For years, a type of bacteria called Enterococcus faecium lurked in Lynn Cole’s bloodstream. Often found in hospitals, E. faecium is usually a gut-dwelling bacteria but can creep into other areas of the body. Her doctors tried various antibiotics, but the bacteria was zombie-like: It kept coming back.

Running out of options after a month-long hospitalization in 2020, Cole and her family agreed to try an experimental treatment called phage therapy. Phages aren’t drugs in the traditional sense. They are tiny, naturally occurring viruses that selectively kill bacteria. Highly specific to the bacteria they attack, phages are showing promise against hard-to-treat infections when antibiotics fail.

Phage therapy is not yet approved in the US, UK, or Western Europe but is used regularly in Georgia, Poland, and Russia. Several clinical trials are underway to confirm its safety and test its efficacy. But to treat Cole, researchers at the University of Pittsburgh School of Medicine first needed to find a phage that would work against her particular bacterial strain.

Phages live in places where bacteria live, which is to say, everywhere. “We have found that a good place to look for phages is in environments where the bacteria you want to target are abundant,” says Daria Van Tyne, assistant professor of infectious diseases at Pitt and an author on a study about Cole’s case that was published today in the journal mBio.

So Van Tyne and her team looked to a source that’s teeming with gut bacteria: wastewater. They screened dozens of phages they had isolated from wastewater samples, but couldn’t find a match. So they reached out to colleagues at the University of Colorado for help.

“The thing about phages is that they’re very much the perfect example of precision medicine, because they are so exquisitely specific to a bacterium,” says Breck Duerkop, an associate professor of immunology and microbiology at the University of Colorado Anschutz School of Medicine and an author on the study.

Phages recognize and attach to certain receptors on the surface of bacteria. After entering a bacterial cell, they make copies of themselves and disrupt the bacteria’s normal function, causing the cell to burst.

Van Tyne’s team mailed a sample of Cole’s bacteria to Duerkop’s lab, which had been studying phages that interact with E. faecium. Duerkop’s group tested the sample against phages they had also fished out of wastewater and found one that they thought would target the bacteria. They sent the phage to Pittsburgh, where Van Tyne and her team prepared it to give to Cole.

Since phages are viruses, they need a host in order to replicate. That means they have to be grown inside cultivated samples of the bacteria they infect. Bacteria grow quickly in the lab, but the phages have to be removed, purified, and then tested to make sure they’re safe for patients to receive. The whole process of making a suitable phage therapy can take weeks or even months from the time a lab gets a request.

Since the E. faecium was in Cole’s gut and bloodstream, the Pitt team made two formulations of phage: a drinkable version and an intravenous one given through a catheter. “We had no idea how much phage we would have to give to have any sort of effect,” Van Tyne says. “So we opted for giving the most that we thought we could safely give.” Phages have been found to be generally safe and produce few side effects since they only infect bacterial cells.

In June 2020, Cole, then 57 years old, started taking the phage three times a day alongside a course of antibiotics. Within 24 hours, her blood infection cleared and she was able to leave the hospital. She continued taking the phage at home, but developed a few short-lived breakthrough infections, which indicated that the bacteria was getting around the therapy.

Bacteria evolve and mutate as they replicate. In turn, a phage will try to coevolve with the bacteria to maintain its infectivity. Sometimes a phage can change to better infect its target bacteria, but sometimes the bacteria can outsmart it. “If you put bacteria and phage together, the bacteria will try and evolve around the phage,” Van Tyne says.

This is a potential liability with phage therapy, because the bacteria could evolve to evade the phage completely. So Van Tyne’s team reached out to Duerkop’s lab again to find a second phage they thought would work for longer. And this time, it did.

The phage cleared the bacteria from Cole’s blood for four months—the longest she’d been infection-free since first coming down with it. She was well enough to travel out of state with her partner and daughter for a much-needed family beach vacation. The Pitt team even shipped vials of the phage to the hotel where Cole’s family was staying.

But Cole’s progress was short-lived. Her blood infection returned, and her doctors determined the phage-antibiotic combination was no longer effective. She passed away from pneumonia in March 2022, seven months after phage therapy was stopped. Cole’s case demonstrates both the hope and limitations of phage therapy.

The problem this time wasn’t just bacterial evolution. When researchers ran follow-up lab tests on Cole’s blood, they found evidence of antibodies against the phage, meaning her immune system activated in a way that blocked the phage from attacking the bacteria. They suspect phage therapy may have a sort of tipping point, where giving too much of it could set off an immune reaction that prevents it from working.

Madison Stellfox, a postdoctoral infectious diseases fellow at Pitt and lead author of the study, says that what they’ve learned from Cole’s case will help inform how to use phage therapy more effectively moving forward, especially as clinical trials of phages are underway at Pitt and elsewhere. “From two to four weeks is probably where we’re getting the most bang for our buck with the phages before the body starts making antibodies against them,” she says. In other words, phages might be better as short-term treatments.

Two additional patients at other hospitals have since been treated with the same phage therapy that Cole received, and a third is about to be treated. About 20 patients total have been treated with phages across the University of Pittsburgh Medical Center’s hospitals, and 60 to 70 percent of them have responded to the therapy.

“Infections are complicated,” says Erica Hartmann, a microbiologist at Northwestern University who studies phages and was not involved in Cole’s case. “It’s not as simple as, there’s a bad guy and we treat the bad guy with whatever weapons we have.”

Persistent bacterial infections are difficult to treat because of the pathogen itself and conditions in the patient’s body. When a patient has an infection for a prolonged period of time, the bacteria has time to change and adapt. With heavy antibiotic use, bacteria evolve to thwart their effects. Add to that factors such as the person’s immune system, microbiome, and overall health—all of which affect how well they’re able to fight off the infection.

Saima Aslam, an infectious disease specialist at the University of California, San Diego and clinical lead of the Center for Innovative Phage Applications and Therapeutics, says one way to avoid phage resistance is to use several phages at once against an infection.

Bacteria can develop resistance to a phage by evolving to have different surface markers, so the phage can no longer recognize it. “Using a combination of three or four that have different ways of attaching to the bacteria is, I think, one way to overcome development or resistance,” Aslam says. If the bacteria changes such that one phage doesn’t recognize it, the others still should, she says.

Aslam says clinical trials will help shed light on which patients and what types of infections may be best suited for phage therapy. Her center has treated 18 patients with around an 80 percent success rate.

While phages are unlikely to ever replace antibiotics, they could be a powerful tool in combating drug-resistant bacterial infections—if researchers can figure out how best to deploy them.

For Cole’s daughter Mya, her final beach trip with her mom was a special one. Even though phage therapy didn’t save her, Mya is grateful for that extra time. “I’m very hopeful that what my mom was able to test out will be helpful for other patients so that they can be cured,” she says.