According to data from the European Antimicrobial Resistance Surveillance Network (EARS-Net), published in Lancet Infectious Disease in early 2019, the problem of multidrug resistant (MDR for short) has increased alarmingly over the past decade. In 2015 alone, writes the Lancet, 671,689 multidrug-resistant bacterial infections were detected in Europe - 63.5% is linked to the world of healthcare - an estimated 874,541 days of daily life are spent on treating multidrug-resistant infections and, alarming data 33,110 were the deaths caused by the ineffectiveness of the antibiotics currently in use. The problem of MDR is particularly widespread among the most vulnerable age groups - children under one year of life and the elderly over 65 - with a sad record for Italy and Greece.

Globally, the World Health Organization (WHO) predicts that by 2050 there will be 50 million people a year who will die from bacterial multi-resistance, now considered the most important challenge in the biomedical world for the next decades. An excessive and unjustified prescription of antibiotics has favored the ability of bacteria to mutate according to their survival within the human organism, developing defense mechanisms such as quorum sensing: aggregation in dense, extended colonies, protected from a biofilm and, therefore, impenetrable by those active ingredients which, since the 1940s, have been the best method available to defeat potentially lethal bacterial infections. Medicines based on cephalosporins, carbapenem, colistin, vancomycin, penicillin are now showing less and less efficacy, especially in patients with important chronic diseases, such as cystic fibrosis, or in the treatment of bacterial sepsis, whose therapeutic protocols include intravenous administration of antibiotic therapies at very high dosage.

PHAGE THERAPY, WHAT IT IS

Given this situation, the science of the Western world - the geographical specification is important - is re-evaluating a method discovered at the beginning of the twentieth century by two European scientists, Félix Hubert d'Herelle (1873 - 1949), born in Canada but later became a researcher at the Institute Pasteur in Paris, and the Englishman Frederick Twort (1877 - 1950), both doctors specializing in bacteriology. Beyond the scientific dispute over the primacy of the discovery, d'Herelle must be given credit for having carried out the first clinical trial on the efficacy and safety of phage therapy in 1919: four children suffering from dysentery were administered in a a single dose was a phage preparation followed by a complete recovery from the disease within 24 hours. At the same time, the same preparation was given to some healthy individuals without detecting negative consequences and thus also confirming the safety of the treatment. A small clinical trial with historical significance.

The microorganism responsible for this result is called bacteriophage, a name that combines the word bacterium with the Greek word -phágos "eater" and is a virus that lives on the surface of the bacterium, its source of nourishment: through a process called lysis, the phage completely eliminates the bacterium to which it is bound. Given their specificity, they are given a name: Muddy, ZoeJ and BPs are the three phages used in a recent clinical case published in Nature Medicine that had international resonance. Only three of the more than 10,000 screened by students of the SEA-PHAGES program at the University of Pittsburgh, but they saved the life of a fifteen-year-old British patient with cystic fibrosis, struck by a serious infection with Mycobacterium abscessus, a bacterium of the category of Nontuberculous mycobacteria (NTM), for which the patient had been treated with antibiotics for eight years.
Following a lung transplant, the only viable therapeutic option in that case, the adolescent underwent a severe postoperative infection caused by both Pseudomonas aeruginosa and, again, Mycobacterium abscessus. Following a positron emission tomography (PET) -CT, the doctors identified, at the sternum level, a swelling due to Mycobacterium abscessus that did not respond to antibiotic therapy but, on the contrary, spread to the arms and legs. up to causing a skin lesion to the breastbone.

The situation was therefore hopeless, to the point that, according to what was reported in an interview with the New York Times, the girl's father himself proposed to the doctors to evaluate the possibility of groped for phage therapy, which he had heard about. Following the intravenous administration of the three phages, a "phage cocktail" technically, the Mycobacterium abscessus infection has been eradicated and the girl is alive and relatively well. The case is very important because phage therapy could be, even in the Western world, a solution against bacterial multi-resistance, albeit amidst major legislative obstacles.

PHAGE THERAPY TODAY

In the countries of the former Soviet Union, bacteriophage is widespread. In Tbilisi, Georgia, there is the most important phage therapy center in the world. "Georgia has over a hundred years of experience in the use of phage therapy, but the political situation with Russia creates enormous problems in the diffusion of this method in the Western world. We, Georgian scientists of the Tbilisi phage therapy center, cannot participate in international congresses or publish our research and reviews on the subject in international scientific journals because the Russian government forbids it ", Zemphira Alavidze, first director and now, told OggiScienza consultant of the Phage Therapy Center in Tiblisi.

The researcher, now in her eighties and with a life behind her dedicated to phage therapy, despite the difficulties she recounts, is optimistic. "In the West, phage therapy is not legal, however I am convinced that very soon it will be optimized and made available in many countries and for many patients with particular types of infections who do not respond to the antibiotic therapies available and, therefore, without therapeutic alternatives". The Tbilisi center was opened above all for patients from abroad, so that they could be treated in a country where this therapy is legal. "We have saved many human lives" says Alavidze "but if before we could send the preparations to the United States so that the sick could continue the therapy, now American laws forbid us to do so".
The re-evaluation of phage therapy in the Western world has seen the birth of many projects and centers in which we are trying to develop a therapeutic protocol that meets the criteria required by the regulatory bodies for the marketing of drugs, Food and Drug Administration. (FDA) and European Medical Agency (EMA). Phages are not drugs, but live organisms and to be effective they must be customized to the individual patient. In San Diego, California, about a year ago, the first phage therapy center in the Western world was born to deal with evaluating therapy through clinical trials.

“They never contacted us, says Alavidze, but if they want to, we are ready to talk to them. I am sure that there is no competition between us, because every hospital has its own patients with specific diseases, but if we could all work together, I think this would be a really great result ”.

ONE WAY TO GO
On the American market front, the Intralytix company was founded in 1998 by Alexander Sulakvelidze, a researcher from Tbilisi who passed, in 1993, to the University of Maryland. "The goal we had was to find a phage-based compound capable of treating dysentery. For this we have started a process of requesting approval from the FDA of various phage-based compounds, we have carried out the first clinical trials for the treatment of skin wounds and burns and now the first approved clinical trial is also underway. by the FDA for the treatment of Crohn's disease at Mount Sinai Hospital in New York, ”says Sulakvelidze. According to the Georgian researcher, "it would be very useful if every hospital, normally equipped with infrastructures to identify the most appropriate antibiotic therapy, could have similar ones to identify phage therapy as well".

While waiting for this to happen, patients arrive in the center of Tbilisi from all over the world: America, Australia, Kenya and South Africa but also European countries such as Germany, Poland, Switzerland, Belgium, United Kingdom, Holland. "They are all chronic patients who, sometimes for decades, have always treated themselves with antibiotics that have caused them major side effects, such as the destruction of the bacterial flora and situations of immunodepression" continues Zemphira Alavidze. “It is really difficult to try to cure these patients within 2-3 weeks, but once you find the specific phage cocktail you can see improvement immediately. After years and years of antibiotic treatment it is very difficult to treat chronic situations and it is necessary to continue the phage therapy for several months ".

Phage therapy has continued to develop in the countries of the former Soviet Union, in India and Bangladesh because it is inexpensive. Epidemics of dysentery have been cured in India by simply putting phages in wells and giving people in villages to drink water that had been cleaned with phages. "Interest is shifting to Europe and America" Criscuolo says "because up to now we have used a lot of antibiotics. So it seems paradoxical but where we have medicines, we also have all the problems related to the use we make of them. In fact, in Russia, Georgia and in poor countries they do not have our problems regarding multidrug resistance because they do not have the excessive use of antibiotics that we have in the Western world ".