It was on The golf course that Barry Rudd first noticed was seriously wrong. A short 60-year-old man who played hockey in his youth found himself breathless and unable to walk more than a few steps. His doctors said he had caught a strain pseudomonas aeruginosaone of the growing number of “Superbug” that have developed resistance to many common Antibiotic medicines,
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Mr Rudd’s experience illustrates a growing problem and a possible solution. Antibiotics are among the most spectacular achievements of medicine. A class of “silver bullet” drugs that destroy disease-causing bacteria while sparing the patient’s own cells, they have eradicated all manner of once-feared diseases, from cholera to syphilis. They have vastly reduced the risks of surgery (patients often die from infections caught on the surgeon’s table) and chemotherapy, which destroys a patient’s immune system.
But his magic is waning. Repeated exposure to a deadly threat has led bacteria to develop resistance to many existing antibiotics, blunting their efficacy. At the same time, most of the pharmaceutical industry has lost interest in discovering new ones. It’s been almost 40 years since a new class of antibiotics was made available to patients. Certain infections, including gonorrhea and tuberculosis, are once again becoming difficult to treat. A guess, published in Knife In 2022, antibiotic resistance is calculated to have directly caused 1.2 million deaths in 2019, and indirectly implicated in 3.8 million more.
With antibiotics unable to cure his illness, Mr Rudd took a risk. He traveled to the Eliava Institute in Tbilisi, Georgia, one of a handful of institutes specializing in the study of bacteriophages. These are viruses that infect and kill bacteria. The Eliava Institute uses them as live antibiotics, hoping to cure a person’s illness by inducing the bacteria that make them sick.
“Phages” are little known outside the countries of the former Soviet Union, which did most of the work to develop the idea. In Georgia they have been part of the local pharmacopeia for decades. (Indeed, 2023 marks Eliava’s centenary.) Small vials containing the rancid-tasting liquid filled with anti-bacterial viruses can be bought at pharmacies in Tbilisi. Now, as concerns grow about antibiotic resistance building, Western companies are taking a second look.
set phase to kill
Despite their name, bacteriophages infect their prey rather than eat them. Due to the abundance of bacterial life, phages are the most abundant biological entities on the planet. Most resemble a cross between a moon lander and a spider. An icosahedral head (think 20-sided die) holds their genome, and is attached to a protein tail that ends in a spray of fibers. When phages encounter a suitable receptor on a bacterial cell wall, they bind to their prey phage, driving their tails through the cell’s membrane and allowing their genome to enter their new host.
One of two possible fates awaits the unfortunate bacterium. “Lysogenic” phages weave their own genome into their host, leaving it alive with its new cargo of virulence dna, If the phage is “lytic”, however, it hijacks its host’s cellular machinery to assemble copies of itself. These expand until they burst, killing the bacteria in the process. It is the latter kind of phase that is interesting to doctors.
As living antibiotics, phages have several advantages, at least on paper. Since they can make more of themselves, the starting dose may be relatively low. Unlike chemical antibiotics, they can evolve as easily as their prey, potentially blunting a bacterium’s ability to develop resistance. And the myriad differences between human cells and bacteria mean they can’t do any harm to the patient.
A century ago, phages were one of the most promising tools in the antibacterial arsenal. Félix d’Herelle, a microbiologist at the Pasteur Institute in Paris, used them to treat the first patient in 1919, after reducing the dose to ensure they had no harmful effects. One of his colleagues was a young Georgian scientist named George Eliava, who returned home to found the institute that now bears his name.
But with the discovery of penicillin, the first antibiotic, in 1928, phages fell from favor. Production of penicillin increased during World War II, which led to the phasing out. This has left a dearth of good quality trial data on their use in humans. (The first and so far only clinical trial on phages in the UK ended in 2009, concluding that they were both safe and effective against ear infections). What data exist indicates that phages are not harmful to humans. Four reviews of the available literature, published since 2020, suggest very low rates of adverse effects (the figure for antibiotics, the Phage researchers are quick to point out, could be as high as 20%).
However, how well the phages actually do at clearing the infection is another question. Although there has been encouraging evidence for decades, regulators require larger, formal clinical trials. A report published last year by the Antibacterial Resistance Leadership Group, an assembly of experts, concluded that a lack of data meant the phages were not ready for clinical use. “We have a lot of catching up to do,” says Stephanie Strathdee, director of the Center for Innovative Phage Application and Therapeutics at the University of California, San Diego.
That uncertainty hasn’t stopped a wave of medical tourism at the Eliava Foundation’s Phage Therapy Center. It treats more than 500 foreign patients in a year. Like Mr Rudd, most are charged €3,900 ($4,300) for two weeks of on-site treatment and months of bottled phage to take home. Patients from over 80 countries have visited the clinic.
Treatment includes three phases. The first thing to do is to find out which bacteria is responsible for the disease. Proper identification is important, as some phages are so target-specific that they can have different effects on two bacteria of the same species. Second, a phage has to be found that can successfully attack the bacterium in question. This can sometimes be done by looking at existing phage libraries, of which Eliava is one of the largest libraries in the world.
However, sometimes, its researchers must go on to find something suitable. The main principle is to look for the phage in the same place where one infects the bacteria. In practice this often involves very laborious sifting through human sewage and hospital waste, as these are reliable sources of resistant bacteria. (There are similar urban rivers such as the Matkavari, which runs through the Eliyava plain.)
Finally, the phage must be encouraged to grow, and the resulting solution must be purified. Although there are a growing number of laboratories that replicate parts of this process, Vakho Pavlenishvili, head of phage production at the Eliava Foundation, says this is the only place capable of handling the entire process, from bacterial analysis to phage prescription.
But expertise is spreading. More clinical trials of phage therapy have started worldwide in the last three years than in the previous two decades (see chart). In 2022, Technophage, a Portuguese company, completed a trial of a phage cocktail designed for patients with diabetic foot ulcers. It hopes to start the next round of trials sometime later this year. BioMax, an Israeli firm, is testing its own phage cocktail P. aeruginosa, a common cause of hospital-acquired infection. Adaptive Phage Therapeutics, a US firm, has three trials in the works: one on cystic-fibrosis patients with opportunistic infections, one for infections in prosthetic joints, and, like TechnoPhage, one on diabetic foot ulcers.
One problem facing potential phage therapists is that, as natural entities, phages cannot be patented. One solution is to tamper with the genome of the phage, as edited genomes are eligible for protection. A Danish company called SniprBiome hopes to produce tweaked phages capable of dealing with e coli Infection. It has completed initial testing in humans, and is expected to discuss larger ones with regulators later this year.
Even if the phages themselves are not patentable, other things made from them can be patented. Phage coated dressings or implants are an example of this. Adaptive Phage Therapeutics has patented parts of its phage library and its high-speed manufacturing process. The firm hopes to be able to go from identification of a bacterium to regulatory approval of the phage to kill it within six months. Its founder, Greg Merrill, says the same process can take 15 years for a new antibiotic.
Regulators are also adapting. The Food and Drug Administration in the US has allowed companies to accelerate their early-stage clinical trials. In 2018 Belgian regulators adopted new rules known as the magisterial pathway, which allow pharmacies to sell Phage to patients who have prescriptions. Researchers lobbying for the new rules hope to see similar changes in the rest of the world European Union, “I feel [British regulators] “To be incredibly engaged and interested,” says Martha Clokey, a researcher at the University of Leicester. He is part of a collaboration that hopes to bring high quality phage manufacturing to the UK and build a national phage library to go with it.
And phages may find uses outside medicine, too. They have been used for almost a century to treat rot in cabbage. Trials have begun on potato, maize, citrus fruit and grape vines. Animal husbandry consumes large amounts of antibiotics, which are given to cattle and pigs to stimulate growth. This makes industry a huge driver of antibiotic resistance. ACD A Norwegian firm, Pharma, has spent 15 years researching the potential application of phages to fish farming. It launched a product in 2018 to combat a single bacterium in salmon. Sales increase by 1,000% in 2022. The firm is also trying to adapt its product to deal with other types of bacteria.
make it so
For now, though, these are all hopes rather than certainties. Many questions remain to be answered. Some are big and conceptual. Since phages are foreign bodies, for example, they are likely to induce the patient’s immune system to produce antibodies to neutralize them. This can be a problem, especially with repeated prescriptions, as the primary body to repel a phage is one in which its effectiveness will be limited. Whether phage can overcome such defenses remains to be seen. Others are banal but necessary: Doctors will need to work out the ideal dosage, the best administration mechanism, and what types of patients might be best suited for the treatment.
Even the most dedicated advocates of phages don’t think they will replace antibiotics. But he hopes they could serve as a treatment for infections for which nothing else seems to work, or as a complement to conventional antibiotics to strengthen their effects. For this to happen though, the infrastructure will need to be built up to properly explore the idea. For now, the facilities to do this do not exist. Back at the Eliava Institute, Dr. Sturua says, “We can get a thousand patients.” “But we can’t get a million.”
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