Steffanie Strathdee: ‘Phages have evolved to become perfect predators of bacteria’

Infectious disease epidemiologist Steffanie Strathdee’s husband survived a deadly antibiotic-resistant bacterial infection thanks to her suggestion of using an unconventional cure popular in the former Soviet Union: fighting the bug with a virus. Now the global health expert at the University of California, San Diego, she has, along with her husband, Tom Patterson, who is also a scientist at the institution, written an account of their nine month ordeal – The Perfect Predator: A Scientists’s Race to Save Her Husband from a Deadly Superbug.

What was the superbug your husband got, and how did he contract it?
It is called Acinetobacter baumannii but nicknamed Iraqibacter because many wounded service members who have returned from the Middle East were infected with it. It was once a wimpy bacteria – mundane and harmless – but its superpower is its ability to acquire antibiotic-resistant genes. It now tops the World Health Organization’s list of the 12 mostly deadly superbugs to human health. It has infiltrated clinics and hospitals all around the world and sticks to hospital linens. Tom likely picked it up in Egypt while we were vacationing there in late 2015 – sequencing later showed it was an Egyptian strain. He came down in Egypt with what turned out to be acute pancreatitis, caused by a gallstone blocking his bile duct. He could have got [the superbug] from the Egyptian clinic we got him to. It could also have come from the swirling red dust we were exposed to while exploring pyramids – the pathogen is also found in soil. We really don’t know. But the football-sized cyst that formed in his abdomen as a complication of the gallstone provided a nice little apartment for the superbug to settle in and fester.

What is phage therapy and how does it work?
Phage therapy is the use of bacteriophages – viruses that attack bacteria – to treat infections. There are trillions and trillions of phages on the planet and they have evolved over millennia to become the prefect predators to bacteria. The phage latches on to and enters the bacterial cell where it takes over its machinery and turns it into a phage manufacturing plant. The newly minted phages then burst out and the bacterial cell dies. To work, phages have to be matched to the bacterial infection. But just how close the match needs to be depends on the bacterial species.

Phage therapy has been neglected in the west. Why?
Phages were first discovered in 1917 by a French-Canadian, Félix d’Herelle, but he had a hard time getting his work accepted – he wasn’t formally trained and was considered a vagabond scholar. Then, while phage preparations were being manufactured in the west up until the late 1930s, the scientific method hadn’t really been worked out. They were, for example, not being matched to specific bacteria and they were sold without being purified, so some actually could cause harm. After penicillin came to market in the early 1940s, phage therapy fell out of favour and political reasons kept it there. Former Soviet countries – where penicillin wasn’t so consistently available – had taken up phage therapy very vigorously. Western researchers and companies feared being labelled “pinko commie” sympathisers.

You got Tom out of Egypt and eventually into intensive care at your institution, UCSD. What turned you on to phage therapy and where did you find Tom’s phages?
We were running out of options to save Tom, whose infection had spread throughout his body, so I started exploring unconventional cures. I found a paper that mentioned phage therapy. Although I’d learned of phages in college, this was the first I had heard of using them as a treatment. My colleague Chip Schooley, chief of infectious diseases at the UCSD school of medicine, agreed it was an interesting idea and said if I could find phages that matched Tom’s bacterial infection he would contact the Food and Drug Administration and get approval to use them for compassionate use. I knew what that meant: officially, Tom was dying.

I began cold-emailing phage researchers asking for help. A phage researcher at Texas A&M University turned his lab into a kind of command centre, looking for phages active against Tom’s specific infection in his centre’s phage library and in sewage and barnyard waste – wherever you find a lot of bacteria is where you find the phages that kill them! He also wrote to researchers all over the world asking them to send any phages they had that might work, which they did. But phages for Acinetobacter baumannii are very picky. Tom’s life depended on finding a match in time. In three weeks, which included a week spent on purification, a cocktail of four phages was ready to give to Tom. The navy – who our FDA contact also put us in touch with – produced a second four-phage cocktail from their phage library.

Did it work at once?
We began the intravenous phage therapy, but Tom’s bacteria quickly became resistant to all the phages except one in the navy’s cocktail. We didn’t realise that a lot of the phages across both cocktails were very similar to one another and were all trying to enter the bacteria by the same receptor. The bacteria’s successful attempt at evading one phage therefore offered resistance to the rest. Luckily, looking again for more phages that would match, the navy found another in the murky waters of a sewage treatment plant in Maryland. From bog to bedside, so we say! It was powerful because it hit a different receptor. Coincidentally, we found there was synergy with one of the antibiotics Tom was getting. Tom woke up three days after we began the treatment and he fully cleared his infection within three months.

How did Tom’s case break new medical ground?
He was the first in the US to get intravenous phage therapy for a systemic superbug infection. In the past when phage therapy has been used, it has usually been topically – sprinkled on somebody’s skin – or inhaled with a nebuliser. Going intravenous was really risky. Even in the former Soviet countries, where phage therapy has been used for decades, they don’t often treat intravenously because they don’t have the hi-tech capability to purify their phage of the bacterial debris that accumulates when you prepare them in large quantities, so there’s the risk of septic shock. We think of what Tom received as 21st-century phage therapy.

Since Tom’s case, you have assisted other patients to get phage therapy and you now, in addition to your day job, co-direct a new phage therapy centre at UCSD – the Centre for Innovative Phage Applications and Therapeutics – the first in North America. How many people have you helped to date?
After Tom’s case was publicised, people contacted me from all over the world wanting phage therapy. Strangers had helped us, and I felt I had an obligation to help them. So far, we’ve treated six other patients here at UCSD, and advised on a couple of dozen cases elsewhere across the US and internationally. We haven’t always been successful, because sometimes we have been contacted too late. But the FDA is now making it easier for people to get phage therapy earlier in the course of their infections. What’s needed now are clinical trials to see if it works on a broader scale.

I understand your centre helped in the case reported last month of the British teenager Isabelle Holdaway. She became the first person to be treated successfully with a genetically modified phage for a superbug infection following a double lung transplant.
Her mother had heard about Tom’s case and asked her UK doctor whether he could consider phage therapy. He contacted Schooley, the doctor who ended up treated Tom and now co-directs the centre with me. Isabelle’s infection – Mycobacterium abscessus – is in the same genus as tuberculosis and was fully resistant to antibiotics. She was receiving hospice care. The team asked a researcher with a mycobacterium phage library at the University of Pittsburgh to help, but most of the phages he found that matched were not predatory enough. So they tweaked one genetically – clipping out a gene – to ensure it killed the bacteria rather than going dormant. The phage was administered intravenously, like with Tom, and Isabelle left the hospital in a week. I wept for joy. Isabelle is now finishing her A-levels and learning to drive.

Even if phage therapy is proven to work, is widespread use ever going to be achievable when it is essentially personalised therapy? How does it scale up?
What is needed are readily available phages to match whatever organisms we face in the bacterial world. Instead of having to resort to environmental sources every time – like we did in Tom’s case with the sewage – imagine a large, ever-expanding, open-source phage library that researchers and students contribute to from around the world, which could be accessible globally as a resource. Genetic tweaking is also clearly a way of expanding the range of bacteria that picky phages like Tom’s or Isabelle’s are able to attack.

What about the problem of the bacteria becoming phage-resistant?
Bacterial resistance to phage can be expected, but how quickly it occurs depends on a number of factors. In Tom’s case, it emerged fast. Isabelle has been treated for about a year and resistance hasn’t emerged yet, since her bacteria is slow-growing. And there are a few ways that issue can be overcome, like using a phage cocktail where different phages “hit” different bacterial receptors. In the future, genetically modified or synthetic phages could be developed that are harder for bacterial resistance to overcome.

What’s your advice to people who do find their loved ones hospitalised with superbug infections? Shout for phage therapy?
For any serious illness, you need to be an advocate. Get educated about what’s going on and be actively involved in your loved one’s care. In the case of a superbug, understand what options are left in terms of antibiotics and also what kinds of side effects exist, because some last-resort antibiotics, like colistin, can be very hard on the body. Because phage therapy is experimental, you can’t necessarily get it if there are still antibiotic options available. If there are not, phage therapy may be possible. Email us.

The Perfect Predator is published by Hachette Books (£20)


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