52: Phage Hunt

She is a Professor of Medicine at the Division of Infectious Diseases and Global Public Health at the University of California, San Diego, or U C S D. She is a Transplant ID physician and is the Medical Director of the Solid Organ Transplant ID service at U C S D. She has also been engaged in phage therapy since 2017 and is the clinical lead at the Center for Innovative Phage Applications and Therapeutics or iPATH.

She currently has funding through the Cystic Fibrosis Foundation for a pilot study to develop a clinical registry of Burkholderia infected patients with CF and develop an associated bacteriophage library.

She is also co-investigator in a NIH grant to combat multi-drug resistance through innovative applications, including phage therapy, and she has been involved in multiple transplant related clinical trials, as well as an ongoing study investigating the use of phage lysin for Staph aureus bacteremia. Welcome to the show.

She's had chronic colonization with resistant Pseudomonas aeruginosa, and her post transplant course has been complicated by a couple things, some primary graft dysfunction. Um, she had prolonged mechanical ventilation afterwards because of that. And then multiple episodes of this Pseudomonas pneumonia that previously has really only been susceptible to colistin on our testing.

And so these have led to multiple long courses of antibiotics and not too surprisingly nephro toxicity, which then led to renal failure. And then after this, the patient has also developed a component of chronic lung allograft dysfunction, in addition to now needing to be on dialysis. And so as the listeners may have guessed by the episode title and the questions we have, and our guest today, we are gonna talk about bacteriophage therapy.

And so I thought we could start first by having you give us an overview about what is this and, and what types of infections do we think we can use this for?

So some are lytic, they go into a lytic cycle in which the virus, once it's in the bacteria, you know, it replicates and basically causes cell lysis. Um, You know, and thus the virions are released and they go in infect other bacteria. And usually when we talk about phage therapy, we're talking about lytic viruses. Uh, you can also have lysogenic phages as well, that go in and integrate within the host genome, um, and you know, can pass on from within the bacterial progeny.

And that's quite common as well. So phages were initially discovered in the pre antibiotic era, um, within the early 1900. Uh, both within France and England. And at that time, you know, the viral structures were not known, but that antibacterial effect was known, which is where the name comes from, which is to eat bacteria or bacteriophage. At that time, the sort of specificity of phage therapy was, uh, noted.

And so there were different sort of phage preparations for GI upset or GI illnesses and different ones for coryza or, you know, respiratory infections. So that distinction, you know, was there. Um, once antibiotics or penicillin, you know, came along was sort of, I think all of us, at least within Western medicine kind of went down that road. Um, and we've, you know, had more and more antibiotics. Uh, and we sort of didn't go back to phage.

Phage therapy has existed in some form since then, actually within Eastern Europe in particular, as well as Russia. There's not a lot published about that experience. So I'm not sure how effective or not it. Uh, but in these countries, phage has traditionally been available sort of over the counter, also sort of within a syndrome, specific formulation. But as far as I know, it's never been used intravenously and these are all oral preparations.

So in 2016 at U C S D one of our faculty members actually developed a highly drug resistant Acinetobacter baumanii infection. So pancreatic abscess, you know, multiple abdominal abscesses at some point septic shock, et cetera. Uh, and this was an Acinetobacter resistant to everything.

So his wife, uh, Dr. Stephanie Strathdee the, um, and one of our I, our previous ID division chair, Dr. Chip Schooley collaborated in, sort of going down this route of phage therapy and they reached out to a variety of different collaborators, including the Navy and certain industry and treated him with intravenous phage as well as phage within the abdominal abscesses. And he, you know, he walked out of that ICU. Um, and I think that really was an eye opener for us.

Um, that case, you know, was written up and widely publicized. And Stephanie wrote a book about it as well. From that case, then we sort of moved on now, you know, to having what we call iPATH or Center for Innovative Phage Application and Therapeutics at U C S D. And this was started in 2018. Um, and we've been treating patients with phage therapy both locally within U C S D, but I also have patients that actually fly in or drive in from other cities or states to get phage as well.

So you asked, you know, I guess how it kind of adds into our antibiotics or, you know, how are we using it? So at the moment, one, you know, it's important to know it's experimental. Um, and so each case that we treat on a compassionate use basis, we do undergo, you know, a review by the FDA, uh, and receive what's called an E I N D before we proceed, because it's experimental and it's not widely available.

There's a lot of delay in, you know, finding a patient, we think that may benefit to actually finding phage to actually manufacturing, to then getting approval and then treating patient. And that can be anywhere from weeks to months. Um, I had one patient that I started the process and treated a year later uh, and part of that delay was actually, you know, then we had a pandemic, right. so that certainly added to that one year, but. When we're talk.

When I talk to other physicians, um, as well as patients, you know, we sort of have this discussion, is the patient one, do we think phage will help this patient? And I think at the moment we're still learning. Um, and I think it's important. It's important to sort of have that discussion with the patient two. Um, at times some people that I assess have so many things that are adding into them being critically ill or severely ill, that the MDR organism is sort of the tip of the iceberg.

And even if we get rid of it, their underlying lung disease, for example, from severe COVID, you know, is not going to get better because we got rid of the MDR Acinetobacter. So I think that's the cert and sometimes it's tricky, but I think that's an important consideration when we assess patients for experimental therapies so that's sort of step one for, you know, in patients that may benefit, I think definitely are those that have highly multidrug resistant organisms.

Um, so sort of, you know, the lung transplant patient in case, uh, you talked about, um, or those that have not tolerated antibiotics. They may be that, you know, it's susceptible to Cipro, but the patient gets anaphylaxis, right? So that's not the best drug for them. Uh, it's also helpful for certain niche sort of issues like biofilm based infections, where we may have an MSSA.

You know, prosthetic joint infection, but it's persistent despite current standard of care, which is, you know, two step I&D um, you know, replacing the joint, et cetera. Um, so some of these cases as well, I, I think are indications for phage therapy as a rescue. So at this point, because we're still learning, um, , you know, I don't think it should be the first thing we think of when we see a patient. Right.

it needs to be, they've already gone through a lot and now we're considering experimental therapy. The other thing I think is important is there's been a lot of, you know, P press, um, or a lot of, um, discussion about all these wonderful cases, including the first case at U C S D. You know, responded very well. Unfortunately, there are also cases that have not responded to phage therapy. And so I think it's important to sort of publish those.

So people have more of a nuanced idea of how phage, you know, works or does not. Um, so that patients also have a realistic understanding of, you know, what they're undertaking.

If there are other isolates from that same patient as we go along, or maybe there's some previous, we need to hold onto all of those, cuz we need the actual bacteria so that we can do susceptibility testing in vitro, uh, looking for phage that may act against that organism. And sometimes we get calls and people talk about their patients, but you know, it's like a week later and the isolates were thrown out. So then that adds into some more delay because then we wait for further positive culture.

But what I wanna point out is currently there's no information truly linking what we see in vitro in terms of susceptibility to clinical outcome. So even though we sort of think of them like phages, or like by antibiotics or, you know, within that framework, we don't know if that's actually the right framework to think about it. Um, and then also. We have phages and we have a patient's bacteria and we do both the agar plate and what's called the biolog.

Um, or that, you know, time kill type test. Sometimes they're actually not even, I mean, there's incongruity between them. And so it's susceptible in one and not on the other. So we don't know actually, which is the better test. Um, and there is ongoing investigation to sort of figure that out so that we have more of a uniform way of saying, okay, well, you know, this phage is going to kill a certain patient's, you know, bacterial isolate. So I, I think that's important to know upfront.

It's not as clear cut or well defined as it is for antibiotic. And because it's only recently that we've started using these for patients. There's a lot of ongoing investigation to actually understand that. And I think some of our failures may be related to the fact that it looks susceptible, you know, on a plaque assay, but perhaps that doesn't translate well to clinical medicine. So, so that's something that is being investigated.

Um, but say we do start off with a phage that is susceptible and we start using it to treat a patient generally so far, especially for gram negative infections. Um, most, most, uh, people would use a combination of phages, not just one.

Usually you want a combination of a few phages that have different receptors for attaching to a certain organism so that if the bacteria does develop, um, resistance and there's sort of a variety of mechanisms that, that it can do that, uh, there's still other phages that can sort of, you know, still kill the bacteria. So we don't always see phage resistance or development of resistance.

In my case, I've treated about 19 patients now with a variety of different organisms and I've noticed the issue more so in the setting of pseudomonas. And I haven't really seen that in Staph aureus. So I think as we're learning more, we'll sort of learn more in terms of, is it a particular phage and bacterial interaction that is more susceptible to development of resistance? Or is it if we target a specific, you know, um, receptor or mechanism that that's more susceptible to resistance.

So that's not really well known at this time, you know, in terms of patient care. I think there's a lot that's known in vitro, but we're not sure right now how that translates into how we treat a patient. so for Staph aureus infections, I've used a single phage successfully and there was no resistance. And, you know, at times we don't see that with the Acinetobacter or Pseudomonas, for example.

And so the concomitant antibiotics were stopped about three weeks after the phage therapy was started. And around that time on day 21, the BAL culture start to show some non Pseudomonas bacterial species suggesting that maybe there's a reestablishment of a, of a different respiratory flora. This therapy is, is so cool and interesting, but I, I think you've started to allude to this, but I wanna make sure that we give pause for what are the challenges.

And there's a lot of unanswered questions that you've already mentioned, but what are some of these challenges in how we use phages that we should think about as research questions moving forward. And, you know, I think, any, any other sort of limitations that you think would be good for us to keep in mind?

And so it is, it's difficult to piece out, especially when you sort of look back at recent published cases, that did the patient get better because we added phage or maybe they would've gone better already if we continued or is it the combination? So, um, in terms of combinations, there is now a lot of interest in when we do phage susceptibility testing to actually look for synergy testing with specific antibiotics as well.

Um, and see if there is actually a synergistic combination and then we would want to use that combination. Um, and you know, and that would lead to greater cell lysis or bacterial lysis than either alone. That doesn't always happen. Uh, occasionally they can actually be antagonism as well. So it's nice to do the in vitro work first, before we go ahead and start treating your patient.

um, what I've started doing now, so sort of to try to figure out, is it really the phage that is helping a patient versus the combination or versus, you know, a tincture of time? Um, I've started treating a few patients with phage alone. Um, but these are patients that are not acutely infected, meaning maybe they have a positive culture, but it's not an indication to treat them with antibiotic.

So, for example, in the setting of kidney transplant, you know, unfortunately patients tend to have recurrent urinary tract infections. And usually in my practice, I've seen that it's the same bug for each patient that comes back again.

And again, whether it's an ESBL E coli or Klebsiella, so I've now treated a couple of patients, um, with phage alone when they're not sick, you know, from that infection, but they may have asymptomatic bacteriuria or they have, you know, it's within their GI tract cuz that's where the organism is coming from and see if we can actually get rid of that colonization.

So I have seen some success in that and we do have hopefully a paper coming out, uh, that sort of goes through the details, but I, I think there are different ways. of looking at how we can use phage depending on what clinical situation we're sort of trying to alter.

And so I think for sure, in the setting of an acute infection, we probably would always treat with phage and antibiotic, unless, you know, there's clinical trial evidence showing it's safe and fine to just give phage alone, but it's always hard to take away standard of care, but, you know, we can add something on to that.

There's been experience using phage intravenously, for sure. And in some of the patients, especially the early ones I treated with the pneumonia pace patient, you mentioned, we actually would treat it with IV alone, got BAL samples to see if the IV phage actually made it to the lung and it did. And then we also later on treated with, you know, nebulized alone and it still got there in good concentration. So I think so that's one part and.

and so, so different administration ways that have been, uh, published, include the intravenous route, nebulization, uh, topical. So maybe for burn wounds, for example, or a driveline, an L V A D driveline infection. That's, you know, superficial as well as rectal instillation uh, oral, we talked about and sort of issues with that.

And then also when I have patients with an LVAD infection, for example, or peach prosthetic joint infection, intraop installation of phage directly at that site of infection. So all these different ways have been tried. I don't think we know what is better, um, or. You know, me are all of them equivalent or not. I don't know. Uh, most of my patients, I have treated intravenously.

One of the issues with nebulized phage is that the nebulization process may actually, um, actually disrupt the phage and it sort of just kills them. And I had that for one of my patients that I wanted to do nebulize, but actually did in vitro testing before. And realized that the nebulization process basically killed off the phage. So that patient, even though it was a pneumonia, I was treating, we just treated intravenously and the patient has responded to treatment.

Yeah. So, yeah, I, I think one of the issues with phage, again, most of us, we think within our antibiotic framework, but all these phages are different. So they're like 11, you know, more than 11 different phage families. Um, and they're not actually all interchangeable. And I think some of the things we're learning is that specific interactions may actually be very specific to phage and, and bacteria.

So we don't actually have that much published experience in terms of intravenous or nebulized, et C. But in general, I think it's quite safe, phages, you know, they're not infecting human cells, so they're basically going to the bacteria and lysing the bacteria. So we're not really worried about, you know, uh, tubular interstitial nephritis, for example. Um, so in general, it's safe, uh, things that we look at. When we develop phage to treat a patient, it's grown within a bacterial host.

So when they develop their filtrates, um, there can actually be endotoxins. It's very important to sort of get rid of the endotoxin and have, you know, and make sure it's, it's sterile, especially when we're going to use it intravenous. So that's one safety aspect and in general, that has not been an issue at all. Cuz we have great ways of getting rid of endotoxin within a phage preparation and we have great ways of ensuring stability.

So that really hasn't been an issue, but it's something you always that's sort of step one in terms of safety. For patients that I treat, I always get baselines for a CBC, you know, CMP and inflammatory markers. And I do them weekly. In general, we'll see, inflammatory markers go down. There've been other studies that sh you know, show that actually increase, and maybe that's related to rapid bacterial lysis. So one thing to always to think about is the bacterial burden in a patient.

And if we're giving very active phage, uh, especially for example, in a biofilm infection, can that lead to bacteremia or if we have a CF patient, that's got all kinds of pseudomonas and other organisms within their lungs, and we're targeting a very specific pseudomonas, will it allow, you know, maybe more pathogenic organisms to take its place. So I think these are real considerations.

And I think, you know, as we learn more we'll know more, uh, but these are things I always talk about to my patients, as well as to other consulting physicians and actually for a couple of my L V a D patients I've seen that what they were not bacteremic at baseline, but once I started treating them with phage within five to seven days, uh, two of them actually developed pseudomonas bacteremia.

It was still susceptible to phage in vitro, but these, uh, organisms had different antibiotic susceptibility profiles than what we started off with. So, you know, just within a week and you change the antibiotic, you keep the phage going. Um, and that was okay, but just to think about cuz these were both actually outpatients, one person had no symptoms and we were like, wow, his bacteremic we admitted him, but one of them actually developed septic shock.

So, so it's not, so I think it's not so much the phage itself. It's sort of how we're using it and in what sort of host milieu we're using it, uh, that we need to be careful about.

Um, I've also had some patients that are in either a rural area or in a private practice setting where it's difficult really to have, you know, the background needed in terms of oversight and research experience, um, to be able to do testing. So some of those we've then. Either. I mean, I've had a couple that came down to San Diego, but again, you know, they were able to do that. Obviously that's expensive for somebody to fly out, you know, fly in here and stay here for a few weeks.

Um, but also there are now many places actually. And again, these usually within the academic setting, uh, that are able to provide phage locally to their patient. So at iPath we worked with many centers, uh, and many physicians to sort of make that happen. . Sara Dong: Yeah, well, I always leave it open one last time at the end, for anything else that you think fellow or an ID clinician who's not as familiar with phage therapy should know as closing thoughts.

I think the key is, is to really think about phage. So, and to think about it early and not when they're critically ill in the ICU, when two. Because in that setting, we're not gonna be able to get phage in time for that patient.

So the time to think about phage is when you see drug-resistant organism or, you know, there's a biofilm based infection, whether it's aortic graft or an L V a D we start saving isolates, start that conversation with the patient, with iPath, you know, or other phage therapy centers. Um, so. You have that lead time to find phage and try to get it to the patient.

But many times we worked, you know, Physicians and patients, and it's too late to really help the patient or by the time we find the phage, you know, unfortunately the patient has already passed. So time is of the essence at the moment.

Stay safe and we'll see you next time.