mentioned in a previous post, phage therapy is becoming a more attractive therapeutic avenue to treat bacterial infections, especially in light of increases in antibiotic resistance prevalence. Interest and support for phage therapy continues to increase, but the US & Western Europe are still in the early stages of developing medical phage therapeutics for approved patient use (only a small number of phage preparations are FDA approved for use on food to prevent food poisoning by bacteria; nothing is approved for patients with bacterial infections). While the progress in the US and Western Europe is still in early stages, phage therapy medicines continue to be used in Eastern Europe throughout Russia and nearby countries.

Microgen is a major Russian pharmaceutical company that
produces many different phage therapies.  Source

Phage therapies are approved for human therapeutic use in Eastern European countries, including Russia.  The major pharmaceutical company that produces general phage therapies is Microgen.  Although these common phage therapies have been used for decades in Russia (before Russia, the et al did exactly this, and recently reported their findings in the journal 'Virology' (reference [1]).
former Soviet Union), their composition, safety, and efficacy have not been scientifically evaluated [1].  If we are to move forward in our endeavors toward using phages
therapeutically, we must address this lack of knowledge by evaluating the composition, efficacy, and safety of phage cocktails which have long been used in Russia.



To provide insight into Russian phage cocktails that are currently in use, McCallin et al evaluated the composition and efficacy of a Microgen phage therapy cocktail which is marketed for use in E. coli and proteus bacteria infections.  The group first assessed the composition of the therapeutic phage cocktails by purifying the phage DNA and performing high-throughput, shotgun sequencing for metagenomic analysis (this means that they obtained an incredibly large number of random DNA sequences from the isolated phage genomic DNA, and were able to use the sequences to determine what phages are present and what genes they contain).  The group found that the cocktail was composed of 18 phage types which had high similarities to known E. coli phages, as well as potential proteus phages.  These finding were also supported by their electron microscopy findings.

Not only did McCallin et al use their phage metagenome to determine the therapeutic phage cocktail composition, they also screened the phage DNA for potentially dangerous genes including virulence factor genes that could be transmitted from the phages to the patient's resident bacteria.  One aspect of potential virulence that the authors did not really go in to was the presence of potential temperate phages present in the phage cocktail.  Temperate phages are often capable of integrating their DNA into their host bacteria, persist as latent infections until the bacteria becomes stressed, and significantly transfer genes between bacteria, including potential virulence factor genes.  I think that the presence of temperate phages in phage therapy cocktails could present a safety concern because its administration to patients may promote gene transfer among bacteria.  As far as I know, there is no literature investigating this concern, so this may become an important point to address as we move forward with development of phage therapies.  If temperate phages in phage therapies do in fact present a safety issue, it will be important for quality control methods to include screenings for temperate phages as the therapeutic cocktails are produced.

Electron microscopy images of phages contained in the
Microgen phage therapy cocktail. Reference [1]

In addition to evaluating the compositions of the phage cocktails, the group also evaluated their safety.  The research group assembled a small, fifteen person cohort including both healthy adults and healthy children in Bangladesh.  The patients received phage cocktails and placebos in random orders and therefore served as their own controls.  McCallen et al reported no adverse effects related to administration of the phage therapy, and no obvious changes to the gut bacterial communities after the phages had been administered.  This therefore supports the safety of Microgen's phage therapy cocktail, and I think efficacy trials are certainly warranted.  Also, because this trial was conducted outside of the United States, and did not appear to be approved by the EMA, I think it would be cool to see such a trial, using existing Russian phage therapies, performed under FDA or EMA approval (although I think a pre-clinical study might be required to demonstrate safety in an animal model before it can be taken to humans, especially children, but I don't know that for sure).  Furthermore, I think it would be cooler to see an FDA or EMA approved efficacy trial on this phage cocktail, because then we would have a better idea of how useful the drug might be.

This study is important because it offers us some initial insight into the composition of existing phage therapy cocktails in an area that has been using this technology for a long time.  This will serve as an important reference for future studies which may use this cocktail, or studies which may compare different phage compositions to different safety or efficacy outcomes.  I also think the suggestion of safety in their human cohort will support further research evaluating the use of phage therapy as a medicine under FDA and EMA approval.  Overall this is an interesting report which provides valuable insight into an important therapy which has been understudied over past decades.

Works Cited

1. McCallin S, et al. (2013) Safety analysis of a Russian phage cocktail: From MetaGenomic analysis to oral application in healthy human subjects. Virology 443(2):187-196.