Dr. Steffanie Strathdee, PhD is a Co-Director of the Center for Innovative Phage Applications and Therapeutics (IPATH) and Associate Dean of Global Health Sciences, Harold Simon Professor, Department of Medicine, UCSD.
She is also an author of “The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug” and was named by Time Magazine as one of 50 most influential people in healthcare in 2018.
Why did you choose epidemiology?
I’ve always been interested in science. And I was really lousy in the laboratory, I kept contaminating my Petri dishes, and had a really hard time envisioning tiny microbes that you couldn’t see. So, I decided that epidemiology was better suited to me, as an applied science. It’s the who, how, and what in terms of understanding the distribution of diseases and hopefully how to prevent it. That attracted me because I was in school when the HIV epidemic first hit. Even my PhD advisor and then my best friend passed away from HIV, so it became a really personal issue.
You have an incredible story about combining your knowledge, experience and intuition to save your husband’s life and bring innovation in treating patients with multidrug-resistant bacteria. Tell us more about it.
I was able to remember some of my early training when my husband got sick. My virology professor from the University of Toronto had taught us about bacteriophage in class, back in the 1980’s. That turned out to be the forgotten cure that ended up saving my husband’s life. I was one of many people who made this happen. It really was a global village that rose to the challenge, not the least of which were faculty and medical staff at UC San Diego.
How did it all start?
My husband and I were traveling in Egypt in 2015. He seemed as healthy as you and me, but what we didn’t know was he had gallstone pancreatitis that manifested itself as if it was food poisoning. We just had seafood dinner and so it was over 24 hours before I realized that he didn’t have food-poisoning; he was really sick. He deteriorated really quickly, and we were able to get a medically evacuated to Frankfurt, Germany. There they put us in isolation as a safety precaution, or so I believed at the time. And it turned out that this was a very good decision, because in addition to gallstone pancreatitis, Tom had acquired what one doctor called the worst bacteria on the planet.
What is a superbug?
A superbug is a bacterial infection that is resistant to multiple antibiotics. In my husband’s case, initially this superbug was resistant to 15 antibiotics and only partially sensitive to three. But by the time he got medivacked home to San Diego a few weeks later, it was resistant to even those. Superbugs are on the rise because of overuse of antibiotics in livestock, and in people. About 70% of all the antibiotics used in the US are actually used in livestock to make them grow fatter, faster. So, one of the most important things that you can do as a consumer is to not eat meat that’s been treated with antibiotics, and to put pressure on companies that are serving meat products not to use antibiotics as growth promoters, or you can become a vegetarian.
What was the turning point?
The doctors were afraid to operate on Tom so they decided to use interventional radiology to insert catheters (drains) into his abdomen to drain off the infected fluid from an abscess that had grown the size of a football. One day, one of the drains inside him slipped and it poured all of that infected fluid into his abdomen and bloodstream, and he immediately went into septic shock. This meant that the superbug fully colonized him now, that it was everywhere. They put him in an induced coma and they admitted they’d run out of solutions. That’s when his daughters and I started to realize that he was going to die. I asked him while he was in coma, if he wanted to live, or if he wanted to give up. He squeezed my hand and indicated that he wanted to live.
How did you find a solution when everyone else gave up?
I may not be a medical doctor, but I am a trained researcher, so I took matters into my own hands. I started researching alternative therapies for multi drug-resistant bacteria and that’s when I came across bacteriophage (phage) therapy. It really struck me because I remembered hearing about this when I was a student, but I didn’t know that they’d been used to treat people. Around the same time, a friend of mine from UCSF emailed me to say that a friend of hers had received phage therapy in the Republic of Georgia, and it cured her superbug infection. It felt like a sign; something I had to look into.
What are phages and how do they act?
Phages are viruses that are a hundred times smaller than bacteria. They have naturally evolved as the predators of bacteria. And they’re everywhere, they’re in soil, the oceans, on our skin, in our guts. Sewage is one place where you can find a lot of bacteria, so you can find a lot of phage there too. But, you have to match the phage to the bacteria, it’s like a lock and key. Not any phage will attack any bacteria, it’s a very specific relationship of predator and prey.
How did you convince the medical team to try phage therapy?
I approached the head of infectious diseases at UC San Diego, Dr. Chip Schooley, who was a colleague of mine. I asked him what he thought of phage therapy to treat Tom. He said, “It’s an incredibly interesting idea, but it might be ahead of its time.” It turned out it was actually behind its time because it had been discovered 100 years ago by a French-Canadian scientist named Félix d’Herelle. He’d actually used it successfully to treat infections in humans and animals, but it fell by the wayside when antibiotics were discovered.
Dr. Schooley said he would help and ask FDA for compassionate use approval, if I can find phages that match Tom’s bacteria. The FDA knew all about phage therapy. They were actually happy to help since this was also an opportunity to gather more data so that they could make informed decisions about its use in other people. It was pretty clear that because his body was fully colonized with the superbug that we needed to treat him intravenously, and that was one of the real innovations in this case. We actually injected phages into his bloodstream. It was the scariest day of my life.
How did you obtain the right phage?
I did more research and made a list of US researchers who were studying the kind of superbug that was infecting Tom and emailed them. Dr. Ry Young at Texas A&M University responded and said that my plea for help really pulled at his heartstrings. He also thought that with my background I could cut through the red tape to make this happen. His team found several phages that matched Tom’s bacteria. When Dr. Schooley called the FDA to tell them we had a phage cocktail ready, they told us the US Navy Medical Research Center has been working on phage as well. And then they agreed to help, so we sent Tom’s bacterial isolate to them too.
US Navy had a whole library of little vials of phage that had already been fully characterized. They developed a phage cocktail too, and chose phages that had super killing potential. Now we had two cocktails and they arrived just in the nick of time. We injected them into Tom and three days later, he woke up from his coma. It was just an unbelievably miraculous moment.
How long did it take from your initial reach out for phage to actually giving your husband the cocktails?
Three weeks from my email to actually having two phage cocktails that were personalized to Tom’s bacteria. Compare that to an antibiotic pipeline that take 10 to 15 years, and cost $80 million or more.
How is phage different from antibiotics?
As great as antibiotics are, they kill other bacteria in addition to one targeted and that is how the microbiome is disturbed. And phage, they just kill the bacteria that they match to and then they’re excreted by the body. So, it’s actually a beautiful concept. And nature gave it to us all along.
However, antibiotics and phage can actually work together and synergize. In Tom’s case, we found that there was a phage that was synergistic with an antibiotic. Prior to that, we also found that the bacteria developed some resistance to phage; and that’s because this is an evolution on a microscopic scale. It’s happening within minutes sometimes, because the bacteria are being attacked by the phage, and the bacteria have their defense mechanisms, like CRISPRs. We detected bacterial resistance to the phages within a few weeks, but the Navy was ready. They developed a second-generation phage cocktail in a couple of days, and then detected synergy between an antibiotic and a phage which was an added bonus. There’s been several other cases of antibiotic-phage synergy reported, which should excite the pharma industry. Up until recently the pharmaceutical industry hasn’t really been interested in phage because they thought they couldn’t make money from it. But if phage can make a failing antibiotic work better, that’s already a game changer.
Why has phage therapy been so overlooked?
Phage therapy was looked down upon because it was embraced by what was then Russia during World War II. And this geopolitical bias was carried over into current day; until we launched IPATH, the only countries with dedicated phage therapy centers were in the Republic of Georgia and Poland. Tom’s case has been described as a watershed moment that brought phage therapy to the forefront in the West. Now that we’re having superbugs emerge as a global health crisis, there’s a lot more interest in phage therapy.
How many other people were you able to save with phage therapy?
We’ve treated five other cases since my husband’s at UCSD, all of them have been treated intravenously as well. And we’ve consulted on a growing number of international cases and so it’s showing quite a lot of promise.
From the biotechnology angle, how can you use your experience and make phage accessible to others?
There are really two general approaches for phage therapy right now. One is to have an off the shelf kind of cocktail. That’s attractive because it’s less costly and you can actually administer it quickly, assuming that you know that the phages are going to be a match to the bacteria that you’re trying to treat. And that’s the approach that AmpliPhi Biosciences is using. They have two phage cocktails that have been approved by the FDA that they’re moving into clinical trials to treat Staph and Pseudomonas. Pseudomonas aeruginosa is a very common superbug infection, especially in patients with Cystic Fibrosis, who develop lung infections that often get treated over and over with antibiotics which selects for multi-drug resistance.
The other approach is a personalized phage cocktail. And that’s the approach that Adaptive Phage Therapeutics is using. Some of the team members that were involved in my husband’s case formed this start-up. They believe it’s more efficient and efficacious to take the bacterial isolate from an individual and have a phage library to develop a cocktail specifically for that case. That’s really personalized medicine.
No one’s sure at this point which of these two approaches is ideal. They each have their pros and cons. On the horizon are therapeutic applications with genetically modified phage, and synthetic phage, which have yet to be tested in human cases. But it’s coming soon.
Based on your experience you have established a Center for Innovative Phage Applications and Therapeutics (IPATH) as a part of UC San Diego School of Medicine. What is your goal?
Our main goal is to develop clinical trials so that we’re not just responding to crises. We’re actually planning a clinical trial with Cystic Fibrosis patients that have a chronic infection, that are shedding Pseudomonas aeruginosa. And we’re hoping to partner with the NIAID, foundations, and private donors to get that study off the ground. We’re also planning a clinical trial with patients that have infected medical devices, LVAD’s in particular. Both should get launched in 2019 with any luck.
How has this experience changed your life?
My husband and I are seeing everyday as a gift and we’re just so thankful that people still care enough to help total strangers across the globe. And we benefited from that generosity; it really instills and inspires your hope for mankind. On a professional level, I became a phage wrangler when my husband’s case became publicized in April 2017. This was about a year after he recovered. I started getting calls from all over the world. From China, Malaysia, Thailand, South America, Canada, all over the US. “Where can I get some phage therapy? I’ve got a family member who’s sick.” And through IPATH, we are now helping a growing number of people.
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