Genetically-engineered phages – viruses that kill bacteria – have been used for the first time to treat a patient struggling with a dangerous, persistent superbug infection.

The 15-year-old girl had been infected with Mycobacterium abscessus, which is in the same genus as the bacterium that causes tuberculosis.

Researchers screened a database of more than 10,000 phages to find those active against the bacterium.

They engineered three phages to make them more lethal.

The patient improved after treatment with the phage “cocktail”, according to a study published on May 8, 2019, in the journal Nature Medicine.

It is “plausible” that the modified phages were responsible, the study said. But making a firm conclusion wasn’t possible, because only one patient was treated.

The treatment was modelled after the phage therapy given to Professor Tom Patterson from the University of California, San Diego (UCSD), who recovered after nearly being killed by his antibiotic-resistant infection.

Dr Robert T. Schooley, a physician at UCSD who treated Prof Patterson, was a study co-author.

Experts not involved with the study said the results represent an advance in phage therapy.

That’s because it was the first use of genetically-engineered phages, and the first time phages were used against this kind of bacteria.

Moreover, there is some evidence to suggest the treatment was effective, said Dr Christine Schneider, a virologist at Carroll University in Wisconsin, United States.

“In this type of study, it is never possible to completely get at causation versus correlation,” she said by email.

“As they state, however, the timing of the improvements did not correlate with changes in other treatments the patient was receiving and they do have some data that suggests the phages they added replicated in the patient.”

The study is “fantastic”, phage specialist Dr Benjamin Chan of Yale University said by email.

“Well designed and nicely executed,” he said. “It certainly advances the field and contributes to a growing body of research suggesting that phage therapy could be applied in diverse infections.”

Prof Dr Derrick Fouts, a phage expert at the J. Craig Venter Institute (JCVI) in Rockville, Maryland, said finding the right combination of phages is tricky.

“One of the challenges that we face include being able to design phages that will work with any patient,” he said by email.

“This is because phages tend to be specific to one or a few strains of bacteria and people can be infected with different strains.

“So, a phage designed for bacteria in one person may not work in another.”

For engineered phages, another obstacle is getting the phages to “boot up”, i.e. to replicate inside the bacteria and package their genome inside the newly-produced phages.

“My team of researchers at JCVI are working on new methods to overcome this boot-up obstacle for engineering of phages for the treatment of wound infections,” Prof Fouts said.

Anyone getting phage therapy is likely to be very seriously ill.

This patient’s condition was particularly precarious because a double-lung transplant had recently been performed to treat cystic fibrosis.

In addition, the patient had diabetes, liver damage and the Epstein-Barr virus.

As the infection progressed, the patient developed more skin lesions and the infection spread inside.

“Over eight weeks, 20 additional skin nodules appeared on arms, legs and buttocks, and the surgical wound showed areas of breakdown,” the study said.

A team led by biologist Dr Graham Hatfull of the University of Pittsburgh, and Dr Helen Spencer at Great Ormond Street Hospital in London, United Kingdom, searched through the SEA-PHAGES database, compiled by students at the University of Pittsburgh.

They found three candidate phages in soil-dwelling mycobacteria that don’t infect people. The phages infected Mycobacterium abscessus, but tended to live as permanent parasites.

Researchers took out a gene that allowed the phage to insert itself into the bacterial genome, said Dr Schooley, adding that that turned the parasite into a killer.

The phages were introduced into the patient’s abdomen and also given intravenously.

Over a six-month period, the lesions gradually reduced, but didn’t disappear. “It is plausible that phage resistance is associated with reduced virulence,” the study said.
Prof Patterson said he’s still recovering, but “feeling great”. “This new case is very exciting and gratifying,” he said.

“For me, all of the time and pain and suffering that I went through, is made worthwhile by the lives that are being saved by phage therapy.” – The San Diego Union-Tribune/Tribune News Service