Phage viruses tailored in Pitt lab used to treat patient with drug-resistant infection Phage viruses

A cocktail of viruses developed at the University of Pittsburgh to precisely attack life-threatening bacteria resistant to antibiotics was successfully used to treat a young double-lung transplant patient in London, according to research reported Wednesday.

It appears to be the first use of engineered viruses known as bacteriophages to fight a Mycobacterium infection in a human — in this case, a 15-year-old girl with cystic fibrosis and other serious conditions, including diabetes and liver disease.

“Phage-hunting” college students were behind the discovery of the phages that could kill the Mycobacterium abscessus that had spread throughout the girl’s body after her transplant. A more widespread Mycobacterium, M. tuberculosis, is causing a health crisis worldwide, though not in the U.S.

The phages were collected and isolated by students participating in Science Education Alliance Phage Hunters Advancing Genomics, a national program administered by Graham Hatfull, the Pitt professor of biotechnology who was co-author on the Nature Medicine paper. SEA-PHAGES is jointly run by the Hatfull group at Pitt and the Howard Hughes Medical Institute, based in Maryland.

Narrowed down to three phages that targeted the patient’s particular strains of the bacteria, two phages then were genetically engineered in Hatfull’s Pitt lab to most effectively eliminate the infection.

“These types of infections are relatively slow to get established, and they’re slow to be resolved,” Mr. Hatfull said Tuesday, explaining that the London patient continues to recover, with a few skin nodules remaining after the phage therapy started in June 2018. Serious infection in the liver was cleared up within six weeks, he said. It’s a single case, so the researchers didn’t conclude definitively whether her recovery was due to phage therapy.

“In general, she’s in better health than she’s been in much of her life,” Mr. Hatfull said.

M. abscessus is in a group of bacteria found in the environment that seems to be increasingly found in people with cystic fibrosis, according to Dr. Joseph M. Pilewski, associate chief of Pulmonary, Allergy & Critical Care Medicine at UPMC.

Although it’s estimated that M. abscessus is in between 10% and 15% of CF patients, that number could be higher, Dr. Pilewski said. “Our sense is that it’s not getting any easier to treat.” There are few drugs to treat it, he said, and new drugs being investigated haven’t fully proved themselves. Phage therapy may help, he said.

Lung transplants are reserved for cystic fibrosis patients with severe lung disease, with lung function down to 30% to 40% of normal, Dr. Pilewski explained.

Now there are about 250-275 transplants for these patients every year in the U.S., he said, adding that among the many who aren’t able to have the operation are patients infected with M. abscessus or another type, M. avium.

“The standard regimen for mycobacteria infection is between three and four antibiotics, many of which have significant side effects that limit their use,” he said, adding that the bacteria is very resistant.

The 15-year-old patient first came to London’s Great Ormond Street Hospital for a double lung transplant. Cystic fibrosis clogged her lungs with mucus and she had persistent infections that wouldn’t go away despite eight years of antibiotics. After the operation the surgical wound and her liver showed signs of infection. Nodules of bacteria pushed up through her skin on her arms and legs.

A London microbiologist contacted Mr. Hatfull about the girl’s condition, knowing of his phage research. About 15,000 phages have been found in his research, but not much is known about the safety and effectiveness of treating people with phages. In 2017, doctors in San Diego successfully used phages to treat a patient with multidrug-resistant bacteria.

The phages used won’t work for every patient, Mr. Hatfull said. Each bacteria strain can vary, including whether or not they can be infected with phages.

“In this case, they were individually tailored and personalized, so they can kill that particular strain,” he said. “Ideally, we can broaden that utility … to have a collection of bacteriophages that have the capacity to help more patients.”

That is a research question that needs to be answered, he said. Phage therapy theoretically has an advantage over antibiotics, he said, because they don’t affect human cells and have no side effects. The drawback now is that they are so specific, compared to antibiotics that can hit a broad spectrum of bacteria.

For now, the single case study indicates the phages got to the targeted bacteria, since the patient did improve, he said. The girl’s doctor had to put her trust in the scientists, Mr. Hatfull said, listening carefully and evaluating their opinions before asking the patient’s family to trust her.

“It’s medicine, and the decisions you make can have important consequences.”

Cystic fibrosis patients have benefited by new medications introduced over the past 5-10 years, adding years to patient survival, now projected into their 40s. Dr. Pilewski said he expects a new drug combination to improve lung function, now being tested in clinical trials, will be approved in the next year.

Lung transplants fix lung problems, Dr. Pilewski said, and the new drugs promise to help with other organs as well: “With better lung function, nutrition goes up and the quality of life gets better.”

Jill Daly: jdaly@post-gazette.com