1 00:00:07,980 --> 00:00:12,990 Sara Dong: Hello, and welcome to Febrile, a cultured podcast about all things infectious disease. 2 00:00:13,020 --> 00:00:18,600 We use consult questions to dive into ID clinical reasoning, diagnostics and antimicrobial management. 3 00:00:18,870 --> 00:00:20,110 I am your host, Sara Dong. 4 00:00:20,340 --> 00:00:22,050 I am a Med Peds ID fellow. 5 00:00:22,140 --> 00:00:25,170 I am excited to welcome our guest today, Dr. 6 00:00:25,170 --> 00:00:26,340 Saima Aslam. 7 00:00:26,564 --> 00:00:34,875 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. 8 00:00:35,085 --> 00:00:41,325 She is a Transplant ID physician and is the Medical Director of the Solid Organ Transplant ID service at U C S D. 9 00:00:41,475 --> 00:00:51,015 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. 10 00:00:51,504 --> 00:01:02,065 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. 11 00:01:02,275 --> 00:01:17,965 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. 12 00:01:18,235 --> 00:01:19,235 Welcome to the show. 13 00:01:19,774 --> 00:01:20,405 Saima Aslam: My pleasure. 14 00:01:20,405 --> 00:01:22,655 Thank you very much for the invitation to join. 15 00:01:23,130 --> 00:01:23,580 Sara Dong: Yeah. 16 00:01:24,000 --> 00:01:31,080 Uh, so before we jump into the case, we always ask one question about whether you could share a piece of culture that brings you joy. 17 00:01:31,080 --> 00:01:36,300 So something maybe non-medical that you have, uh, had fun with recently? 18 00:01:36,630 --> 00:01:48,755 Saima Aslam: Well, uh, a couple of things recently, , but I guess as recent as yesterday, , um, we had, uh, sort of, what's a religious holiday for us called Eid, e-i-d. 19 00:01:49,264 --> 00:01:53,984 And I always have a party the night before in which girls get together and we do henna. 20 00:01:54,915 --> 00:01:57,905 And we haven't done that for a couple of you know, years. 21 00:01:58,125 --> 00:01:58,415 Yeah. 22 00:01:58,420 --> 00:02:04,295 And so Sunday night, uh, I had a bunch of girls and their moms and, oh, it was wonderful. 23 00:02:04,295 --> 00:02:08,225 We had lots of henna and I know you can't see it on the podcast, but I got some on my hand. 24 00:02:08,295 --> 00:02:08,895 Sara Dong: Oh, that's awesome. 25 00:02:09,355 --> 00:02:10,975 Saima Aslam: so it, it was, it was a lot of fun. 26 00:02:11,700 --> 00:02:12,150 Sara Dong: Yeah. 27 00:02:12,540 --> 00:02:17,190 Well, it's always nice to hear about people being able to, to gather and see family again. 28 00:02:17,730 --> 00:02:17,940 Saima Aslam: Yes. 29 00:02:17,940 --> 00:02:19,080 Sara Dong: Um, great. 30 00:02:19,590 --> 00:02:22,050 So, you know, today's consult question. 31 00:02:22,170 --> 00:02:34,025 Uh, we have a lung transplant recipient with a multi-drug resistant Pseudomonas and, there is already a little bit of a question about, you know, what therapies are available to us. 32 00:02:34,085 --> 00:02:36,995 And so I'll give a little bit of a snippet of the case. 33 00:02:36,995 --> 00:02:46,115 So we have a 55 year old female who has a history of cystic fibrosis and had a bilateral lung transplant in, uh, about. 34 00:02:46,370 --> 00:02:47,480 Let's say two years ago. 35 00:02:47,600 --> 00:02:57,260 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. 36 00:02:57,680 --> 00:03:02,030 Um, she had prolonged mechanical ventilation afterwards because of that. 37 00:03:02,150 --> 00:03:10,220 And then multiple episodes of this Pseudomonas pneumonia that previously has really only been susceptible to colistin on our testing. 38 00:03:10,280 --> 00:03:19,040 And so these have led to multiple long courses of antibiotics and not too surprisingly nephro toxicity, which then led to renal failure. 39 00:03:19,070 --> 00:03:28,250 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. 40 00:03:28,310 --> 00:03:37,965 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. 41 00:03:38,415 --> 00:03:47,295 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? 42 00:03:48,315 --> 00:03:48,765 Saima Aslam: Okay. 43 00:03:49,245 --> 00:03:57,825 Well, I was gonna actually start saying that the patient you described, unfortunately, is all too familiar in the transplant ID setting, as well as the cystic fibrosis. 44 00:03:57,825 --> 00:04:03,835 So it's important for us to come up with alternatives when we, you know, don't have good antibiotic choices. 45 00:04:04,755 --> 00:04:08,055 So in terms of bacteriophages also known as phages. 46 00:04:08,115 --> 00:04:16,760 Um, these are viruses that specifically bind to their bacterial host and are internalized, you know, within the bacterial cell. 47 00:04:17,060 --> 00:04:26,100 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. 48 00:04:26,240 --> 00:04:30,790 Um, You know, and thus the virions are released and they go in infect other bacteria. 49 00:04:31,210 --> 00:04:35,200 And usually when we talk about phage therapy, we're talking about lytic viruses. 50 00:04:35,620 --> 00:04:45,820 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. 51 00:04:45,910 --> 00:04:48,190 And that's quite common as well. 52 00:04:48,760 --> 00:04:55,570 So phages were initially discovered in the pre antibiotic era, um, within the early 1900. 53 00:04:56,055 --> 00:04:58,005 Uh, both within France and England. 54 00:04:58,185 --> 00:05:08,625 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. 55 00:05:08,985 --> 00:05:14,685 At that time, the sort of specificity of phage therapy was, uh, noted. 56 00:05:15,045 --> 00:05:24,105 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. 57 00:05:24,165 --> 00:05:26,325 So that distinction, you know, was there. 58 00:05:27,245 --> 00:05:34,715 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. 59 00:05:35,255 --> 00:05:37,925 Um, and we've, you know, had more and more antibiotics. 60 00:05:37,955 --> 00:05:40,385 Uh, and we sort of didn't go back to phage. 61 00:05:40,895 --> 00:05:46,835 Phage therapy has existed in some form since then, actually within Eastern Europe in particular, as well as Russia. 62 00:05:47,345 --> 00:05:49,745 There's not a lot published about that experience. 63 00:05:49,750 --> 00:05:52,085 So I'm not sure how effective or not it. 64 00:05:52,950 --> 00:06:00,450 Uh, but in these countries, phage has traditionally been available sort of over the counter, also sort of within a syndrome, specific formulation. 65 00:06:00,570 --> 00:06:05,430 But as far as I know, it's never been used intravenously and these are all oral preparations. 66 00:06:05,820 --> 00:06:13,140 So in 2016 at U C S D one of our faculty members actually developed a highly drug resistant Acinetobacter baumanii infection. 67 00:06:13,520 --> 00:06:19,159 So pancreatic abscess, you know, multiple abdominal abscesses at some point septic shock, et cetera. 68 00:06:19,640 --> 00:06:22,909 Uh, and this was an Acinetobacter resistant to everything. 69 00:06:23,450 --> 00:06:24,770 So his wife, uh, Dr. 70 00:06:24,770 --> 00:06:30,409 Stephanie Strathdee the, um, and one of our I, our previous ID division chair, Dr. 71 00:06:30,409 --> 00:06:46,255 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. 72 00:06:46,705 --> 00:06:49,615 And he, you know, he walked out of that ICU. 73 00:06:49,674 --> 00:06:53,610 Um, and I think that really was an eye opener for us. 74 00:06:53,640 --> 00:06:57,480 Um, that case, you know, was written up and widely publicized. 75 00:06:57,480 --> 00:06:59,430 And Stephanie wrote a book about it as well. 76 00:06:59,520 --> 00:07:09,180 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. 77 00:07:09,180 --> 00:07:11,100 And this was started in 2018. 78 00:07:11,730 --> 00:07:22,640 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. 79 00:07:23,300 --> 00:07:29,719 So you asked, you know, I guess how it kind of adds into our antibiotics or, you know, how are we using it? 80 00:07:30,170 --> 00:07:33,469 So at the moment, one, you know, it's important to know it's experimental. 81 00:07:34,099 --> 00:07:48,110 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. 82 00:07:48,110 --> 00:07:59,010 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. 83 00:07:59,159 --> 00:08:01,950 And that can be anywhere from weeks to months. 84 00:08:02,010 --> 00:08:10,229 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. 85 00:08:11,039 --> 00:08:13,650 so that certainly added to that one year, but. 86 00:08:14,020 --> 00:08:14,710 When we're talk. 87 00:08:14,710 --> 00:08:23,859 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? 88 00:08:24,070 --> 00:08:26,409 And I think at the moment we're still learning. 89 00:08:26,859 --> 00:08:28,359 Um, and I think it's important. 90 00:08:28,359 --> 00:08:31,219 It's important to sort of have that discussion with the patient two. 91 00:08:32,049 --> 00:08:43,200 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. 92 00:08:43,710 --> 00:08:53,030 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. 93 00:08:53,550 --> 00:09:10,569 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. 94 00:09:10,600 --> 00:09:17,260 Um, so sort of, you know, the lung transplant patient in case, uh, you talked about, um, or those that have not tolerated antibiotics. 95 00:09:17,880 --> 00:09:23,130 They may be that, you know, it's susceptible to Cipro, but the patient gets anaphylaxis, right? 96 00:09:23,130 --> 00:09:25,110 So that's not the best drug for them. 97 00:09:25,650 --> 00:09:32,790 Uh, it's also helpful for certain niche sort of issues like biofilm based infections, where we may have an MSSA. 98 00:09:32,980 --> 00:09:42,910 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. 99 00:09:43,630 --> 00:09:50,230 Um, so some of these cases as well, I, I think are indications for phage therapy as a rescue. 100 00:09:50,710 --> 00:09:57,704 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. 101 00:09:57,704 --> 00:09:58,005 Right. 102 00:09:58,395 --> 00:10:04,214 it needs to be, they've already gone through a lot and now we're considering experimental therapy. 103 00:10:04,755 --> 00:10:16,454 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. 104 00:10:16,890 --> 00:10:18,449 You know, responded very well. 105 00:10:18,840 --> 00:10:22,500 Unfortunately, there are also cases that have not responded to phage therapy. 106 00:10:22,500 --> 00:10:25,560 And so I think it's important to sort of publish those. 107 00:10:25,560 --> 00:10:31,319 So people have more of a nuanced idea of how phage, you know, works or does not. 108 00:10:31,890 --> 00:10:37,350 Um, so that patients also have a realistic understanding of, you know, what they're undertaking. 109 00:10:37,830 --> 00:10:38,160 Sara Dong: Yeah. 110 00:10:38,790 --> 00:10:54,210 And I love how you went through that timeline and a little bit of the history, cuz that's not something, I didn't know until recently that, uh, there was as much history, I knew that phage had been around for a while, but the way that it had been used in Europe, I don't think I really had any sense of that. 111 00:10:54,270 --> 00:11:02,775 Um, and we'll definitely put a link to, uh, Stephanie's book The Perfect Predator, which I think is good reading for anyone an ID. 112 00:11:02,895 --> 00:11:03,285 Saima Aslam: Yeah. 113 00:11:03,405 --> 00:11:03,555 Yeah. 114 00:11:03,555 --> 00:11:12,735 We also have actually several patient interviews on our iPATH website that they talk about their experience, including one of my patients who speaks Spanish. 115 00:11:12,915 --> 00:11:13,665 Sara Dong: Oh, awesome. 116 00:11:13,725 --> 00:11:13,935 Okay. 117 00:11:13,935 --> 00:11:15,135 So we'll put a link to that too. 118 00:11:15,314 --> 00:11:15,795 All right. 119 00:11:15,795 --> 00:11:16,245 And so. 120 00:11:17,100 --> 00:11:39,490 We call up a friend like you, cuz let's say we're getting to sort of a salvage point for our patients and you've hinted a little bit at this, but what are as a fellow, what do we have to be thinking about as far as the steps and data that we need to collect to help identify whether or not this therapy could be, could be, even be considered for the patient that you're 121 00:11:39,490 --> 00:11:39,880 seeing. 122 00:11:40,060 --> 00:11:47,560 Saima Aslam: So I think whenever as a clinician, we're seeing a patient and we think, Hmm, maybe we could consider phage therapy in this. 123 00:11:47,860 --> 00:11:50,439 Step one is really saving the patient's isolate. 124 00:11:50,439 --> 00:11:54,180 So calling your microlab and saying, please, can you hold on to this. 125 00:11:54,430 --> 00:12:10,640 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. 126 00:12:11,060 --> 00:12:17,810 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. 127 00:12:18,320 --> 00:12:22,370 So then that adds into some more delay because then we wait for further positive culture. 128 00:12:22,949 --> 00:12:23,280 Sara Dong: Yeah. 129 00:12:24,000 --> 00:12:32,010 And then I know that there is sort of two ways to determine if a phage would be susceptible. 130 00:12:32,069 --> 00:12:38,010 And I think also that raises the question of how do we think about resistance in phage therapy? 131 00:12:38,010 --> 00:12:43,170 Are there things that we need to consider to sort of counteract the risk of resistance? 132 00:12:43,170 --> 00:12:44,880 Can you tell us a little bit about that? 133 00:12:45,240 --> 00:12:45,780 Saima Aslam: Yes. 134 00:12:46,230 --> 00:12:50,430 So in terms of susceptibility testing, as you said, there's sort of two main ways. 135 00:12:50,430 --> 00:12:52,410 One is sort of regular agar plates. 136 00:12:52,545 --> 00:13:02,535 And we look for basically, uh, plaques, um, you know, clearings within that bacterial carpet in which phage has, you know, exerted lytic activity. 137 00:13:02,925 --> 00:13:06,824 There's also something similar to a time kill curve that can be done. 138 00:13:07,094 --> 00:13:09,854 And that also gives you an idea of susceptibility. 139 00:13:10,475 --> 00:13:19,954 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. 140 00:13:20,345 --> 00:13:29,675 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. 141 00:13:30,214 --> 00:13:31,865 Um, and then also. 142 00:13:32,370 --> 00:13:39,210 We have phages and we have a patient's bacteria and we do both the agar plate and what's called the biolog. 143 00:13:39,240 --> 00:13:42,450 Um, or that, you know, time kill type test. 144 00:13:42,540 --> 00:13:46,710 Sometimes they're actually not even, I mean, there's incongruity between them. 145 00:13:46,710 --> 00:13:48,990 And so it's susceptible in one and not on the other. 146 00:13:49,230 --> 00:13:52,020 So we don't know actually, which is the better test. 147 00:13:52,569 --> 00:14:05,230 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. 148 00:14:05,680 --> 00:14:08,260 So I, I think that's important to know upfront. 149 00:14:08,380 --> 00:14:11,650 It's not as clear cut or well defined as it is for antibiotic. 150 00:14:12,365 --> 00:14:15,925 And because it's only recently that we've started using these for patients. 151 00:14:16,105 --> 00:14:19,464 There's a lot of ongoing investigation to actually understand that. 152 00:14:19,855 --> 00:14:30,145 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. 153 00:14:30,714 --> 00:14:34,165 So, so that's something that is being investigated. 154 00:14:34,665 --> 00:14:46,545 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. 155 00:14:46,875 --> 00:14:51,785 Um, most, most, uh, people would use a combination of phages, not just one. 156 00:14:52,605 --> 00:15:10,605 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. 157 00:15:11,355 --> 00:15:16,395 So we don't always see phage resistance or development of resistance. 158 00:15:17,235 --> 00:15:25,785 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. 159 00:15:25,815 --> 00:15:27,985 And I haven't really seen that in Staph aureus. 160 00:15:28,005 --> 00:15:32,295 So I think as we're learning more, we'll sort of learn more in terms of, 161 00:15:32,695 --> 00:15:38,335 is it a particular phage and bacterial interaction that is more susceptible to development of resistance? 162 00:15:38,635 --> 00:15:45,775 Or is it if we target a specific, you know, um, receptor or mechanism that that's more susceptible to resistance. 163 00:15:46,045 --> 00:15:51,205 So that's not really well known at this time, you know, in terms of patient care. 164 00:15:51,505 --> 00:15:57,715 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. 165 00:15:58,325 --> 00:16:03,665 so for Staph aureus infections, I've used a single phage successfully and there was no resistance. 166 00:16:04,115 --> 00:16:07,865 And, you know, at times we don't see that with the Acinetobacter or Pseudomonas, for example. 167 00:16:08,495 --> 00:16:08,795 Sara Dong: Yeah. 168 00:16:08,945 --> 00:16:37,975 Well, I'll take us back to our example case and say, you know, this patient ultimately, who I have structured off of one of the published cases, um, received three week course of both IV and nebulized phage cocktail, um, but also had ongoing systemic antibiotics with piperacillin-tazobactam and colistin and around the two week mark, she starts to have some decreased inflammation with, uh, decrease in secretions, um, noted on bronchoscopy. 169 00:16:38,465 --> 00:16:44,335 And so the concomitant antibiotics were stopped about three weeks after the phage therapy was started. 170 00:16:44,425 --> 00:16:56,065 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. 171 00:16:56,125 --> 00:17:05,744 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. 172 00:17:06,194 --> 00:17:16,835 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. 173 00:17:17,234 --> 00:17:23,149 And, you know, I think, any, any other sort of limitations that you think would be good for us to keep in mind? 174 00:17:23,599 --> 00:17:23,990 Saima Aslam: Right. 175 00:17:24,470 --> 00:17:28,149 I have to say this case sounds very familiar or it sounds like a, 176 00:17:28,389 --> 00:17:29,230 Sara Dong: I don't have a good example. 177 00:17:30,860 --> 00:17:31,100 yeah. 178 00:17:31,105 --> 00:17:32,899 I merged details together. 179 00:17:32,899 --> 00:17:34,280 Saima Aslam: Yes, no worries. 180 00:17:34,760 --> 00:17:37,145 Um, So, yes, several points. 181 00:17:37,145 --> 00:17:51,035 One, especially when we first started a few years ago, because it was so new and because we were treating active infections, the FDA would only allow us to use phage in addition to standard of care, which would be antibiotics. 182 00:17:51,125 --> 00:18:04,740 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? 183 00:18:05,400 --> 00:18:15,805 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. 184 00:18:15,805 --> 00:18:21,845 Um, and see if there is actually a synergistic combination and then we would want to use that combination. 185 00:18:22,355 --> 00:18:27,725 Um, and you know, and that would lead to greater cell lysis or bacterial lysis than either alone. 186 00:18:28,024 --> 00:18:29,345 That doesn't always happen. 187 00:18:29,405 --> 00:18:32,495 Uh, occasionally they can actually be antagonism as well. 188 00:18:32,764 --> 00:18:37,445 So it's nice to do the in vitro work first, before we go ahead and start treating your patient. 189 00:18:38,495 --> 00:18:47,400 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? 190 00:18:48,030 --> 00:18:51,000 Um, I've started treating a few patients with phage alone. 191 00:18:51,450 --> 00:19:00,660 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. 192 00:19:01,260 --> 00:19:07,650 So, for example, in the setting of kidney transplant, you know, unfortunately patients tend to have recurrent urinary tract infections. 193 00:19:08,010 --> 00:19:13,800 And usually in my practice, I've seen that it's the same bug for each patient that comes back again. 194 00:19:13,805 --> 00:19:30,030 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, 195 00:19:30,389 --> 00:19:37,500 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. 196 00:19:37,949 --> 00:19:46,439 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. 197 00:19:47,115 --> 00:19:53,145 of looking at how we can use phage depending on what clinical situation we're sort of trying to alter. 198 00:19:53,745 --> 00:20:11,205 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. 199 00:20:11,504 --> 00:20:13,274 Sara Dong: And is, can I ask one question? 200 00:20:13,605 --> 00:20:16,095 We've mentioned a couple that I know that there are phage. 201 00:20:16,635 --> 00:20:28,065 You can do different routes of administration, whether it's IV or inhaled and back, it sounds like had oral previously, how do you, how do you think about that and use that? 202 00:20:28,070 --> 00:20:37,845 Is it just, it's hard cuz I know we're not really relying on a ton of prior experience, but is there anything that can help you decide on, on which formulation might be. 203 00:20:38,175 --> 00:20:38,805 Best. 204 00:20:39,014 --> 00:20:45,555 Saima Aslam: So the issue with oral formulations is that phage are actually inactivated by a gastric pH. 205 00:20:45,645 --> 00:20:53,355 And so there are now ongoing studies looking at oral phage, but actually specially formulated so actually gets down to the lower intestine I see. 206 00:20:53,805 --> 00:20:58,125 Or, um, sort of, you know, an enema uh, way of delivering it. 207 00:20:58,665 --> 00:21:04,860 So in terms of how I would use in terms of administration, as you know, step one is what are we treating? 208 00:21:04,860 --> 00:21:06,090 Is this a pneumonia? 209 00:21:06,090 --> 00:21:09,210 Is this, you know, prosthetic joint infection, et cetera. 210 00:21:10,020 --> 00:21:12,840 There's been experience using phage intravenously, for sure. 211 00:21:12,840 --> 00:21:24,920 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. 212 00:21:25,310 --> 00:21:30,470 And then we also later on treated with, you know, nebulized alone and it still got there in good concentration. 213 00:21:31,070 --> 00:21:33,680 So I think so that's one part and. 214 00:21:34,320 --> 00:21:43,050 and so, so different administration ways that have been, uh, published, include the intravenous route, nebulization, uh, topical. 215 00:21:43,050 --> 00:21:49,710 So maybe for burn wounds, for example, or a driveline, an L V A D driveline infection. 216 00:21:49,710 --> 00:21:57,120 That's, you know, superficial as well as rectal instillation uh, oral, we talked about and sort of issues with that. 217 00:21:57,209 --> 00:22:07,439 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. 218 00:22:07,830 --> 00:22:09,939 So all these different ways have been tried. 219 00:22:10,290 --> 00:22:14,040 I don't think we know what is better, um, or. 220 00:22:14,409 --> 00:22:16,419 You know, me are all of them equivalent or not. 221 00:22:16,419 --> 00:22:17,169 I don't know. 222 00:22:17,800 --> 00:22:20,770 Uh, most of my patients, I have treated intravenously. 223 00:22:21,100 --> 00:22:29,110 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. 224 00:22:29,620 --> 00:22:35,439 And I had that for one of my patients that I wanted to do nebulize, but actually did in vitro testing before. 225 00:22:35,774 --> 00:22:40,094 And realized that the nebulization process basically killed off the phage. 226 00:22:40,334 --> 00:22:46,574 So that patient, even though it was a pneumonia, I was treating, we just treated intravenously and the patient has responded to treatment. 227 00:22:47,445 --> 00:22:47,655 Yeah. 228 00:22:47,774 --> 00:22:56,145 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. 229 00:22:56,145 --> 00:22:59,655 So they're like 11, you know, more than 11 different phage families. 230 00:23:00,225 --> 00:23:02,504 Um, and they're not actually all interchangeable. 231 00:23:02,879 --> 00:23:10,860 And I think some of the things we're learning is that specific interactions may actually be very specific to phage and, and 232 00:23:10,860 --> 00:23:11,639 bacteria. 233 00:23:11,970 --> 00:23:18,210 Sara Dong: And then I think one thing that we can also end on that we haven't necessarily focused on is how safe these are. 234 00:23:18,210 --> 00:23:25,050 And do we need to think about impact on, uh, things that we don't expect other than the infection that we're treat? 235 00:23:25,995 --> 00:23:28,815 Saima Aslam: Yeah, no, I think that's a really important consideration. 236 00:23:28,845 --> 00:23:32,265 Um, especially within the regulatory framework, the FDA. 237 00:23:33,060 --> 00:23:39,270 Um, at least for E I N Ds has really prioritized safety of each patient, given that this is experimental. 238 00:23:39,990 --> 00:23:46,800 So, you know, I started off saying it's been around for a hundred years, but all, all, most of that experience is oral. 239 00:23:47,070 --> 00:23:52,892 So we don't actually have that much published experience in terms of intravenous or nebulized, et C. 240 00:23:53,445 --> 00:24:01,455 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. 241 00:24:01,455 --> 00:24:06,675 So we're not really worried about, you know, uh, tubular interstitial nephritis, for example. 242 00:24:07,034 --> 00:24:10,965 Um, so in general, it's safe, uh, things that we look at. 243 00:24:11,850 --> 00:24:16,199 When we develop phage to treat a patient, it's grown within a bacterial host. 244 00:24:16,530 --> 00:24:20,699 So when they develop their filtrates, um, there can actually be endotoxins. 245 00:24:20,699 --> 00:24:30,000 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. 246 00:24:30,000 --> 00:24:33,959 So that's one safety aspect and in general, that has not been an issue at all. 247 00:24:33,989 --> 00:24:41,815 Cuz we have great ways of getting rid of endotoxin within a phage preparation and we have great ways of ensuring stability. 248 00:24:42,115 --> 00:24:47,125 So that really hasn't been an issue, but it's something you always that's sort of step one in terms of safety. 249 00:24:47,695 --> 00:24:53,425 For patients that I treat, I always get baselines for a CBC, you know, CMP and inflammatory markers. 250 00:24:53,425 --> 00:24:54,534 And I do them weekly. 251 00:24:55,014 --> 00:24:58,075 In general, we'll see, inflammatory markers go down. 252 00:24:58,524 --> 00:25:04,314 There've been other studies that sh you know, show that actually increase, and maybe that's related to rapid bacterial lysis. 253 00:25:05,004 --> 00:25:09,345 So one thing to always to think about is the bacterial burden in a patient. 254 00:25:09,645 --> 00:25:30,625 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. 255 00:25:30,625 --> 00:25:33,480 So I think these are real considerations. 256 00:25:33,660 --> 00:25:58,065 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. 257 00:25:58,395 --> 00:26:06,525 It was still susceptible to phage in vitro, but these, uh, organisms had different antibiotic susceptibility profiles than what we started off with. 258 00:26:06,525 --> 00:26:10,725 So, you know, just within a week and you change the antibiotic, you keep the phage going. 259 00:26:11,115 --> 00:26:23,625 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. 260 00:26:23,955 --> 00:26:27,975 So, so it's not, so I think it's not so much the phage itself. 261 00:26:28,094 --> 00:26:34,604 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. 262 00:26:35,430 --> 00:26:35,790 Sara Dong: Yeah. 263 00:26:36,600 --> 00:26:54,900 And for just thinking about patient access, or I guess you could say patient and clinician access to phage, do most patients have to travel to a center that has this, or are they working collaboratively and getting it phage therapy shipped to them and sample shipped back and forth. 264 00:26:54,960 --> 00:27:02,040 And I think in that latter scenario, how are there challenges with storing and shipping materials? 265 00:27:02,040 --> 00:27:03,840 I suspect the answer is yes. 266 00:27:04,935 --> 00:27:05,205 Saima Aslam: Yeah. 267 00:27:05,205 --> 00:27:15,885 So I think part of it is if we are talking about a center that's sort of academic, they have, you know, an IRB, they have a research laboratory that can make dilution of phage. 268 00:27:16,245 --> 00:27:27,364 So in those places we've certainly help, you know, help teams in developing protocols, their IRB consent form, et cetera, so that patient can get phage where they normally get treatment. 269 00:27:28,105 --> 00:27:44,335 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. 270 00:27:44,695 --> 00:27:45,895 So some of those we've then. 271 00:27:46,415 --> 00:27:46,745 Either. 272 00:27:46,745 --> 00:27:50,975 I mean, I've had a couple that came down to San Diego, but again, you know, they were able to do that. 273 00:27:50,975 --> 00:27:56,195 Obviously that's expensive for somebody to fly out, you know, fly in here and stay here for a few weeks. 274 00:27:56,705 --> 00:28:00,304 Um, but also there are now many places actually. 275 00:28:00,304 --> 00:28:06,665 And again, these usually within the academic setting, uh, that are able to provide phage locally to their patient. 276 00:28:06,935 --> 00:28:12,335 So at iPath we worked with many centers, uh, and many physicians to sort of make that happen. 277 00:28:13,304 --> 00:28:25,095 . 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. 278 00:28:25,605 --> 00:28:29,925 Saima Aslam: I think the key is, is to really think about phage. 279 00:28:29,925 --> 00:28:35,345 So, and to think about it early and not when they're critically ill in the ICU, when two. 280 00:28:36,104 --> 00:28:40,125 Because in that setting, we're not gonna be able to get phage in time for that patient. 281 00:28:40,514 --> 00:28:56,594 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. 282 00:28:56,925 --> 00:28:57,915 Um, so. 283 00:28:58,679 --> 00:29:03,120 You have that lead time to find phage and try to get it to the patient. 284 00:29:03,510 --> 00:29:14,355 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. 285 00:29:14,775 --> 00:29:17,385 So time is of the essence at the moment. 286 00:29:17,835 --> 00:29:18,075 Sara Dong: Yeah. 287 00:29:18,945 --> 00:29:23,145 Um, well thank you again so much for coming on the show and teaching us about this. 288 00:29:23,150 --> 00:29:27,315 And I think everyone is looking forward to, to seeing more about the cases. 289 00:29:27,585 --> 00:29:27,795 Saima Aslam: Okay. 290 00:29:27,795 --> 00:29:28,335 Awesome. 291 00:29:28,335 --> 00:29:28,905 Thank you. 292 00:29:29,280 --> 00:29:30,570 Sara Dong: Thanks for listening everyone. 293 00:29:30,870 --> 00:29:33,630 This is just scratching the surface on a pretty big topic. 294 00:29:33,630 --> 00:29:42,600 So we'll have tons of references available on the Consult Notes, which are written complements of the show with links to references available on our website febrilepodcast.com. 295 00:29:42,690 --> 00:29:47,940 You will also find the library of ID infographics and a link to our merch store on the website. 296 00:29:48,390 --> 00:29:52,890 Please reach out if you have any suggestions for future shows or wanna be more involved with Febrile. 297 00:29:53,160 --> 00:29:54,000 Thanks for listening. 298 00:29:54,030 --> 00:29:55,860 Stay safe and we'll see you next time.