Phage therapy treats patient with drug-resistant bacterial infection

The patient, a 15-year-old girl, had come to London's Great Ormond Street Hospital for a double lung transplant.

It was the summer of 2017, and her lungs were struggling to reach even a third of their normal function. She had cystic fibrosis, a genetic disease that clogs lungs with mucus and plagues patients with persistent infections. For eight years, she had been taking antibiotics to control two stubborn bacterial strains.

Weeks after the transplant, doctors noticed redness at the site of her surgical wound and signs of infection in her liver. Then, they saw nodules - pockets of bacteria pushing up through the skin - on her arms, legs, and buttocks. The girl's infection had spread, and traditional antibiotics were no longer working.

Now, a new personalized treatment is helping the girl heal. The treatment relies on genetically engineering bacteriophages, viruses that can infect and kill bacteria. Over the next six months, nearly all of the girl's skin nodules disappeared, her surgical wound began closing, and her liver function improved, scientists report in the journal Nature Medicine.

The work is the first to demonstrate the safe and effective use of engineered bacteriophages in a human patient, says co-corresponding author. Such a treatment could offer a personalized approach to countering drug-resistant bacteria. It could even potentially be used more broadly for controlling diseases like tuberculosis.

"The idea is to use bacteriophages as antibiotics - as something we could use to kill bacteria that cause infection," co-corresponding author says.

In October 2017, co-corresponding author received the email that set his team on a months-long bacteriophage-finding quest.

A colleague at the London hospital laid out the case: two patients, both teenagers. Both had cystic fibrosis and had received double lung transplants to help restore lung function. Both had been chronically infected with strains of Mycobacterium, relatives of the bacterium that causes tuberculosis.

The infections had settled in years ago and flared up after the transplant. "These bugs didn't respond to antibiotics," co-corresponding author says. "They're highly drug-resistant strains of bacteria."

But maybe something else could help. The co-corresponding author, a molecular geneticist, had spent over three decades amassing a colossal collection of bacteriophages, or phages, from the environment. The researchers asked whether any of these phages could target the patients' strains. The team searched their collection for phages that could potentially target the bacteria.

They tested individual phages known to infect bacterial relatives of the patients' strains, and mixed thousands of other phages together and tested the lot. They were looking for something that could clear the whitish film of bacteria growing on plastic dishes in the lab. If a phage could do that, the team reasoned, it might able to fight the patients' infections.

In late January, the team found a winner - a phage that could hit the strain that infected one of the teenagers. But they were too late, co-corresponding author says. The patient had died earlier that month. "These really are severe, life-threating infections," co-corresponding author says.

The team had a few leads for the second patient, though: three phages, named Muddy, ZoeJ, and BPs. Muddy could infect and kill the girl's bacteria, but ZoeJ and BPs weren't quite so efficient. The researchers tweaked the two phages' genomes to turn them into bacteria killers. They removed a gene that lets the phages reproduce harmlessly within a bacterial cell. Without the gene, the phages reproduce and burst from the cell, destroying it. Then they combined the trio into a phage cocktail, purified it, and tested it for safety.

In June 2018, doctors administered the cocktail to the patient via an IV twice daily with a billion phage particles in every dose. After six weeks, a liver scan revealed that the infection had essentially disappeared. Today, only one or two of the girl's skin nodules remain, the bacteria haven't shown any signs of developing resistance to the phages, and the team has prepped a fourth phage to add to the mix.

Finding the right phages for each patient is a big challenge, co-corresponding author says. One day, scientists may be able to concoct a phage cocktail that works more broadly to treat diseases, like the Pseudomonas infections that threaten burn patients.

"We're sort of in uncharted territory," co-corresponding author says. But the basics of the young woman's case are pretty simple. "We purified the phages, we gave them to the patient, and the patient got better."

https://www.hhmi.org/news/phage-therapy-treats-patient-with-drug-resistant-bacterial-infection

https://www.nature.com/articles/s41591-019-0437-z