A British teenager made a remarkable recovery after being the first patient in the world to receive a genetically modified virus to treat a drug-resistant infection.
Isabelle Holdaway, 17, nearly died after a lung transplant left her with an intractable infection that could not be treated with antibiotics. After a nine-month stay at Great Ormond Street Hospital, she returned to her home in Kent for palliative care, but recovered after her consultant joined an American laboratory to develop experimental therapy.
Scientists behind the breakthrough said that bacterial killer viruses, known as phages, have the potential to be used as an alternative treatment to fight the growing crisis of human resistance to antibiotics.
Isabelle's mother, Jo, who made the initial suggestion of phage therapy to doctors on Great Ormond Street after reading about it online, said her daughter was "the luckiest child in the world" to have received treatment on time.
"It's an incredible medical science, it's been a miracle," she said.
Isabelle has cystic fibrosis, a genetic disease that results in frequent infections that clog the lungs with mucus. By the summer of 2017, her lungs had less than a third of their normal function and she had been plagued by two stubborn bacterial strains for eight years. She and her doctors decided that a double lung transplant was the best option, although this meant that their existing infections could spread.
After transplantation, this fear became a reality: a tuberculosis-like bacterial strain settled, colonizing its surgical wound, then the liver, until pockets of bacteria known as nodules began to push the skin off its arms, legs, and buttocks .
"She lost a lot of weight, she was literally like a skeleton," Jo said. "The bacteria was just passing through her skin, there was nothing they could do to make her comfortable, it was horrible."
She searched the internet for alternative treatments and read about phage therapies, asked Isabelle's consultant, Helen Spencer, whether that might be an option.
By chance, a colleague from Great Ormond Street was in contact with Professor Graham Hatfull, a scientist who had spent more than three decades accumulating a collection of phages stored in 15,000 frozen jars at the University of Pittsburgh. Hatfull agreed to help find treatment for Isabelle and another teenage patient on Great Ormond Street who had a life-threatening infection.
Phage works by infecting and killing bacterial cells, but they are very specific in which they can attack bacteria. Hatfull and colleagues identified dozens of phage known to infect bacterial relatives from patients 'strains, and tested thousands of combinations of them on petri dishes to see what decimated patients' bacteria.
"The idea is to use [phages] like antibiotics – as something we could use to kill the bacteria that cause infections, "Hatfull said.
In January of 2018, they found a phage that could reach the tension that infected one of the adolescents. But they were far behind: the patient had died earlier that month. At the same time, Jo had told her that her daughter was unlikely to survive.
Each experiment took a week because the bacteria grow slowly. Shortly after Isabelle was sent home on a palliative care plan, Hatfull's lab identified a phage that eliminated the infection and two other phages that could infect it, but did not kill it efficiently. By removing a single gene, they were able to increase the efficiency of these two phages by making a cocktail that they believed could kill the infection. One combination was used to avoid the possibility of the infection becoming resistant to phage.
In June 2018, Isabelle returned to Great Ormond Street and, after a few safety tests, received the cocktail twice a day intravenously and on her skin. Six weeks later, a liver scan revealed that the infection had essentially disappeared.
Jo said, "The open wounds on her wrist healed, you could see her glow returning to the point where she got up, eating, arguing with her sister."
There were almost no side effects.
Hatfull said: "We did not think we would have a point of using these phages therapeutically. It is a brilliant result.
Isabelle is still on the treatment and has been a slow and steady recovery. All but one of their nodes on the skin disappeared. She went back to school, is studying for levels A, started a part-time job and is learning to drive.
His case, outlined in the journal Nature Medicine, tracks the success of last year's treatment of an American patient infected with a drug-resistant superbug and arises when the impending antibiotic resistance crisis is fueling a growing interest in phage research.
Since Isabelle's treatment was not part of a clinical trial, it is impossible to know how effective therapy would be for others; the authors want to see larger clinical trials to establish this.
Spencer said: "The big question is whether it can be used to treat other resistant bacteria."
Finding the right phages for each patient is a great challenge. In the future, scientists hope it will be possible to perform automated phage library searches to identify personalized treatments. Some infections, such as the superbugia of the hospital Staphylococcus aureus, are known to be genetically homogeneous enough that some phages can treat almost all strains of the infection, increasing the perspective of phage therapy to become routine.
"We are in unknown territory," Hatfull said.
Jason Gill, a senior scientist at Texas A & M University's phage technology center, said phage could have enormous potential to fight drug-resistant infections.
"Phages are likely to be really effective under some conditions and others will not work as well," he said.