Could a century old treatment be an answer to antibiotic resistance?

In a first in Canada, a patient with an antibiotic resistant artificial joint infection has received treatment with phage therapy and is showing promising early responses.“This is cutting edge stuff, and a potentially new technology,” said Dr. Marisa Azad, the infectious diseases physician who treated the patient. She is also an assistant professor of medicine at the University of Ottawa. The patient presented with severe periprosthetic joint infection (PJI) in the summer of 2023. She had already undergone multiple surgeries and had experienced several relapses and infections with the same persistent bacteria.“She’d been on multiple very prolonged courses of antibiotics and had a severe drug allergy to two major drug classes of antibiotics. I was extremely limited in what I could use to treat her,” Dr. Azad told the Medical Post in an interview.That’s when the idea arose of trying an experimental treatment course with phage therapy. The team got approval for doing the experimental treatment from Health Canada, and worked with Winnipeg-based Cytophage, which supplied the phages.“We developed a protocol and gave her therapy over two weeks while she was admitted to hospital. She’s completed her therapy. Now we’re monitoring her closely and giving her adjunctive antibiotics,” she said.The idea didn’t come out of the blue. In the medical literature, a study from just last year in Clinical Infectious Diseases provided a review of 33 previously published cases of patients with end-stage, refractory bone and joint infections (BJI) who underwent treatment with phage therapy. The authors found that from those case reports, “29 (87%) achieved microbiological or clinical success, two (5.9%) relapsed with the same organisms, and two (5.9%) with a different organism” with no serious adverse events.The conclusions of that paper stated there were “important advantages, disadvantages, and barriers to the implementation of phage therapy for BJIs.” Yet, at the same time, the authors added they, “believe that if phage therapy were to be used earlier in the clinical course, fewer cumulative antibiotics may be needed in an individual treatment course.”The word phage is short for bacteriophage, a word coined in 1917—literally meaning bacteria-eater. They are viruses whose lifecycle depends on certain types of bacteria. “They latch on to specific types of bacteria and inject their genetic material into the bacterial cell." Dr. Azad explained. "They take over the bacterial cells’ machinery to produce more little viruses inside and explode or burst open the bacteria,” releasing viral particles that can go and infect other cells of the same type of bacteria.Intriguingly, each phage targets a specific type of bacteria. The plus side is that phage treatment is associated with a low risk from treatments, with some reports saying they may be less likely to target non-targeted or ‘good’ bacteria. But, this targeting also means the treatment has to be matched to each individual patient’s infection, which takes time, and finding a match is not guaranteed. Unlike antibiotics—which can treat a variety of bacteria—phages have more discerning appetites.Various centres around the world have phage libraries used for research, and in some countries for treatment. In Canada, Cytophage’s library is used for research for agricultural applications as well as potential therapeutics. In the meantime, Dr. Azad said the PJI patient is showing some signs of improvement. “The indicators are heading in the right direction, but we’re monitoring her very closely,” she said. Her mobility has improved and there are hopeful signs some of the infection and inflammation are subsiding. The phage treatment is being used as an adjunct to antibiotic therapy, as evidence suggests phages can actually improve the effect of antibiotics, possibly by making the bacteria more vulnerable to them.There are a variety of potential applications in rheumatology and orthopaedics, Dr. Azad said. “If you have a patient with a joint infection, you often get septic arthritis, osteomyelitis and if there is underlying hardware with a metal implant, a periprosthetic joint infection. And they can even happen all at the same time. Phages can potentially be used to treat all of these infections, but we have to find the best ways to do this.” A long historyThe story of phages started over 100 years ago. They were independently discovered, first in 1915 by a British pathologist, Frederick Twort, and then again in 1917 by French-Canadian microbiologist Felix d’Herelle. D’Herelle isolated what he had described as an “anti-microbe” of Shigella and did further investigations of them as potential therapeutic agents against bacterial infections. Among his findings was that the presence of phages correlated with disease clearance in patients with dysentery. Throughout the 1920s and 1930s, several phage treatments were marketed for bacterial infections. However, at this time, other antibacterials became prominent, were more reliable, were cheap to produce, and many people moved away from phage research. However, the approach continued to be used in Russia, Poland and Georgia.While the approach has led to a lot of excitement, reliability and predictability of response continues to be an issue. A 2022 overview of the technology in Antibiotics stated that phage therapy clinical trials have not consistently reported efficacy even though there are “promising efficacy rates from a sizeable and compelling body of observational literature.”There is a need for large clinical trials, a sentiment echoed in an editorial in Nature Biotechnology which noted several limitations to the therapy. The need to find specific phages that can target a patient’s infection takes time, but computational methods may speed up the identification of phages that are good matches. In addition, future genetic engineering of phages may allow for the creation of phages that can better target troublesome bacteria and can be tailored to individual patients. The paper also stated that phage resistance can happen too, “although we’re also seeing that this can be avoided by using combinations of phages to target a bacterium, as it’s unlikely that a strain will evolve to be resistant to all phages in a cocktail.”The authors concluded that “It’s not likely that phage therapies will take the place of general antibiotic use, but hopefully as soon as they are shown to be broadly safe and clinically useful, they will be a much needed complement to the antibiotic armamentarium.”

Could a century old treatment be an answer to antibiotic resistance?

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