Phage therapy: Researchers sharpen another arrow in the quiver against antibiotic resistance

Lynn Cole was in a never-ending cycle of getting recurrent blood infections. And no antibiotic drugs managed to kill off her zombie-like bacteria.

“It just got so frustrating over the years because we couldn’t find the source, so we couldn’t figure out how to treat it and prevent it from happening,” said Mya Cole, Lynn’s daughter. Lynn would be in and out of the hospital. And because she had Sjogren’s syndrome — an autoimmune disease — her health continued to deteriorate.

In June of 2020, her doctors turned to one last resort: an experimental therapy involving the use of a bacteriophage — a virus that infects and multiplies in bacteria, effectively blowing the bacteria up. With her family on board and “compassionate use” approval obtained from the Food and Drug Administration, doctors at the University of Pittsburgh School of Medicine administered the phage therapy. Within 24 hours, there were no signs of bacteria growing in her blood and Lynn was eventually well enough to go on a beach vacation and see her favorite Ocean City Air Show in Maryland with her daughter and her partner, Tina Melotti — a tradition that had been on pause because of the uncertainty surrounding Cole’s condition.

Every couple of years, it seems, a case like Cole’s — published in mBio last week — surfaces, and there’s renewed excitement about the prospect for wider adoption of bacteriophage therapy as a much-needed antidote to the growth of antimicrobial drug resistance. By 2050, up to 10 million people could die every year, according to a 2016 review on antimicrobial resistance. Phages are found in waste and sewage water, can be closely matched to bacterial strains, and once purified seem to possess an almost magical ability to slay drug-resistant bacteria. But they don’t always work — indeed, Cole seemed to develop antibodies to the phage that was used against the Enterococcus that reared up in her yet again, and she died some months later.

Yet phages are promising enough that medical researchers and small biotech companies are now working hard to address some of the hurdles that have stood in the way of their more widespread adoption: building “libraries” of thousands of phages, improving the purification process by genetically engineering phages, and running clinical trials, so that treatments can finally gain FDA approval, rather than be attempted on a case-by-case basis.

Phage therapy has been around for more than 100 years, but with the advent of antibiotics and a possible influence of an unfavorable review published in the Journal of the American Medical Association in the early 1930s, phages fell out of favor and became a distant memory.

That all changed in 2016, when HIV researcher Tom Patterson, infected with antibiotic-resistant Acinetobacter baumannii from a trip some months earlier to Egypt, was cured with phage therapy. His wife, infectious disease epidemiologist Steffanie Strathdee, jumped into action on their return to the U.S., and researchers across the country helped her find the bacteriophages that cured him. She is now the co-director for the Center for Innovative Phage Applications and Therapeutics (IPATH) based out of the University of California, San Diego, which helps streamline the process of securing the right phage for a sick patient as quickly as possible.  

Building libraries

While IPATH and other research groups in this space are starting to assemble more robust libraries of phages — building on work begun after the discovery of phages in the early 1900s — they can’t possibly encompass all the strains of particular bacteria. Researchers at the University of Pittsburgh did not have a phage in their libraries that could target Enterococcus faecium, the bacteria that infected Cole. So the next step in 2020 was to “phone a friend” in their network of colleagues, said Daria Van Tyne, assistant professor of infectious diseases at the University of Pittsburgh and senior author of the case study. Looking in wastewater and sewage treatment plants, researchers at the University of Colorado were able to find the phages that helped Cole. 

The first thing to consider is the sheer number of phages found in nature. There are thousands upon thousands of phages — it’s impossible to know how many — that behave differently and can kill very specific bacterial strains. 

It’s kind of like having 100,000 different forms of ibuprofen, said Ryland Young, a bacteriophage expert and professor emeritus, biochemistry & biophysics, biology, at Texas A&M University.

In order to compensate, institutions have created libraries of phages organized by bacterial strain so researchers can quickly identify which phage is needed for a specific case. Expanding those libraries, said Strathdee, would help researchers spend less time hunting and more time matching phages with patients.

“If we had a phage library that was large and very well-characterized phages, we wouldn’t have to go to environmental samples,” Strathdee said. 

Varied outcomes

There is a spectrum of outcomes with phage therapy, Van Tyne told STAT. Some patients are completely cured. Conversely, there may be no response. In Cole’s case, her team was hoping for a total cure. “That’s what we hope for every patient we treat with phage,” said Van Tyne.

Cole’s positive response lasted six months, and greatly improved her quality of life. When she started to have breakthrough infections, the researchers even added an additional phage to her phage-antibiotic combo, which seemed to work. But then, Cole’s health took a turn for the worse.

Her body started making anti-phage antibodies and she was out of options. “As a family we decided that we would just enjoy our time and deal with it as it came,” said Mya Cole. After stopping phage therapy in the summer of 2021, Lynn Cole died of pneumonia in 2022. “My mom was a very firm believer that even if it didn’t help her, she wanted it to have some sort of impact on the medical world so it could impact somebody else’s life.”

Van Tyne and her colleagues are not sure why the phage therapy failed, but they think it either was because the introduction of the phages alerted her immune system or it could be that her gut microbiome changed. However, they do know that Cole’s bacteria never became resistant to the phages or antibiotics used.

There’s still a lot that is unknown about what makes a patient have a full, partial, or a non-response to phage therapy, said Madison Stellfox, a physician and postdoctoral infectious disease fellow in Van Tyne’s lab.

In order to find out more about how these phages work, Van Tyne and Stellfox are growing their program and planning to treat more patients. Since starting her lab in 2018, Van Tyne and her colleagues have treated almost 20 patients with phage therapy. Van Tyne believes that as more institutions do this research, phage therapy will move away from fringe medicine and into something mainstream.

It’s still the case, though, that whenever there’s a therapy available, it is usually for people who are very sick and can only get treatment through the FDA’s so-called compassionate use or expanded use program.

Clinical trials of phages

Standard approval won’t come with more such cases, because it “doesn’t matter if you do a thousand of them,” said Pierre Kyme, vice president of Armata Pharmaceuticals, a small biotech in Los Angeles. “The FDA is not going to approve phage therapy based on those cases, because there’s no way to determine safety.” There simply need to be more clinical trials, he said. There are about 90 clinical trials involving bacteriophages going on worldwide, with 41 studies in the U.S. IPATH has been involved in four clinical trials, with more in the pipeline, Strathdee said.

Armata has finished a Phase 1b/2a clinical trial for Pseudomonas phage in cystic fibrosis patients. It is also in the middle of a Phase 2 study for non-cystic fibrosis bronchiectasis patients using Pseudomonas phage. In addition, it currently has an ongoing Phase 1b/2a clinical trial that is using Staphylococcus aureus phage in bacteremia patients.

Armata has partnered with the Department of Defense — which awarded them about $16.3 million — on S. aureus bacteriophage research, and company CEO Deborah Birx told STAT that DoD is interested in research in connection with antibiotic resistance in Ukraine. Although DoD didn’t comment directly, Military Infectious Disease Research Program director Colonel Christian Hofer stated that: “Effective and timely mitigation and treatment of wound infections is critical for future near-peer conflicts where prolonged care will be required, especially due to the risk of antimicrobial resistance.”

Next year, Armata is planning an efficacy study. If Armata is able to find a funding partner, preferably a government-private corporation partnership, Birx believes that this study will provide the answer to whether phages are effective. Birx, a physician and HIV/AIDS immunology expert who was the White House coronavirus response coordinator under President Trump, continued: “We need a definitive answer as to whether phage can help us confront the growing antimicrobial resistance in a safe manner that’s effective, and preserves a patient’s microbiome, so that their integrity of their microbiome is not compromised.” 

But at the same time, researchers and biotech companies will need to find out ways to make the process of matching phages quicker and purifying them in a way that will not lead to side effects and other unintended consequences.

Bacterial debris

When growing phages, researchers need to start out with the target bacteria and infect it with the phage. The phage multiplies and blows the bacteria up. But all the bacterial debris, including the outer envelope, the proteins, and the toxins inside the bacteria, are also floating with billions of newly made phages. 

Getting rid of the bacterial debris is even more important when you consider bacteria like E. coli or Klebsiella, which are coated with toxins that can cause toxic shock, Young said, “so you have to get rid of that.” Young added that every phage has its own purification process, which can complicate mass production. As a result, companies might have to focus on certain phages with similar purification methods.

In Patterson’s case, the researchers were able to reduce the endotoxin levels in his phage therapy to meet FDA guidelines, but it took considerable effort.

Armata is trying to work its way around purification challenges, by genetically engineering the host bacteria to be as harmless as possible.

“We have engineered our host to remove a lot of those unwanted elements and made our production process as optimal as possible to provide the highest … number of phages in a production run as pure as we possibly can,” said Kyme.

But that’s where the engineering stops. Kyme and other researchers who spoke with STAT believe that using a natural phage is the way to go. Other companies, like Locus Biosciences in North Carolina, engineer different features in their phages.

On-demand phages and phage cocktails

Aside from manufacturing, getting the therapy to the patient might be another issue. For now, centers like IPATH and TAILΦR Labs need to go through the FDA in order to get an investigational new drug certification. Anthony Maresso, the founder of TAILΦR Labs, which is run out of Baylor College of Medicine in Texas, makes personalized therapies for compassionate use cases. The current turnaround time from a doctor’s request to treatment is at best three to four weeks, but it could take months, mainly because of the FDA’s approval process.

Maresso hopes that, one day, hospital pharmacies will be able to get their phages off the shelf to cut down on prep and FDA approval time. “We call it ready phage or on-demand phage,” said Maresso. “Instead of a month, we can have this ready in theory, in a couple of days.” Last June, TAILΦR Labs spun off a new biotech venture, PHIOGEN, to commercialize its work and bring phage therapy to more people. Maresso, who has currently helped create therapies for almost 30 patients so far, hopes that both the academic lab and the biotech startup will give more patients access to treatment.

Another area where researchers disagree is whether phages should be used in combination with antibiotics. Most of the researchers who spoke with STAT think that phages could be used in addition to antibiotics to help overcome antibiotic resistance.

“And it’s possible that would end up shortening the courses of antibiotics,” said Marcia Goldberg, an infectious disease physician at Massachusetts General Hospital and professor of medicine at Harvard Medical School. 

Armata, on the other hand, believes in using a cocktail of about five phages with no antibiotics, with each phage acting to counterbalance the risk of antimicrobial resistance.

“I look at phage as an alternative to antibiotics,” said Armata’s Birx. “There’s a lot of people in science who will say things can’t be done. I believe it’s our job for those of us who are driven to actually ask and answer those questions to prove that they can be done.”

The story has been updated with a comment from the DoD and clarification that Tom Patterson’s phage therapy involved multiple bacteriophages, and the purification process for those phages reduced endotoxins to levels required by the FDA.