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Q&A: Phage Therapy

Interview with Robert Schooley, Steffanie Strathdee and Tom Patterson

Robert “Chip” Schooley, MD

Robert “Chip” Schooley, MD (physician)
Professor of Medicine
Chief, Division of Infectious Diseases
Academic Vice-Chair,
Department of Medicine
UC San Diego School of Medicine

Thomas Patterson, PhD

Thomas Patterson, PhD (patient)
Professor in Residence
Department of Psychiatry
UC San Diego School of Medicine

Steffanie Strathdee, PhD

Steffanie Strathdee, PhD (patient’s wife)
Harold Simon Professor
Associate Dean of Global Health Sciences
Chief, Division of Global Public Health,
Department of Medicine
UC San Diego School of Medicine

QUESTION: What is Acinetobacter and why is it worrisome?

Schooley: Acinetobacter has been around for a long time. And for a long time people didn't think it was very pathogenic. We used to isolate it from patients who weren't having any obvious clinical difficulties.

But over the last 15 or 20 years, it has increasingly become a problem for patients in the hospital because it's very good at developing resistance to multiple antibiotics. We’ve been using antibiotics more vigorously and ultimately selecting Acinetobacter (that has evolved resistance).

It's very promiscuous and picks up from other bacteria in the environment genetic elements that can make it resistant to every antibiotic we know. We see it now in U.S. hospitals in intensive care units. It has also been an organism that has caused a lot of problems for our troops coming back from the Middle East, so it's an organism we have a lot of respect for now.

QUESTION: Can you describe the situation before Tom came back to UC San Diego?

Schooley: Steffanie texted me from Egypt and said that Tom had developed abdominal pain and was unable to eat and she was worried that he had developed food poisoning. She then texted me and said, "The pain is going through to his back, could this be pancreatitis? What should I do?"

I said, "You need to get him to a hospital because he's an older guy who has a pacemaker in place, a little bit of diabetes and the last thing you need is pancreatitis in the middle of Egypt."

There was no hospital in Luxor, so they took him to a clinic which was able to stabilize him. They confirmed the diagnosis of pancreatitis; gave him some antibiotics, gave him some fluids. And Steffanie contacted UC San Diego Health Plan Evacuation Services.

Within three days, they evacuated him to Frankfurt. When he got to the University Hospital in Frankfurt, he was taken care of by some colleagues of mine who did a great job with him. They very quickly realized that he didn't just have pancreatitis, he had a large pancreatic pseudocyst—a collection of fluid behind his pancreas. They felt it was important to drain this pseudocyst because he was quite ill. They felt that it was important to get what they thought was an infection drained, so they put a drain through the wall of his stomach into this pseudocyst, which was abutting the stomach and got fluid which grew Acinetobacter.

They discovered pretty quickly that it was not just an Acinetobacter; it was an Acinetobacter with resistance to most antibiotics that are currently in clinical use. They were quite concerned because they'd had several outbreaks of multidrug-resistant Acinetobacter in their hospital and felt that it would be very good to get him out of the hospital there and back here.

QUESTION: What was Tom’s condition when he arrived in San Diego?

Schooley: When he arrived, he was still quite ill. He was delirious. He had a fever and a very elevated white count. He had multiple abscesses throughout his abdomen. The initial assessment was that he had pancreatitis brought on by passing a gallstone that contributed to the formation of a pseudocyst, which had become super-infected with an organism that would be very difficult to treat with traditional antibiotics.

Normally we would have liked to have drained all of his infected cavities. The surgeons felt Tom was too ill to survive surgical drainage so we asked interventional radiology to drain those they could reach with catheters passed through the skin. Unfortunately they could not reach all areas that the Acinetobacter had reached and we were confronted with a man who was infected in multiple locations with an organism that was not sensitive to the antibiotics we had available and that we couldn't drain adequately. Over the course of the next couple of months, he got progressively sicker and sicker in front of our eyes.

Strathdee: They didn't know if (Tom) was going to make it. He wasn’t really conscious and, unfortunately, by the time Tom was medevacked to UC San Diego, the infection (had become) pan-resistant. It was resistant to every known antibiotic that Tom could tolerate. That's when our journey began. We had this fantastic team of doctors and nurses in the ICU, and they did everything that they could to help but you were starting to slip away. Do you remember any of that?

Patterson: I don't remember anything. What the doctors have told me is that it’s good that I don't remember it because there was so much pain in the process that it's beyond your ability to cope. So I'm happy not to remember.

Strathdee: The whole experience was surreal. I would have nightmares. I had a nightmare where I was actually searching for phages with this broken bedpan. I remember he had a broken bedpan back in Egypt. And all this sewage water was seeping through and I woke up thinking, “How am I going to find these phages with this cracked bedpan?”

Of course, that's ridiculous because you can't see phages or any viruses or even bacteria with the naked eye. I remember thinking you know how people have these nightmares and wake up thinking, “Whew, am I ever relieved that isn't true.” I would have nightmares and realize, “Oh my God, this is my life. I'm in this. I can't believe this is happening to me and Tom.”

And it just kept getting worse and worse. I was on a conference call one day trying to do a little bit of work when Tom was still very sick. And as I was getting ready to hang up, I could hear some of my colleagues on the phone ask if anyone had told Steff that her husband is going to die?

I knew that they didn't know that I was still on the phone. I hung up and I sat there with the receiver in my hand. And I thought, “No, nobody has told me. I guess we're at this point where I have to face the reality that we may lose Tom.”

(But) I didn't want to lose you. I wasn't ready to let you go.

I came to you and I held your hand and I said, “Honey, they're doing everything that they can do and there's nothing that can kill this bug, so if you want to fight, you need to fight, but do you want me to pursue some alternative therapies? We'll, we'll leave no stone unturned. You remember a little bit of that?

Patterson: I vaguely remember you saying, “Do you want me to try or not because it's going to be a tough time and it's not certain that it will work.” I remember squeezing your hand, but it was just a flash in the whole process.

QUESTION: How did the idea of treating Tom with bacteriophages emerge?

Strathdee: Every day I saw him getting weaker and weaker. It was breaking my heart. I started to do some research on alternative therapies for multidrug-resistant bacterial infections. Around that time, a colleague of ours at UC San Francisco said that a friend of hers had been treated with phage therapy in Tbilisi, Georgia. She had this miraculous cure.

I remembered learning about phages when I was an undergrad at the University of Toronto so I thought, “Wow.”

(But) phage therapy was stalled in terms of individuals like Tom. What it really needed was a patient who was dying of a multi-drug resistant infection, that antibiotics no longer worked for so that compassionate use approval could be obtained from the FDA. It needed an institution like UC San Diego that was willing to take the risk and to deliver the treatment. It needed to have investigators and physicians that were willing to put their reputations on the line.

So I wrote Chip an email and I asked, “What do you think about phage therapy? And he said, “What an interesting and intriguing idea. If you can help identify some phages that are active against his (bacterial) isolate, I'll give it a whirl.”

Schooley: One of the things about being at a place like UC San Diego is that you want to keep turning over rocks. If things aren't working, you want to see if there are other things that may be out of the box that might be used to a patient's advantage.

So after a little bit of reading, it became clear that (phage therapy) was worth trying. Steffanie was able to get in touch with a group at Texas A&M University who had been working on animal models with bacteriophages for a number of years. They listened to Tom's story and to their credit, they said, "We've never done this before, but we think it's time. And we think we can come up with a bacteriophage cocktail that would be active against Tom's bacteria."

In the meantime, as the person who was going to be administering the phages, I needed to get in touch with the Food and Drug Administration. We got into touch with an extremely committed member of the FDA who understood the problem and took the position of a patient advocate rather than a regulator and she introduced me to scientists at the US Military Biodefense Command who were also working on bacteriophage therapy; in their case because of interest in dealing with difficult infections coming back with our troops.

I contacted them and the people at Navy said, "You know we think this is an important thing to do. We'd be glad to give it a try." And they also began to develop a phage cocktail for Tom's Acinetobacter.

So with these two groups working in parallel, we then turned to the institutions involved—UC San Diego, Texas A&M, and the US Navy—to try to deal with the bureaucracy and they very quickly coalesced to allow this experimental therapy to go forward.

Strathdee: In addition to finding phage biologists who received the isolate in time to save the patient, all of these different steps had to be taken. And we had to do it in record time. People had to go flat out, put everything on hold. And people did that—all around the world for Tom. And even though we only needed phages from Texas and the Navy, we needed the folks from San Diego State University stepped in at the last minute to help us purify the phages. It really took a village.

Patterson: Even the Environmental Protection Agency got involved, just from the standpoint of shipping the phages through the mail. They were worried about how they might affect others. People had to make arguments to allow that to happen, but the EPA and the FDA got together and allowed it.

QUESTION: What happened after Tom was given the phages?

Schooley: Texas A&M had a little head start. They got us their bacteriophages about 48 hours before the Navy so we began to give these bacteriophages into the abdominal abscess cavities through drains that had been placed earlier in Tom’s illness.

There may have been a subtle change in his clinical status, but two days later the Navy phages became available. Tom was clearly still extremely ill and if we were going to turn the process around, we needed to get the bacteriophages everywhere his organism—his Acinetobacter—was growing. We felt the only way to do that was to give the bacteriophages intravenously. So when the Navy phages arrived, we continued to administer the Texas A&M phages into the abscess cavities and we began to use the Navy phages intravenously.

Within about 48 hours, Tom woke up, lifted his head off the pillow, recognized his daughter and kissed her hand. We began to see his blood pressure stabilize. His white blood cell count began to come down. It was very clear that he was having a clinical response to the bacteriophages.

It's difficult to know whether it was a delayed impact of the intra-cavitary bacteriophages or whether it was the sum of the bacteriophages into the cavities and intravenously, but it was very clear within that 72 to 96 hours, Tom’s clinical course, which had been progressively worsening since leaving Egypt, was finally turning around.

Patterson: When I first woke up, it isn't like it's portrayed in the movies and on television. The experience is a gradual awakening. The initial awakening is really a confusion. When people are talking to you, you don't understand what they're saying. You can't write. They had done a tracheotomy so I couldn't speak, which meant that I was using sign language, which was not something that people could understand because I’m not trained in sign language.

Gradually, you become aware of what's going on. The confusion goes away. But initially there is shock. After being in bed, at that point for four or five months, I looked at my arm and it was nothing but a bone, and I started to cry because I had become so wasted. It was the inactivity, the inability to eat; being fed through a tube isn't equivalent to eating.

So there was a period where I couldn't, I didn't have the strength, to do anything. I mean silly things like opening up a little cereal box. I couldn't do it. I couldn't open up a bottle of water. It takes time to even regain the smallest sense of ability.

QUESTION: What has rehabilitation been like?

Patterson: When I got out of the hospital and came home, initially I had a hospital bed. I was using a wheelchair. I was still pretty sick.

QUESTION: Both in the hospital and at home, you had hallucinations?

Patterson: The hallucinations are incredibly scary. I mean it's your reality when you're in them. One of the things that really helped that process even while I was hallucinating was having people talk to me. I felt them talking to me. There was the body side where my body—all my hallucinations were related to death—but at the same time, I had a spirit that really wanted to live. People were talking to me, providing me with their energy. It buoyed my spirit and allowed me to live.

For example, one hallucination I had was being filmed as I transitioned from life to death. My body was dying. That was my interpretation of what was going on. I was a snake, and the snake only had life in its tail. And this play is being held out in a canyon. And (the doctors) ran out of money, so I was left to die by myself.

In the real world that wasn't going on, but from the voices around me I heard things that I wasn't able to accurately interpret. I was interpreting in this goofy way because the toxins were in my brain. And despite the great care you get being in a hospital, it’s not a great place to get rest. You end up getting woken up every hour or two for one or another jab. Those things fatigue you. I think you get a bit psychotic from lack of sleep.

As I became more conscious, the interesting piece of all this was that when I got home, people started to talk to me about experiences that I had had years ago. And it was as if somebody had touched my brain in places with an electric shock. Suddenly a cascade of memories would come back that I had, but previously wasn’t able to access. Suddenly I could. Relighting all of these pathways was a really emotional process.

Some of it was pretty funny, too. Like when I discovered that Trump was a presidential candidate.

Strathdee: He thought he was hallucinating again.

QUESTION: How would you describe Tom’s case as his doctor?

Schooley: As a treating doctor, you usually have a plan and a path. You know dosages and how often to treat. You can look for improving vital signs as a good way to know you’re progressing. But when you're doing it for the first time, you don't have anything to compare to so you’re best-guessing on some stuff.

There had not been a lot of experience with treating people with bacteriophages and almost none giving them intravenously in the U.S., so we relied on some literature from the Soviet Union, a lot of that kind of uncontrolled experiences using phages topically or orally.

We relied on some animal studies that had been done at the National Institutes of Health. There was an outstanding scientist who had retired from the NIH about 10 years ago after spending his life working on bacteriophage therapy named Carl Merril. I spent some time talking to him. Carl said that the day Tom woke up from his coma after phage therapy began was the happiest day in his career.

And with information from these sources, we came up with a plan that sought to always have the bacteria confronting the phages, but still giving a low enough dose that we thought it would be safe. We measured the amount of bacteriophages in the bloodstream to get an idea about whether we were delivering what we thought we were. We monitored the response of his Acinetobacter to the phages to see if it was changing. We had both clinical and microbiological evidence that the bacteriophages were having an effect and we eventually had good evidence that the bacteriophages were persisting in his bloodstream and getting inside the infection.

But a lot of it was really being worked out kind of on a first-patient basis using a combination of the previous literature, our own intuition about how these phage would circulate and advice from people who had been thinking about this for a long time.

QUESTION: What are the research and clinical implications of Tom’s case?

Schooley: There's a growing international interest in bacteriophage therapy. Efforts to develop more traditional antibiotics have not really made the progress people had hoped for (in terms of dealing with multidrug resistance). Bacteriophages are a “back to the future” approach to revitalize an old approach with cutting-edge technology.

Bacteriophage therapy has a number of complexities. You have to develop a cocktail for each patient's isolate. They seem to be relatively safe to give, but it is difficult to develop an active cocktail from both the regulatory and technical perspectives. Unlike “next-generation” antibiotics that are developed to kill everything standing after our current armamentarium is exhausted, bacteriophage therapy requires the development of a unique combination of bacteriophages tailored specifically for the patient in front of you. This is a challenge because it is the ultimate form of personalized medicine, but also a major advantage because the phages only go after the organism you need to treat and leave the patient’s “normal” bacteria alone. This allows the patient to reestablish a normal balance of bacterial colonizers rather than to continuously escalate the battle to more and more resistant bacteria.

What the FDA is used to is saying, "This is an antibiotic, we know what the structure is, and you're giving this antibiotic to multiple people." With bacteriophage therapy, we are dealing with an approach that requires a specific cocktail for each patient. It is the ultimate personalized medicine.

The good news is we now have extremely powerful tools to do this, such as robotics and much more sophisticated molecular tools. Ten or 15 years ago, phage therapy like this would have been impossible to contemplate. There's a lot of research to be done, but I think there are going to be a lot of clinical applications where this approach may be very beneficial to patients.

Patterson: I wasn't really aware of the phage therapy until I woke up. When I started hearing about it, the way they find them is through sewage, and they purify them, and Steffanie said to me, “So how does it feel to have purified sewage pumped into your system and having it cure you?”

And I was, like, well, this is a little bit odd. But I was so happy to be alive at that point. And the phage therapy has really been a miracle for me, and to, to say that it might mean that millions of people are cured from this in the future is really a privilege. I think it’s the future of medicine.

I can't tell you how much it's reinvigorated me. I feel like I'm going to enjoy the rest of my life enormously. And I'm going to try to raise a little hell, as much as I can, for the rest of my life.