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Dr. Ashish Khanna: Hello and welcome to the Society of Critical Care Medicine, icritical Care Podcast. I'm your host Dr. Ashish Khanna. Today I will be speaking with David R. Cameron, PhD, on the article Nebulized Bacteriophages for Prophylaxis of Experimental Ventilator Associated Pneumonia Due to Methicillin Resistance to Staphylococcus Aureus. Published in Critical Care Medicine. To access the full article, please visit ccmjournalorg. Dr. Cameron is currently a Research Group Leader in the department of intensive care medicine at Inselspital, Bern University Hospital in Bern, Switzerland. Welcome Dr. Cameron, thank you for sparing time for us and talking to us all the way from Switzerland.

Dr. Cameron: It's a pleasure. Thank you for having me.

Dr. Ashish Khanna: Dr. Cameron, do you have any disclosures to report to our audiences before we start?

Dr. Cameron: No, I do not.

Dr. Ashish Khanna: All right. So jumping into this excellent work it is certainly very exciting. What was your inspiration, what started you off on this bat? Were you guys seeing a lot of multidrug resistant ventilator associated pneumonia in your clinical practice group? And tell us a little bit about your previous work in this area, if any?

Dr. Cameron: Thank you for the question. So, yes. So as you may know that a ventilator associated pneumonia is a daily challenge in the ICU. And so that's where we started and I'm actually a fundamental microbiologist. So I've always been interested in infectious diseases and trying to think about novel ways that we can tackle these clinical problems. So what are the important questions that are occurring at the patient bedside? And so how can we address them in new ways? So that's why we started working with phage therapy purely because, you know, we've facing some sort of antibiotic resistance crisis where it is spreading through the hospitals. And we think that, complimentary strategies or alternative strategies really need to be investigated. So that's sort of where this project kicked off from and based on our position in the intensive care unit, we did chose choose a sort of ventilator associated pneumonia just because of its frequency.

Dr. Ashish Khanna: Sure. Well, I'm looking at the authorship on your paper David, and I do see that there are folks from the Institute for Infectious Diseases as well. So was this a, I'm sure this was collaborative work, but the move to answer this question, come from some of your colleagues who practice infectious diseases?

Dr. Cameron: Yes, certainly. So it is, we have a nice translational team that we've developed here at the University of Bern. So we, we do have you know, infectious disease physicians and we have infectious disease sort of microbiologists, as well as our intensivists and small animal surgeons. And so it was a very nice group effort, this study,

Dr. Ashish Khanna: David, why did you choose the phages that you chose for this work?

Dr. Cameron: So that is one of the first questions that will always pop up because I'm not sure if you were aware, but bacteriophages are one of the most sort of abundant biological entities that exist. And so everywhere that you may find bacteria, you'll also find some of these phages. So how do we choose the one that's going to be best? And also, is it one that is going to be best or is it a selection? And so the majority of these phages that we are using come just from a wastewater. And what we tried to do was we tried to develop a cocktail. So this consists of four different phages, and we selected these phages based on their capacity to Lise the bacteria. So they need to be efficient. They need to be able to destroy the bacteria and they need to be able to have what we refer to as a wide host range. It's not going to be so useful if we choose phages that are only down to infect, say, you know, 1% of the bacteria that we're targeting. So we actually designed this multiple phage cocktail based on its capacity to Lise 90% of MRSA strains that we tested. And that's what we started. So certainly this all started with in vitro assessment of our phages to make sure that we are likely to start with a really efficient sort of therapeutic.

Dr. Ashish Khanna: Sure. But then I also read in your paper that you chose a method of delivery, is that method of delivery you choose, is that the usual conventional method of delivery for therapy or experiments such as this, or is there a novelty in the method of delivery that you chose as your optimal method of delivery?

Dr. Cameron: So certainly, I think there is some, some novelty to the way that we approach this. So we actually, we nebulize the bacteria phages so that we could deliver them directly to the lung. So in a previous study from our group, we tried to administer them via IV. And what we found was that maybe we could get, say 50% efficacy. So we would be able to rescue 50% of our experimental animals. But then when we were able to concentrate our therapeutic and we were able to nebulize it and send it directly to the side of the infection, which is the lung. We found that we were able to improve the efficacy. And so in the current study, we actually, we nebulized these phages and delivered them to the animals before the infection. So I guess this is a prophylactic approach and we were able to, to rescue 70% of the animals and we're able to really efficiently try to minimize the amount of bacteria that was present in the lung, which seems to correlate well with improved outcomes.

Dr. Ashish Khanna: Excellent. And was the whole approach of prophylactic nebulized, bacteriophage therapy in and of itself. Has that been done before David or is this absolutely new into our world?

Dr. Cameron: For MSRA Infection, certainly, this has not been shown before, so it's novel in that regard, but so nebulizing therapeutics for infectious diseases does get done. So for instance, you can nebulize tobramycin for individuals that maybe have a chronic lung infection. So yeah, the nebulized delivery of anti-microbials is not new, but our sort of our application is a novel way of doing it.

Dr. Ashish Khanna: And how about your results in terms of pharmacodynamics and pharmacokinetic outcomes from this work?

Dr. Cameron: So, this is of interest. So in a previous study, yeah, so we administered the phages intravenously and we found that in the absence of a bacterial infection, the phages did not accumulate into the lung rather, they ended up being sequestered by the spleen. So this was interesting to us, but then what we found now is when we deliver these directly to the lung. So it's more of like a topical application using our nebulized phages. We can really get these phages to stay localized in the lung tissue, which we think would be beneficial. So, but certainly there are a number of questions that still remain about the PK and PD for phage therapy.

Dr. Ashish Khanna: Right. And we're obviously hopeful that this initial work is just a trigger for a lot of future work that you and your colleagues are going to do in this area.

Dr. Cameron: That's exactly right. So it did trigger a number of additional research questions. And so we're tackling them at the moment. So our most recent studies where we're looking rather than doing this sort of prophylaxis, we also now want to treat the animals that have an established MRSE infection and certainly using the information that we learned from this this previous study, was able to really give us a start. And so I think that we're starting to understand these PKPD parameters a little bit better. And so, yeah, but still I would say that there's still a lot of questions to be answered because let me, if I may continue with that. So the interesting thing about the phages when it comes to that is that they will actually replicate when there is a susceptible host. So they will actually the concentration of phages in theory, they should increase when there is a susceptible bacterial host. Now that is something that you certainly don't see for an antibiotic, which typically is only going to reduce in concentration. So that's why sometimes it's quite difficult for us to model and for us to interpret our data because there are going to be times when the therapeutic will amplify in concentration. And then on the other side of that coin is sometimes when we have very successful elimination of the bacterial host in the lung, what we do find then also is then we start to lose our phages, but that is actually, we are interpreting that as a good thing because we are reducing the bacterial load.

Dr. Ashish Khanna: This is fascinating, David just listening to all of this. I think this is just, it's so intriguing to see how this world of bench research is sort of in alignment with some of the principles of clinical critical care research. Now on that note you know, were these immune responses to phages, did you see some of these immune responses in your current study, the sort of immune responses you just described to me?

Dr. Cameron: So, in the current study that we're discussing, we didn't look necessarily at the immune responses, but we have subsequently, so I can give you a little taste of what we're doing in current studies. So what we've found is that when you, so because phages are this biological entity, so it's essentially DNA encased within a protein capsid, it will stimulate some immune response now. From our team, it's not a real focus of ours, like, so, but certainly we've, we've identified a marker, which has been useful for us to look at the immune response. And that is IL1 beta. And so what we found when we have delivered this intravenously over many different deliveries over a 96 hour period, is that you do see a spike in IL1 beta, even in the absence of a bacterial infection. So these are in sham animals. Now that did concern us. But then on the other side of that is we were able to show that when we did this localized therapy with the nebulized phages delivered directly to the lungs, that we did not stimulate the same degree of immune response, which we think we actually think that that's probably a positive thing. But it's again, there's still some more questions that we need to ask with regard to that, but we do think that the localized therapy is advantageous over intravenous therapy. And that's just one of the reasons why.

Dr. Ashish Khanna: Correct. Correct. And I'm also as I'm thinking about it I'm also wondering if there is any role for you know, the antibiotics we use in critical care practice and how they would align with some of this therapy. And is there a role for any synergism with antibiotics and the phage therapy?

Dr. Cameron: It's certainly, that's a very good question. So we think, our team thinks that most realistically, this in its first iteration will most likely be a combination therapy where we try to exploit the possible synergies that occur between the antibiotics that are already approved and already well used within the ICU. And then we could we could use this as a combination. And so what we're trying to optimize in some current studies is to, yes, is to add, perhaps like an intravenous antibiotic that can be used in combination with this localized phage therapy with the phages being delivered directly to the lung. So we think that that's certainly worth investigating, and that's something that we'll hopefully have some answers to. So the best combination. So, yeah, it's an important to say which antibiotic should we target? So that's what we're trying to look at the moment.

Dr. Ashish Khanna: So, if you're doing MRSA would you just generally target something like IV clindomyosin? Or would that be a most obvious choice?

Dr. Cameron: Yeah, so yes, it would. So we've tried the glycopeptide in the past, but however, this was IV treatment with IV treated bacteria, phages. Yeah. So we, haven't quite got to the point where we try IV Ticoplanin, with nebulized topically delivered phages, but we did not see any synergies with this glycopeptide phage combination. So we didn't see that in vitro. So just in test tubes, and also we didn't see it when we delivered it into the animals. The, some of the next questions that we want to ask is to look at linezolid in this context, because it seems to have some potential and yet in the context of pneumonia. So we want to exploit some potential synergisms there. We have seen again in a test tube, so it's obviously very different to our animals and obviously different to the humans, but we do see that there are some synergisms between linezolid and our bacteriophage cocktail. So that's something that we wanted to look at in our model.

Dr. Ashish Khanna: Alright. And David, I'm looking at your paper again, and the final line here on your conclusion gives us a taste for what you're planning to do in future. So, you write here, our current findings pave the way for future phase one or two trials that will address safety dosing and tolerability of phages in patients at risk of MRSA, ventilator associated pneumonia, including those colonized with staph aureus, and expected to require prolonged ventilation. Is that typically where we're going for a next step after this?

Dr. Ashish Khanna: I think that that's, I would call that our long-term objective. I do think that there are still important questions that need to be answered in our animal models that haven't been answered satisfactorily yet. But yes, the long-term goal is to look at these in really well controlled clinical trials. Now there's been some recent well publicized cases. So just individual cases where patients with different infections have been treated with phages, and has been quite successful, but we need to, yeah, so we need to feed off of that momentum to get phage therapy into some real clinical trials to look at safety and efficacy. So I think I mean to date, few trials have been performed, and I must say that the results have not always been really like fantastic, but, so I think that by performing more experiments with our animals, we'll be able to better design our clinical trials and we'll be able to push this therapy closer to the patient's bedside.

Dr. Ashish Khanna: And David, tell me, if I'm clinical doctor in critical care medicine, and I have no clue about any bench research at all and I come across your paper, what would be like one thing I would change in my clinical practice today? Certainly, I'm not sure that this is enough to change clinical practice right away, but what would be one thing I could take to translate into my clinical practice from your excellent work?

Dr. Cameron: Well, I think that what we need to do is we need to increase the exposure for phage therapy just in and of itself. So there is a number of different infective settings where it could be useful. So what you might find is you might say, in my day to day, I'm challenged by this type of infection. And then you might already find that somebody somewhere is looking into this into this question, and then it's something that you could work on together and then push it forward in that particular field. We've started with VAP, because it was a problem that we continue to encounter, but then, you know, yeah. So each clinician might be encountering different problems, but we think that phages may have a place in all of these different infections settings, but they need to be tested rigorously.

Dr. Ashish Khanna: Yeah. All the more reason that clinical practice and bench research should be talking to each other all the time, because I mean, the only good questions that are answered are sometimes based out of observations in clinical medicine.

Dr. Cameron: Absolutely. And I think that at the moment that's certainly a strength of our team is that I feel like we are asking the right questions, but then it's important to establish a team that has the capacity to, to answer these questions. So, as I say, I am a fundamental microbiologist. And so when you are, when you're treating a bacteria with a virus, then that is nothing more than fundamental microbiology.

Dr. Ashish Khanna: Well, Dr. David Cameron, thank you again for your time today.

Dr. Cameron: It was a pleasure. Thank you.

Dr. Ashish Khanna: Thank you, David. This concludes another edition of the icritical Care Podcast. For the icritical Care Podcast, I'm Dr. Ashish Khanna.

Conclusion: Ashish K. Khanna, MD FCCP FCCM is a Staff Intensivist and Anesthesiologist, Associate Professor of Anesthesiology, and Section Head for Research with the Department of Anesthesiology Section on Critical Care Medicine at Wake Forest University School of Medicine in Winston Salem, North Carolina USA. Dr. Khanna is heavily involved in SCCM sections, committees, and task forces, and has received the SCCM presidential citation multiple times. He has written more than 80 peer reviewed articles and two dozen book chapters, as well as editorials, non peer reviewed articles, and online educational videos. He has been invited to talk about his work at prestigious national and international forums. His research interests include prediction of postoperative respiratory and cardiac events on the wards, outcomes of hypotension in critically ill patients, and use of novel vasopressors in shock states in the ICU.

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