Many deaths worldwide every year are due to antibiotic-resistant bacteria. The silver bullet of antibiotics has become obsolete a good 90 years after their discovery. In the search for alternatives, attention turns to a treatment that has been used for decades, especially in the former Eastern bloc: phage therapy.
Just earlier this year, scientists published a systematic analysis of the “global burden of bacterial antibiotic resistance” in the journal The Lancet. According to it, around 4.95 million people lost their lives to antibiotic resistance-related diseases in 2019 alone. Among them, 1.3 million people died from the direct consequences of antibiotic resistance. The researchers analyzed data on 369 diseases and injuries in 204 countries and territories. Alone from the consequences of an infection with antibiotic-resistant Escherichia coli (E. coli) around 200,000 people died in 2019.
Doctors are now rediscovering a therapy that was used a long time ago but is not known to many: phage therapy. It uses so-called bacteriophages to fight infections. They were discovered by English bacteriologist Frederick Twort and French-Canadian microbiologist Felix d’Hérelle more than a decade before penicillin was discovered in 1928.
An adult human has 40 trillion bacteria and 300 trillion phages
“Due to the use of antibiotics, with their much broader effectiveness and ease of use, the use of phages in Western countries receded into the background after the Second World War,” explains physician Christian Kühn, head of the National Phage Center at Hannover Medical School. In the so-called Eastern Bloc countries – where there was initially no broad access to antibiotics – phages continued to be used. To this day, institutions from such countries are world leaders, most notably the Georgi Eliava Institute in Tbilisi, Georgia.
Bacteriophages are viruses that specifically infect and kill bacteria. They are always around and within us. “Where there are bacteria, there are always phages,” says Holger Ziehr, Head of Pharmaceutical Biotechnology at the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM). An adult human consists of about 30 trillion body cells, 40 trillion bacteria – and 300 trillion phages, says Christian Willy, Director of the Clinic for Trauma Surgery at the Bundeswehr Hospital in Berlin. These viruses don’t know what to do with human cells, they only know one target: bacteria. “A zoonosis of phages in higher cells is completely unimaginable,” says Holger Ziehr.
While antibiotics work more like a weapon of mass destruction against bacteria, phages only attack one type of bacteria, very often only a specific strain of a type. “There are no broad-spectrum phages,” says Ziehr. The viruses dock onto specific receptors in the bacterial cell, which, like a key in a lock, have to fit the phage structures exactly. They then set multiplication programs in motion in the cell – until the mass of newly produced viruses causes the bacterial cell to burst.
The right bacteriophages have to be found for each disease
Due to their specificity, bacteriophages do not destroy any bacteria that are important for health, for example in the intestine, as is the case with antibiotics. The problem with therapy, however, is that the appropriate phage must first be found for the respective bacterial strains of a patient. “And usually more than one strain plays a role in a critical infection,” says Ziehr. Different strains and subtypes can also dominate regionally.
But where can you find suitable phages to fight a pathogen? Often in the sewage. First, the bacteria against which phages are to be used are cultivated on special nutrient plates. A wastewater sample is then placed on this bacterial lawn. This is called a lysis test: If a phage that kills the bacterium is present, a hole is created in the bacterial lawn – the attacker is isolated from this spot and multiplied in the laboratory.
A suitable phage can usually be found quickly, says Wolfgang Beyer from the National Phage Forum (NFP), who conducts research at the University of Hohenheim. Examples from the USA show that it is possible to create a phage therapy for a patient within ten days, says Christian Kühn from the Hannover Medical School. During therapy, it must then be monitored whether the germ remains sensitive to the phage. Within a short time, a germ can change in such a way that the initially suitable phage can no longer fight it.
The world’s leading Georgi Eliava Institute in Tbilisi has the most knowledge and experience, “the institute’s phage bank contains well over 1,000 phages,” says Wolfgang Beyer. The institute mainly works with five phage mixtures and one single-phage preparation for common diagnoses such as infections of wounds, gastrointestinal tract, urogenital system and ear, nose and throat area.
There are initial successes with infections of the lungs where antibiotics fail
Phage research has also been revived in the West for several years. “Since the international community realized that the problem of antibiotic resistance will be associated with millions of deaths every year,” says Beyer. However, as Christine Rohde from the Leibniz Institute DSMZ in Braunschweig says, there are still no results from large clinical studies, such as in drug research, on the phages that can often only be used individually. Individual case reports, however, showed success. Infections of the lungs, for example, which had been treated for years and where antibiotics failed, were successfully combated with phages.
In Germany, the “Phage4Cure” project started in 2017, which is a therapy with inhalable phages against the hospital germ Pseudomonas aeruginosa should develop. This germ often colonizes the lungs of cystic fibrosis patients. A clinical phase I study should start in late summer, says Christine Rohde. In this phase, tolerance is tested on a small number of healthy people. Contrary to what is usually the case, there is also a group with cystic fibrosis patients. “If phase I is successful and the patients feel better, then a real milestone for phage therapy in Germany will have been reached.”
The work on the project has shown one thing, says Ziehr, whose team produces the phage solution used: “Phages should not be underestimated in terms of complexity and cultivation in the laboratory.” But there is still a lot to be clarified. There is currently no general legal framework for the therapeutic use of phages in Europe, says the Berlin phage researcher Christian Willy. Approval authorities such as the European Medicines Agency (EMA) and the Federal Institute for Drugs and Medical Devices (BfArM) have a hard time with this. “The researchers have been waiting for years, neither production nor purification and use have been regulated so far,” says Wolfgang Beyer from the National Forum Phage (NRP).
Of the Western European countries, Belgium is ahead in phage therapy. Willy says that it has been used more intensively there for about 15 years. France and the USA are also active. There was only recently reported on a lung transplant in a young cystic fibrosis patient, which was only made possible by phage therapy. The man is now 26 and leads a normal life, according to the journal Cell.
Resistant bacteria could become sensitive to antibiotics again through phages
In addition to “Phage4Cure”, the second major German project also relies on individual production for individual patients: the “PhagoFlow” project carried out at the Bundeswehr Hospital in Berlin. Here, different illnesses caused by different pathogens are to be treated, as project manager Willy explains. Regarding the status of the project, he says: “The decision of the trade inspectorate in cooperation with the BfArM is still pending.” The struggle for the permits is a long struggle. “We could be so much further with the German projects,” says Willy. He is hopeful that there will be a solution by June. “The first patients could then be treated from the second half of the year.”
But even in the event of approval, phage therapy will by far not be a solution in every case. According to researchers, there are places in the body that phages cannot reach. Diseases that could hardly be treated included tuberculosis and borreliosis because the pathogens hid in body cells. In the future, the combination of bacteriophages and antibiotics could be particularly promising – based on the so-called phage-antibiotic synergy (PAS). According to the Berlin researcher Christian Willy, it has been shown that resistant bacteria in a patient can become sensitive to antibiotics again if the patient has previously been treated with phages. (dpa/fwt, BLZ)