Regulating Bacteriophages: The First Steps into the Post-Antibiotic Era
by Luka Kotrikadze
It was in the year of 1915 when Frederic William Twort published the paper in The Lancet describing the discovery of an infectious agent that causes the lysis of the Staphylococcus hyicus bacteria . This served as the first ever published description of bacteriophages, therapeutic potential of which was only later assumed by Fe´lix d’Herelle . Serving as the cornerstone for the research in the therapeutic applications of bacteriophages, it was the country of Georgia that first started actively researching the field which was supposed to eliminate, or at least on some level, deal with the issue of the infectious diseases caused by bacteria. However, the advancements into the research were soon foregone with the discovery of the antibiotics, which happened shortly after the first successful therapeutic bacteriophage human trials were conducted .
Nowadays, with the increasing attention towards the antimicrobial resistances, the bacteriophage therapy is slowly stepping into the light of its come back.
In November 2015 a paper was published in The Lancet describing the first ever bacterial strain (E. coli SHP45) to be resistant towards Colistin, one of the strongest antibiotics which for years served as the “last line of defense” . In September 2016 researchers from Harvard Medical School published a report in The Science magazine showcasing how easily can bacteria develop resistances towards antibiotics by demonstrating a live experiment where microbes within 12 days, develop a resistance towards the concentration of antibiotic that is x1000 greater than the lethal dose . Adding the fact that in the EU alone 25,000 deaths are registered per year due to antibiotic resistant bacteria  adds up to the events often described as the “antibiotic crisis”, thus creating an urgent call for the alternative methods for fighting the new generation of microbes. So why is it that the bacteriophage therapy is struggling to see its return on the market?
Product Associated Issues
Whether a bacteriophage product has to be personalized or presented in a shelf-product form, is a topic of debate. Typically, the bacteriophages have a narrow host range, implying that each bacteriophage can lyse only 1 or at most a few types of bacteria. In order to improve this it has been suggested to use Listeria P100 or S. aerus phi812 that have a wider range of the hosts. Nowadays, companies that are specializing in providing such products for the applications in therapy are using a cocktail of bacteriophages. However, it has been believed that such methods do not lead to 100 % efficiency and will lead to resistances in the long run .
On the contrary, one distinct point that scientists make in comparison of the bacteriophages to the chemical antibiotics, is the fact that the former one is a living organism, which means that as the resistances towards the bacteriophages will rise, bacteriophages as living organisms will keep developing as well so that they find new ways and methods to infest the hosts. That aside, considering the limited number of antibiotics that are available to the world compared to the number of alternatives that one can find for a host-specific phage, provides another positive insight on the availability of the methods and approaches that one can use in tackling each specific bacterial disease .
All research that has been conducted in the use of bacteriophages for therapeutic purposes show neither any side nor any adverse effects either in children or in pregnant women, but the fact that so many questions exist regarding the interactions of the bacteriophages with the different hosts, with each other, with the non-pathogenic cells, or even with the endotoxicity dealing with the high number of bacterial cytoplasm suddenly ending up floating freely, leaves space for the scientists and the regulatory organizations to contemplate about the lack of research and clinical trials in the field .
The key issue with the regulation of phage therapy medicinal products (PTMPs) remains the categorization of such products. The two types of umbrellas under which PTMPs can fall are the magistral formulas and industrially made medicinal products .
Magistral formulas are classified as the “medicinal products prepared in a pharmacy in accordance with a medical prescription for an individual patient”, which assumes that such products fall outside the European legislation and thus do not require registration. As discussed before, one of the issues associated with the use of PTMPs is the indecisiveness regarding the form in which the product has to be provided. In the case, of personalized medicine the PTMPs would fall under this category and thus would not be requiring authorization .
In the other case, the product is industrially manufactured and thus would be complying with the directive assuming that the product represents “any ready-prepared medicinal product placed on the market under a special name in a special pack”. This would imply a manufacturing process of the product on the industrial scale in which case the product will require an authorization according to the EU legislation .
However, in the earlier 21st century the directive was replaced by the new one, now relating to human medicinal product: “either prepared industrially or manufactured by a method involving industrial processes” . As a result, the current state of the regulatory framework pushes the definition of PTMPs outside of both scopes: tailor-made PTMPs now fall outside of the regulation of marginal products as they will be neither industrially prepared nor involve any of the industrial processes if prepared by the pharmacist. In the case of the PTMPs prepared on the industrial scale the product will require market authorization for which there is no regulatory infrastructure, that will allow for such products to end up on the market. This results in the regulatory environment for the PTMPs being categorized in between the marginal formula and the industrially manufactured products. Thus, a new regulatory framework is necessary for PTMPs to be authorized and to allow such products to be either tailor-made for personal use, or to be authorized to allow for the production on an industrial scale .
Two things remain obvious in the discussion of the future for the bacteriophage regulations: they provide a safe alternative to the antibiotics and in the times when the efficiency of antibiotics decreases day-by-day and EU alone has 25,000 registered cases of deaths due to antibiotic resistance every year, the alternative methods for dealing with the crisis need to be implemented, as soon as possible. The second would be the fact that many countries that are more specialized in the phage-based therapy do already have regulatory frameworks in which PTMPs are manufactured on industrial scale, while still being able to offer them as personalized treatment. Companies with this technology are already holding their products waiting for the regulatory guidelines, to undertake the steps for obtaining market authorization. Until then, it will be the responsibility of the regulatory organizations to create a sound and safe regulatory framework to start making the first steps in handling the crisis in the post-antibiotic era we’re entering.
Biopharma Excellence has the in-depth knowledge on the development and regulatory strategies of bacteriophage based products. If you want to learn more, do not hesitate to contact us.
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