[00:00:00]

[00:00:07] Erin: Hello and welcome back to Communicable, the podcast brought to you by CMI Communications ESCMID's, open Access Journal, covering infectious diseases and clinical microbiology. My name is Erin McCreary and I'm the Director of Infectious Diseases Improvement and Clinical Research Innovation at UPMC, which is in Pittsburgh, Pennsylvania, United States.

[00:00:25] Erin: I'm joined by two other fantastic CMI communications editors today to continue our discussions on the clinical trials and late breakers presented at ESCMID Global 2025. This is part two, so if you missed the last week, be sure to check that episode out. We talk about all the wonderful aspects of the ESCMID meeting and several other awesome trials.

Today we're going through five more. So first let me introduce Josh Davis, who's an infectious diseases physician at John Hunter Hospital in Newcastle and the head of Infection Research. At the Hunter Medical Research Institute At the University of New Castle.

You are a clinical trialist. You are just an ID guru. We're so excited to talk trials with you, Josh. Welcome to Communicable.

[00:01:06] Josh: Thank you, Erin. I haven't had an introduction quite like that before. And, great to be back and sorry to leave everyone hanging after part one of this two part episode, but it was too long to fit into one.

[00:01:16] Josh: also with us tonight or today is Emily McDonald, a general internal medicine specialist and clinical trialist at McGill University Health Center in Montreal, Canada. Welcome, Emily.

[00:01:27] Emily: Happy to be here again for part two. I'm gonna kick us off with the Alabama trial. This is a penicillin allergy assessment pathway versus usual clinical care for primary care patients with a penicillin allergy record to assess safety de labeling and antibiotic prescribing.

[00:01:45] Emily: And it's from the Alabama Trial Research Group who are not in Alabama, but are in fact in the uk. so first author Jonathan Sando and senior author Susan ptt. so what do we know on this topic already? Well, most of us know that penicillin allergy labels emphasis on the label component are extremely common.

[00:02:06] Emily: and North America, I was looking it up. It's about 10% of the population. And in the UK where the study took place, it's about six to 8% of the population. fact is though of those people with the label. Only a small percentage, maybe five to 10% of people actually have a true allergy. So why does this matter?

[00:02:26] Emily: We know from other studies that people with the label are more likely to get, second line antibiotics. They actually receive more prescription for antibiotics and they have worse health outcomes. And the presence of a penicillin allergy label, perhaps not surprisingly, based on those other factors, is also associated with a greater likelihood of having resistant microbes.

[00:02:48] Emily: So important to delabel people. The researchers hypothesized that having a pathway initiated out in the community in primary care would be quite an effective way. at de labeling people increasing the use of more narrow spectrum penicillins when antibiotics were required and they thought it would also improve health outcomes.

[00:03:08] Emily: So this was an open label, multicenter parallel group, RCT. They included adults with a penicillin allergy label and people who'd also had an antibiotic prescription in the prior 24 months. this would be, I guess, to concentrate the population on people who would be likely to receive more antibiotics.

[00:03:24] Emily: so to. target that population to enrich their outcome, which was an increase in narrow spectrum penicillins as opposed to other classes of antibiotics. Exclusions were obviously known in severe allergy to penicillin, so true allergy anaphylaxis, for example. pregnant breastfeeding. Use of steroids, unstable coronary disease and unstable asthma.

[00:03:46] Emily: Patients were not allowed to be in the study. Participants were randomized one-to-one to the assessment pathway or usual care and pathway. Patients were assessed to receive either a direct oral challenge with penicillin. Or skin testing followed by an oral challenge test. Depending on what the history of the allergy sounded like and whether or not there was some risk of it being a true allergy.

[00:04:09] Emily: And this happened in the outpatient department of a hospital with immunologist oversight. I. The primary endpoint was penicillin prescriptions up to 12 months after randomization, and they also had several secondary outcomes such as, response, failure to treatment, duration of symptoms, antibiotic prescribing death, MRSA, C diff, and very importantly, de labeling not only at three months, but the persistence of de labeling at 12 months, which is a great outcome.

[00:04:36] Emily: Again, the study took place in the uk and recruitment took place, between 2019 and 2023. Across the pandemic. And they also assessed incremental cost per quality from the pathway from EQ five D, five L, and measured, this at baseline 12 months and at the time of any primary events. So kudos to this team for running this, likely logistically complex study.

[00:05:00] Emily: They had a large sample size, and they were all also looking at the impact on quality of life and cost, which are often neglected outcomes. I'll just pause here. I don't know Erin. Josh, have you ever been for allergy de labeling?

[00:05:14] Josh: Do you mean ourselves personally? Have we been delabelled Yeah.

[00:05:17] Emily: Yeah. Personally, have you ever gone for allergy de labeling? No,

[00:05:21] Erin: I have not. I, I did not have a penicillin allergy, but I will say this is something we've done across my health system. It really focused on since 2018, and I've given this lecture many a time, and I will say inevitably it ends with someone being like, oh, can I talk to you on the side about my son's penicillin allergy or my personal penicillin allergy?

[00:05:39] Erin: And I feel like we've successfully delabelled people just inadvertently through doing this teaching, even amongst hospital administrators. Mm-hmm. So it's really awesome work.

[00:05:46] Josh: have you, Emily?

[00:05:47] Emily: Yeah. So my personal anecdote is that about a year ago I received an egg allergy label. and this was actually really difficult.

[00:05:55] Emily: I had to carry an EpiPen. I was also worried when I was going to eat out. but because my reaction wasn't clear, my hospital immunologist had me undergo medically supervised blinded oral egg challenge. Okay? So you had to make your own egg. And bring it in. And then they would give you aliquots of egg in blinded capsules.

[00:06:16] Emily: and you didn't know if you were getting egg or placebo and you had to say if you thought you were having a reaction. So it was very cool. And at the end of it I was delabelled Okay, so this, actually, this really improved my quality of life. So I think it's something very cool that they do in the allergy world.

[00:06:30] Emily: you know, that crosses over with, infectious diseases. We have a very cool program at my hospital, in Montreal. And yeah. So I think it's great that they looked at quality of life for this because it really can affect people.

[00:06:41] Erin: Yeah, I think that's really cool to your point, because we have been pretty aggressive with greater challenges or full dose penicillins or full dose cephalosporins, even in penicillin allergic patients.

[00:06:51] Erin: But when you talk to patients, Hey, I'm gonna challenge you. This is the best antibiotic for you there we do see. Reactions that are really anxiety and, and teasing those out are definitely challenging and, and it is very, very meaningful for patients. So that placebo controlled challenge is so interesting.

[00:07:05] Erin: I love that.

[00:07:06] Emily: Yeah, it's very cool. so, onto the results, there were about 1600 people who were interested and about 950 who went to the appointment and they were assessed for eligibility and they ended up with. 411 randomized to the pathway and 412 to usual care. most of these patients were included in the primary analysis.

[00:07:24] Emily: So 401 pathway patients, 410 usual care patients. I mean, I found the results of this study outstanding. The pathway significantly increased. Penicillin prescriptions, so. If you were in the pathway, you were, 18% of patients got a penicillin as opposed to 3.4% of people in usual care. So if no one pre-labeled you, there was almost no chance that you were gonna get a penicillin because of that label.

[00:07:48] Emily: so for the primary outcome, that was an adjusted risk difference of 14.2. that's a number needed to treat of about seven. So, you know, pretty good outcome. Even more incredibly, I think, is that 87.9% of the pathway patients remained delabelled at 12 months. And that is compared to the usual care pathway where 0.5% of patients were delabelled and remained de labeled at 12 months.

[00:08:14] Emily: So like hugely effective intervention for people. finally just to say there was no important differences in safety outcomes or other secondary outcomes. And the pathway was associated with an incremental cost effectiveness ratio of about 11,000 pounds per quality gained relative to usual care. And they did an analysis that showed that there was about a 60% probability of it being cost effective.

[00:08:38] Emily: And you could imagine that over time that would probably increase in terms of cost effectiveness. So very cool study. Probably logistically challenging to carry out, but with a really nice outcome that I think will impact our practices. Something we should definitely think about doing is, you know, referring our patients proactively to get delabelled anyone going for a transplant, people who are going to get chemotherapy.

[00:08:59] Emily: I think if you've got this kind of pathway available in your hospital, really something interesting to think about implementing.

[00:09:06] Erin: Yeah, I couldn't agree more. I think there's a lot of thought leaders around the world in the allergy space a lot, Josh in your neck of the woods in Australia, and their colleagues in Europe and others.

[00:09:14] Erin: And this has been, I think, one of the greatest swings in medical research in the past decade of we didn't really know that much and we just were very conservative in teaching to avoid all cephalosporins. And that was probably bad. And we've swung the pendulum in the other direction. So we've been preaching in the pharmacy space, at least for about the last five to six years.

[00:09:31] Erin: If you're doing nothing else with your antimicrobial stewardship teams this year, if you're gonna pick one project, one thing that's gonna highly impact patient care work on having an allergy assessment tool work on having an allergy pathway. So love seeing randomized trials in this space. Now, to kind of put the nail in the coffin on how valuable this is.

[00:09:47] Erin: I also went to school in Alabama. That's where I went to pharmacy school. So partial to the name of the trial.

[00:09:53] Josh: I'm partial because the Neil Young song is playing in my head right now. That too, also an option. Yeah. And [00:10:00] I was also gonna say that, I feel like this completes the trifecta in that we've had clinical trials in hospital inpatients, clinical trials in intensive care, in patients, and now clinical trials in outpatients, all randomized trials, all of which showing that, de labeling is safe and effective.

[00:10:17] Josh: And so we now have. These strong data, it's time to just implement it, rather than do more trials. I think.

I agree. Yeah. I, you know, my, my background is quality improvement and I think one of my big take home, points from this trial is that if you don't have a process in place, usual care leads to that label just staying put.

Very little happens when we just follow usual care. So I think, institutions really need to think about. Putting a, quality improvement, pathway process in place to make this happen.

[00:10:47] Erin: Well, and the patient needs to be a part of the decision. I think that's why I love this trial 'cause it's outpatient, inpatient, you are not your best self.

[00:10:53] Erin: You don't remember anything. I think it's so funny when we survey patients, when they leave the hospital, they're like, I don't know if what's going on. And so that's not the time to give them an IV drug when they have a million things going on and alarms and they're not sleeping. And then have them remember that they're not allergic.

[00:11:06] Erin: Your penicillin allergy, like you said, Emily, is like an intensely personal thing. You've carried it with you sometimes for decades. It's not just something you're gonna not comment on in the outpatient space. And so after you transition from inpatient, and so we've always said we do challenges inpatient and we just document extensively that the allergy.

[00:11:25] Erin: Was there and that they've tolerated cephalosporin. We never delete them from inpatient records because I do think the right place to truly delabelled is outpatient. When the patient's a part of that conversation,

[00:11:35] Emily: All right. I'm gonna turn things over to you, Erin, for the Oral fosfomycin after Carbapenems as deescalating therapy trial.

Yeah, for sure. So this was an interesting trial. This was presented as an oral poster in Arena three. .

[00:11:48] Erin: So much amazing trial content at ESCMID were everywhere, so you had to look in all kinds of forums . This was out of Thailand. This was a single center study. And why did they talk about this? I think there's a lot of interest in fosfomycin as a carbapenem sparing therapy and complicated and uncomplicated urinary tract infection.

[00:12:05] Erin: And so that's what the authors were commenting on, that there's been a rise in carbapenem resistant Enterobacterales causing urinary tract infections, and we need to find safe and effective treatment options and maybe we can reduce carbapenem use if we switch to fosfomycin. So that's what they sought to do.

It was an open label, non-inferiority, randomized control trial. Again, single center in Thailand of patients with complicated urinary tract infection which they defined as either being male or having presence of a catheter immunosuppression or structural abnormality. All the patients in the trial received intravenous carbapenem for the first three days, and then so at day three, they were then randomized to either step down to oral fosfomycin or continue IV ertapenem for a total of seven days of therapy.

They didn't say the dose of fosfomycin explicitly, but we assumed the three gram oral dose. And then the audience did question what days they got fosfomycin and the author that was presenting stated they got a dose on day four and then a dose on day six. And so if they got three days of IV lead-in, you assume day four is that first day of randomization.

[00:13:10] Erin: And then, if they got it again on. Day six, it would be Q 48 hour dosing, basically for two doses. They did perform susceptibility testing to fosfomycin, but they said e coli was the causative pathogen in 92.5% of cases. So that's a lot. I mean, it tracks with epi of UTI, we think at least 70%. E coli 92 is a lot of e coli, So it wasn't a hundred percent e coli and we don't know what the like 8% is. That wasn't e coli. And we know there's susceptibility testing issues with phospho outside of really e coli and maybe enterococcus. So like eh, on those other 8% of patients. But for the most part, we're talking about e coli UTIs here.

[00:13:45] Erin: I. The primary outcome was clinical cure, seven days post-treatment. So they were looking at outcomes. On day 14, they enrolled 80 patients, 40 to oral, step down, and 40 continued on ertapenem. The mean age was 73 years old, 65% were female. No patients had concomitant bacteremia, which I honestly found a little.

[00:14:03] Erin: Odd. It's not really aligned with our current operating definition of complicated UTI. I know there's, you know, guidance is ongoing and, I think the IDSA updated, complicated UTI guidance is available for public comment right now, but no one had bacteremia. So just a little interesting, but maybe why they're more inclined to switch to oral phospho step down.

[00:14:21] Erin: 30% had an indwelling catheter, 17% neurogenic bladder, 5% recent surgery. Four of the patients that enrolled in the fosfomycin arm had retained stones. None in the ertapenem. Clinical cure rates at seven days were comparable between the groups. 97.5% for fosfomycin and 97.5% in the ertapenem arm. And then interestingly, a hundred percent of patients had microbiological cure.

[00:14:46] Erin: So. And then they actually followed patients out to day 28. And at day 28, cure was 90% versus 87% for ertapenem. And so overall they said there's no difference. You know, this is a reasonable step down option, but I will admit the audience had a lot of questions after this trial was presented.

[00:15:01] Erin: It's something I love about this conference is the dialogue and these trials presenting kind of this real time feedback on, on what people wanna know. And those are extremely high micro and cure rates for a UTI trial especially. When we look at new trial endpoints, which tend to combine micro and clinical cure, so it does, it makes me kind of question this patient population again, no bacteremia.

[00:15:22] Erin: Were they truly complicated? Is three days enough treatment? Were they all fine after three days of ertapenem? Did the oral step down, do anything? one thing that is important is that hospital length of stay was significantly shorter in the fosfomycin group. 8.7 days versus 13 days. But again, they were only treated for seven days.

[00:15:38] Erin: So on one hand you read that and you're like, yeah, oral step down gets you outta the hospital. Let's go. It's so great for transitions of care. It's good for patients. But then the length of stay was longer than the treatment. So I don't know that the shorter hospital stay really had anything to do with the fact that they were no longer receiving ertapenem or fosfomycin.

[00:15:56] Erin: So all in all, I think a great trial. I I love seeing centers from all over the world bring forward these kinds of data. I think this is something. people love fosfomycin. I'm still very meh on fosfomycin if you know me. but you know, we wanted to bring it here to show this trial and to, I think a question, honestly, that still remains unanswered, because I'm not a hundred percent sure of the role of fosfomycin in really any infection.

[00:16:17] Erin: But what are your guys' thoughts on fosfomycin?

[00:16:20] Josh: Mean I like it for this indication for, UTI, particularly. The patient has an ESBL producing e coli or there are limited other, you know, it's cipro resistant organism. to me this kind of trial begs the question of why wouldn't you step down to oral If someone is well at, they're tolerating oral intake and they're become afebrile and so on, like, why would you continue iv, but

[00:16:44] Erin: Right.

[00:16:44] Erin: Agree. And then so in that case, it opens up to other oral options. I mean, dare I say the word fluoroquinolone. You have trimethoprim sulfamethoxazole. There are other oral options for complicated uti. I, so, but still, kudos to the author team. We love randomized clinical trials. and interesting data.

[00:17:01] Emily: Yep. I like it as an option. I have a fosfomycin Dream trial that I'd like to do. I'll say it online because I don't have a ton of time to do it, so if someone wants to take the lead on this, I think that fosfomycin for UTI is probably better dosed. At night. So you would take it right before you go to sleep and then it would sit and kind of slosh around in your bladder all night.

[00:17:21] Emily: and, and maybe have more exposure to the surface area. So I wanted to do a 'phospho when' trial and randomize people to kind of taking it when you leave the hospital or when you first get the dose or waiting and taking it as the last thing you do before you go to sleep. So that's 'phospho when' trial if anyone's interested.

[00:17:37] Erin: Oh, that's so interesting. Yeah, you heard it.

[00:17:39] Josh: You heard it first here. You heard it first.

[00:17:41] Erin: Yeah. You heard it at first. I just, I just think fosfomycin is the greatest asymptomatic bacteria drug in the world 'cause it has like minimal collateral damage. It's like one and done usually. It's actually not that, cost effective.

[00:17:53] Erin: At least in the United States. It's actually like that little one sachet actually quite costly. I'm not like a hundred percent convinced if you actually have a UTI that it works. And I look at trials like this and I'm like, maybe you just only need three days. You know, maybe, maybe the difference is because you don't need seven days of therapy, but maybe I'm just, a phospho pessimist.

But anyway, Josh, why don't you tell us what the next cool trial?

[00:18:15] Josh: Yeah, so this was a trial from Israel, that title with neutralizing plasma versus placebo for hospitalized patients with West Nile Virus. so West Nile virus to remind ourselves is a Flavi virus, and it's an arbovirus, meaning arthropod born virus.

[00:18:31] Josh: So mosquitoes, transmitter, it's closely related to Japanese encephalitis virus, which has been in the news a bit in Australia recently because it's become endemic in Australia. Only recently. And West Nile virus causes encephalitis and , older people might remember.

this virus being called New York encephalitis in around 19 99, 2000, there was a big outbreak, the first outbreak in New York, that's the same virus. So there's no effective treatment for West Nile virus. Another place where, there's endemic seasonal outbreaks is Israel, which is where this trial was run.

[00:19:07] Josh: So the trial was presented by Dr. Michal Canetti from Sheba Medical Center in Tel Aviv, where they ran the trial. like I said, they have seasonal outbreaks and there was a big outbreak in 2024 of 934 cases with 600 hospital admissions and 74 deaths. And most years they get around 100 cases.

[00:19:27] Josh: So that, that was a lot more than usual. so because of no treatment being available and these large numbers of hospitalizations and deaths, the workers at Sheba Hospital were thinking, How can we treat this? And one way, based on the Covid pandemic and the convalescent plasma story was, they were thinking about was convalescent plasma.

[00:19:46] Josh: So, they invited all the healthcare workers who worked in this large hospital system to have their blood tested and, found those who had neutralizing antibodies in their plasma. they screened 2000 healthcare workers and, about [00:20:00] 15% of them were seropositive. so a lot of them would've had asymptomatic previous infections.

[00:20:06] Josh: and so in the end they narrowed it down to 50 healthcare workers who had, high titer and neutralizing antibodies in their plasma. and those 50 healthcare workers donated 95 units of plasma. with all of that background, they then, conducted a randomized trial. So to be eligible for the trial, the patient had to be hospitalized, aged over 60, or if they were under 60, have immunocompromised.

[00:20:28] Josh: So they were picking people at higher risk of complications of West Nile virus, and they had to have had West Nile virus diagnosed in the last 72 hours with either fever or neurological symptoms. And they were randomized on a two to one ratios, two thirds of patients received the convalescent plasma, and the primary outcome was death or functional deterioration by day 30.

[00:20:50] Josh: So 34 patients were randomized in total 12 to saline and 22 to. 30% of the patients were B-cell depleted at baseline. It's important to note, so, you not just a little bit immunosuppressed, average seven days of symptoms prior to randomization. So the primary outcome was no different in the two groups.

[00:21:10] Josh: And, and you recall a primary outcome was a, composite of mortality and, functional deterioration by day 30. But the mortality component of that outcome was much lower with convalescent plasma. So, the mortality was two out of 22, which is 9% in the plasma group, and four out of 12, which is 33% in the control group.

[00:21:31] Josh: those numbers are, pretty small. the conclusion of the authors was, I think, a little bit, Far away from the data. So their conclusion was, Hey look, there's this sort of signal here that this approach works, so therefore, monoclonal antibodies should be used for prevention and treatment. I think in the background, they're trying to develop a monoclonal antibody.

[00:21:52] Josh: I. my thoughts overall on this is, I mean, congratulations for them doing this randomized trial during an outbreak. That would've been a huge amount of work and so much better than the usual knee jerk approach of, Hey, let's just start to use this new thing in a crisis. I. They saw an opportunity and did a randomized trial.

[00:22:10] Josh: I don't agree with their conclusion because monoclonal antibodies are completely different kettle of fish than convalescent plasma. Convalescent plasma is not just the antibody against West Nile virus. It's got millions of other antibodies and, other factors in it as well. So for similar reasons that intravenous immunoglobulin.

[00:22:28] Josh: It helps people with severe sepsis. It doesn't help because there's a monoclonal antibody against the organism causing the sepsis. It helps because it's immunomodulatory and there's anti ideotype antibodies and all that kind of stuff. so therefore monoclonal antibodies, yeah. They may or may not be effective, but I don't think this trial shows that they would be effective.

[00:22:49] Josh: and the other kind of conclusion is the likely benefit, if there is one, is in the immunosuppressed. Hypo gamma globulin, anemic patients, which is also what we kind of ended up seeing with Covid. what did you guys think of this trial

[00:23:01] Erin: brings all these covid memories back. So, we ran a very large monoclonal antibody trial in, in COVID-19 and.

It was exactly what you said, that the gut reaction in terrible times is to do anything. So kudos to them for running a randomized trial to try to see if doing something was helpful. And I think the lessons we continue to see with plasma and with antibodies, they are distinctly different entities. They don't always work The patient matters. So the more immunosuppressed you are, the more this is gonna help in general as a trend and then titer matters with plasma. So that's something that's really challenging, at least was in the pandemic, is like. All CP is not created equal. And , what does that even mean?

[00:23:39] Erin: And how do we even begin to do that? But at the end of the day, whether you're talking antibodies or plasma, they were generally very safe, possibly effective therapies. So patients really liked them. We found like patients really enjoyed coming to get their antibodies or their plasma. At least we saw that in the pandemic.

[00:23:57] Erin: So it's an interesting thought, I feel for people trying to develop these for viruses because. Bugs are smarter than us, and viruses change far faster than we can change a commercial antibody or plasma or whatever it may be. So it's just hard to operationalize this on a global scale, I think. Emily's like, I don't wanna talk about Covid.

[00:24:16] Emily: No, I, I,

[00:24:17] Erin: I actually think Emily's like, I'm not commenting on viruses. Thank you very much.

[00:24:21] Emily: , I'm part of a, national, coalition in Canada called Accelerating Clinical Trials because we felt that we could have done better during the pandemic. We did not randomize a lot of people, in Canada.

[00:24:33] Emily: this is the type of trial and pandemic preparedness that I think we, were, we are striving for now. So, so much to be learned from, how they mobilized people made that happen over that short period of time. And I, I think they said that it was kind of the equivalent, in New York, of 20,000 people being infected.

[00:24:51] Emily: If you look at like the kind of percent of people who are infected per population. So, you know, having that ready, spinning that up, and making that happen to me is just so incredible that, I was blown away by, you know, there being able to do that during, during that outbreak. I think that's something that we all wanna strive for in our respective, trials environment.

[00:25:10] Josh: Yeah, I agree.

[00:25:11] Erin: People wanna do something, right? And so what you have to do to be effective to learn and randomize in these times is to, is to help them see that randomizing to placebo or saline or standard care is something. And that takes preparedness and, and time. And I think I live in the critical care world, uh, Dr.

[00:25:29] Erin: Derek Angus kind of. He calls it, he wrote this beautiful JAMA editorial in the pandemic called Learning while Doing and the art of like randomization in times of fear and things like that. And I love that learning while doing Phrase, and it really helped us, at least culturally change our prescribers to say like, randomizing them to standard care or to placebo is doing something for that patient.

[00:25:50] Erin: So that is, it is cool. I imagine there would've

[00:25:53] Emily: been a lot of random care had that not been in place. Yeah. Correct. You know, who knows what people would've received? yeah.

[00:25:59] Erin: Oh my gosh. Most definitely. But, alright, let's talk about the next trial.

[00:26:03] Erin: Yeah. yeah.

[00:26:04] Josh: erin, tell us about the solar trial.

[00:26:07] Erin: Yes. This in your wheelhouse. Josh is bone and joint. Very cool. Randomized trial. So the Solario trial stands for short or long antibiotic regimens and orthopedics. And this was also presented in an arena, I think, because this was an encore presentation. So this had been presented at a bone and joint conference a couple months prior to ESCMID because, you know, this is, this is a huge game changing trial.

[00:26:30] Erin: So, but this was presented in one of the arenas, by Maria Dudareva from Oxford University Hospitals of the NIH Foundation Trust. , For those that were not there. The arenas, we've gotten feedback over the years that it's hard to hear the presenters 'cause they used to be in these open areas amongst the posters.

[00:26:46] Erin: So this year they closed 'em off with these sound walls, which was a great idea for sound. But it made this like, they looked like igloos. They're very cute. Which. It was great again for the sound, but it was very challenging to see because there was a big wall there if you couldn't get in.

[00:26:59] Erin: And then because of this igloo formation, it was actually very hard to get in 'cause you couldn't stand in the back 'cause the igloo was like on your head. 'cause it was rounded. So there wasn't much space. So when I tell you there were people lined up, outside of this bubble to try to see this trial presented and trying to like.

[00:27:14] Erin: Peek over each other into the doorframe holes. And when I tell you I got on my hands and knees and crawled into here. 'cause I knew we were doing this podcast and I knew I was responsible for this trial and I crawled under people to sit on the floor to get into this presentation. I truly did that. So I was very dedicated to bringing you these results.

[00:27:32] Erin: Okay, so why this trial? Well, the International Consensus guidelines for prosthetic joint infections, fracture related infections, and chronic osteo say give four to six weeks of oral or IV antibiotic therapy. After surgery, and we're not even having the oral verse IV debate, but I'll say in the United States, oral antibiotics for osteo are still not, we're still not quite there.

[00:27:52] Erin: We know we need to move there, but four to six weeks of therapy. However, we know antibiotic side effects are common during treatment, prolonged to durations of treatment, continue to breed. Antibiotic resistance, unnecessary antibiotic effects. And we know that a lot of surgeons in the orthopedic space are using implantable antibiotic carriers or local antibiotic therapy when they're operating for people with bone and joint infections.

[00:28:15] Erin: So the question of this trial was. Does treatment of orthopedic infections with local antibiotics combined with either less than or equal to seven days of systemic therapy, and that could be IV or oral. Is that non-inferior to getting local antibiotics and greater than or equal to four weeks of systemic therapy, again, IV or oral, and that's assessed by treatment failure at one year.

[00:28:37] Erin: So basically we're taking standard care, which is at least four weeks of systemic therapy and cutting it all the way down to less than or equal to seven days as long as you have locally implanted antibiotics. They had a non-inferiority margin of 10% and they actually, this I thought was very nice.

[00:28:52] Erin: They set that threshold with patient representatives and they said that that reflected true patient decision making in clinical practice and what they deemed a clinically significant difference in the treatments. They also wanted to compare adverse events and symptoms associated with antibiotic treatment, including c Diff and clabsi.

[00:29:08] Erin: And then they wanted to compare resource allocation and quality of life for different treatment strategies. So I love that we're seeing a theme where these RCTs are going just beyond these objective endpoints and really talking about, are we making patients' lives better in the eyes of our patients?

[00:29:23] Erin: Which is the most important thing. So the study population was adults who consented to participate that had signs and symptoms of orthopedic infections. This was pain, erythema, fever, discharging, sinus tracts, et cetera. They had to get surgery for their orthopedic infection with curative intent. They had to have local antibiotic therapy with a licensed antibiotic carrier combination placed.

[00:29:43] Erin: So this wasn't like. Can I have a gram of amphotericin to dump in the bone? Like this was a licensed product. Antibiotic carrier, removal of all infected orthopedic implants. Wound closure at the completion of surgery with no planned re-look. Operation and specimens had to [00:30:00] be taken for microbiological analysis during surgery.

[00:30:03] Erin: The fact that they just got all these surgeons to actually send OR cultures is a feat in and of itself. So, you know, kudos to them. Exclusion criteria if you were getting a dare retained, infected orthopedic implant, if you had microorganisms identified from the surgical specimens that were fully resistant to local antibiotics administered at the site of infection.

[00:30:23] Erin: If you had a concomitant systemic infection like staph aureus, bacteremia or endocarditis, and if you were already participating in a different trial, so again, our treatment arms are the long arm, which is standard therapy, greater than or equal to four weeks, and what we will call the short arm, which is less than or equal to seven days.

[00:30:40] Erin: They followed these patients at six weeks, three to six months, and then 12 months after surgery, and they broke them out into definite probable and possible treatment failure, which was ascertained by an independent blinded endpoint committee using a predefined criteria. They were able to enroll quite a bit of patients, so they enrolled 241 patients into the long therapy arm and 234 patients into the short therapy arm.

[00:31:04] Erin: 70% of these patients were male. The median age was 59 years. About 30% had an a SA of three plus. So this was a surgically complex population. 45% underwent debridement for osteomyelitis or fracture related injury. About 33%. About a third had implant removal. 10% was a first stage PJI or removal. About 9% was a PJI single stage revision, and about 3% were complex septic arthritis.

[00:31:32] Erin: 20% of the patients had a new metal implanted during their surgery. 20% had plastic reconstruction and 86% of these patients had had surgery before, which is interesting. A third of the causative pathogens were staph aureus, which tracks with what we know about bone and joint infections, and about a third of them were polymicrobial.

[00:31:51] Erin: Of interest, 43 people ended up having fully resistant microorganisms, so they were excluded upfront. 11 patients were enrolled and they weren't identified to have these fully resistant organisms until after enrollment, so they were included in the overall population. The median duration of systemic therapy in the short group ended up being six days, so people actually stopped before that day seven.

[00:32:14] Erin: And when we look at the outcomes and they have really beautiful odds ratios and nice non-inferiority margins here, within 12 months of surgery, when we break this out by definite definite or probable, definite probable or possible failure in the long and short groups, there was no difference in any subgroup whatsoever.

[00:32:31] Erin: And that 10% non-inferiority threshold was met across the board. When we look at incidents of symptoms associated with treatment, so this is really these patient quality of life symptoms, antibiotic adverse effects, two participants in the long group contracted C difficile infection, whereas no participants in the short group did.

[00:32:50] Erin: That is also consistent. C diff is pretty rare, one to 2% of patients in trials. but more common in the longer antibiotics you tend to receive. No participants in either group reported a K clabsi. so that was just c diff, which again, two verse zero, you could. Consider that quite meaningful.

[00:33:04] Erin: C diff is incredibly morbid, but when you look at just diarrhea reported, there was significantly more diarrhea in the long therapy group, and I liked that. This was actually something the presenting author spent some time on, and this was something the audience asked questions about. So I wanna share with you guys this dialogue.

[00:33:20] Erin: They said, so is diarrhea a big deal outside of c diff? What do we care if 10 versus 4% of patients had diarrhea? And the author said, well. If you have just had a major operation on your leg and you find yourself in a place where you can't really walk and you have to go to the bathroom much more frequently than someone else, I would say diarrhea is a major factor in your treatment dignity.

[00:33:43] Erin: And I have never quite heard it phrased like that. And boy is that not so true. Like if you are. Not that mobile post-surgery, and you have a lot of pain getting up and down and going to the bathroom requires help, like diarrhea is a big problem. And so she said that not only is that a thing that we should consider, but patients reported diarrhea as a major factor in their quality of life.

[00:34:03] Erin: Postoperative care. The main duration of hospital stay for participants in the short group was three days shorter than for those in the long group. And here, unlike our other trial, the antibiotic exposure could actually impact dispo and getting them out of the hospital faster. So that's a huge plus. The probability of survival was similar, but numerically higher in the shorter group.

So in conclusion, shorter systemic antibiotic therapy was suitable for patients with orthopedic infections who have surgical treatment that includes a licensed local antibiotic carrier implanted at the site of infection. They said shorter systemic antimicrobials were associated with fewer symptoms including nausea, diarrhea, and fatigue.

The study did not assess importantly whether a shorter systemic antimicrobial strategy would be suitable for people with orthopedic infections who are not treated with local antibiotic therapy or. Local antibiotic therapy that is an unlicensed product or simply sprinkled antibiotic powder during their operation.

[00:34:59] Erin: Or patients who have retained implants like a DARE procedure. And I think that is so important when we translate these results, because I know for a fact people are gonna say this, and I know for a fact that the local antibiotic care is not standardized in any which way. So it is important to point out they're using like a commercially available licensed product of local antibiotic therapy.

[00:35:20] Erin: The audience asked at the end of this, so has this formally changed your practice at Oxford in light of this study? And the, presenting author simply goes, yes, of course. So I think they've moved to this. And then someone doubled down and asked about sprinkling vanco and wounds and, you know, dumping cement and antibiotics and things like that.

[00:35:38] Erin: And they said. Please again, wanna underscore this was only studied a very specific licensed antibiotic character and they just said, on the basis of this study, I'd really encourage people to think quite carefully about extending durations of antibiotic therapy if patients do have this licensed implanted carrier.

[00:35:54] Erin: So, I mean, what do you guys think?

[00:35:56] Josh: when I heard that they were doing this trial a few years ago, I thought this is audacious. Like, I was kind of a bit scared. I thought, wow, that's, that's a really, I'm glad they're doing the trial. I wanna, I wanna wait and see what the results are because, it's been a big enough of a change over the last few years for us to accept going to oral antibiotics, and then still giving six weeks or longer.

[00:36:19] Josh: this six weeks of antibiotic dogma that we've all grown up with now is also out the window. so I think it's a fantastic trial. I think one thing you, you haven't mentioned, Erin, that's really important to emphasize is you need good surgeons. Like basically surgery pretty much does nearly the whole job of antibiotics.

[00:36:38] Josh: Just mop up a little bit If the surgery is done well. so these are all obviously specialized engaged surgeons and the UK has this network of bone and joint infection reference centers, which have surgeons that do this all day, every day, as well as ID and micro people that work with them. so you can't just take this to, I think like a district hospital and a surgeon who's not used to doing this, who kind of nibbles away a little bit.

[00:37:03] Josh: you have to have good surgeons, good surgery. As you emphasize, Erin, you need to use proper antibiotic carrier, devices such as serin or stimulant beads, I think is the most, most of the patients in Solario got that. And then thirdly, you have to have a suitable bone infection, which is able to be debrided.

[00:37:21] Josh: So, prosthetic joint infection, most of them are treated with debridement and implant retention. So the implant is still there and therefore this Doesn't apply to those patients. They still need 12 weeks of antibiotics actually. but yeah, I love this trial. I think it's great. will it change practice?

[00:37:36] Josh: Let's see. As you alluded to the OVIVA trial that this same group did, the early oral switch trial is, is taking a long time to slowly percolate out into clinical practice.

[00:37:48] Erin: And I'm glad you mentioned OVIVA because that most patients, I think it was 86 or overwhelmingly patients in that study had surgical debridement as well.

[00:37:56] Erin: And I think that does get lost. I mean, I think in most places surgery is standard care, but again, you need good surgeons, and that's a cornerstone of all of these Bone Studies first and foremost before looking at antibiotics. But I agree, I mean, again, OVIVA came out in what, 2019 I think. And so we're still trying to get people to be comfortable with oral and now that we're going from.

[00:38:15] Erin: Four weeks of therapy to six days. it's very bold. I love it. I love it.

[00:38:20] Emily: One thing I wanted to understand about the trial is we said there was about 50 patients who had fully resistant organisms. So I guess how did they figure out? I guess they excluded them after the fact. They took tissue samples, would've randomized them.

[00:38:33] Emily: They would've gotten, or not the intraoperative product, but then if it turned out that the organism was fully resistant to the intraoperative antibiotic, then they would've been excluded post hoc.

[00:38:44] Erin: There were 40 something patients that they got the micro and it was fully resistant, so they weren't randomized, but they were just saying like they, I guess they had interest from those patients or maybe just remarking on antibiotic resistance in general.

[00:38:55] Erin: I mean, that's a decent chunk of the possible patients. There were 11 that ended up. Enrolled and randomized despite having fully resistant infections, even though that was an exclusion criteria. And we know that happens in the real world just with delays in micro and whatnot. So there's only a handful. I think they had almost 500 patients, 11 that had resistant infections and they were included in the ITT.

[00:39:16] Erin: But, they had screened almost 50 more. And I think that's just a commentary on, wow, 10% of the infections were completely antibiotic resistant. That's just speaks to antibiotic resistance in general.

[00:39:27] Emily: so most of them had micro before the surgery, I guess they had microbiology results before they went into be operated on

[00:39:34] Erin: they had to have micro performed.

[00:39:36] Erin: it's a great question, Emily. I'm not a hundred percent certain. The way I read it was they had to have or culture sent. and then we're randomized after the fact. . Josh, do you know exactly.

[00:39:45] Josh: I dunno for sure that question, but I was just gonna comment on what does antibiotic resistant mean?

[00:39:50] Josh: so if you think about something that, whose MIC is 32, for example, local antibiotics, you know, you'll end up with a local antibiotic concentration of [00:40:00] hundreds. So something that is technically in vitro resistant probably will still be, effectively killed by these super high concentrations of local antibiotics.

[00:40:10] Josh: Oh, interesting. I think that's why they use the term fully antibiotic resistant. So if it was intermediate or whatever, that, that was fine. And even if it was supposedly fully resistant, if the MIC was 64, you'd still probably effectively kill it.

yes, Josh, that's a good point. And then Emily, I'm pulling up the study schema and the participant flowed a better answer your question. So it looks like they screened 1,211 patients. 405 did not consent, and then 43 had those fully resistant microorganisms. So they had to have had that data on screening.

[00:40:40] Erin: But the flow says they're randomized within seven days to either stop systemic antibiotics or continue. And so they must have tried to approach them after surgery then.

[00:40:50] Emily: okay. They then they all got intraoperative antibiotic.

[00:40:53] Erin: Yes. So they had to it says to be included, you had to have specimens taken for microbiological analysis during surgery, and you had to have the local antibiotic therapy implanted, and then in theory you'd start systemic therapy postoperatively as well. I see. Okay. So, so yes. So that's, so it's, you have this surgery type.

[00:41:12] Erin: You have this infection type, you have to have micro specimens sent during surgery. You have to get this licensed antibiotic carrier locally implanted during the surgery and then after that you're eligible to approach for the study. And in that, by the time they got micro data back, 43 couldn't enroll 'cause they were fully resistant, but 11 ended up enrolled despite being fully resistant.

[00:41:33] Erin: Probably just 'cause of the delay in the micro. Okay. Very cool. Yeah, good question. That was good to clarify that. So yeah, a very, very cool study. So, okay, cool.

all right, Josh, why don't you take us home, with the gepotidacin for gonorrhea trial.

[00:41:48] Josh: Sure. So this was part of a late Breaker Lancet session.

[00:41:52] Josh: So The Lancet Stable have this session at Eced the last few years. and they talked about just release publications from their journals. there was a few other papers presented. One on Arapo virus, which I love the name of. but this, trial that I'm talking about now is the EAGLE-1 trial, which is a trial of a novel antibiotic called gepotidacin.

and for gonorrhea, so this is a part of a new antibiotic class, a triazaacenaphthylene antibiotic. It inhibits back. Yeah, it inhibits, bacterial DNA replication. and there's been a previous phase three trial showing efficacy in uncomplicated UTI and in fact, it's recently been approved by the FDA, in March this year for that indication for UTI.

[00:42:40] Josh: So Eagle one was this phase three open label, commercially sponsored trial by GSK, who, market the antibiotic. And it was a non-inferiority trial. the population was people aged over 12 years weighing over 45 kilos with uncomplicated urogenital gonorrhea, or who had a positive lab test for gonorrhea.

[00:43:00] Josh: I dunno what the difference between those two things is. the intervention was oral gepotidacin three grams orally. two doses, 12 hours apart. So three grams, then three grams 12 hours later. the control was intramuscular, ceftriaxone, 500 milligrams, single dose plus azithromycin, one gram orally single dose.

[00:43:21] Josh: and the outcome was microbiological success at four to eight days after the treatment. There was a 10% non-inferiority margin, and they ended up with 628 patients randomized, 314 in each group, which was convenient that they were exactly the same size. the modified intention to treat population was, ended up being only 406 patients.

[00:43:44] Josh: Was a little bit unclear from the presentation. What happened to the gap between the patients randomized and the modified intention to treat population? 92% of the patients were male, and most of them were men who had sex with men, 70%. So the microbiological success outcome was achieved in 93% and the gepotidacin group, and 91% in the control group.

So it met their non-inferiority margin. . There were more adverse effects in the gepotidacin group, and these were mostly gastrointestinal, nausea and diarrhea. there were. Adverse effect in 67% of the gepotidacin group and only 16% of the control group. These were nearly all grade one or two, in other words, mild to moderate. and I did ask the presenter about this and say, can you give us more detail about these?

[00:44:32] Josh: Were they nausea or were they diarrhea? Were they vomiting? apparently most of them were nausea without vomiting. In, in the majority of them, but you know, bad enough to have been reported as an adverse event. There was a subgroup with pharyngeal infection and they actually did numerically worse with gepotidacin, although the numbers were pretty small, it was only 35 patients.

[00:44:56] Josh: So my thoughts overall on this is it, it's great to have a new drug for gonorrhea. We haven't had a new drug, for this infection for quite a long time. It was a bit unclear about whether this is going to work against ceftriaxone resistant gonorrhea, you know, which is obviously the big area of need or quinolone resistant gonorrhea.

[00:45:15] Josh: and they didn't present data to, to address that question, so hopefully that's coming. I wasn't. Sure whether we really need such a high dose. three grams twice. I wonder if a lower dose would cause less nausea, but still work. But again, those data were not presented and presumably as part of the drug's development, they've worked out pharmacokinetically.

[00:45:36] Josh: This is the dose. So, What are, what were your thoughts, Emily, on gepotidacin?

[00:45:41] Emily: I guess my only thought is they had to take a second dose of the antibiotic, right? Yeah. So I, just wonder, real world, would you lose people, if they have to take a second dose as opposed to kind of a one and done regimen?

[00:45:54] Josh: True. That's a good point. The control is just a single dose of the two different antibiotics, whereas this is a repeat dose 12 hours later,

[00:46:02] Emily: getting the treatment done and, and not having to follow up and say, take a second dose.

[00:46:06] Emily: But I guess that will remain to be seen with some real world data. But yeah, like you said, great to have another option.

[00:46:13] Josh: So, That brings us to the end of this, second episode ESCMID Global is such a great meeting. It's growing, and there were so many good late breaker trials that we had to break it into two episodes.

[00:46:25] Josh: Maybe next year it'll be three. but thanks Erin and Emily and thank you listeners so much for the conversation and for listening to Communicable the CMI Comms podcast. This episode was edited by Dr. Angela Huttner, and it was peer reviewed by Dr. Emmanuel Rando From Seville, Spain, Theme music was composed and conducted by Joseph McDade.

[00:46:46] Josh: This episode will be citable with a written summary referenced by A DOI in the next eight weeks, and any published literature we've discussed today can be found in the show notes. You can subscribe to Communicable on Spotify, apple, wherever you get your podcasts, or you can find it on ESCMID's website for the CMI COMMS Journal.

[00:47:04] Josh: Thanks for listening and for helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along.