A woman's leg's superbug was slain by viruses released into her wound.

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Bacteriophages are the technical term for the viruses in question.

After nearly two years of antibiotic therapy to eradicate the bacterial infection, a woman's seeping lesion remained unhealed. That's why they unleashed the superbugs.

Antibacterial viruses, sometimes known as bacteriophages or "phages," were used in the study. Antibiotics alone had failed to heal the patient's infection, according to a new report published Tuesday (Jan. 18) in the journal Nature Communications. However, according to the report, a combination of antibiotics and phage therapy seemed to work.

In just a few days after treatment, the patient's wound had already dried, meaning that pus had stopped leaking from the wound, and the skin had changed color from greyish to pink, according to Dr. Anais Eskenazi, the study's first author and a specialist in internal medicine and infectious disease at CUB-Erasme Hospital in Brussels, Belgium.

After three months of phage therapy, the patient was free of the superbug, and her wound was healing normally. And the bacterial illness hasn't resurfaced in three years following the treatment.

According to Paul Turner, an evolutionary biologist at Yale University, "I regard this as compelling evidence that you can achieve antibiotic and phage synergy," indicating that the bacteriophages and medications work together to kill superbugs more efficiently. Synergistic effects, such as the one that Turner has observed, have been documented in other studies before, and this latest example shows how it may be beneficial to human patients.

The synergy between phages and antibiotics

As far back as 1912, a paper in the World Journal of Gastrointestinal Pharmacology and Therapeutics found that employing viruses to destroy bacteria was already being discussed. Phage research was abandoned after the discovery and development of antibiotics, as scientists' understanding was insufficient at the time. However, researchers in the former Soviet Union and Eastern Europe continued to study phage therapy and conduct human trials with varying degrees of success.

As scientists sought new ways to combat antibiotic-resistant superbugs, interest in phage therapy reignited in the last decade. There is a twist in that phage therapy isn't fool-proof — according to a 2021 report published in the journal Proceedings of the National Academy of Sciences, bacteria can acquire resistance to specific phages just as bacteria can outwit antibiotics. One of the phages' distinct advantages is their ability to quickly evolve a defense mechanism against the host. According to Turner, phage-resistant genes cannot be swapped out as easily as antibiotic-resistant genes.

In light of this, researchers are investigating how phages' genetic flexibility can be used to combat superbugs. Phages can be "taught" to kill specific bacteria through a process known as "pre-adaptation," as demonstrated in the latest case study.

Following a significant operation on her left thigh, the patient acquired a superbug infection in this case. An attack on Brussels Airport in March 2016 damaged her femur or thighbone, and doctors had to use a stabilizing frame along with pins and screws to put it back together.

Klebsiella pneumoniae, a bacterium that can cause various health-care-related infections, was found to have contaminated the woman's surgical wounds (CDC). There are a number of ways in which individuals might become infected with the bug, such as when they're on a ventilator, taking medication through IV, or undergoing surgery.

According to the CDC, many Klebsiella bacteria have developed resistance to antibiotics. One of the K. pneumoniae strains in this patient had an "extensively drug-resistant phenotype," discovered through biopsies. After three months in the hospital and "different regimens of antibiotics," Eskenazi later stated, "the patient's femoral fracture was still not consolidating, and the infection was persisting." The medical team was now discussing phage treatment.

Eskenazi said a biofilm-related infection made the patient an ideal candidate for phage therapy. Bacterial colonies develop biofilms by adhering to a surface and producing a 3D matrix that acts as a protective barrier for the cells. Despite the best efforts of antibiotics, some bacteria can evade them by becoming dormant in these coatings. Live Science previously stated that antibiotics don't work on dormant cells because they interrupt a bacterial cell's activity, basically shorting it out.

Eskenazi said that even if antibiotics fail to break down biofilms, phage therapy may be able to bring down these superbugs.

To make it easier for antibacterial drugs to reach their targets, many phages are known to be capable of eliminating the biofilm, she said. There is a non-profit institute in Tbilisi, Georgia that investigates phages and their possible applications. Therefore, the medical team submitted samples of the patient's K. pneumoniae strains to the George Eliava Institute in Tbilisi, Georgia.

Researchers used the institute's large collection of bacteriophages to find a phage capable of easily infecting and killing the patient's K. pneumoniae strains. These cuculative mutations enabled the phages to kill the bacteria more effectively over time when placed in lab dishes with the phage and bacterial strains. Phage infection led to phage replication and genetic mutation. As soon as they were done with this experiment, they had to repeat it with the "winning" phages to find the most effective bacteria-killers.

They were able to generate a phage mutant strong enough to fend off the patient's K. pneumoniae after 15 rounds of this approach. "Pre-adaptation" has been utilized in prior phage therapy research to increase the potency of a bacteriophage before it is tested against a bacterial adversary, Turner said.

The ethical council at Erasme Hospital gave the operation the green light in November 2016 and approved the patient to receive this tailored phage therapy. However, the treatment was put on hold until February 2018 due to a lack of agreement among the treating physicians. She had been taking medications for 702 days after her first injury to treat her infection.

Doctors performed a surgical operation to remove dead and damaged tissue from the incision. These implant bone grafts had been "impregnated" with an antibiotic and repaired the frame that stabilized the patient's broken bone before administering phage therapy. Using a catheter, the scientists delivered the pre-adapted phages directly into the incision.

The catheter was left in place for six days while phage therapy and antibiotics were administered to the patient. According to Eskenazi, the patient's condition began to improve within two days of initiating phage therapy. In addition, she was given a new medication for drug-resistant K. pneumoniae.

After three months, the patient's wounds and femur bone had healed, and she was no longer infected. This was when doctors removed the patient's leg's supporting frame and ceased all of her antibiotics therapy.

Pneumococcal-antibiotic combination treatment has allowed patients to regain mobility and participate in sports like cycling three years after treatment ended. I can tell that there are no indicators of a relapse of the K. pneumoniae infection."

Antibiotics and phage therapy can be used to treat drug-resistant K. pneumoniae, according to the case study. Whether or not the phages played a significant role in this patient's recovery is impossible to tell from the case study. It is possible, however, that the phages made a difference, as the patient had shown some improvement before the switch in antibiotics, and no previous antibiotic treatment had worked.

Phage therapy may be used in conjunction with antibiotics in the future, as in this case. Still, it may also be useful in isolation, "particularly if you're going after pan-drug-resistant bacteria" that don't respond to any antibiotics, Turner predicted in the future.

According to him, we'll need to conduct large-scale clinical trials to understand better how phage therapy might be implemented. In reality, he asserted that the future of phage therapy depends on a wealth of data from clinical trials. We're doing gold-standard testing, and the same must be done for phages. Existing clinical trials in this area are already underway.

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