iIt was on the golf course that Barry Rud first noticed something was seriously wrong. A slim 60-year-old who played hockey as a young man found himself unable to take more than a few steps without gasping for breath. His doctors said he contracted a strain of Pseudomonas aeruginosa, one of the growing numbers of “superbugs” that have developed resistance to many common antibiotics.
Mr. Rud’s experience illustrates a growing problem – and a possible solution to it. 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 defused all sorts of once-dreaded diseases, from cholera to syphilis. They have dramatically reduced the risks of surgery (patients often died from infections caught on the surgeon’s table) and chemotherapy, which destroys the patient’s immune system.
But their magic is waning. Repeated exposure to a deadly threat has caused bacteria to become resistant to many existing antibiotics, reducing their effectiveness. At the same time, the pharmaceutical industry has lost interest in finding new ones. It’s been nearly 40 years since a new class of antibiotics has been available to patients. Some infections, including gonorrhea and tuberculosis, again become difficult to treat. An estimate, published in the Lancet in 2022, estimates that antibiotic resistance directly caused 1.2 million deaths in 2019 and was indirectly involved in 3.8 million more.
Since antibiotics could not cure his illness, Mr. Rud took a chance. He traveled to the Eliava Institute in Tbilisi, Georgia, one of the few institutions 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 human’s illness by inducing a germ within the germ that makes him sick.
“Fagen” are little known outside of the former Soviet Union countries, which did most of the developing the idea. In Georgia, they have been part of the local pharmacopoeia for decades. (Indeed, 2023 marks Eliava’s centenary.) Small bottles of stale-tasting liquid full of antibacterial viruses can be purchased from pharmacies throughout Tbilisi. As concerns about antibiotic resistance mount, Western companies are taking a second look.
Set phages to kill
Despite their name, bacteriophages infect their prey rather than eat it. Due to the abundance of bacterial life, phages are the most abundant biological entities on Earth. Most resemble a cross between a lunar lander and a spider. An icosahedral head (think of a 20-sided die) holds their genome and is attached to a tail of proteins that opens into a bundle of fibers. When the fibers encounter a suitable receptor on a bacterial cell wall, they bind the phage to its victim, drive its tail through the cell membrane and allow its genome to enter its new host.
One of two possible fates awaits the unfortunate bacteria. “Lysogenic” phages weave their own genomes into their host’s, keeping it alive with its new load of viral DNA. However, if the phage is “lytic”, it hijacks its host’s cellular machinery to make copies of itself. These proliferate until they erupt, killing the bacteria in the process. It is the last type of phage of interest to physicians.
As live antibiotics, phages have several advantages, at least on paper. Because they can make more of their own, initial dosages can be relatively small. Unlike chemical antibiotics, they can evolve as easily as their prey, potentially weakening a bacteria’s ability to develop resistance. And because of the myriad differences between human cells and bacterial cells, they are unlikely to harm the patient.
A century ago, phages were the most promising tool in the antibacterial arsenal. Felix d’Herelle, a microbiologist at the Pasteur Institute in Paris, used them to treat the first patient in 1919, after he himself reduced a dose to make sure 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 out of favour. During World War II, penicillin production increased sharply, displacing the phages. This has led to a shortage of good quality research data on its use in humans. (The UK’s first and only clinical trial of phages ended in 2009 and concluded they were both safe and effective against an ear infection). Available data indicate that phages are not harmful to humans. Four reviews of the available literature, all published since 2020, suggest very low rates of side effects (the figure for antibiotics, phage researchers are quick to point out, can be as high as 20%).
However, how well phages do to cure infections is another question. While encouraging anecdotal evidence has been trickling in for decades, regulators need large, formal clinical trials. A report published last year by the Antibacterial Resistance Leadership Group, a gathering of experts, concluded that the lack of data meant that phages were not ready for clinical use. “We have a lot of catching up to do,” said Steffanie Strathdee, director of the Center for Innovative Phage Applications and Therapeutics at the University of California, San Diego.
That uncertainty has not stopped a wave of medical tourism to the Eliava Foundation’s Phage Therapy Center. It treats more than 500 foreign patients per year. Most, like Mr. Rud, pay €3,900 ($4,300) for two weeks of on-site treatment and months of bottled phage to take home. Patients from more than 80 countries have visited the clinic.
The treatment consists of three steps. The first is to find out exactly which bacteria is responsible for the disease. Proper identification is crucial, as some phages are so target-specific that they can have different effects on two bacteria of the same species. Secondly, a phage must be found that can successfully attack the bacteria in question. This can sometimes be done simply by looking into existing phage libraries, of which the Eliava has one of the largest in the world.
However, sometimes the researchers have to hunt for something suitable. The core principle is to look for a phage in the same place where the bacteria it infects would be found. In practice, this often means a lot of laborious sieving of human sewage and hospital waste, as these are reliable sources of resistant bacteria. (So are urban rivers such as the Mtkvari, which flows past the Eliava’s grounds.)
Finally, the phages should be encouraged to grow and the resulting solution purified. While the number of laboratories that can replicate parts of this process is increasing, Vakho Pavlenishvili, the Eliava Foundation’s head of phage production, says it remains the only place capable of handling the entire process from bacterial analysis to phage recipe.
But the expertise is spreading. More clinical trials of phage therapy have been 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 begin the next round of testing sometime later this year. BiomX, an Israeli company, is testing a proprietary phage cocktail against P. aeruginosa, a common cause of hospital infections. Adaptive Phage Therapeutics, an American company, has three studies in the works: one in cystic fibrosis patients with opportunistic infections, one for infections in prosthetic joints and, like Technophage, one in diabetic foot ulcers.
One problem that potential phage therapists face is that phages, as natural entities, cannot be patented. One solution is tinkering with a phage’s genome, as edited genomes are considered for protection. A Danish company called SniprBiome hopes to produce tweaked phages capable of tackling E. coli infections. It has completed initial human trials and hopes to discuss larger ones with regulators later this year.
Even if the phages themselves can’t be patented, other things made from them can. Bandages or implants covered in phages are an example. Adaptive Phage Therapeutics has patented parts of its phage library and its rapid production process. The company hopes to go from identifying a bacteria to regulatory approval of a phage to kill it within six months. The same process can take 15 years for a new antibiotic, says Greg Merril, the founder.
Regulators are also adapting. In America, the Food and Drug Administration has enabled companies to accelerate their early-stage clinical trials. In 2018, regulators in Belgium passed new rules, known as the magisterial pathway, allowing pharmacies to sell phages to patients who hold a prescription. The researchers who lobbied for the new rules hope to see similar changes across the rest of the EU. “I find [British regulators] to be incredibly engaged and interested,” says Martha Clokie, a researcher at the University of Leicester. She is part of a collaboration that hopes to bring high-quality phage production to Britain, building a national phage library in the process.
And phages can also be used outside of medicine. They have been used to treat rot in cabbage for nearly a century. Trials have begun with potatoes, corn, citrus fruits and vines. Livestock farming consumes huge amounts of antibiotics and prescribes them to cattle and pigs to stimulate growth. That makes the industry a major driver of antibiotic resistance. ACD Pharma, a Norwegian company, has been researching the possible application of phages in fish farming for 15 years. In 2018, it launched a product to target a single bacteria in salmon. In 2022, sales increased by 1,000%. The company is trying to modify its product to target other types of bacteria as well.
Make it so
For now, however, these are all hopes rather than certainties. There are still plenty of questions to answer. Some are big and conceptual. For example, because phages are foreign bodies, they are likely to prompt a patient’s immune system to produce antibodies to neutralize them. That can be a problem, especially with repeat prescriptions, since a body ready to fight off a phage will have limited effectiveness. Whether phages can be adapted to overcome such defenses remains to be seen. Others are mundane but essential: doctors will have to work out the ideal dosage, the best delivery mechanisms and what kind of patients are best suited for treatment.
Even the most committed proponents of phages don’t think they will replace antibiotics. But they hope they can serve as a treatment for infections for which nothing else works, or as an adjunct to conventional antibiotics to boost their effects. However, for that to happen, the infrastructure needs to be built to properly explore the idea. The facilities to do that are simply not there right now. “We can receive a thousand patients,” says Dr. Sturua, back from the Eliava Institute. “But we can’t receive a million.” ■