A woman's oozing wound failed to heal after nearly two years of antibiotic treatments intended to vanquish the bacterial infection. So her doctors unleashed viruses to slay the superbug.
The experimental therapy specifically involved viruses that infect bacteria, known as bacteriophages, or "phages" for short. And although antibiotics alone had failed to heal the patient's infection, a combination of antibiotics and phage therapy seemed to do the trick, according to a new report of the case, published Tuesday (Jan. 18) in the journal Nature Communications.
"A few days after the treatment, the patient's wound was already dry," meaning pus no longer seeped from the wound, "and the skin was changing color from greyish to pink," Dr. Anaïs Eskenazi, the study's first author and a specialist in internal medicine and infectious disease at CUB-Erasme Hospital in Brussels, Belgium, told Live Science in an email.
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Three months after the phage therapy, doctors could find no lingering signs of the superbug in the patient and her wound was steadily healing. And in the three years after the treatment, the bacterial infection has not returned.
"I see this as convincing evidence that you can get antibiotic and phage synergy," meaning that the bacteriophages and drugs work together to kill superbugs more effectively, said Paul Turner, a professor of ecology and evolutionary biology at Yale University, who was not involved in the study. This kind of synergistic effect has cropped up in prior studies, including Turner's own work, and the new case report provides further evidence of how that effect could be helpful to human patients.
Phage-antibiotic synergy
The concept of using viruses to kill bacteria first emerged more than a century ago, nearly a decade before the discovery of penicillin in 1928, according to a 2017 report in the World Journal of Gastrointestinal Pharmacology and Therapeutics. However, scientists' understanding of phages was limited at the time, and following the discovery and pharmaceutical production of antibiotics, the field was largely abandoned. However, various research groups in the former Soviet Union and Eastern Europe continued to study phage therapy and ran human trials of the treatment, with varied success.
Interest in phage therapy resurfaced within the last decade, as scientists began searching for new strategies to take down antibiotic-resistant superbugs. One wrinkle is that phage therapy isn't fool-proof — just as bacteria can evolve to outwit antibiotics, they can also evolve resistance against specific phages, according to a 2021 report in the journal Proceedings of the National Academy of Sciences. The difference is that phages can readily evolve to overcome that resistance and fight back. Plus, bacteria can't easily swap phage-resistance genes as they do antibiotic-resistance genes, Turner noted.
With this in mind, scientists are now studying how they can leverage the genetic flexibility of phages in the fight against superbugs. The new case study provides an example of how phages can be "trained" to kill specific bacteria very effectively, through a process called "pre-adaptation."
The patient involved in this case developed a superbug infection following a major surgery on her left thigh. Her femur, or thighbone, was broken during the bombing that took place at the Brussels Airport in March 2016, and doctors used pins, screws and a stablizing frame to fix the bone in place after tending to her other traumatic injuries.
Unfortunately, the woman's surgical wound then became infected with Klebsiella pneumoniae, a bacterium that causes various health-care-related infections, according to the Centers for Disease Control and Prevention (CDC). That means that patients can become exposed to the bug while using a ventilator, receiving medications through an IV, or undergoing surgery, as in this patient's case.
Many Klebsiella bacteria have evolved resistance to antibiotic drugs, according to the CDC. In this case, biopsies revealed that the patient carried two strains of K. pneumoniae, one of which exhibited an "extensively drug-resistant phenotype." After three months in the hospital, "the patient had been under various regimens of antibiotics but the femoral fracture was still not consolidated and the infection was persisting," Eskenazi said. At this point, the medical team began considering phage therapy.
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The patient was a good candidate for phage therapy, in part, because her infection was associated with biofilms, Eskenazi said. Biofilms form when colonies of bacteria stick to a surface and produce a 3D matrix that surrounds their cells, like a kind of protective barrier. Antibiotic drugs struggle to penetrate these films, and even when they do, some bacterial cells survive the antibiotic onslaught by going dormant. Antibiotics typically work by disrupting a bacterial cell's function, essentially causing it to short-circuit, so the drugs don't work on dormant cells, Live Science previously reported.
But even when antibiotics fail to destroy bacteria locked behind biofilms, phage therapy may bring down these superbugs, Eskenazi said.
"Many phages are known to have the capacity of destroying the biofilm and thus make it easier for antibiotics to reach their targets," she said. To identify the best phage for the job, the medical team took samples of the patient's K. pneumoniae strains and sent them to the George Eliava Institute of Bacteriophages, Microbiology and Virology, in Tbilisi, Georgia, a nonprofit institute that studies phages and their potential applications.
Drawing from the institute's extensive library of bacteriophages, researchers identified a phage that could efficiently infect and kill the patient's K. pneumoniae strains. They then placed that phage and the bacterial strains into lab dishes, which allowed the phage to infect the bacteria, make copies of itself and pick up genetic mutations as it did so; in time, these cuculative mutations helped the phages kill the bacteria more efficiently. At the end of this experiment, the researchers sifted through the resulting phage mutants to identify the very best bacteria-killers, and then they repeated the process with the "winning" phages.
After 15 rounds of this process, the team produced a phage mutant potent enough to fight off the patient's K. pneumoniae. This type of directed evolution, which the authors called "pre-adaptation," has been used in other phage therapy studies to make a bacteriophage more potent before pitting it against a bacterial foe, Turner said.
The patient was initially cleared to receive this optimized phage therapy in November 2016, after the ethical committee of Erasme Hospital green-lighted the procedure. However, due to a lack of consensus among the treating physicians, the treatment was put on hold until February 2018. At that point, 702 days had passed since the patient's initial injuries, and she had been on antibiotics for much of that time.
The patient finally received the phage therapy following a surgical procedure, during which doctors removed dead and damaged tissue from her wound; introduced bone grafts that had been "impregnated" with an antibiotic; and replaced the frame that helped to stabilize her broken bone. At the end of this procedure, the team inserted a catheter into the wound through which they could send the pre-adapted phages.
They left this catheter in place for six days and applied the phage therapy each day, while also providing the patient antibiotic drugs. The patient began showing improvement within two days of starting phage therapy, but on top of that, she was also switched to a newly-available antibiotic against drug-resistant K. pneumoniae, Eskenazi said.
Three months later, the patient was free of infection and both her wounds and femur bone were finally on the mend. At this point, doctors removed the stabilizing frame on the patient's leg and discontinued all her antibiotic treatments.
"Three years after phage-antibiotic combination treatment, the patient has regained ambulation and mobility, usually with the aid of crutches, and participates in sporting events," such as cycling, the study authors reported. "And there are no signs of recurrent K. pneumoniae infection."
The case study suggests that a combination of phage therapy and antibiotics can effectively treat drug-resistant K. pneumoniae, Turner said. The case study cannot show how much of the patient's improvement could be attributed to the phages and how much came down to her new antibiotics regimen. But given that the patient showed some improvement prior to the switch in antibiotics, and that no previous antibiotics had worked at all, the results hint that the phages made a difference.
In the future, Turner said that he anticipates that, when the use of phage therapy becomes more widespread, the treatment will sometimes be used alongside antibiotics, as in this case, though it could also be effective in isolation, "especially if you're going after pan-drug-resistant bacteria" that don't respond to any antibiotics whatsoever, he said.
To figure out how phage therapy can best be applied, we'll have to gather more data through large-scale clinical trials, not just isolated case reports, he said. "Really, the future of phage therapy does rest upon abundant data from clinical trials," he said. "This is just the gold-standard … phages have to be held up to the same gold standard." Such trials are already underway.
Originally published on Live Science.
