© Academy for innovation in medical sciences
According to data from the European Antimicrobial Resistance Surveillance Network (EARS-Net), published in Lancet Infectious Disease at the beginning of 2019, the problem of bacterial multiresistance (multidrug resistant, abbreviated as MDR) has increased worryingly over the last ten years. In 2015 alone, writes Lancet, 671,689 multidrug-resistant bacterial infections were detected in the European area – 63.5% are linked to healthcare settings – an estimated 874,541 days of daily life were spent treating multidrug-resistant infections and, alarmingly, 33,110 deaths were caused by the ineffectiveness of currently used antibiotics. The problem of MDR is particularly widespread among the most vulnerable age groups – children under one year of age and the elderly over 65 – with a sad record for Italy and Greece.
Globally, the World Health Organization (WHO) predicts that by 2050, 50 million people per year will die due to bacterial multi-resistance, now considered the most important challenge in the biomedical world for the coming decades. Excessive and unjustified prescription of antibiotics has favored the ability of bacteria to mutate for their own survival within the human body, developing defense mechanisms such as quorum sensing: aggregation into dense colonies, extended and protected by a biofilm, and therefore impenetrable to those active ingredients that, since the 1940s, have been the best available method to defeat potentially lethal bacterial infections. Drugs based on cephalosporins, carbapenems, colistin, vancomycin, and penicillin now show ever decreasing effectiveness especially in patients with major chronic diseases, such as cystic fibrosis, or in the treatment of bacterial sepsis, whose therapeutic protocols involve intravenous administration of extremely high-dose antibiotic therapies.
Given this situation, Western science – the geographical specification is important – is reassessing 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 a researcher at the Pasteur Institute in Paris, and the Englishman Frederick Twort (1877 – 1950), both physicians specialized in bacteriology. Beyond the scientific dispute over the primacy of the discovery, credit must be given to d’Herelle for conducting in 1919 the first clinical trial on the efficacy and safety of phage therapy: four children suffering from dysentery were given a single dose of a phage preparation, which was 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 any negative consequences, thus also confirming the safety of the treatment. A small clinical trial of historical significance.
The microorganism responsible for this result is called a bacteriophage, a name that combines the word bacterium with the Greek term -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 attached. 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 received international attention. They are just three, among over 10,000 screened by students of the SEA-PHAGES program at the University of Pittsburgh, but they saved the life of a British fifteen-year-old girl suffering from cystic fibrosis, affected by a severe infection from Mycobacterium abscessus, a bacterium in the Nontuberculous mycobacteria (NTM) category, for which the patient had been treated with antibiotics for eight years.
Following a lung transplant, the only possible therapeutic option in that case, the adolescent developed a severe post-operative infection caused by both Pseudomonas aeruginosa and, again, by Mycobacterium abscessus. Following a positron emission tomography (PET)-CT scan, the doctors identified, at the level of the sternum, a swelling due to Mycobacterium abscessus that did not respond to antibiotic therapy but, in fact, spread to the arms and legs, eventually causing a skin lesion on the sternum.
The situation was therefore hopeless, to the point that, according to what is reported in an interview with the New York Times, the girl's own father suggested to the doctors that they consider the possibility of trying phage therapy, which he had heard about. Following intravenous administration of the three phages—a "phage cocktail" technically—the Mycobacterium abscessus infection was 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 multi-drug resistant bacteria, albeit among great legislative obstacles.
In the countries of the former Soviet Union, bacteriophage therapy is widely used. 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 spreading this method in the Western world. We, Georgian scientists at the phage therapy center in Tbilisi, cannot participate in international congresses or publish our research and reviews on the subject in international scientific journals because the Russian government forbids us,” says to OggiScienza Zemphira Alavidze, former director and now consultant of the Phage Therapy Center in Tbilisi.
The researcher, now eighty years old and with a life dedicated to phage therapy behind her, 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 that do not respond to available antibiotic therapies and, therefore, have no therapeutic alternatives.” The center in Tbilisi was opened mainly for patients coming 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 while before we could send the preparations to the United States so that patients could continue the therapy, now American laws forbid us from doing so.”
The re-evaluation of phage therapy in the Western world has led to the creation of many projects and centers where efforts are being made to develop a therapeutic protocol that meets the criteria required by regulatory bodies for the marketing authorization of drugs, Food and Drug Administration (FDA) and European Medical Agency (EMA). Phages are not drugs, but living organisms and to be effective they must be personalized for each individual patient. In San Diego, California, about a year ago, the first phage therapy center in the Western world was established, which is dedicated to evaluating the therapy through clinical trials.
"They have never contacted us," says Alavidze, "but if they wanted to, we are ready to talk with them. I am certain that there is no competition between us, because each hospital has its own patients with specific diseases, but if we could all collaborate together, I believe this would really be a great achievement."
On the American market front, in 1998 the company Intralytix was founded by Alexander Sulakvelidze, a researcher from Tblisi who moved to the University of Maryland in 1993. “Our goal was to find a phage-based compound capable of treating dysentery. For this reason, we began the process of seeking FDA approval for various phage-based compounds, we carried out the first clinical trials for the treatment of skin wounds and burns, and now the first FDA-approved clinical trial for the treatment of Crohn’s disease is also underway 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 infrastructure to identify the most appropriate antibiotic therapy, could have similar infrastructure to also identify phage therapy.”
While waiting for this to happen, patients from all over the world arrive in the center of Tbilisi: America, Australia, Kenya and South Africa, but also European countries such as Germany, Poland, Switzerland, Belgium, the United Kingdom, and the Netherlands. “They are all chronic patients who, sometimes for decades, have always been treated with antibiotics that have caused them major side effects, such as the destruction of the bacterial flora and situations of immunodepression,” says Zemphira Alavidze. “It is really difficult to try to treat these patients within 2-3 weeks, but once the specific phage cocktail is found, improvements are immediately seen. After years and years of antibiotic treatment, it is very difficult to treat chronic conditions and it is necessary to continue 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. In India, epidemics of dysentery have been treated simply by putting phages in wells and giving people in the villages water that had been purified thanks to the phages. “Interest is shifting to Europe and America,” says Criscuolo, “because up to now we have used a lot of antibiotics. So it seems paradoxical, but here, where we have medicines, we also have all the problems related to how we use them. In fact, in Russia, Georgia, and poor countries, they do not have our problems regarding multi-resistance because they do not have the excessive use of antibiotics that we have in the Western world.”
© Academy for innovation in medical sciences