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GENERAL ASPECTS
1) Bacteriophages (more commonly called phages) belong to different families of viruses, which are highly represented in all natural environments—soil, water, air—and are capable of lysing bacteria. It is known that humans are in continuous contact with phages, as they are ubiquitously present in water (about 104-108/ml), in soil (109/gr), and in the human body (they have been isolated from saliva and feces).
2) Towards their natural targets, phages show an extremely narrow host range, linked to the recognition of specific bacterial receptor molecules to which they bind uniquely through viral structures with an attachment function (plate and fibers)
3) The activity of phages is very specific. In fact, they attack only their natural host without having any influence on the rest of the microscopic flora. This is a fundamental aspect of phages, especially in relation to their potential therapeutic use in humans, since they are able to attack exclusively bacterial cells, lacking the ability to enter and reproduce in any eukaryotic cell (including human cells), for which they are therefore totally harmless.
4) The ability of phages to have a specific target, to destroy a specific bacterium, and to replicate exponentially within the bacterium they infect identifies their potential role in the treatment of bacterial infections.
5) Phages have further advantages over antibiotics:
a) they are ecologically safe (for plants, animals, and humans)
b) they are easy to prepare in pharmaceutical formulations
c) easy to apply
d) they do not have significant side effects even when prepared as multicomponent (cocktails)
6) The increasing incidence of antibiotic-resistant pathogens is leading scientists to rediscover the possibility of developing phage therapy as a reliable therapeutic alternative.
7) The therapeutic use of phages has a long history, dating back to their first isolation in 1917 in Paris by Felix D’Herelle, who prepared a solution for the treatment of dysentery.
8) This branch of microbiology experienced significant development until the 1930s, when the discovery of penicillin led to the abandonment of these lines of research. This was mainly due to the broad spectrum and rapid use of antibiotic therapy, compared to the highly selective action of phages.
9) A second reason for the abandonment of phage therapy was the difficulty, at that time, in characterizing the etiological agent of a given infectious disease and the absence of established protocols to accurately identify in vitro the susceptibility of the bacterium to the phage.
THE DEVELOPMENT OF BEANS IN THE FORMER SOVIET UNION
1) Lower production costs and development of therapeutic protocols. Less pressure from multinational pharmaceutical companies.
2) Phages remained in the pharmacopoeia of the USSR even in the 60s and 70s, when the world saw the peak of effectiveness and distribution of antibiotics.
3) They were used in particular for the treatment of dysentery, purulent infections, such as infections of burns, wounds, and organ inflammations.
METHODS OF PREPARATION AND APPLICATION OF FAGI
Bean preparations can be made in two main ways:
a) Cocktail of phages directed against certain species of pathogens that are generally the cause of specific infections
b) Personalized therapies In this case, the development of the therapy requires:
1) Absolute necessity to know and characterize the pathogen causing the infection we want to treat.
2) Before treatment, the pathogen must be tested in vitro against the available phage library in order to select the most effective phage for therapeutic application.
3) At present, the success of the therapeutic use of phages depends on the diagnostic laboratory and the availability of a well-characterized phage library.
4) The selection of phages in the preparation of therapeutic cocktails is the key factor in preventing the selection of phage-resistant bacteria.
5) The phages used must have a definite lytic activity on the target bacterium, and a possible transfer of virulent genes through lysogeny or transduction must be excluded. In the best possible scenario, the DNA of the phage chosen for therapeutic purposes should be sequenced to ensure that it does not include genes for toxins, pathogenicity islands, or genes that can integrate into the bacterial DNA genome.
6) Set up a preparation that remains stable from the moment of its production to its use in the field.
7) The knowledge of phage biology is essential to avoid bacterial resistance to phages. Although this event is rarer than the emergence of bacterial resistance to antibiotics, it is possible for it to occur. In this regard, the construction of an appropriate cocktail is of fundamental importance. Since the receptors on the cell wall are specific and different for each phage, it is practically impossible for the bacterium to mutate enough to become simultaneously sensitive to a cocktail containing different phages. Furthermore, the simultaneous application of phages and other antibacterials decreases the emergence of resistance phenomena to the same antibiotics.
THE ROLE OF THE ELIAVA INSTITUTE OF TBILISI GEORGIA
1) The Eliava Institute, founded in the 1920s, produces phages for the treatment and prevention of intestinal and purulent infections. It is the institute with the greatest clinical experience in the world in this field.
2) The produced preparations are easily available and can be administered in different ways: oral (solutions or tablets), local (swabs, creams), endorectal, aerosol, intrapleural, aerosol, intravenous.
3) There is a substantial body of literature produced by the institute on the subject, carried out in collaboration with some institutes in Switzerland, Belgium, and the United Kingdom. In Italy, there is no experience in this regard.
POSSIBLE DEVELOPMENTS AND STRATEGIC IMPORTANCE OF RESEARCH ON PHAGES
Based on existing results and the emergency related to antibiotic resistance, phage therapy is therefore currently of great interest, especially for treating infections that do not respond to conventional antibiotic-based therapy.
In recent years, consequently, there has been a marked increase in the number of publications and international conferences on the subject (Bacteriophages, London 2016; Phage therapy-TID-Paris 2016), in which the need to conduct controlled and randomized clinical studies has been repeatedly emphasized, in order to provide adequate clinical data for a scientifically rigorous evaluation of the effectiveness of phage therapy.
In a document published in 2015 (EMA/389257/2015, http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/07/WC500189409.pdf) the EMA (European Medicine Agency) emphasizes the potential importance of phage therapy in light of the increasing spread of antimicrobial resistance, while at the same time lamenting the scarcity of randomized and controlled clinical studies that would allow for the evaluation of its efficacy and safety.
The Eliava Institute is historically the most important phage research center, collaborates with numerous international centers (in the USA, Canada, UK, Germany, Ireland, Denmark, Belgium, Switzerland, France), possesses a library of phages already selected and tested against the major strains of human antibiotic-resistant pathogens, and has a long and proven experience in the use of phage therapy.
THE PROBLEM OF EXPERIMENTATION
Given that phage therapy could play a key role in combating multi-resistant bacterial infections and in reducing the costs for infection control and therapy in the coming years, many European researchers and many governments have realized the strategic role of research in this field, but the introduction of the therapy in Italy and in the European Union faces major regulatory obstacles.
First of all, phages, being naturally occurring products and not synthetic ones, cannot be protected by intellectual property, that is, by patents. This makes them less attractive to the pharmaceutical industry. The other aspect that makes management by pharmaceutical companies complex is the need for substantial know-how for the customization of therapies and for the preparation of phage cocktails.
Phage preparations, having therapeutic activity, cannot be classified as food supplements (as is the case for probiotics, for example) but rather as biological drugs, and like these, they would need to follow the experimental and clinical process before being authorized as therapeutic agents. This applies to direct administration to humans and animals. As agents to be used in the environment, regulations are obviously less stringent and some phage-based preparations are already authorized by EFSA (European Food Safety Authority) for the prevention of certain foodborne illnesses.
AIMS AND BACTERIOPHAGES
Based on a scientific collaboration agreement with the EPTC (Eliava Phage Therapy Center), AIMS is involved in promoting the use of bacteriophages in patients suffering from infectious diseases that do not respond to antibiotic treatments and for whom no reasonable therapeutic alternatives are available. In the absence of approval from European drug regulatory agencies, the therapy can be administered to patients who need it, based on the criteria defined in the Declaration of Helsinki. In fact, even in the absence of a defined regulatory framework, many European countries, in particular Belgium, France, and Germany, have started some clinical experiences within hospital facilities.
AIMS doctors, together with their EPTC colleagues, assess patients' eligibility for phage therapy based on clinical and microbiological findings. They coordinate treatment with the patients' attending physicians, whom they do not replace but rather integrate with, so that patients can continue their conventional therapies (particularly antibiotic therapy), with which phages do not interfere; in fact, in many cases, they increase the infection's susceptibility to pharmacological treatment. They follow patients throughout their therapeutic journey, ensuring that they adhere to current guidelines for the treatment of their specific condition.
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