Dr. Robert T. Schooley, MD, Professor of Medicine at UC San Diego talks about phages, how they work, and how they are being studied for potential use in the future.
Interview conducted by Ivanhoe Broadcast News in March 2018.
Tell me about the situation in the world and the US about with the antibiotic resistant bacteria.
Dr. Schooley: Over the last twenty years we’ve had an increasing problem with multi drug resistance bacterial pathogens. Part of it is the use of antibiotics in medicine, part of it is the use of antibiotics in food and animals and part of it is antibiotics that end up in the environment. And the places where you wouldn’t expect to see multidrug resistant bacteria like rural parts of Africa are having that occur as it is here. In the middle of all that we’ve been trying to develop new antibiotics to stay ahead of the evolution of bacterium environment in our hospitals and have not been doing a very good job of staying ahead of it.
Is this a situation that’s appearing more and more often or how quickly is it appearing more often?
Dr. Schooley: It’s been occurring steadily and as people in the hospitals get sicker and stay in the hospitals for longer periods of time with more serious illnesses we have more and more problems with patients who have these multi-drug resistant organisms that are difficult to treat.
What is the standard of care for this?
Dr. Schooley: We try to use antibiotics that are still active against the organisms they have. Sometimes we have to go back to antibiotics that we stopped using twenty years ago because they were toxic and we have to deal with the toxicities of them. But we don’t have a lot of new antibiotics in the pipeline that are going to fundamentally change what we have to offer patients over the next several years.
With Tom Patterson you guys went totally off the grid with the phages. Tell us a little bit about how that works and why you guys went there.
Dr. Schooley: He had been in the hospital both here and in Europe for about four months. And had been through multiple courses of antibiotics that we’ve been shifting each time the organism shifted its susceptibility testing. We were running out of options. He had steadily become more ill with progressive multi organ system disease. We had multiple drains in his abdomen trying to drain the organism from his pancreatic bed from abscess cavities. The organism was in his lungs, he was unable to breathe on his own. He was intubated, he was delirious, his kidneys were beginning to fail as was his liver and it was clear that the trend was not going the right direction. There were not a lot of other antibiotics on the shelf that we could give him. And we’re beginning to see a lot of toxicity from the antibiotics we had given him. When Stephanie came across the article about bacteria phages it seemed like something that was very worthy of being tried.
She said that you were receptive to it right away, she wasn’t totally convinced that she was going to get that reception. Why did you think that it might work?
Dr. Schooley: They have been doing to bacteria for millions of years what antibiotics do. They try to kill bacteria, and unlike antibiotics they actually grow in bacteria and multiply and then go kill the organism next door. In a lot of ways they’re much better than antibiotics from the standpoint of knocking off organisms you want to kill.
Because it’s natural does that mean limited side effects, fewer side effects?
Dr. Schooley: The bacteria phage themselves have some theoretical concerns that we had to think about as we were thinking about beginning to use them in terms of other genes they might carry. They could be dangerous for the patient. Bacteria phage have to be grown in bacteria themselves and you have to purify the phage preparation so we don’t carry some of the toxic materials from the bacteria to the patient. There were some concerns about it but as a first critical endeavor with these organisms intravenously certainly had us anxious.
What exactly is it for the person that’s going to see this on the five o’clock news?
Dr. Schooley: Phage means eat, bacterial eaters. And they were named this way before we knew about viruses. The observation was made in the early nineteen hundreds, around the second decade of the nineteen hundreds and some people were looking at bacteria that grew in the rivers in India. And found that you could if you grew the bacteria on a lawn of auger and then filtered the river water from which you grew and isolated the bacteria and then just poured the river water over the plate you would see holes being eaten in the bacterial lawn. There was something in those eating bacteria and they hence called them bacteria phage. It took quite a while to figure out these were actually viruses that made a living eating bacteria. And we’re surrounded by them and have been surrounded by them for millions and millions of years. That’s how they were discovered and that’s what they’ve been doing for time in memorial and what we’ve been trying to do in medicine the last few years is to learn how to use them to the advantage of the patient by turning them loose on the organism that’s causing the patient troubles.
Does it really come from sewage?
Dr. Schooley: You and I are loaded with them right now in our GI tracts. There are hundreds of millions of phage. So while we’re sitting here they’re in this Darwinian dance with all the bacteria in our GI tract. You’ll be able to find them on our skin, they’re just part of the environment. The sewage is a good place to go to find them because there are so many bacteria in stool and that’s what they eat. It’s like Willie Sutton you go where the money is.
To find the phages that were used for Tom I know it was a big multi directional operation, how did that come about?
Dr. Schooley: There are two major groups that collaborated to do that. Ry Young who is a really brilliant bacteria phage researcher from Texas A&M has a large group down there that’s been working on basic bacteria phage biology for years. When Stephanie called him and told him the story of her husband he said, I’ve never done this before but it seems like this is the time to make an exception. I’ll turn my lab over to this for the next however long it takes and we’ll find some phage that will kill his bugs, send him to me. In the meantime I was talking with the Food and Drug Administration about the steps that would need to be taken to be able to administer them to Tom. And the FDA reviewer said, I know some people who have some phage over at the Navy you might want to call. So she referred us to the medical defense research director of the Navy in Washington and they were delighted to participate as well.
Are they growing them, are they farming them, how are they getting them?
Dr. Schooley: They’ve been collecting bacteria for years and looking at environmental sources for phage that will kill the bacteria library they have. They have hundreds of different islets of staforous, hundreds of different islets of vasleno bacteria and they grow those as libraries. And then they take individual members of those libraries and see what phage they have that will kill them. Then they purify and put those phage in a phage library. They’ve been building phage libraries for a number of years that are able to kill the organisms that we like to kill as doctors.
After they do their work what do they do? Like the phages that were given to Tom?
Dr. Schooley: They run out of food. They die and so they are no longer around. That’s one of the nice things about them.
We’re obviously going to see more and more cases of the antibiotic anti-resistant bacteria, is this the path that we need to go to save people?
Dr. Schooley: I don’t think there’s any “the path” I think there are multiple paths we need to follow and we need to evaluate them in the same way. In the same ways we need to understand how best to kill the bacteria we need to kill without damaging the host. We need to learn to use them together. We used the phage in Tom with antibiotics, the best antibiotics we have and if we had a new antibiotic we wouldn’t use it by itself either. These are just kind of living antibiotics in a way. It will take some rigorous research to understand more about how often to give them, what the dosing should be, how many different phage should be turned loose on a given organism in a patient. Those are the kinds of questions that will require a structured research program which is where the field is now.
Do you think clinical trials would be next?
Dr. Schooley: Clinical trials really are critical. Tom was a fantastic example of a success story but it was an antidote. We were doing a lot of other things at the time and if you’re a doubting Thomas, I’m a doubting Thomas you go well, you changed his antibiotics too and maybe that’s why he got better. Or maybe the drains finally worked. And so to really understand in a more objective way what they’re doing you have to do really rigorous controlled observations not just antidotal patient experiences. You can learn a lot from patient experiences but you really to be able to understand how to use new therapeutics you have to study them rigorously.
Anything on the agenda for that coming up?
Dr. Schooley: We have several groups we’re talking to about doing clinical trials. The National Institute of Allergen Infectious Diseases has a very robust program to study multidrug resistant antibiotics. And they’re interested in looking at phage as one of the things that might go in their armamentarium. The Cystic Fibrosis Foundation has been doing research off and on with phage and we’re hoping that they’ll be interested in it because multidrug resistant gram negative organisms cause a lot problems with CF. So there are a number of groups who are interested in in this as a treatment modality.
Is there timeline to start a trial, to start gathering information?
Dr. Schooley: We’ve already drafted a trial we’d like to do and we’re hoping to get it started in the next few months.
What else haven’t I asked you about this that you would like to be in the story?
Dr. Schooley: Well I think one thing you might ask is, when you told me they’ve been around since the turn of the last century, why now?
Yes, why now?
Dr. Schooley: For a long time what we didn’t understand about phage is that although you can find a phage will kill any given bacterium, a phage themselves are very narrow in their spectrum. An antibiotic is generated or antibiotics are generated to try to be as broad as they can be so you can kill as many different types of bacteria at a time. And that’s one of things that’s both an attraction because it gives you a cushion as you’re waiting for the laboratory to tell you what you really need to use. But it’s also a curse because it wipes out a whole swath of bacteria and leaves a vacuum for multidrug resistant organisms to move in. With phage they only kill a small sliver of the bacteria of a given type. And what you have to do is you have to take the bacteria the patient has, their own organism, and then screen for phage that are active against their organism. And you can’t tell right now which phage that will be without actually testing it. All the experiences in the past have been mainly just using phage empirically without understanding we need to match them this way. We now have robotics and a much larger library to choose from and it’s possible now to come after the bacteria that a patient has with phage and know we’re going to be active in the laboratory.
Kind of grown in to it now or evolved.
Dr. Schooley: We’ve evolved in to it and we understand now how to be throwing phage that will kill the bug at the bug rather than just hoping that maybe you have a phage that will work.
END OF INTERVIEW
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