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[00:00:00] Angela: Hello, communicable listeners. It's Angela Huttner, editor-in-chief of CMI Comms. The episode you're about to hear is a special one. It marks communicable very first birthday. Yes, it was exactly a year ago that we launched this podcast.

[00:00:15] Angela: Little did my dream team of journal editors know just how much of their job at CMI comms was really going to be about another medium entirely. None of us, except for a notable exception, had any experience being podcasters. Some of us are shy, all of us are nerds, so it wasn't entirely clear how it would work out, but somehow it worked out.

[00:00:37] Angela: I'm thrilled with their abilities, their insights, and maybe mostly their willingness to do this new thing just for the love of it, of infectious diseases, of medicine, of moving things forward, we hope in our own small way. So thank you to Mark Bonten Josh Davis. Annie Joseph, Erin McCreary, the notable exception, the one who does know podcasting, . and who patiently taught me everything I now know about podcasting. Emily McDonald, Nav Narayanan, Josh Nosanchuk and Thomas Tangden. Yes, there's a second Josh in there. You haven't met him yet as a podcast host, but you may have encountered him as the journal's key fungal editor, fungal and beyond.

[00:01:18] Angela: You'll be hearing him soon enough in an upcoming episode on Fungi and Climate Change. And thank you to our peer reviewers, mostly from the Trainee Association of ESCMID. Their input and insights guide us and enrich us in the podcast's programme. And thank you to Katie Hostettler-Oi, who pulls off being editorial manager of CMI, comms and Communicable podcast producer. You do not see her, but she is in everything you do, see and hear. Finally, thank you to you, our listeners, scattered all over this wide world. Thanks for being part of this thing that we envisioned. for forming these invisible but very strong connections that cross borders and bind us all together in our common goal of moving our field forward and thus making life a little more livable.

[00:02:16] 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, in the United States.

[00:02:34] Erin: I'm joined today by three other fantastic CMI communications editors to discuss the clinical trials that were presented at ESCMID Global 2025, which happened in April and Vienna. This is part one of a two-part series because there were so many fantastic trials at ESCMID this year. I think there were RCTs presented in five or six different sessions all throughout the conference, which is really just amazing to see how much science is coming forward in our community.

[00:03:02] Erin: So the first editor I wanna introduce is Josh Davis. He's an infectious diseases physician at John Hunter Hospital in Newcastle, Australia, and the head of the Infection Research Program at the Hunter Medical Research Institute at the University of Newcastle. Josh is also a clinical trialist who had a trial of his own presented, and we talked about that in our last episode of Communicable.

[00:03:23] Erin: So Josh, welcome back to the podcast.

[00:03:24] Josh: Thanks Erin. And, nice to be here because there's so much to talk about with regard to ESMI Global. And I'm gonna introduce, the next, guest or editor, mark Bonton. So Mark is an ID physician, clinical microbiologist, and clinical trialist as well at UMC RET in the Netherlands.

[00:03:43] Marc: Hello. Yes, a pleasure to be here again. We started, this, podcast last year with the clinical trials late breakers at ECCMID, and very happy to do it again. It was indeed a marvelous ECCMID this year for clinical trials. first I will introduce the next guest on the podcast or not guest editor Emily McDonald. She's a specialist in internal medicine and a clinical trialist working at McGill University in Montreal, Canada.

[00:04:08] Emily: Thanks, mark. Hi everyone. It's great to be here. As our listeners know, we usually start these episodes with a get to know you question for our guests and also for our hosts. so we're all hosts this week. last week, we covered, where you would like to travel, so there was a lot of great discussion about some, , dream destinations for this week.

[00:04:26] Emily: We're gonna take a little bit of a twist on that, and we're gonna talk about what's a, clinical trials team that you'd like to visit, somewhere in the globe to meet the people running their research and see their institutions mark, why don't you go first?

Well, then thinking about this, Oxford would be a place, but that's close by where I live, and it usually rains there.

[00:04:46] Marc: So I will choose the group of guide traits. He is at the Oxford University Clinical Research Unit in Hoshi Min City in Vietnam, and they're doing great trials already for many years, and I would really be interested to see how they manage and how they execute these difficult clinical trials so successfully.

[00:05:03] Emily: very nice. Josh, do you wanna go next?

[00:05:06] Josh: Sure. Yeah. I was thinking along similar lines to Mark, and I think probably the one I'll pick will be Oxford. I think it's Oxford because particularly the recovery trial, that was a trial run during the Covid pandemic, which was put together so impressively rapidly.

[00:05:23] Josh: the entire protocol was written pretty much in one night, and the CRF was written on one piece of paper and all those sorts of things. And so how they managed to operationalize that in such a short period of time and get a large number of patients enrolled rapidly. I'd love to, hear the stories behind that.

[00:05:39] Josh: And how about you, Emily?

[00:05:41] Emily: when I thought about this, I immediately thought of someone who I wanted to meet and I wanted to meet their team. So that's David Ware. He and I ran trials together during COVI, but we never met, so everything was done virtually and I thought it would be really neat to meet him.

[00:05:56] Emily: But unfortunately David lives in Minnesota, so it's not the most exciting destination.

[00:06:01] Erin: Minnesota's actually a lovely in the summer, Emily and you live in Canada, so you know, you're right. I'm, I'm, I'm biased against the cold weather. Along the lines of the ESCMID theme. At. Esid, there's a really lovely reception. I think we were all there where the CMI teams and editors, anyone can come.

[00:06:16] Erin: And it's this very cool reception And Josh and I actually had a cool conversation with three young Italians from all different parts of Italy. And I love gram negative resistance. So I was thinking about this and I, I wanna go to Italy and meet all different teams of investigators.

[00:06:29] Erin: One, because they have tremendous resistance and I think it'd be just fantastic to understand their patient population and those isolates. And then two, I know there's some seasoned trialists in Italy, but then it sounds like there's a lot of eager, very cool young folks we got to meet that wanna break into the scenes.

[00:06:44] Erin: It'd be cool to sit down with them and try to talk to them about trials, I think what we just learned is all around the world there are so many fantastic scientists doing wonderful things, and so many of those trials were presented at ESCMID this year.

[00:06:58] Erin: So let's get started talking about some of the highlights. Before we get into the actual trials though, let's talk about the ESCMID meeting guys, thoughts and and reactions from the conference.

[00:07:08] Josh: Uh, I'll, I'll go first. ESCMID has grown in size and also reputation, I would say over the last five to 10 years from an Australian point of view. We used to regard the large American ID meetings as the kind of go-to meetings, but now it's very clear that ESCMID Global's the kind of premier.

[00:07:27] Josh: Global ID meeting. and that was obvious I think, just based on the size of it or the quality of science being presented. and it's always in nice cities as well. Great places to visit.

[00:07:38] Emily: I could go next. I loved it this year. This was only my second ESCMID, so I'm comparing it to last year in Barcelona.

[00:07:45] Emily: thought the energy was great. I loved that there was a session, dedicated to trials. I thought that was a, really neat session to try out and I really enjoyed, attending it. I liked the geography and the layout of the conference this year, was very intuitive and Vienna was fantastic.

[00:08:01] Emily: So, a great destination.

Nothing to add to all these things. Especially, the conference center indeed was sorry, Barcelona. Much better than the year before, as was the weather. Again, sorry, Barcelona, but of course also the science. it is very difficult to compare the quality of science between two ECCMIDs because you only get to see 1% of that is presented.

[00:08:23] Marc: And, the 1% I saw this year was, very impressive and very good. So many clinical trials. Indeed, and I like that. Happy to hear that, even in Australia now, they consider ESCMID the meeting to go. That's good.

[00:08:35] Erin: I agree. you can't possibly see it all. There's so much good. So I'll say a good thing about the meeting too is the online platform is fantastic.

[00:08:41] Erin: I was watching a lot of content over the past couple of days. They do a beautiful job recording. So the people that put on this meeting, kudos, I think there were over 16,000 people at ESCMID this year. It just continues to grow. And this is so silly, but I think so important I've been coming to ESCMID since 2018 and I'll say over the years the number of coffee carts and water stations has grown exponentially, which is.

[00:09:04] Erin: Welcomed and so ESCMID team, thank you. And please continue to have ample coffee and water because that is so essential when you're walking around the conference center. one of the best things about the meeting this year was this new clinical trials format. We talked a lot about this In the communicable episode that published two weeks ago where we specifically went through the SNAP trial.

[00:09:25] Erin: And so I encourage everyone to listen to that. It's a fantastic episode featuring Josh's amazing work and his whole team. But we discussed in there this new trials format where all clinical trials were considered by the committee. And rather than having a 10 minute presentation, which is the traditional format of late breakers, the authors had much more time to go through the depths of the trial.

[00:09:48] Erin: Multiple trials were presented and then there were two facilitators who commented on the trials. And then the audience had a solid 30 minutes for q and a. So it was a two hour session. I hope this session [00:10:00] continues in the future. so we talked about snap, which was one of the studies presented, and then the other trial presented in this session was the CloCeBa trial, another Staph Aureus trial, and this was a French trial and it was just really, really fantastic. So, Emily, can you tell us a little bit more about this trial?

[00:10:17] Emily: Yeah, very excited to talk about CloCeBa. I think first of all, it was fantastic to have it, presented alongside Snap. It really brought home the messaging to see these trials that, as you'll find out, were aligned in their findings. I guess we can call CloCeBa, Snap's, little sibling trial. I don't think they would take offense to that, who presented it, understood, that they were, presenting, the results of their trial alongside Snap.

[00:10:46] Emily: And everyone was really excited to do so. So they enrolled their first patient back in 2018, um, and should be very proud that they survived and completed their trial through the pandemic. That was something really difficult to do, especially for non covid studies. During the pandemic in our center, many of us had to stop enrolling to trials, unless they were related to covid.

[00:11:07] Emily: So, kudos to them for running the trial and finishing it throughout that, momentous event in history. It was a randomized non-inferiority clinical trial. It really came out of the idea that, they wanted to look at, you know, what is the impact of the blasey genes in the case of high bacterial inoculum.

[00:11:26] Emily: when looking at staph aureus, Many clinicians have concerns about this inoculum effect in cases such as endocarditis or deep infection. So there's, you know, been some question about whether or not there's a reduced efficacy of cefazolin. And so they were comparing cefazolin versus anti staphylococcal penicillins and looking at a composite criteria for an outcome.

[00:11:46] Emily: So, you know, survival at day 90, bacterial success at day three or five with negative sets of blood cultures absence of relapse at day 90. And then clinical cure, they also looked at adverse events, they looked at premature discontinuation of antibiotics, due to adverse drug events and also collected information on c difficile.

[00:12:05] Emily: So their inclusion was, uh, a a little bit different, but similar to snap, but they were looking at, Gram-positive cocci with a time to positivity of less than 20 hours. And then confirming with a PCR. For MSSA, people were excluded if they were on active treatment in the 72 hours before randomization.

they were also excluded if they had stage four renal failure, long-term intravascular devices. And also if there was any signs of CNS infection, people had severe allergy. Also, were were excluded to a allergy to the study drug. So the primary endpoint, they looked at it in the intention to treat population and the per protocol population.

[00:12:42] Emily: And if there was missing data, it was imputed. They were really looking at, non-inferiority on the lower bound of the 95% confidence interval, looking at the difference of proportions of patients with therapeutic success at day 90, which again, was that composite outcome. The other interesting thing is that they collected, some biobanking, samples in order to perform whole genome sequencing.

[00:13:05] Emily: And, this wasn't, necessarily fully presented at this, meeting, but, we'll look forward to that data as well. So many, many patients assessed for eligibility 3,616 in order to get 315 patients randomized. 158 to Cefazolin and 157 to and that ended up having about 146 in each of the intention to treat arms.

[00:13:28] Emily: the populations were similarly balanced, so median age of around 63 more men than women. I believe that's also similar for snap. So that's something interesting, that we can , talk more about at some point, very few people who inject drugs. Only 3% of participants overall low pit score. Also similar to snap, the time to positivity was about 14 hours.

[00:13:53] Emily: And, if we look at the types of infections, a lot of catheter associated, so about 36% in some cases, it was really unknown where the infection came from, so that was about 30% of participants, 35% bone and joint infections, and then 20% skin and soft tissue infection. So the usual candidate infections for staph aureus, and again, a, fairly similar distribution is snap.

[00:14:17] Emily: About 70% of the patients, were with Blasi and about 30% of these were a, so if we look at the primary outcome, 75% success with zolin. 75.5% success with Oxacillin in the attention to treat group. And so that worked out to a difference of about 0.008 with a confidence interval of 0.11, 1.095. So, uh, non-inferiority was indeed met.

[00:14:43] Emily: The other interesting thing, which aligns with the SNAP trial and, I'm sure Josh can speak more about this, but Cefazolin was also less nephrotoxic than coill. So all around results aligned between the studies, you had about 0% nephrotoxicity in patients on cefazolin and 6.2% in Oxacillin. And when they looked at each different time point along the way in the trial, cefazolin was better tolerated.

[00:15:09] Emily: So, really nice to see these trials again presented alongside of snap, with kind of harmonized results. Some more information about the biobanking and the whole genome sequencing I think is gonna be interesting to see when that gets published and discussed.

[00:15:23] Josh: Yeah, we were really relieved when we heard the CloCeBa results were basically the same as the SNAP trial results, because it would've been awkward if the trial showed the opposite to each other. I think their complimentary, the style and the approach is a little bit different.

[00:15:38] Josh: Snap is a lot more pragmatic. this trial had a lot, more eligibility criteria, which is why only 10% of people got into it and they collected more detailed data. so I think it's, really good having two trials that took different approaches to a similar question, but came up with the same answer basically.

[00:15:57] Emily: what did you think about the confirmatory testing, the PCR being positive for MSSA? To me that was, a different type of approach. was there any thought to going that route with Snap?

[00:16:06] Josh: We did think about that, but because snap's a pragmatic trial, we had to use whatever microbiology methods were being used in every, you know, all hundred participating laboratory.

[00:16:15] Josh: So we couldn't insist on PCR being used. But now that you mentioned that, one very important difference with CloCeBa is they didn't exclude penicillin susceptible staph aureus. So in the Snap MSSA trial, it's methicillin susceptible, but penicillin resistant staph aureus, and by including penicillin susceptible staph aureus that kind of dilutes the potential for, keole and two b inferior.

[00:16:40] Josh: In other words, it biases towards non-inferiority. However, I think when we see their results, including, the subgroup. By blase PCR, that concern is allayed because, they demonstrated non-inferiority even in the subgroup, even when they excluded the PSSA patients.

[00:16:59] Josh: just one other thing that we noticed that was really different, which I haven't quite worked out, why is the, rate of acute kidney injury was far lower in the CloCeBa trial than the SNAP trial. And in fact, the rate of acute kidney injury in the SNAP trial was a lot lower than it is in large observational data sets.

[00:17:16] Josh: So I don't really know why it was so low in the CloCeBa trial.

[00:17:20] Emily: It remind me, but in SNAP we excluded dialysis but not stage four. And I suppose in this study they excluded stage four and higher. So maybe the baseline level of chronic renal insufficiency, it might've differed between the two studies, but that's the only hypothesis I can come up with.

[00:17:39] Josh: Yeah, that's a good point.

[00:17:40] Erin: I also excluded more patients with potentially more severe infections, whereas SNAP was pretty much, you have staph aureus in the blood, you're in, CloCeBa, excluded, brain abscess, meningitis, anyone with a recent stroke, implanted devices, things like that. So potentially a less sick cohort.

[00:17:56] Emily: Yeah, very good point. Yeah. Alright,

[00:17:58] Josh: Let's move on to a another trial, which actually Emily was the lead investigator on. So we're gonna ask Erin to present this one, the Taper V trial.

[00:18:07] Erin: Yes. I'm so excited to present the Taper V trial, which as Josh said, was presented by the one and only Emily McDonald, so we're so lucky to get to interview here again today.

[00:18:16] Erin: So this stands for initial Vancomycin Taper for the prevention of recurrent c Diff infection. So why did they embark on this study? Always like framing around the why. Why do we wanna answer this question? I think as anyone who takes care of patients or is adjacent to taking care of patients knows c diff is common, costly, and harmful.

[00:18:33] Erin: As Emily so eloquently stated, in North America, there's about half a million cases a year with an attributable cost of over 5 billion, and there's higher mortality if you recur. We always say this when I'm teaching my residents, like one in four patients with c diff recur with 25%, right? Which that's like a staggering number that we just brush off.

[00:18:51] Erin: And I think it's because c diff has a very easy way to diagnose it, at least objectively, right? Like you're positive or you're not. And then there's. Two, maybe three treatment options. And so it's quote, easy from a clinical mind, from a diagnosis and treatment standpoint. And so I don't think people really appreciate how morbid this is for patients and how common it is, to not be fully treated and to have this infection again.

[00:19:14] Erin: So love that you looked at this. I also love Emily went into the history of where our treatment durations come from. And so right now for an initial episode, we do 10 days of oral vancomycin. That duration is derived from very limited animal and observational data and potentially stems from a single case report.

[00:19:32] Erin: So Emily and I both have a passion for myth busting and understanding where our recommendations come from. So I love that she took the time and the presentation to go through that because it is important framework when we're like, this is what we do. Right. It's always good to challenge that. And then the other thing that is important to set the stage for some of the outcomes they looked at in this trial is the fed dexamycin studies where we saw that fed dexamycin significantly reduced recurrent c diff compared to 10 days of vancomycin, 15% versus [00:20:00] 25%.

[00:20:01] Erin: But that reduced recurrence was most pronounced within the initial 14 days of follow up. So it really reduced early recurrence and we'll come back to that time point metric in a minute. And so the question was, should we use longer taper, vanco regimens because this is done unofficially in practice all the time.

[00:20:18] Erin: In fact, it's even guideline recommended to use a Vanco taper. But I will tell you like no one knows what dose for how long we make a lot of this up. So the hypothesis of the study was that a brief vancomycin taper following initial therapy would be superior for the prevention of recurrent c diff when compared to a standard duration of vancomycin.

[00:20:39] Erin: And I think this is really important 'cause as Emily pointed out as well, our other options to prevent recurrence are potentially fed dexamycin, which unfortunately is still cost prohibitive for much of the world. They're either not universally available. A lot of countries don't even have access to these drugs.

[00:20:53] Erin: Some of our newer agents like Rebi, ota, or vst, are, which, apologies for the brand names, but they're. Their generic names are like chemical compounds, which I, I'm not gonna get into. But, those are very, very cool new therapies for recurrence, but they're very expensive and storage and access is, problematic.

[00:21:11] Erin: We don't have evidence for a lot of therapies or some are even unfortunately being removed from the market. recently, Belo Uxb was announced that it'll no longer be manufactured. So super important to take our old drugs and try to use them in creative ways to help our patients and have robust evidence to guide how we use these drugs.

[00:21:28] Erin: So this was a multicenter, randomized clinical trial, placebo controlled for the purest way to go. Emily, 16 hospitals 4 Canadian provinces. They included adult patients who tested positive for c diff and were undergoing treatment. And this was either a first episode or a first recurrence. They had a robust definition of positive that was standardized across all sites.

[00:21:50] Erin: So you had to have three or more episodes of diarrhea in 24 hours and be either NAT positive or toxin positive. And you may ask, well, why would you include PCR only? We know that may over call the diagnosis, but remember, they had to be getting treatment. So a clinician decided they were sick, they had to be symptomatic.

[00:22:07] Erin: and not everyone in Canada has access to toxin testing. And so that's why they included PCR. So to Josh's point, I, love this, like you have to be pragmatic. I always say if you have these groundbreaking scientific results, but you can't actually operationalize it for the average community hospital, you're not actually gonna change the care of patients.

[00:22:24] Erin: So I love that you explained to that Emily. The exclusion criteria were patients who the clinician decided to prescribe more than a hundred milligrams of oral vanko per dose. So we see sometimes these also unstudied 200 5500 milligram doses. So those were out patients who were not better by the end of day 10.

[00:22:41] Erin: So something was up with that. if they got metronidazole monotherapy for more than three days, we know that's no longer a preferred agent for c diff. if they received Fed Dexamycin and FMT or any kind of immunoglobulin, if they had a previous or current total colectomy allergies, of course, more than two episodes of c diff within the past five years, and then there were some additional exclusions.

[00:23:02] Erin: These, I love that you explain this cause when we read these studies, when they're published, we're always like. Why did you exclude this patient population? And you try to understand the why. So it sounds like the Canadian regulatory bodies had you exclude patients that had documented hearing loss of certain degrees over the theoretical concern of ototoxicity with Vancomycin, which that was like fascinating to me 'cause we would not,, suspect that oral Vancomycin would cause any kind of, substantial blood concentration, but good to know that that's why those patients were excluded.

[00:23:31] Erin: I did have a quick question for you on these exclusion criteria, Emily, the no more than two episodes of c Diff within five years, where did that timeframe come from? I was having trouble piecing together. Why That would be something that would raise a flag for you in that patient population. Why five years?

[00:23:46] Erin: Why two episodes? Yeah.

[00:23:48] Emily: when we started our study, the majority of our patients we were recruiting from our local center. It was during the pandemic and we were permitted to keep recruiting to acet Difficile study. Our electronic medical record went back at that time, about five years.

[00:24:03] Emily: We also thought it might be difficult for patients to remember episodes prior to five years. It was really kind of just a, local, issue that we didn't. Really want to bring in people who had had 3, 4, 5 recurrences. We had to put some kind of limit, matched with, how long do our records go back with patient memory?

[00:24:20] Emily: And so I think we arrived at five years as being something that we thought was reasonable.

[00:24:24] Erin: I love that. Thanks for explaining that again, pragmatic decision making that sometimes it's not an exclusion based on necessarily a. At five years, you're medically more inclined to do this or that. It's just we couldn't look back more than five years.

[00:24:36] Erin: Okay, so trial structure. So day one was the first day a patient received a dose of oral vancomycin, any dose.

[00:24:43] Erin: So even if they didn't get all four doses on that day, and I think we often struggle to define day one. And then the last day of initial treatment is day 14, and then you were randomized to placebo or vanko taper. So you received a study drug from days 15 to 28 where study drugs started on day 15.

[00:25:00] Erin: I'm gonna pause here again, Emily, since we kind of talked about the standard for a first treatment is 10 days. Why did you guys require 14 days of treatment?

[00:25:09] Emily: Yeah, we actually, locally again, had already adopted many of us a 14 day treatment. there is some observational studies showing that 14 days, might be better than 10.

[00:25:22] Emily: And what we really wanted was, to ensure that people were treated. We wanted a little bit of window, 10 to 14 days of recruitment. We thought for sure at 14 days most people would be resolved and there would be, no question that entering into the trial, that they were better. we were recruiting people who were at risk of recurrence.

[00:25:42] Emily: It was opposed to people who had ongoing infection. so yeah, like you said, Erin, it was kind of just based on our local practice. Many of us were giving 14 days, and so to recruit patients to a trial, it has to be acceptable to the clinicians. In retrospect, we, lost four days of our, intervention looking better.

[00:26:02] Emily: and so it might have made our intervention look better had we recruited at 10 days as opposed to 14. But it was just one of those many hundreds of decisions you make when you're setting up your trial that we said, this is what most people are doing. at our center, they're already giving 14 days, so we'll make it acceptable and, and we'll recruit around,, day 14 and it'll give us a little extra wiggle room to catch patients.

[00:26:21] Erin: Interesting. Thanks for explaining that. 'cause I think our standard is still 10, so that's something, you know, my team would have to discuss on, applying these results. Okay, so you guys followed people out to day 90. The primary outcome, however, was day 56, which was based on the IDSA Shaa definition of recurrence.

[00:26:37] Erin: And then you also looked at patients at day 38 as a key secondary outcome because that was the follow up period for the fed registration trial. So love that you're anchoring to these other key c diff studies and you looked at side effects, emergency department visits, quality of life, et cetera. As your other secondaries, you did have a strict definition for recurrence, which again, you had to be PCR or toxin positive plus diarrhea plus receiving treatment.

[00:27:02] Erin: Or if you had alias toxic megacolon or pseudo membrane colitis, you're automatically in and you adjudicated recurrence by three reviewers with consensus. So these were definitely. Recurrences. It was an adaptive trial with Bayesian binary regression with pre-specified stopping rules for superiority and futility.

[00:27:21] Erin: A large majority of the study took place during the pandemic. You were able to randomize 275 participants after screening 2,190 patients. one of the main reasons patients were not eligible for the trial was because they only got treatment for 10 days or because physicians wanted to prescribe a taper.

[00:27:37] Erin: They were already convinced that that was the right thing to do, so they were unwilling to randomize, which is interesting. Your participants had a median age of 60 years, more women than men, A little bit reversed from Staph aureus trials, and it was about a third outpatient, a third in the emergency department and a third in the hospital that were able to enroll.

[00:27:55] Erin: And more than 90% of the patients, this was their first episode of c diff, which I think that's interesting too. This wasn't really a looking at patients who already had recurrence.

[00:28:05] Emily: Well, and and you can see it kind of goes back to that people are already bought into the taper. Yeah. Right. So a lot of our first recurrence patients who are eligible, the clinician already wanted to do a taper.

[00:28:15] Erin: That's actually an excellent point. So that's why you had more on the first episode. I think we studied too many things in people that are already so sick and failing and it's like, why don't we just do better upfront? So I like that this is a first episode way to maybe potentially do better.

[00:28:28] Erin: So looking at your outcomes, the primary at day 56, there is a 74% probability of superiority of vancomycin compared to placebo. 14.8% recurrence in the vancomycin arm versus 17.7% in placebo, which was an adjusted relative risk of 0.84 at day 38. This is interesting, a 99% probability of superiority of vanko taper compared to placebo, 6.7% versus 15.4% by day 90.

[00:28:58] Erin: That kind of levels out 62% probability of superiority, 17% versus 18.5%, and you displayed the Kaplan meier curve of time to event, which I love. Thank you. When I peer review, I always ask for these if they aren't in there. 'cause it's so important because this is why the devil's always in the details.

[00:29:17] Erin: You show how. Despite early recurrence being very favorable, the curves essentially catch up by day 90. And you said only one patient had recurrence while on vanko. And this is what I've taught. So it was validating to see this, like, if you're getting oral vancomycin, you're not going to get c diff. And so it's a matter of are we just kicking the can down the road?

[00:29:39] Erin: I liken this to CMV prophylaxis in a way. If you're on valganciclovir, you're not going to get CMV, but what we see in the extended prophy trials is patients just get late onset disease as soon as prophylaxis stops. ,

[00:29:52] Emily: This was why it was so important actually to placebo control.

[00:29:55] Emily: Yeah. 'cause when we say that you can't recur on treatment, part of that could [00:30:00] be a bias against testing for it. So if you see somebody on Vancomycin, you may just not. Test as much. Yeah. so placebo controlling it was really important.

[00:30:08] Erin: Yeah. It, it's amazing. It's amazing work. So those are the results.

[00:30:12] Erin: So Emily, what is your team doing with these results?

[00:30:15] Emily: So, I have to say, I'm sold on the results. I've started treating patients with the Taper v regimen upfront. I think it's really interesting that it, Certainly pushes your recurrence. we don't know what happens with Axo Mycin long term.

[00:30:33] Emily: And so it is very possible that all the treatments that we have to prevent recurrence, push out, recurrence., We don't know what happens day 56. Day 90 in randomized trials with Oxo Mycin. We see what happens if you use a Vancomycin taper, you're pushing out your recurrence, most likely, that's probably not a bad thing and is actually probably a good thing for most of my patients.

[00:30:55] Emily: So I, work in the hospital. I treat a lot of older adults. I think when you're sick in the hospital is not the time when you want your c difficile to come back. you're already perhaps dealing with some other medical event like a heart failure exacerbation or a pneumonia. and so having your recurrence, take place a few weeks away and maybe never, like, maybe it's a cure for some people, is an overall good thing for me.

pretty available drug worldwide. very inexpensive. So, this regimen is always gonna win out on cost. The unanswered question of course is,, what happens if you compare this taper to fed dexamycin and you follow people out to day 56 and day 90? do you see that, the effect of fed dexamycin persists long term?

[00:31:44] Emily: I think we don't know. But in the meantime, I'm gonna be using the, taper v regimen on my. patients. I mentioned older adults, but quite frankly,, younger people, you have a life too. Maybe you don't want your c difficile to recur and you wanna increase the chance that it's cured.

[00:32:02] Emily: so yeah, I'm pretty sold on the regimen, but, would love to hear what others think.

[00:32:06] Erin: Can you detail for our listeners the regimen? 'cause I think what I've already heard from colleagues is like, we have an RCT supported dose finally. So you get, you did two week taper. What exactly was the dose?

[00:32:18] Emily: Yeah. So everybody got 14 days of QID four times a day, and then you were randomized to continuing for another two weeks of placebo versus vancomycin. So the recipe for week three and week four is really BID for week three, and then once a day for week four.

[00:32:35] Erin: Awesome. So a hundred BID for seven days, a hundred daily for seven days.

[00:32:38] Erin: And then you're done.

[00:32:40] Emily: Yeah, we do 1 25, but, uh,

[00:32:42] Erin: oh, 1 25. Duh. Oh my gosh. Yes. Thank you. No, that's fine. Okay.

[00:32:47] Emily: you might ask why we didn't do the six week taper, because a lot of people do a six week taper for multiple recurrences. and at the time we were worried a little bit about what people would say about the impact on the microbiome.

[00:33:02] Emily: and so we, decided to do an abbreviated taper. so we did a four week instead of a six week. There, there's pretty good observational data showing it doesn't increase your risk of VRE, for example. But in terms of impact on the microbiome, there's still discussion about, you know. Does it impact the microbiome more than say, Axo Mycin?

[00:33:21] Emily: And, is that why you push out the recurrence? But then maybe people recur later because of that impact on the microbiome. And so we wanted to try and have a successful regimen, but one that had a more limited impact on the microbiome by stopping it at four weeks as opposed to six.

[00:33:38] Emily: Yeah, I like that.

[00:33:38] Emily: Well, I don't think patients wanna take drugs for two weeks longer than they need to either. So I think that was Sure. Patient focused as well. Awesome. Amazing work. Thank you so much for going through that with us and answering some of those questions. Mark, do you wanna talk about the next trial? Yes,

[00:33:52] Marc: sure.

[00:33:52] Marc: That's the temocillin versus meropenem for targeted treatment of bacteremia due to third generation. Cephalosporin resistant Enterobacterales, and it's a pragmatic RCT coming from Spain. The clinical problem addressed here is that for the empirical treatment of presumed gram-negative infections, we, let's say increasingly rely on carbapenem as a first gift, then see what's causing the infection, and if it is indeed a negative infection, then, at one time point, is there a question?

[00:34:21] Marc: Should we change the winning drug? Should we step down from carbapenem to something else? And in many places, that is not done Now, temocillin is a beta-lactamase resistant penicillin that could fill the gap, could be used for treatment of ESBL producing or mc positive re negatives and could therefore serve as a carbapenem sparing antibiotic.

[00:34:43] Marc: The problem with temocillin is that it is not available in many countries. According to the presentation at ECCMID. , It's only registered in Belgium, Luxembourg, uk, Iran, and Germany. So this trial was obviously set up to get evidence for Spain, hopefully if there would be a positive result that it can then be used.

[00:35:03] Marc: So the trial got the name ASTARTÉ, and that probably has a Spanish meaning, but for me it's a multicenter open label, phase three, and randomized Control, pragmatic investigator initiated trial. So the patient eligible for this trial were those with a documented gram-negative bacteremia with an enterobacterales that was resistant to ceftriaxone, but susceptible to meropenem.

[00:35:28] Marc: And the inclusion occurred at three days. after the start of antibiotic therapy and then the patients were randomized. the primary endpoint was defined as clinical cure at the test of cure about seven to 10 days after the end of treatment. And in addition to that, there should be an absence of a recurrent bloodstream infection at day 28.

[00:35:49] Marc: The patient should still be alive at day 28 and there should not be any need of to stop or change the, treatment of the patients. They predefined their sample size with a 10% non-inferiority margin, which gave them a pursuit sample size of 334 patients. And in fact, they randomized 330 in two groups of 165 and 165 for the modified intention to treat analysis, which was based on these primary endpoints.

[00:36:18] Marc: Now, the patient population that wasn't ruled, here we go again. 33% were female. So there was 75% was urinary tract source. Almost all isolates were e coli, 70%, but completely unexpected to me. With 75% of infections from a urinary tract source. 33% of the population was female and 40% of the infections were considered community acquired.

[00:36:44] Marc: So this was a largely hospital acquired, or healthcare institute acquired infection, predominantly male patients with documented gramm negative breia. 70% of the IS isolates were e coli, And 20% were clai. 94% were ESBL produced, and then 6% were mc. Now patients were randomized and then followed up.

[00:37:07] Marc: And guess what the clinical success was? 1.5%, exactly the same in both groups. So 0% difference between the groups and the lowest margin of the non-inferiority, range was minus 8.2. So they met the primary endpoint that they demonstrated non-inferiority, in this patient population. I mentioned specifically this patient population as the overall day 30 mortality was 30%, which I think is very low for a group with documented gram-negative bacteremia, mostly hospitalized patients.

[00:37:42] Marc: so their conclusion was that this study demonstrated non-inferiority for temocillin, uh, temo thein in this patient population and they recommend the treatment or the use of this, antibiotic for patients with, e coli bacteremia from a UTI source. And there are many, let's say, remaining questions for other indications or patient populations.

[00:38:01] Marc: It's an interesting study. But there were some questions also already in the session, and even having the time to think more of it. One important questions, and that's also the one I addressed, is what treatment did the patients get before they were randomized? Were they all treated with meropenem?

[00:38:18] Marc: Well, meropenem definitely was one of the options and one of the antibiotics used. I think frequently, but we have to wait for the data, but also atezo, but also some patients apparently with amoxicillin, CLA acid, for a median of two days. So after a median of two days, the patients were randomized.

[00:38:35] Marc: And then the other aspect of this study was that the patients could switch to oral therapy after a total of four days of IV treatment and good response. So from the presentation, it is not clear for how long the patients now were really treated with the randomized IV treatment. For clarity, temocillin can only be given intravenously.

[00:38:56] Marc: And then what also was, let's say surprising is the number of patients that could not be enrolled because of resistance to tamin. It was expected that the resistance to temocillin. Would be very low. Well, it was not, I don't have the exact percentage, but from the flow chart, it was apparent that many patients were excluded for that reasons.

[00:39:15] Marc: So, I think a great study done in 29 hospitals in Spain, giving a clear answer for a question that's hanging in the air for quite some time. It also may help us to get this, antibiotic temocillin available more broadly. but still we have to wait for the final publication to get answers to these details and hopefully the peer review process, we'll make them answer the questions.

[00:39:38] Josh: it would be great if this pans out because we've been looking for a carbapenem sparing regimen for years, right? The merino trial and, so on have failed to find one so far. So we're stuck with meropenem and carbapenems for these organisms.

[00:39:51] Josh: So if, temocillin turns out to be, effective when all your questions that you are posing Mark, turn out to be supportive of [00:40:00] it. I guess it comes down to availability, but it would be an attractive alternative to Meropenem.

[00:40:05] Marc: Yeah. Fully agree.

[00:40:06] Erin: Awesome. Yeah, that's not a drug we have in the States, so something I'm not familiar with, but love seeing these studies done. All right. Next and kind of a pivot maybe. But Josh, there was a trial about cap, everyone's favorite infection common.

[00:40:19] Erin: We still don't really know what we're doing. So talk to us about shortened antibiotics for cap.

[00:40:25] Josh: Yeah, so this was the CAP5 trial, which was a multicenter trial from, Denmark. and just to cycle back for a minute to the why, as you were talking about Erin, it's, interesting, I guess to recall or to note that, when penicillin first started to be used for pneumonia in the 1940s and fifties, it was one.

[00:40:45] Josh: Day worth or one to three days worth. That was the standard. and it was only in the sixties and seventies, people started to think, hold on. Maybe we need to use longer courses, because some people relapse and, maybe resistance emerges. And then it became pretty routine to use 10 days or so.

[00:41:02] Josh: Now in the ensuing years, there have been at least 30 randomized trials that look at the duration of therapy in community-acquired pneumonia. and there've been at least three metro analyses of less than seven days versus more than seven days. And these have all shown, that, the shorter regimens were not inferior in terms of variably defined clinical cure or treatment success.

[00:41:26] Josh: and in fact, there've been two more recent trials of looking at three days versus seven days, and they both showed three days was non-inferior, in terms of clinical cure after 15 or 90 days. now these are all in fairly selected populations, which we'll talk about in this trial in a sec, and so on all of that background guidelines, most guidelines still recommend five to seven days.

[00:41:49] Josh: so this was the rationale presented by the investigators. You might wonder after what I've just told you, why would you do another trial? And, I think that is a very valid question. their rationale was, look, the other trials were not powered to look at mortality as an endpoint.

[00:42:04] Josh: They were looking at clinical cure, or treatment success as an endpoint. And this trial focused on 90 day or cause mortality. the inclusions for the trial were adults hospitalized with pneumonia, and they had to have met clinical stability criteria after three to five days of treatment. And those were based on heart rate, blood pressure, temperature, respiratory rate, and oxygen saturation.

[00:42:27] Josh: So basically that had to be getting better and be stable after three to five days. They had to have radiologically confirmed, community acquired pneumonia, and they were excluded if they were immunosuppressed, had infection outside the lung. Importantly, if they were in ICU, they were excluded.

[00:42:46] Josh: It was an open label non-inferiority trial with one-to-one randomization. The choice and the root and dose of antibiotic was all left up to the trading clinicians. So this is a pragmatic trial. It's just the duration that was randomized, not the choice of antibiotic. a non-inferiority margin was 6%.

[00:43:05] Josh: And, the expected mortality before they started the trial was 6%. So they seemed like a very large non-inferiority margin to plan the trial. And, someone got up and asked this question in fact, and, they didn't really answer it satisfactorily in my mind.

[00:43:20] Josh: In the trial, 196 patients were randomized to short course therapy and 197 to, control, or longer course therapy.

[00:43:30] Josh: The median age was 75. About 40% had a Charleston score over one, in other words, had at least one comorbidity. and it was mild to moderate cap. So the curb 65 score was less than three in nearly all patients, meaning they didn't have severe pneumonia. and the primary endpoint of mortality occurred in 3.1% of patients in the five day treatment group, and 2% of patients in the, longer treatment group.

[00:43:58] Josh: I said before, it was five versus seven days, and in fact, the shorter treatment group was five days. The longer treatment group was at least seven days. So on average, they got about eight days. so 3.1% versus 2%. So this did meet their non-inferiority definition, even though it was numerically slightly higher in the short group.

[00:44:19] Josh: and there was also a per protocol, population where the mortality was 1.7 in the short group and 1.5 in the standard group. The hospital readmission and relapse rates were similar in both groups, and there were no difference in adverse effect. So my main thoughts around this is, firstly, what does this add to previous randomized trials?

[00:44:40] Josh: It adds out to our confidence that shorter course regimens are as good as longer course regimens in a selected group of patients who do not have severe pneumonia and who have responded to therapy. However, you could argue that if someone's Respondent to Thein has become stable after three days.

[00:44:57] Josh: They probably don't need any more antibiotics. so the other thing to consider is that, patients with community-acquired pneumonia, a lot of them do not have a bacterial infection. So probably around half of them actually have a viral infection. which is why. , There was a randomized trial in Pakistan in children with outpatient pneumonia, and they were randomized to no antibiotics.

[00:45:21] Josh: So some antibiotics and no antibiotics was not inferior.

[00:45:26] Erin: So,

[00:45:26] Josh: I mean, it just means that it's difficult to do trials like this, but they're kind of self-fulfilling prophecies in a way because a lot of the patients you're treating don't need any antibiotics at all. and then if you focus only on the group of patients who have actually are rapidly improving, they probably don't need any antibiotics beyond that.

[00:45:44] Josh: But, I think it, adds to the existing data, it adds to our confidence around this. But I would discourage people from doing more of these trials really. it's also important for us to remember, and we look after these patients. Some pneumonia patients end up with complicated courses getting EMAs and septic shock and respiratory failure and so on.

[00:46:04] Josh: And they need individualized, you know, antibiotic durations, that really trials like this can't address.

[00:46:10] Erin: Yeah, absolutely. And I think we have a trial of, three days, right? but people don't wanna believe that and then they look at that and they're like, oh, well to get to the inclusion criteria for my patient, it's so niche when really it's not, it's actually the vast majority of patients that present with pneumonia, but perhaps not the hospitalized ones.

[00:46:25] Erin: But, Yeah, interesting results and, I guess just like nail and coffin, although I feel like we were already quite there, we actually built this order set at my hospital that I'm quite proud of, that when prescribers go to order IV therapy in the ED or on admission, they only are allowed to order two doses and then it's linked to an oral step down order for three more days max.

[00:46:46] Erin: And they can stop it at day three if they want to. And so they sign both orders on day one. So we've kind of flipped the mental paradigm of please go from IV to PO and shorten the course to like, this is the standard. You should be on oral and home by day three and if you wanna continue iv, you have to justify that.

[00:47:02] Erin: And I think that it's been a cool thing to, to look at. So

[00:47:06] Emily: yeah, we're, we're enrolling to a pneumonia trial at our center right now, so it's, anticoagulation for pneumonia, for cap. And I have to say it is so messy to figure out who has pneumonia., We get the imaging, we get the impression. And it's really difficult to, actually understand who has a bacterial pneumonia in order to include them in the trial.

[00:47:26] Emily: Which is why I think, like you said, Josh, a lot of times it's non-inferior to give shorter that trial that showed you could give no antibiotic at all. Like some of these patients just simply don't have bacterial pneumonia.

[00:47:37] Emily: Yeah,

[00:47:38] Erin: Super interesting. Okay, Marc do you want to take us home with this episode yes, indeed. This one is about tuberculous meningitis. I've never seen that in the Netherlands to be honest. but I haven't seen everything., But the good news here for my me presenting this is a textbook story about clinical trials.

[00:47:58] Marc: So the trial is the harvest study. It's a phase three multi-country randomized controlled trial testing, the concept of high dose rifampicin treatment for tuberculous meningitis. So increasing the dose. Now it's a very, severe infection with a high mortality and a sequela rate and, better treatment is needed.

[00:48:16] Marc: That was clear. Now, several years ago it was proposed to increase the doses of rifampicin because the problem was that rifampicin levels in the brain were considered too low for effect of treatment. It's a very simple reason. Let's increase the dose and see what happens. They called it a phase two study, and in that study they used Rifampicin IV for the first two weeks in high dose to get higher levels.

[00:48:42] Marc: Indeed, they got higher concentrations as with oral therapy in blob and , cerebral spinal fluid. It was safe and they found in a small study a 50% higher survival for dose at day 60 for the 60 patients that were in the trial and randomized small trial impressive results. So based. On that and on all the samples that were taken, they did a lot of PKPD modeling and came up with a model to optimize the, oral dosage for rifampicin to get the same outcome.

[00:49:14] Marc: And predicted that, they would increase the dosage from 10 milligrams per kilogram per day, which was the standard dose to 35 milligrams per day. They would get a survival benefit, a reduction of, mortality from 75 to 60%. So that was the hypothesis that now needed to be confirmed in the phase three , large study.

[00:49:34] Marc: That's the harvest study that was done in Uganda, South Africa and Indonesia. And that, was, I said treatment, standard treatment for tuberculosis in. Combination with corticosteroids, corticosteroids and the tapering dosage. And the patients were randomized to have either 35 or 10 milligrams per kilogram per day, of Rifampin in their regimen.

[00:49:54] Marc: The study was powered for an absolute 13%, survival benefit, and [00:50:00] 529. 529. Patients were randomized in 14 months, which I think is very, very impressive for this diagnosis. In the intention to treat an analysis, there were 249 and 250 patients, and in the protocol analysis, 237 and 244, the median age of this population was 37 years.

[00:50:23] Marc: 61% also had HIV, and 70% had received drugs before a randomization, but only for an average of three days. So no long pre-treatment now, the outcome, no difference at all between the two regimens. So the data from the phase two study were not reproduced at all. In this larger phase three study. The mortality was 43% versus 30%

[00:50:51] Marc: at six months in both groups and actually the higher dose did even worse with secondary outcomes. So this was a clear rejection of the hypothesis, something that looked very convincing in phase two based on small patient numbers. So this underlines the importance of confirmation of, very spectacular results that were also unexpected in phase two or smaller trials by a large conclusive trial., This one is conclusive. There are more studies underway testing this higher dose use of Rifampin for this indication. We'll see what they bring, but this was a very, very impressive study, presented.

[00:51:31] Josh: I've gotta say I agree. I love, this was my favorite trial at ec ESCMID Global.

[00:51:37] Josh: Sorry. Because I really like, trials that prove something doesn't work that everyone has started to use because of early data. and it's just a really good example of don't change your practice based on phase two trials. That history is littered with examples just like this. , The other interesting thing that came up is, as you mentioned, some of the secondary outcome measures, the disability endpoints and so on, were worse in those on high dose Rifampicin.

[00:52:03] Josh: And in the discussion, section, the investigator hypothesized or said that people have hypothesized that it may be that the high dose rifampicin is inducing metabolism of the steroids that are given to decrease the inflammation as standard therapy now with TB meningitis. So a again, an unintended consequence, but they're looking into that in, some mechanistic studies.

[00:52:27] Josh: I think that brings the end of this first set of trials, this first episode so thank you so much to all our, hosts for this conversation. And thank you to the listeners for listening to Communicable to CMI COMMS podcast. This was part one of a two part episode as I mentioned, and we'll be back soon with more trials.

[00:52:50] Erin: And I also wanna give a shout out to Dr. Barbara Piva from the Czech Republic, the peer reviewer for this episode.

Theme music was composed and conducted by Joseph McDade. 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, or wherever you get your podcasts, or you can find it on ESCMID's website for the CMI COMMS Journal.

[00:53:19] Josh: Thanks for listening and helping CMI, comms and smid move the conversation in ID and clinical microbiology further along.