#134 – ESCMID Global Trials: PETER PEN and ASTARTE

Podcast Collaboration, Introductions, and ID Pharmacist Day Hello and welcome to Breakpoints, the Society of Infectious Diseases Pharmacist Podcast. My name is Erin McCreary, and I'm the Senior Director of Infectious Diseases Strategy at the University of Pittsburgh Medical Center and a Clinical Associate Professor at the University of Pittsburgh School of Medicine. Today we are bringing you our third collaboration podcast between Communicable and Breakpoints. Speaker 2 Hi everybody, and welcome back to Communicable, the podcast brought to you by CMI Communications, Eskmid's Open Access journal covering infectious diseases and clinical microbiology. My name's Josh Davis and I'm an editor at CMI Communications and an infectious diseases physician at John Hunt Hospital in Newcastle, Australia, and also a professor at the University of Newcastle and a clinical trialist. And I have to say before we launch into it that it's really fantastic to do this collaboration with Breakpoints because the Breakpoints audience, you guys that are listening now is far more established than the communicable audience. And we really like the interaction between the two groups of hosts and audience. So if you're listening to one of the podcasts in the past, please listen to both of them in the future. Speaker 1 Thanks, Josh. That is, it's a joy for us to to expand into the estimate global audience, especially as we try to globally raise the role of an infectious diseases pharmacist, which is so timely that we're doing this collaboration because we actually have a very special announcement. So this episode's releasing the beginning of May, but I do want everyone around the world to mark their calendars for May 22nd for ID Pharmacist Day. This year, we're celebrating the theme beyond the prescription ID Pharmacist. As educators and advocates, we invite all of you to join us on your favorite social media platform to share how you or an ID pharmacist you may know goes beyond the prescription, way beyond medication dispensing, and talks about how pharmacists really optimize antimicrobial pharmacotherapy. You can use hashtags ID Pharmacist Day and Beyond the RX for your chance to win a prize. Yes. So if we see your posts, the Society of Infectious Diseases Pharmacist, we are giving out very cool prizes. You can visit sidp.org/ID Pharmacist Day For more information and for our many, many listeners from the Communicable and Eskimid global community who may be in countries without clinical pharmacists or may not know a clinical pharmacist. We really hope you can use this day to learn a bit more about our profession. One of the driving missions and goals of SIDP over the next several years is to enhance and collaborate on the global training of antimicrobial stewardship pharmacists and ID pharmacists around the world, which is a shared mission we have with our friends at Eskimid who are working with us on this very important endeavor. So super excited, very timely. Speaker 2 Thanks. That's great, Aaron. It's fantastic. There is an ID Pharmacist Day because ID pharmacists are so important to patient care in general. I mean in Australia in my work, the ID pharmacists I work with are fantastic and and really important to our care. But the whole I guess profession of ID pharmacists are far less developed in Australia than they are in the United States. Peter Pen and Astarte Trials at ESCMID Global And we really like to learn from what you guys at SIDP do for today, just like our first collaboration episode between Breakpoints and Communicable last year, we're going to discuss and review the trial run session at ESKMID Global, which was a week or so ago. This really cool session format was first presented at ESKMID Global last year. And in that year, we covered the MSSA and PSSA domains of the SNAP trial. And today we're covering the gram negative side with the Peter Pen trial, which was Piprasil and Tazabactam versus mirapenem for treatment of bloodstream infections caused by kefalosporin resistant enterobacteralis. And also the Astarte trial, which was a treatment of bacteremia due to 3rd generation kefalosporin resistant enterobacteralis as well. So first, I'm going to introduce the presenter from the Peter Pen trial, which is Mihal Paul Mihal is a professor in the research track at the Ruth and Bruce Rappaport Faculty of Medicine Technion, the Israel Institute of Technology. She is the head of Infectious Diseases Institute at Rambam Healthcare Campus and an editor for CMI. And Mihal also serves as the ESMID guidelines methodologist. Mihal, welcome to break breakpoints and communicable. Speaker 3 Thank you very much, Dawson. I appreciate that you know how to say Mihal. Speaker 2 I've been practicing. Speaker 1 And next we have the presenter from the estarte post hoc analysis, Jesus Rodrigo Banyo, Professor of Medicine, University of Sevilla, head of Infectious Diseases Department, Hospital University at Macarena. Is that you? Say it like the dance. Yes, yes, OK, I was hoping so. That brought me a lot of joy. Past president of ESKVID CMI editor in chief. This is a big moment for all of us. I think such an honor to meet you and Michael, but me in particular, I've read dozens and dozens of of both of your papers over the years. And so it's super exciting to be able to podcast with you. Welcome to Breakpoints and Communicable. Speaker 4 Thank you very much. It's my pleasure to be here. Thank you for the invitation. And you pronounce Spanish names and surnames very well. Speaker 1 Oh my gosh, thank you. I've really I practiced as well. From Fantasy to Fiction: Our Favorite Book Recommendations OK. So as our listeners know, we start these episodes where they get to know you question for our guests and also our hosts. So the question where we've asked for this episode is what book have you read recently or you're currently reading that you'd think is excellent and that you'd recommend? So maybe Erin and I will go after and I'll ask Michael to answer that one first. Speaker 3 Well, I have to confess that when I get home, it's after the hospital and after and usually either kickboxing or spinning and I'm completely, completely, I have to regress when I get home at the time I get to bed with with my book and I really need something stupid that doesn't require any concentration. So now I have to confess I'm reading The Hobbit and then I'll have to read The Lord of the Rings and, and go back to childhood. But. Speaker 2 They're not stupid. Those are fantastic canonical books. You. Speaker 3 Can just get lost and not think about anything. Speaker 2 Yeah, I thought you were going to say you get home and you don't read anything. You have no brain. It's impressive that you're reading The Hobbit and Lord of the Rings after kickboxing. And Jesus, how about you? Speaker 4 Well, I'm reading now for the set time in my life, Don Quixote de la Mancha. It's a classic book that I love, and I recently read a review from a Spanish author about that. So I got very curious to read it again. And despite being a classical book and something that was written in the 17th century, I do recommend it to everybody. It's so funny and it's so full of life and full of of real life, I would say. So I do recommend it. Speaker 2 Is the Spanish language in Hesos very similar to modern? Is it easy to understand for you? Speaker 4 It's you can understand perfectly and and translations, as far as I know are also well adapted, so I think it's very recommended. Speaker 2 Oh, I'll add that one to my list. And Aaron, how about you? Speaker 1 Well, Mikhail, I'll make you feel better because when you started on that I said, oh, she's going to be just like me because I science all day, you know, and then I come home and I do totally need to decompress. So I read a lot of like trash romance novels or less trashy, but still romance novels. So not a shame to admit it. So I just finished one Golden Summer by Carly Fortune. It's just, you know, such light, light, lovely reading. But the other book, because I feel like I have to say a sciency book, I also just finished for the second time, everything is Tuberculosis by John Green, which if you have not read it, it is a quick, easy read. It is phenomenal. So John Green is actually a young adult author who became very intrigued by how everything is tuberculosis and the history of tuberculosis care and tuberculosis patients and how it's threaded throughout history and human migration and social norms and fashion even. And it's just really tremendous. And so for a medical audience, it's maybe a little, you know, a level under how we understand tuberculosis. But I think it's so important to understand how other people understand tuberculosis, and John Green's journey with it is just truly, truly phenomenal. So highly recommend that book to anyone, but especially those of us in the science sphere. Speaker 2 Yeah, I've heard others recommend that one too. And my book, probably the best book I read last year was called Damon Copperhead, went by an American author called Barbara Kingsolver. She's she's a fantastic writer. I've read some other books by her as well. But Damon Copperhead is a kind of reimagining of David Copperfield, the Charles Dickens book, but this time it's set in modern day in rural Virginia, among the opiate epidemic. And she just really gets inside the mind of the main character, who's a boy and then a teenager and adolescent male, just incredibly well. It's just really compelling read as well and beautifully written. So I recommend that. And in fact all her books, but that's probably her best one that I've read. Speaker 1 That is an amazing book, Good pic, right? And a level up for my romance novels. But OK, let's get into the trials. Peter Pen Trial: Replication, Eligibility, and Primary Outcomes So Michael, we'll start with Peter Penn. You presented first in this beautiful 2 hour session at Eskima Global. Again, the 2nd year the Congress organizers have had this session and I think we would all encourage them to continue. It's been this really fantastic way to really deep dive into two large trials. I think one of the most interesting things is you got up and kind of explained how this trial came to be. Because I think it's very easy for us all to see a publication and say thanks for the data and then immediately tear it apart, right, and have all this feedback and all this peer review. But these things take decades sometimes, and there's a lot that goes into this. So can you tell our listeners about the timeline of this trial and particularly how it intersects with the Merino trial? Speaker 3 Yeah. So we do one trial at a time. We finished the seven verse 14 Victorina trial and then we said we need another trial to run. And the question that was most burning to us was really this question on beta lactam, Beta lactam as inhibitors versus CORBA pennants for ESPN. We wrote the protocol. We knew when you write a protocol, you you do a literature review. We knew there was one trial ongoing, but it seemed far away. Australia, we don't know what they're doing. We don't know where, where, where, where Australia is. I was young. So we went ahead. We wrote the protocol. We had everything set to start the trial. And then the Marino publication came out, not only came out, but it was very surprising the result that we completely did not expect. Then it took us time to decide if really we want to do a second trial. It's a bit disappointing to do a second trial because someone already published it in JAMA, but we decided that we had to replicate, we had to repress things. Marino where I think we'll talk about it was stopped early. We wanted to confirm these results, want to convince ourselves that indeed there's an advantage because in Israel where carbopenem and resistant endemic, we have in the endemicity of carbapenem resistant bacteria. The most important antibiotic stewardship target for us is to limit carbapenem use, the big driver of carbapenem resistant bacteria. And I think it's different if you live not in a carbapenem resistant endemic setting, you look differently at things. We looked very seriously at the decision that we have to use carbapenems for ESPN's, for all ESP NS and it goes beyond the just treating ESPN bacteremia because if it's so much better than PPT Taser, you have to use it empirically. You have to use it maybe for a severe infection is a turn off bacteremia. It goes much beyond this carbapenem use. So we started the trial and we decided to do a replication trial, meaning to mimic everything that Marino did. Speaker 2 So I mean, even though, as you say, Mikhala was disappointing for you guys to not be the first trial and to be a replication trial, that's so important. I think it's good for us to remember that, you know, history is littered with practice change that happened because of a single trial that turned out to be wrong when there were other trials done. So it's really important to have more than one trial addressing a question. So with the Peter Pen trial ME, how can you describe to us the trial setting the eligibility criteria and what the primary outcome was? Speaker 3 So this is like Merino, an investigator initiated trial. When you do an investigator initiated trial, you ask yourselves who is the patient that I'm treating, who is the patient that needs the treatment? And these are the inclusion material patients with the bloodstream infections due to the ESBL phenotype. And who do we not include? The patients that I cannot include in the trial, for example, if they're allergic to penicillin, if they need another antibiotic in addition to the antibiotic for the SBL, then we will have a problem not giving them the other antibiotic. We want the clean trial of good days of your Smearopenim and situations where we will not learn from the treatment of the patient for example and sections that require very long antibiotic durations that will overlap with our outcome assessment time points. So these are the exclusion fritter that derive from clinical considerations, nothing but the clinical considerations of who can we recruit, who can we not recruit and The Who will not allow us to appraise the differences between the pitays and neurocanin. Our primary outcome was similar to the Mourinho and we thought this is the appropriate outcome to assess. Overall, the mortality is what matters most to the patient. It's a severe infections patients need to survive. It's an objective outcome. You can debate whether 14 days is the optimal time point after bacteremia. So is not to involve too much background mortality from comorbidities or 30 day. The longer you follow the patient, the more patient relative the outcome is, because patients want to survive not two weeks, but to continue living for longer and longer. But in 14 days maybe is more infection specific and mortality is more related to the infection. But overall, we copied the merino and we went to 30 day mortality. Speaker 2 And that you have a Co primary outcome as well, right? Speaker 3 Yeah, we calculated the sample size for a death and we black in front of our eyes more than 1000 patients needed to prove non inferiority with their current mortality rates and bacteremia trials. So we consider that we do not have funding, we don't have a large network of centres to to recruit the likelihood of reaching the target sample size of not huge. We define a Co primary outcome 2 primary outcomes, one which requires a target sample size of about 500 patients. And we tried to define this second primary outcome as meaningful as as much to the patient. And we defined it as a patient doing well on day 7 or failing the opposite on day 7, meaning not stilfebra and not symptomatically cured, still with bacteremia, not hemodynamically stable, a composite outcome of clinical failure. And day 7 was our second primary outcome. We made sure to register these two outcomes to make clear that we defined in advance per protocol and two primary outcomes to the trial. One where we stop at 500 and analyse this primary outcome, not being powered to show different non inferiority for mortality and hoping to reach the target sample size for the second mortality primary outcome. Speaker 2 Can I just do a brief tangent here, You mentioned, Mikhael, that the patients have an ESPL phenotype. But just to clarify, you and I think the Astarte trial as well and the Marino trial are using Kevtrixan or kevtazidine resistance in the lab as being a screening tool for ESPL production, right? Speaker 3 Yeah, yeah. Following CSI guidance, I think we're not testing ESP LS, but we're looking at both subtracts and units of testing and requiring them to be resistant for eligibility. And we're we're saving the isolates for future analysis of beta lactamases and ESP NS. Speaker 1 Which I think is very pragmatic because no one would be able to do that in real time, right? Best case scenario, you know, CTXM if you have a rapid diagnostic, but there's no way like even if you're doing disc confirmation that adds another day and then that delays enrollment even further. And no one's doing real time PCR of non CTXMESBLS to my knowledge. So outside of research. So I think that makes good sense. We'll come back to that later. Peter Pen Interim Results and Marino Trial Critiques In terms of these trials looking at really you know day three enrollment and not really empiric treatment of ESBLS, which I think is quite an important point. But so me called hearing all that which was excellent. Do you mind walking our listeners explicitly through your power calculation? And I know you mentioned the 500 patients, but you know how many patients did you guys go into this and say we need this many to conduct this trial? And then related to that ongoing enrollment, do you want to jump right in and share what those interim results were? Speaker 3 OK so some precise calculation for non inferiority trials. I've not invented them, I don't understand too much in the statistics. But there is software for you to do that and and it gives you a number and depending on your non inferiority limit and the non inferiority limit for failure can be larger than the non inferiority limit for mortality. You allow yourself more flexibility in a softer outcome like failure compared to the hard outcome of mortality with the signs that percent the absolute and non inferiority limit and the 10% the absolute non inferiority limit for the clinical failure outcome, which results in this big difference in the sample sizes required to prove they're not inferiority. So we started in 2017. We were going on for seven years with a recruitment patient by patient. We have eventually we are recruiting now in eight centers in Israel, but they did not all start together. Centre by centre. We convinced people to join the trial and in Canada, Professor Carter and me and Emily McDonald joined the trial after a year or two. They also recruited a few centers and are still recruiting more centers to join the trial. We reached now our target 500 and conducted the analysis. We looked only at clinical sailor would not look at the comparison of mortality. We found failure rates on the first. Let me maybe say that we compared between the pitazo and then called the panel group. I'm used to observational studies and two differences between groups that I have to adjust for, and I was really surprised to see how similar the treatment groups were within all the factors that we measured the comorbidity of the baseline. Sepsis measures, everything was very, very similar between the groups. That kind of wow. People will think I'm inventing the numbers here. They're too, too similar. But, but that's the beauty of randomization, I guess. And then we compare the treatment and we calculated the clinical, the composite treatment failure outcome from the different components that we collected in the data extraction form. And then we found about 25% failure, which was pretty similar between the groups exactly. The numbers are 24.6% with Peptaso and 28.1% with miropinib for a cool difference of -3.5% failures with Peptaso. We also adjusted the risk difference to the strictification factors and reached pretty similar numbers. And we also did a protocol analysis, meaning the patients that actually received the Peptazo nectar received we're opening for five whole days from randomization and the results were also similar there meaning proving non inferiority and the treatment failure outcome at day 7. Speaker 2 OK. So maybe not what one might have expected to find if you've read the Marina results, but maybe what you were expecting to find, not inferiority. One of the most controversial things, I guess in the session where you presented these results and then they were editorialised and discussed was the fact that you guys decided to report on this analysis, which you could variably define this as an interim analysis. I mean, it's the final analysis in some ways of your seven day treatment failure outcome, but it's an interim analysis of your 30 day mortality outcome. And there are pros and cons to doing that. And it also leaves you now with the conundrum of do you continue the trial for the full sample size for the mortality, which one could argue is the most important outcome, Or now that you've made these public, what decisions does that leave you with? Speaker 3 We planned in advance to analyze the treatment failure outcome when we reach the sample size for that. What does it do to know that these are the results at this interim stage, given that there's no difference? A thing gives a big push to continue because now we're more more comfortable with a try because some centers might have been not very comfortable with giving patients the peptasia following the Marino results, I think it opens the door for more centers to participate, more acceptability of the try. We should consider what would have happened if we saw some difference between the groups and like the Marino. What we have done then I'm not sure we're at the situation where we see similar results. We're not confident and they're not inferiority because we're not yet and at the mortality time point overall, it gives us a drive to continue. Speaker 1 Yeah. And for our listeners, just again to summarize, thank you so much for that. So what was presented with the clinical failure endpoint, Co primary endpoints, we don't have the mortality data, but the aspects of that Co primary again were sofa deterioration, 7 day mortality was in there, persistent bacteremia from days four to seven, being febrile on days five to seven, symptoms not resolved by day 7 and then this composite of clinical failure. So I think some of the things that were brought up in the audience was while these feel very objective, they could actually be quite subjective. You know, especially we see this too. And when we do protocols at our hospital of OK, you can go IVDPO if they're afebrile for 24 hours and we see, OK, well if you have 100.3 for one minute because they had a blanket on and something else, does that count as a fever? And even something that seems objective can sometimes in clinical practice not be. And so I think that, Josh, I echo your question, I'll be super intriguing. And you know, I'm glad you guys are still enrolling to get more patience, but I am interested in how that plays out open label. And I think that's what some of the audience response had to say about some of the composite. But the other interesting thing about this session was that the session did have 3 moderators that shared commentary on both these trials and the Marino trial since it's so relevant to Peter Pan. Those moderators were David Patterson, Angela Huttner and Steve Tong. So David shared some additional background on the Marino trial. And yeah, we call before we get into that. Yeah, go ahead. Speaker 3 Yeah, just mentioned it's true. And the principle is that in open trials, the outcome should be completely objective. And here in our composite outcome, there might have been some subjectivity in the assessments that the physicians wrote. But we have to think where does this bias take us? If you were a physician and the patient received by the meropenem or piptaso, where would you be more inclined to suspect no improvement or to take blood cultures? You know the answer. So you know where this bias is taking us in favour of the neuropenem. So if there was bias here, it would have worked in favour of neuropenem and a difference between the groups, not in favor of non inferiority. But it's true we have to look at an objective outcome in an open trial and that's why we have to continue. Speaker 2 Oh look, that may be true. That's what you'd expect me how? But maybe if in the mind of the assessing clinician, their hypothesis was actually, I don't believe that peptosers inferior in American and I think they're probably the same, then it might drive them in the opposite direction subjectively. Speaker 1 I think what you started with is so true. People don't want to use carbapenoms. You know, we've worked so hard to push the principles of antimicrobial stewardship potentially too far in that people want to avoid a lot of these antibiotics. And so I actually, I mean that could I agree completely, Josh, I think that's very true to some, but I think others would fiercely want to believe in Pip Tazo being just as good. And the bias could swing the other way too, which is I mean, and maybe those people balance out. Maybe we should randomize people to their, you know what, whether they prefer Pip Tazo or Ameripena. But I know I cross my health system. There are absolutely people who still die on the hill that Pip Tazo's fine, don't want to believe the merino results and are very excited about these results. So I think that goes both ways, which is really super interesting, which is so David shared that background on the Marino trial. And of course, when the Marino trial came out, that was not what anyone wanted to hear, right? I think we can all admit that no one wanted to hear the results of the Marino trial in that Piptasa was not non inferior. And David had a funny quote. He was almost a little sheepish and he said, we are antibiotic stewards. We conducted this trial to take good care of our patients. We're not carbapodum freaks. He said, you know, and I think that's fair. I think across the world people thought like the Marino trialis had no control over the results. They didn't seek to find what they found and so we need to be kind when we approach these kinds of respectful dialogues. But it did find peptais of not non inferior to miropenem. That doesn't seem to be the direction the Peter Pan results are heading. The critiques of the Marino trial were one that it was stopped too early, that it was therefore underpowered. Extended infusion beta lactams were not given because Bling 3 was being designed at the time of the Marino trial, that many of the deaths were later in that 90 day endpoint and related to terminal cancer or things like this. You know, the trials have said it's very difficult to ascribe deaths in that way. And who knows what a sepsis incident might do to quote, push people over the edge. And then finally that the results don't gel with our clinical experience, which is what we're describing now, our inherent bias of I've used this antibiotic for years and years and my patients aren't dropping dead. So this can't be true. And I think that's why we need clinical trials. So Steve Tong then walked us through this called off too early aspect, which I think is very, very important for our listeners to understand. And he described it very nicely as it relates to power calculations when you're assuming a percent outcome in both arms and you're not inferiority margin. So, Josh, can you walk us through what Steve described in terms of the power calculation for Merino? Speaker 2 Sure, I guess there were a couple of concepts here. 1 is in general, trials that have stopped early find a larger effect size than trials that recruit to their full target sample size. And there are a lot of examples of trials that were stopped early found a large effect, and then repeated trials of larger sample size found no effect or a smaller effect. So as a general principle, it's good to avoid stopping a trial early unless there's a really good reason for it. The second concept Steve talked about is the sample size calculation for Moreno. It was done in a slightly unusual way for a non inferiority trial. So they made the assumption in their sample size calculation that the expected mortality in the piptaso arm would be 14% and 10% in the meropanema. Rather than doing the usual way, you assume the same mortality rate in both arms and then you calculate it on a non inferiority margin, which they used 5%. If you've done it in that way, 14% in both arms, 5% non inferiority, then you'd get around 1500 participants needed. If you do it in the way that they did it, which was a differential mortality assumption in the two arms plus a 5% non inferiority margin, then you then the sample size calculations more around 450. Now they didn't just make up that concept. It is a seen as a legitimate thing to do to use different sample sizes in the two arms, but it's an unusual thing to do. And it's only supposed to be done if you have quite high certainty that the mortality is different in those two groups. And they based that on observational data, which there was not a huge amount of to be fair. And I suspect reading between the lines, it's because they thought, oh, there's no way we'll be able to get 1500 participants. However, actually even that is a little bit irrelevant to why they stopped. So they're they calculated sample size of 450 which was probably too small, but they actually stopped after 379 because of an interim analysis. So even if their sample size was 1000, they still would have stopped after 379. In their third interim analysis, they had pre specified a stopping rule using what looks to me like the hey Bittle Pito approach, which is like having a really extreme P value for efficacy. If that's met at an interim analysis, you stop. And they had P less than point double O one was their threshold. The P value was actually point double O 4, so not quite point double O one. But the DSMC looked at all the data and they thought it was actually really unlikely that they were going to find non inferiority no matter what number they got to. And then they stopped. So the bottom line was the sample size calculation was probably a bit small, but the trial wasn't stopped because of that. It was stopped because of an interim analysis. Speaker 1 Yeah. So me call any final thoughts on your trial before we move over to Jesus? Speaker 3 Referring to your very clear explanation, Josh, the importance of knowing what should have been the appropriate sample sizes to know at which time point they stopped, at which ratio of the overall sample size they stopped. It gives us the level of confidence in the result at that time point. But going back to Peter Pan and what Todd Lee, the Co primary partner and I decided was to go forward for another 6-12 months and see if we can increase the recruitment pace because continuing for another seven years is not realistic. It to a news the relevance will not be able to do that. But if in three years we can recruit increase the recruitment pace more centers, more dedication to the trial and in the existing trial and centers. I'm now moving between centers in Israel and and they're motivating people to recruit more than they're doing because I know that they have more use bills than they're actually the cool thing. If we're successful, then we'll continue. If not, we'll probably stop in one year and then and then whatever we have, we publish the interim analysis also for maternity. Speaker 2 Can I just make a couple of final comments or questions about Peter Pan? So one is it's really impressive that you guys have got the numbers you've got so far on the smell of an oily rag. In terms of the funding, I think you presented at Eskimet and it will be like one of the cheapest trials per patient that time ever been done. So that's a very impressive effort. And I really hope that you are able to continue recruitment at a rate that's high enough to meet your outcome. And one way of doing that would be for more centres to join, right? So if there's people out there that are interested and especially if they can get some funding, they should get in touch, right? And my final thing is this has been bugging me for years. Why didn't you call it Peter Pan? Like as in the book character, the fictional character Peter Pan. Speaker 3 Yeah, just we said so much. We were asking me because of the Back to American name. It turned out to Peter Pan just the same. Yeah, not the time. Too much affiliated with the book. Speaker 2 It's closer to the names of the antibiotics, but than. Speaker 3 To the book, yeah. Speaker 1 Come to our podcast for the most provocative questions, which is why did you not name it Peter Pan? Astarte Trial: Setting, Eligibility, and Composite Primary Endpoint All right, hey, Zeus, we're coming over to you. So before we get into the Estarte trial, I do want to know what are, what are your thoughts on Peter Pan? What do you think are some of the reasons we may have seen differences in Marino versus Peter Pan? Speaker 4 Well, actually there are some small differences. Despite Peter Pan was designed to try to be similar to Marino, David Patterson nicely show those differences. One is the difference of that we discussed in primary endpoint that was analyzed in the preliminary analysis of Peter Pen. There was no inclusion of septic shock patient in Peter Pen. But I don't think that make a big difference because the numbers of Marina was not higher. For that maybe what is relevant. The issue that Peteiser was administered in sheer was infusion in Peter Pen. That can make a difference if you have a good number of isolates near the break point, which seems to be the case in in Marina and probably happens the same Peter Pen. Because the MIC distribution for Potato shows us that for ESBL producers that many of them are near the break point. So that could really be relevant here, I think. And something that is tricky is that difference in in overall mortality that the house shows us in, in the trial that it's like 3 times higher than was showed in Marina. And therefore we would need to go into details about the baseline characteristic location in both trials. But some of them are similar, but there may be some subtle differences that could be the reason for that difference in 10 to day mortality. That is very intriguing. But apart from that, we'll love to see whether the difference is also in the MI CS and Oxo 1 producing, because you know, all the problems with up someone producers showing forces susceptibility to give Taser, whether different ASD tests were performed or they were really being able to capture real susceptibility to give Taser, I think those are relevant aspect to analyse in the future. Speaker 2 Cool. All right, let's move on to the start a trial now. Hey, source. Can you tell us about their start a trial and describe the setting of the trial, the eligibility criteria and the primary outcome? Yes. Speaker 4 The trial was a multi centered randomized control pragmatic trial academic driven. It was performed in city hospitality in Spain and we included patients with monomicrobial bacteremia due to surgery resistant enterobacterialis, whatever Introbacterialis was and whatever the mechanism of resistant was, although and 87% of them were ESPL producers. As a result, it's a, it was a targeted therapy trial. So patients were randomized. Once we had the information about sustainability and the patient was randomized to receive either a carbapenem, a standard therapy that could be mirapenem or etapenem, a standard dosing and the decision was taken by the physician in charge. And the other arm for randomization was tamosaline that was experimental arm at the dose of 2 grams every 8 hours. As I said, we included patients with monomicrobial bacteremia. There were other patients that would in the opinion of treating physician would need at least four more days, four days in total of intravenous treatment. And we excluded patients who were only a exclusively on palliative care or have a high probability of dying in the next 24 hours, patients who were receiving more than 72 hours of empirical active empirical treatment before randomization and patients who did. The elapsed time from susceptibility testing to randomization was higher than 48 hours. So we needed to recruit patients in a time window of 48 hours when the testing was performed. And also we excluded typical infection that would need more than 14 days of treatment like endocritis or meningitis or chronic bursatitis, for example. And yeah, just about primary endpoint Prep, we decided to use a composite primary endpoint because we wanted to capture as much as possible the effect of the drug. So we included in the composite it was failure and failure included all 'cause mortality until day 30 included not being cured, a test of cure that was one week after the end of treatment, recurrence until they treat 30 of the infection and no need to change or stop the study drug because of perceived failure or serious adverse events. So we included here also clinical failure and we discussed because it's an open trial about, but this is a soft outcome, it's not as hard outcome as mortality. But we thought that one week after the end of treatment you can safely said that the patient is cured. I mean the patient had no fever. We tried to use as much objective criteria for declaring the patient as cure. And so the investigator have to mark these let's say objective criteria and there was a blind assessment of those criteria by someone who was blinded for the exposure. So we're quite confident that despite of not being a very hot outcome, the outcome was well assessed. Temocillin Non-Inferiority and Availability Challenges Thank you for that. And then one part of your primary composite was stopping or changing study drug because of adverse event or failure. But just to be clear for our listeners, this trial I love because patients were allowed or investigators were allowed to step patients down to oral therapy after four days on study drug. Is that correct? OK. Speaker 4 That's correct. Speaker 1 What if they change to a different IV therapy? Not that would ever have been so if it wasn't like, oh, they're having an adverse event or we feel they're failing Mirapetum. But what if they're like, were they allowed to be on Mirapetum for four days and then go to Erdepenum or? Speaker 4 No, that would be the fallout. So if patients were in the Muslim arm, they could only be changed to an oral therapy after four days of intravenous therapy. That was the only option if another drug was used, if the reason was perceived failure of the treatment or at first event that was considered a failure as an outcome. If there was any other reason it was protocol aviation and but it didn't happened in the carbapenem. Some, we thought that some patient would start on neuropenem and be changed to elsapenem later or being discharged on elsapenem or facilitate at home therapy. And it happens, I don't remember the number, but the very low number of patients, I think was 10 or 12 patients and it didn't happen the other way around. There was no patient or atopenem who were switched later to neuropenem. It didn't happen Thursday. That that would have been a load would have collected that that would have been a load. And if patient were changed to other treatment because of procedure of failure, again that would have been a failure. Speaker 1 OK. Thank you for explaining that. So can you tell our listeners what your sample size calculation was then and the results that you found? Speaker 4 So we could not find, of course, a trial using the same primary endpoint. So we need to go back to our databases in observational studies and classify patients in our observational studies in ESBL producers causing bacteremia. And then we calculated the estimated number of patients that could be failing because of that. Fortunately, the numbers in the trial were similar to what we have estimated. And we also try to see whether they think Marina could help us a little bit to make that estimation. But Marina may measure mortality and did not have the data that could help us or we could not use that. But fortunately, the estimation that we have for failure 25% was very similar to what would find the study. Speaker 2 So he's also in the main start a trial really. You found that temicillin is it was not inferior to carbapenems and looks like a really good viable alternative. One of the problems is temicillin's got very limited availability at the moment. There's only a few small countries where it's available, I think. Do you know if there's any plans to change that or if there's a distributor of temicillin that will make it available in other countries? Speaker 4 Yes, that's a very important point. And when we designed the study, we have the challenge and the difficulty that even in Spain it was not available when we started the study. So we needed to contact the company producing the drug and have an agreement with them. They were kind to provide us the drug for free and without intervening in the design or analysis or publication of the study. So that was very fine for them to do. We didn't have also the susceptibility testing on our automatic system in space. So we need to implement for the study the use of E strips at the same time that that this typical automatic testing was done in the North hospital. So we needed to implement that. So we use also rapid test for detection of Cephalosporin resistance to speed up the whole process and recruit patient before 48 hours after the testing and that was challenging. So as far as we know the company producing the drug is now approaching other so far European countries. And as far as I know it's already been used in Belgium, United Kingdom, France recently Germany is approved there and the near future Sweden, Spain and Italy probably would be options for the approval. And the reason is that in Europe if a drug is accepted, it is approved in using the, let's say all criteria, 1970s criteria, they could be approved in other countries if there are enough data. So they don't need to go like for a whole Europe approval that they can go country by country. But I'm not sure what will happen outside Europe. And that will be something that I don't have the information. And for sure, for example, for the FDA, they will need to do 2 trials that they don't have as far as I know, I don't know in Asia or in Australia will be the situation. But I think in terms of stewardship, the trial was designed as stewardship trials for the DA's. You have this bacteria isolated, it's susceptible to the drug. What would you do? Would you continue miropenem? What would you change to even if it for two days or three days or four days or 10 days, whatever to Tamosiline, I think the trial shows that you can switch to Tamosiline and avoid as Mihal was saying, we try to avoid the use of carbapenem as much as possible. I hope that the trial result will help that there are to be available in more countries. Speaker 2 So when I said temasellons used in small countries, I misspoke a bit there because you named countries there with massive populations, although I must say that in terms of surface area, they're small compared to Australia. So that was the main estate trial. And what you presented for the first time at SN with this year was the post doc analysis comparing ERTA Penham with Merapenem. And that was much smaller numbers, right? And akin to an observational study because that was not randomised. What's your interpretation? Do you think in your mind Typanem would be OK to use moving forward in these patients? Speaker 4 So we were aware that the potential criticism to the trial was that the standard of care arm would include two potential carbapenems, maripenem and tapenem and that there were some observational studies suggesting and a small trial, a very small trial comparing the 2-3 SPL showing similar results. And there was also some observational studies suggesting that elsapanem might not be that efficacion in patient with septic shock. And the issue is because of dosing and because of PKPD facing with septic shock who may be having high creatinine clearance might not have enough concentration of elsapanem. For those, the Ms. CS are a bit higher than for myopanem. So because of that potential criticism, we try to see whether we could compare patient who have been in the standard of care arm and compare a tappanine and miropenem. So one problem here is that we stated in the protocol that basin in septic shock that could be included in the trial if they were randomized to the Kabapenem map should not receive a tappanem, but should receive miropenem instead. So that's the key difference and there was some patients with that. So when we try to compare both groups, neuropenem and etopenem, the features of the patients have some differences. Patient in the eltopenem group were older and some more comorbidities. Patient in the neuropenem group were sicker and many acute severity of disease. Because of what I said about potentially having septic shock, we tried to do confounding control by different methods like propensity score, invest probability of treatment weights, propensity score matching And with all those analysis and trying to be as transparent as possible, we could not find relevant difference as expected. So when we could let's say eliminate patient with septic shock in the matching having patient that were really quite similar that were not relevant reference. So I think that reinforces our data that never mind which carbapenem you would be using, tamosaline would be non inferior to those. Speaker 1 Did you happen to look? I know when you're presenting in the short time it's harder to include all the data, but I think in the demographics table presented for the carbapenem patients, there isn't mention of their albumin status at time of enrollment, which that is our biggest fear and one of the reasons we don't prefer using erdopenem in patients with septic shock. One, to cover Pseudomonas, but two, because those patients tend to be more profoundly hypoalbuminemic and erdopenem is heavily protein bound, which would then lead to it clearing faster. You know, even sometimes if patients have an albumin less than two, sometimes we give irdopenem Q12, which admittedly we make up, but just because from a PKPD standpoint that seems to be quite important. Same with cefazolin, which is heavily protein bound as well. So did you guys look at patients albumin status in the groups? I imagine there may be a difference because the patients in the Mira Panama are more sicker, but is that something you're exploring? Speaker 4 No, we collected whether patients have acute renal insufficiency because we measured the sofas core. So we know whether patients have increased renal failure or decreased renal function compared to base to expected baseline. We have that information. There was no relevant difference in that, but we didn't measure that. From Empiric Treatment to Meta-Platforms: The Future of ID Trials OK, cool. Thank you. All right. Well, I think to wrap up the discussion of both these trials, we'll come to both of you in a key point that Angela Hutner brought up when she went through a picot of both trials in the moderator session, she really emphasized how neither of these trials are about empiric treatment of ESPL bacteremia, which I think is an important point. So Jesus, what are your thoughts on that? And is that even possible to do in a trial setting? Speaker 4 Yes, that's a very important point. I think both trials were aiming targeted therapy and our thoughts about stewardship way of thinking. But empirical treatment is also a very important point here. And the only issue is that the design have to be completely different. We have thought for a while doing that and it's something that we are planning. So for empirical treatment, first you will, if you want to enrich your population with ESBL producers, you will need to include patients with risk factors for having SBAESBL producer. This is something that is typically done clinically. So for example, in most of our local guidelines for local protocols, we provide to our colleagues in the emergency department with information about risk factors and the way to manage that. When patient have a severe infection, they could cover that and then when they have not less severe infection but one or two risk factor, they should also cover ESB, LS. So that's first issue. We should enrich the population by including this type of patients. And 2nd, we will need to decide what will be the comparators, whether carbapenem would be the standard of care in that high risk population and what would be the comparator. What the comparator could be the potato, could be tamosiline or could be another option like an aminoglycoside. This is something that we are considering to design for a future trial. So I think it's the next step to be done that it's a different approach. And of course, you need to incorporate here emergency department colleagues and and because in an empirical treatment trial, you need to recruit patients very fast. You don't have time to discuss with the family, with the patient for many hours. You have to take a decision in less than one 2-3 hours and the patient have to sign informed consent very rapidly. So it's a different approach, but I think we should try to do that. Speaker 1 Yeah. Minka, any additional thoughts on that on an empiric type trial? Speaker 3 Yeah, I think I'll mainly repeat was so, so saying these were trials asking the question. I've treated the patient empirically. Now I'm receiving from the lab a result on a sense of tracts on resistance. What do I do now? What do I change the therapy to from the empirical therapy, which by definition you don't know what the pathogen is or what the resistance is like Hassle said and maybe I'm jumping to one of your next questions. A very interesting trial for me would be in glycoside versus betelactal for a complicated UTI and pyelonephritis. And we thought about the design of such a trial. And then we said that this is a trial requiring huge resources. We have to have someone standing in the ER and maybe evening shifts also, if not the night, and recruiting the patients as they come into the ER and as the decision to admit them is done even before that because they received the first dose of antibiotic very early in the emergency room nowadays. So you'd have to recruit them just before this first antibiotic dose or else the trial doesn't have much meaning because really for UTI, you're cured very, very SAS. So maybe so we can collaborate on something similar? Speaker 4 That's right. Speaker 1 That sounds like an awesome trial, and it's a perfect segue. You're right for the time has come to our Breakpoints faithful listeners for the I Feel Nerdy section of the podcast. I Feel Nerdy is meant to be a safe place and closing segment for our panelists to nerd out over their favorite ID topics, quirks and fun facts. Stop making me laugh, Josh. So for today's I Feel Nerdy, I was going to ask what trial you want to do next. So I mean, we call. That was an amazing answer. I don't know if you have a second trial you want to talk about or is that your answer? Speaker 3 I wanted to talk about the two things, another trial and a vision for an intelligent medical system in the future where clinical effectiveness trials and pragmatic investigator initiated trials of common treatments that you're not and you antibiotic. Or they're just comparison between two options that we currently use that we have on the shelf that one physician uses this one physician uses that. The Netflix committee will sit and decide whether this trial is worthy. And then we can ask the patients only for permission to collect the data and not for their comparison. Because it's a very uncomfortable situation trying to explain the patient why am I doing the trial on 2 medications that I can give him in any case, and according to my decision, without any therapy. So I'd like a wise committee of people to sit and approve trials that are worthwhile to do. And the patients don't have to deliberate on whether they want to participate in a trial for a treatment they're going to receive in any case. And that is a vision. Speaker 1 I love that so much. I'm very much a big believer in that with, you know, absolutely putting patients and all of their rights first. But it's like the ACORN trial out of Vanderbilt where they randomized to the prescriber, right? They said, are you going to give Piptaser Ocephopene? We make that decision all day, every day, right? There's complete safety and equipoise for patients. And so this concept of randomizing to prescribers, I think is intriguing and untapped across the globe. So I couldn't agree with you more. Jesus, what trial do you want to do next? Speaker 4 Well, we are engaged now in two trials. One Josh knows very well because we are going to start the Spanish participation in SNAP for Star Wars bacteremia and we will be opening a new sub domain within. There is a phase two trial investigating whether clopidogrel and antiplatelet track should have any activity against the forest bacteremia as an adjunctive therapy to a standard therapy. And we really want to start the trial as soon as possible. And we are also engaging in another trial which is the three GMB trial. This is a trial for Gran negatives for Kappa Panem persistent Gran negatives. It has three silos, one for Intrabacterialis, another for Pseudomonas and another for Azenitobacter. The trial is being coordinated from Singapore from advance ID David Paterson at Moyen. And we are also starting Spanish participation with several options. And the interesting thing for that trial is that we will try to use the practical design, meaning that patient will be randomized not to A versus B, but to all the options that according to the isolate these patients have. So patient may be randomized to septacin, MB, bactam, meropenem, virabactam. Or for example, if they have an OXA 48 producer that is susceptible to meropenem and they have a UTI, they could be randomized to meropenem even if it's a carbopenem producer. So the trial is going to start recruitment in Spain hopefully the next few weeks and we are also very much likely to start that. Speaker 1 And I love that. Thank you, Josh. Speaker 2 Yeah. Well, I guess in terms of the big vision type concept that Mihal was talking about, I love that as well. The vision I've been thinking about is a a meta platform, so a platform of platforms for gram positive trials. So we've talked in the past about the Snap trial. There's another gram positive platform trial called Strap, which we're just starting with colleagues about Group A, Strap and other Stratoccocci and then a third one that's been in the planning stages for a while about enterococcal bacteremia, then we're calling TENT. But what I'd really love to see is a meta platform of gram positive trials. So those three together, that would share infrastructure, they may share one umbrella protocol, they'd share a site research team so that you'd know the patient has a gram positive bloodstream infection. And then they'd go down the pathway of one of those three things and it could add efficiencies, but it also has a lot of complexities with how you would make that work together. Speaker 1 Yeah, I'm telling you that is the dream. Make doing the right thing easy. We did that in the United States across my system for Remap CAP. So we on admission anyone with COVID, the nurse did an intake form and we asked them like, are you interested in hearing about experimental COVID therapies? And if they said yes, it sent an e-mail to a centralized team and then they reached out via FaceTime and they consented the patient for every single domain of Remap CAP, right? And then as other investigators came up with other smaller COVID trials, it just all went through the same infrastructure of shared resources. And I think that's really the Holy Grail. I can say this, 'cause I'm American, like it shouldn't cost this much to do trials in America. It's really not that expensive. It's actually not that hard. And so we have to bring this cost down of trial infrastructure to answer some of these questions. So I would round out with I have two. One is Jesus along your line. So I think non carbapenemase producing carbapenem resistant enterobacter Alice is very fascinating is particularly enterobacter cloacier and it comes up all the time. If your mirror penum MIC is 2 or 4, but you don't have a carbapenemase there and your ceftazine may be back to MIC is 1. Are they equal? You know, a lot of people want to use ceftazine may be back to him in that case because the MIC is 2 dilutions lower and maybe I mean maybe inhibiting all that amp C is helpful. So I'd love to randomize to that. It'd be super hard because it would only be a day three unless you had rapid AST and you would need thousands and thousands and thousands of patients. But I'm very interested in that. And then secondly, we call this is along your lines. So I have wanted for like a decade to do a trial where patients over the age of 65 that present to the emergency department relatively stable but with altered mental status that have a dirty UA randomizing them to a dose of ceftriaxone or nothing like fluid and rest. And I think that's such an important question to answer. And I've pitched it many, many times. And essentially the answer I get is no one cares because those patients are typically in and out of the hospital in a day or two. We get paid well for those kinds of admissions, at least in the United States. And like no one cares about a single dose of ceftriaxone. But that's a real bummer because we should care. And I think that's such an important question to answer because the 2019 ASB guidelines, you know, we're like altered mental status alone is not enough. But I think that's on our fields and not actually on any good evidence. So that's mine. Speaker 2 Yeah, I really love that idea and I've thought about that in different ways as well. And it's not just hospital like nursing homes or aged care facilities. Asymptomatic bacteria and then unexplained delirium are the two biggest drivers of antibiotic use in aged care and in my hospital setting. They don't come in and out in a day. Elderly people are meeting with delirium, stay for days and days, and they nearly always get antibiotics because they nearly always have asymptomatic bacteria with their delirium. So I think that would be a fantastic trial. Speaker 1 Yeah, right. It's like randomized to sleep. But I'll come to Australia and do it with you, Josh, because it'll never, never go in the United States, but. Speaker 3 Maybe you want to join and there was a horizon colon long term outcome following infections and then we just now submitted the proposal to move underneath out of their beds early on when admitted for sepsis and having a severe infection, presuming this will allow them to return to their functional and cognitive capacity after the bacteria. Speaker 2 Yeah. So early mobilization kind of approach. Speaker 1 Oh, I love that. I think there's nothing worse for patients than being in the hospital, actually. So right. Too many alarms. We need to sleep. Thank You and What's Next for Communicable Sleep cures cancer, but overnight. Well, thank you so much to our guest, Mikhail Paul and Jesus Rodrigo Veno. This was very fun. We learned a ton. And while we're wrapping up here, we're not entirely done with Eskimid Global. So in our next communicable episode, Josh, myself, and other editors at CMI Communications are going to get together to unpack the late breaker trials to understand whether those results should change our practice. And so actually this year at Esquid Global, there wasn't one late breaker session as there's been in the past. There's so many good trials going on in ID now that there were multiple sessions grouped by disease state. So there's a lot going on in bone and joint that isn't presented yet, but Josh is enrolling in those. There was a lot of presentations from major journals. So we'll go through 10 trials in our next episode, so stay tuned. But for now, thank you for listening to Communicable, the CMI Comms podcast, and Breakpoints, the Society of Infectious Diseases Pharmacist podcast. This episode was peer reviewed by Emily Pleaucher and Jeanette Bouchard, and it was edited by Lacey Warden. Communicable theme music was composed by Joseph Mcdade and Breakpoints theme music was recorded by Doctor Steve Smoke. You can subscribe to both Communicable and Breakpoints on Apple, Spotify, or wherever you get your podcasts. Speaker 2 Thank you, Aaron for the podcast collaboration as always and Muchis Mas Gracias a Jesus and Tara Raba at Amihal. And thank you to the all our listeners for listening and helping CMI Comms and ESPID move the conversation in ID and clinical microbiology further along and also to helping SIDP achieve the vision of safe and effective antimicrobials for now and in the future.