Viruses to Fight Superbugs? Scientists Are Working on It

Phages may help fight drug-resistant infections—but finding the right ones for each bacterium is no mean feat.

In 2015, Steffanie Strathdee, distinguished professor of medicine and associate dean of global health sciences at the University of California, San Diego (UCSD), was confronted with an antimicrobial-resistant infection the likes of which she had never come across. The patient involved was a man who had developed pancreatitis, an inflammation of the pancreas, but further investigation revealed this was just the tip of the iceberg. A CT scan revealed a large pseudocyst—a sac inside the man’s abdomen—that had likely been there for months. The pseudocyst had offered a perfect environment to harbor bacteria, and it had become home to a particularly nasty bug: a multidrug-resistant strain of Acinetobacter baumannii, a bacterium that tops the World Health Organization’s priority list of pathogens for which new antibiotics are critically needed. 

In this case, the infection was resistant to almost all antibiotics, with just partial sensitivity to a few “last-resort” drugs that are reserved for the most serious resistant infections and come with the risk of hefty side effects. Faced with an infection that was rapidly getting worse, Strathdee was desperate to find a solution that might save the man’s life. It was particularly crucial to her because this wasn’t just any patient. It was her husband.

Strathdee and her husband, Thomas Patterson, had been on holiday in Egypt when things had started to go wrong. They’d just enjoyed a final dinner on their trip, a romantic meal under the stars aboard a cruise ship on its way to Luxor, when Patterson had begun to feel unwell. He then vomited through the night. “I just thought he had food poisoning, and I was a bit annoyed because he was keeping me up,” Strathdee says. But as the night turned to morning and Patterson’s condition worsened, a trip to the local clinic resulted in the diagnosis of acute pancreatitis. Patterson was medevaced to Germany, where the pseudocyst was discovered—about the size of a football and full of murky brown liquid, indicative of a microbial infection. A sample was cultured, and the results were even more worrying: A. baumannii.

For Strathdee, the implications of the test results were not immediately apparent. An epidemiologist rather than a medical doctor, she recalled studying A. baumannii during her undergraduate microbiology training decades previously. Back then, she says, it was seen as a “really wimpy organism.” But with antimicrobial resistance on the rise, A. baumannii has evolved into a much more dangerous threat. In the US, it has gained the nickname “Iraqibacter” because of its prevalence among wounded soldiers who have picked up infections while serving in Iraq and other Middle Eastern countries. The reason it is such an urgent threat is because it is particularly adept at gaining resistance via multiple mechanisms—including through plasmids, DNA molecules that bacteria pass between one another—meaning many infections are multidrug-resistant or even pandrug-resistant. “I consider it something of a bacterial kleptomaniac,” Strathdee says. “It’s really great at stealing antimicrobial resistance genes from other bacteria and the environment.”

An antibiotic sensitivity test revealed that Patterson’s infection was indeed highly drug-resistant. Patterson was ultimately medevaced back to San Diego, where he took up residence in the intensive care unit. In one sense, Strathdee and Patterson had everything on their side: They were back on home turf, and the leading experts treating Patterson’s infection were not just colleagues but friends. Robert “Chip” Schooley, head of infectious diseases at UCSD, had been offering advice from the onset of Patterson’s illness, first over the phone and then in person on their return. Yet with the infection becoming resistant to all antibiotics, there was not much to be optimistic about. The pseudocyst was still there, and Patterson was now so frail that surgery was not an option; without any drugs in their arsenal, there was too great a risk that the infection could get into the bloodstream.

Over the course of several months, he kept getting sicker. One of the drains placed in his abdomen to remove infected fluid slipped, and the bacteria spread to his bloodstream, causing him to go into septic shock. After that, the bacteria were everywhere; he was fully colonized. His organs began to fail and he was in a coma. Strathdee could barely believe it: Not so long ago he’d been climbing into pyramids and jumping onto boats, and now he was fighting for his life. “I’m an infectious disease epidemiologist, so it was really like God’s cruel joke,” she says.

With antibiotics offering no solution, Strathdee resolved to leave no stone unturned in trying to find a cure for her husband. “I did what anybody would do,” she says. “I hit the internet.”

It was while browsing results from the biomedical search engine PubMed that Strathdee came across an unconventional idea: bacteriophages. A bacteriophage (often just known as a phage) is a type of virus that infects bacteria but doesn’t infect human cells. Once a phage has infected a bacterial cell, it effectively hijacks the cell’s mechanisms to turn it into a phage-producing machine. The resulting phages eventually burst out of the cell, destroying it, in an action called lysis.

It’s an attractively simple idea: Use a virus to infect the bacteria that are infecting a person. And it’s by no means new. Bacteriophages were discovered in the early 20th century and were even used to treat bacterial infections in the 1920s and 1930s, especially in the former USSR. But with the discovery of antibiotics, bacteriophage research became largely forgotten, at least in the West. Antibiotics were so good at treating bacterial infections, and the early research around phages was not enough to convince many researchers to pursue them as a potential therapy. There was perhaps an element of geopolitical stigma that put off Western researchers, too: Phages were still being used in the USSR, particularly in Georgia, where the Eliava Institute, an influential center for bacteriophage therapy, was opened in 1923.

Strathdee found a paper referencing phage therapy in relation to A. baumannii, but she couldn’t find any record of it being used in humans. Nevertheless, she decided it had to be worth a shot.

One of the difficulties of phage therapy is that you need to match the right phage with the right microbe. Phages are found in the same places as the bacteria they feed on: in the environment and inside our own bodies. To find ones that might be effective against particularly nasty bugs, you need to look where you might also find those particularly nasty bugs—like in a festering swamp, or a sewage system. But phages can be picky: The team treating Patterson would not just need to find phages that worked against A. baumannii in general but ones that worked against the exact bacteria taken from his sample—his “bacterial isolate.” And one phage wouldn’t be enough; as with antibiotics, bacteria can evolve to defend themselves against phages, so it would be more effective to use a cocktail of different phages attacking from multiple angles. “If you only have one phage, you’re giving the bacteria a leg up to develop resistance to the phage,” Strathdee explains. Thus began a search for laboratories with phage libraries that might have one active against Patterson’s infection.

Testing a phage is quite straightforward in principle. First, you take a sample of the bacteria from the infected person and grow it in the lab. Researchers then use something called a plaque assay: They take a Petri dish of agar and spread the bacteria over it, then add small drops of different phage solutions and let the whole thing incubate. The bacteria grow, forming an opaque layer. But in some places, it may appear to have small holes, like a slice of Emmental cheese. Here, the bacteria have been killed, leaving a small clearing or “plaque”—and indicating that the phages placed on that spot have succeeded in infecting the bacteria. Researchers then test these promising phages further against the bacterial isolate.

With the assistance of many helpers, the UCSD team managed to identify several phages that showed promise. The full story, which involves several laboratories around the world, assistance from the US Navy, and a race to get permission to apply the phages under compassionate use, is detailed in Strathdee and Patterson’s book, The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug.

Just as difficult as finding the phages was then figuring out how to purify and administer them. Phages aren’t a standard therapy by any means; there was no handy guide. The team had little to go on in terms of dosage or how to apply them, but with Patterson by that point facing almost certain death without any intervention, they pushed ahead with the best regimen they could think of. “We injected a billion phages per dose every two hours in his body, and it was the scariest day of my life when we did that because it could have cured or killed him, nobody knew,” Strathdee says. (This dose was later reduced.)

A couple of days after treatment started, Patterson woke up from his coma. Against almost all expectations, the phage therapy had worked. “One of the doctors described it as a Hail Mary pass in the last quarter of the football game, where the quarterback is blindfolded, throwing the ball over 100 yards down the field and hoping that somebody will catch it,” Strathdee recalls. “And they did.”

Engineered Phages

Patterson is a member of a very small club of people who have been treated with bacteriophages in this way. But since his recovery, there has been more interest in using phages when patients are out of other options.

Graham Hatfull, a professor of biological sciences at the University of Pittsburgh in Pennsylvania who studies phages, says he had never really been involved in therapeutic applications. He’s not a physician or a clinician, but a “nerdy basic biologist.” He is interested in characterizing the genetic diversity of phages and works with thousands of students to isolate and catalog them, with a focus on phages that infect a group of bacteria called mycobacteria. The Mycobacterium genus includes Mycobacterium tuberculosis, which causes TB, as well as many other species that are important to human health.

But in 2017 Hatfull was contacted by James Soothill, a consultant microbiologist at Great Ormond Street Hospital in London, about a patient who was in a bad condition. The patient was a 15-year-old girl with cystic fibrosis who had been fighting an infection caused by drug-resistant Mycobacterium abscessus, which got worse after she had a double lung transplant (likely aided by the immunosuppressive medication needed to support the transplant). The wound from the transplant turned red and infected, and her body was covered in infected sores and nodules. Standard treatments weren’t working.

Prompted by the girl’s mother, Soothill was considering the idea of phages. Might Hatfull have something in his catalog of phages that could work against this patient’s M. abscessus?

Hatfull and his team tested the girl’s isolate against their collection and came up with a few potential matches—“but not very many, and we had to look really hard to find them amongst our collection,” he says. There’s another step to finding effective phages, however. For phages to kill bacteria, they need to be “lytic,” causing lysis of the cell by rupturing the cell membrane. But some phages, known as temperate phages, don’t always do this. They may kill bacterial cells most of the time, but sometimes they are instead “lysogenic,” which means they enter the bacterial cell but then become incorporated within it, allowing the bacteria to survive. “A phage that only kills 90 percent of the time isn’t going to be very good therapeutically, because 10 percent of quite a lot of bacteria is still a lot of bacteria,” Hatfull says.

Not only do you need to find the right phages for a particular bacterial infection, then—they must also be lytic ones. But many phages in Hatfull and his team’s collection are temperate, including two of the three they wanted to combine into a cocktail to treat this patient.

Their solution? Genome editing. They engineered the genomes of the phages such that they would always be lytic, by removing the genes needed for lysogeny. By doing this, Hatfull explains, “We’ve essentially converted a naturally occurring temperate phage into one that’s now lytic, and essentially moved it from the ‘can’t use’ category into the ‘potential use’ category.” He credits the basic biology his lab has been doing for the fact that they had such tools at their disposal; only by studying the genetics of phages did they have the knowledge and ability to do this engineering.

To decide on the details of how to administer the phages, Hatfull and his colleagues worked with Chip Schooley, who had been instrumental in Patterson’s treatment. Again, they had very little to go on; there is no real known optimal dose for intravenous phage therapy. They decided on a dose of a billion phage particles, twice a day. Giving such an experimental treatment, says Hatfull, is scary: “You spend a lot of time thinking about all the things that could go wrong, and then worrying about all the things that [you’re] not smart enough to think about.”

The treatment, as Hatfull and colleagues reported in Nature Medicine, was well tolerated, and the girl’s condition improved. It took a few weeks, but there was a reduction in bacterial load, the wound from her lung transplant closed, and her skin cleared up. Since this experience, Hatfull has been approached by many physicians—he estimates more than 200—who are interested in exploring phage therapy for their patients. But at the moment, in the US at least, phage therapy is still very experimental, permitted only on a case-by-case basis when there is no alternative.

For his part, Hatfull says he remains skeptical about whether phages will ever become a common therapy. In their paper on the M. abscessus case, the researchers noted that the patient’s condition might have improved anyway—it’s hard to draw solid conclusions from a one-off attempt. Clinical trials will be needed to see if phages could have widespread application.

One particular challenge with using phages on a larger scale is their specificity—the fact that they need to be tailored to a particular bacterial isolate rather than just a species of bacteria. This, Hatfull says, is “the critical factor that has complicated the advancement of phage therapy in the big picture.” Tailoring a treatment to an individual is expensive and time-consuming, and would make it difficult to adopt phage therapy as a straightforward alternative to antibiotics.

Perhaps, Hatfull suggests, phages could be a boutique treatment for certain infections where patients have little other recourse. Or they could be useful as an adjunct to antibiotics to treat specific infections if clinical trials show that combining the two therapies leads to better results. A future approach to phage therapy could be to design and make them synthetically, engineering them to be maximally effective. This could potentially help with the problem of specificity: If you could engineer a phage so that it works against more bacterial strains, maybe it would be possible to deploy it more broadly.

All of this is a long way off—there are regulatory and commercial hurdles, as well as scientific ones to overcome—but research groups and companies are starting to study phage therapy with renewed interest. Strathdee is now codirector of UCSD’s Center for Innovative Phage Applications and Therapeutics, which she founded with Chip Schooley in 2018 and which treats patients with phages on a case-by-case basis, according to the US Food and Drug Administration’s compassionate use program.

She also sees phages as a potential adjunct to, rather than replacement for, antibiotics. In her husband’s case, the bacteria mutated to stop the phages from working but in doing so made themselves more vulnerable for one of the antibiotics to attack. “So that kind of synergy where phages and antibiotics can be used together can be very powerful,” she says.

She hopes that phage therapy will allow us to use fewer antibiotics—crucial for keeping resistance at bay. As well as being used in medicine, perhaps they could find applications in veterinary care, agriculture, or aquaculture. It’s early days. But based on her experience, she is keen to act as an advocate for phage therapy. She recognizes that she and Patterson were incredibly privileged to have access to the resources they did. “The majority of people dying from superbug infections are in low-resource settings that don’t have access,” she says.

Vicki Turk is the author of Superbugs: How to Prevent the Next Global Health Threat. Find out more and order your copy of the book.

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Viruses to Fight Superbugs? Scientists Are Working on It

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