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Communicable takes on hot topics in infectious diseases and clinical microbiology. Hosted by the editors of CMI Communications, the open-access journal of ESCMID, the European Society of Clinical Microbiology & Infectious Diseases.
Hello, and welcome to Communicable, a podcast brought to you by CMI Communications, the open access journal of ESCCMID, the European Society of Clinical Microbiology and Infectious Diseases. My name is Angela Huttner and I'm associate professor of infectious diseases at the Geneva University Hospital in Geneva, Switzerland as well as editor in chief of CMI Communications, Esmed's open access journal covering infectious diseases and clinical microbiology. I'm joined by 2 co hosts to discuss new clinical trial results presented at the late breaker sessions of this year's ECCMID, or as we now call it, ECCMID Global. I'm delighted to introduce Marc Bontin. Marc is a fellow editor at CMI Comms.
Speaker 1:He's also professor of molecular epidemiology of infectious diseases at the University Medical Center in Utrecht, the Netherlands, and CEO of E Crate.
Speaker 2:Hello. Happy New Year.
Speaker 1:I'm also thrilled to introduce Erin McCreery, who is editor at CMI Comps as well. She's clinical assistant professor of infectious diseases medicine at the University of Pittsburgh School of Medicine and director of infectious diseases improvement and clinical research innovation at UPMC in Pennsylvania, USA. She's also president-elect of the Society of Infectious Diseases Pharmacists and cofounder and host of that society's excellent podcast, Breakpoints.
Speaker 3:Hey. Nice to be here. I'm so excited to do this with you guys and launch our journal and our new podcast.
Speaker 1:Erin and Mark, I am delighted to be doing this with you. So all 3 of us attended the late breaker sessions at Esmid Global. We have each picked a trial that intrigued us, a trial whose results could or maybe even should be relevant to daily clinical practice, or at the very least, a trial that people should know happened. So we'll go into detail on those. Then we will dedicate a little time to a few other trials whose results have something to teach us, whether clinically or otherwise.
Speaker 1:Mark, will you begin by telling us about the DOTS trial?
Speaker 2:Yes. Certainly. Mhmm. The DOTS trial. This is a very let's say an excellent trial again from the Antibiotic Acquisitions Leadership Group in the United States with a strong focus on treatment of staph aureus infections and with a very relevant research question.
Speaker 2:And the research question was, can we safely use dalbavansin, which is given twice IV with an interval of 7 days in patients with complicated staph aureus bacteremia or right sided endocarditis that cleared the bacteremia with IV treatment within the 1st 10 days. So that's the patient population. Complicated staph aureus bacteremia or right sided endocarditis, and a good clinical response to antibiotic treatment in the 1st 10 days. If the answer to the question would be yes, then darbansin, given twice with 8 days in in between or 7 days in between would be a very, very interesting alternative to 42 days of IV treatment, frequently necessitating patients to stay in hospital. Now this study was designed to demonstrate the superiority of dalba dalbavansin based on the door analysis at day 70.
Speaker 2:I will explain in a minute what that is. In addition to the primary endpoint, which was based on that door analysis, there was a secondary endpoint, which was based on the more classical way of defining clinical efficacy. And in that analysis, a non inferiority margin of 20% was used to at least look also at non inferiority. Now let me first explain a little bit about the door. The door stands for desirability of outcome ranking, and it creates a gradual scale from the best to the worst outcome for patients in the trial.
Speaker 2:The best outcome is full recovery without any complications measured at day 70. And the worst, of course, is being that. And then there are several steps in between. Of all these outcomes, a ranking is made, and if the ranking is 50%, there's no difference between the groups. That's the way that the door works.
Speaker 2:Now in the DOTS trial, 200 patients were randomized of which 30% had MRSA, the rest had methicillin susceptible staph aureus. And as mentioned, all these patients had successful induction treatment to clear bacteremia in the first two let's say, the first 10 days. Now half of the patients were randomized to the 2 shots of Darbavansin, and the other half got 42 days of step, let's say, the standard of IV treatment. If you look at the primary outcome of the study at day 70, the door ranking was 47.4% with a 95% confidence interval going from 39.8 to 55.7%. And that was interpreted as that dalbafenci is non inferior, but certainly not superior to standard of care.
Speaker 2:A score less than 50% favors the standard of care. The result was very close to the 50%, meaning no real difference between the 2, and the confidence interval allowed them to conclude that the double fenced in approach was non inferior. The secondary endpoint was the more classically defined efficacy, which was determined by a treatment blinded educating committee. And they concluded that clinical efficacy at day 70 was reached in 73% of the patients that received dalbafencine and 72% of the patients in the standard of care, building yielding a risk difference of only 1% with a lower bound of the confidence interval of minus 12%, meeting the definition of non inferiority. These were the results of the study.
Speaker 2:And if we wanna evaluate the quality, let's say, of a randomized controlled trial, I always like to to use the 3 criteria, which is the validity, the precision, and the generalizability. Now this is a randomized trial, very well described and designed. So I think the validity of this trial is high, and that is, of course, because of the randomization. There are no biases between the groups, no bias for the outcome between the groups. Now the outcome was a relevant outcome.
Speaker 2:It's based on the door, but they also used the clinical evaluation. And, that evaluation does not rule out a relevant benefit, though, of standard of care. So there is some uncertainty in that outcome still. The 20% non inferiority for clinical efficacy, I think, is large, but it's frequently used in these kind of trials. And the 12% lower clinical efficacy is within that confidence interval.
Speaker 2:So there's still, let's say, the possibility that indeed the standard of care may do better. And then the generalizability, and I think this is an important point in this study. The question of the generalizability always is, would this apply to my patients with complicated staph aureus bacteremia, the results of this study? Or framed in another way, would my patient have been in the trial? It's not stated, and the information, I think, is not available on how many patients were screened for enrollment.
Speaker 2:200 patients were enrolled, and the study ran in 23 sites during a period of 33 months. Now if all these hospitals would have started at the same day, which is, of course, highly unlikely, there would be, on average, one patient randomized per site every 4 months. That means probably that there still was, let's say, a strict screening and selection of patients that eventually ended up in the trial. But that information is not available. And I think that's an important thing that we need to know if we talk about the generalizability of the study results.
Speaker 3:I think that's a good point. I mean, we always wanna know how many patients end up being included because, Mark, I like that you mentioned Sabato because that trial was striking because they screened over 5,000 patients to include 200. And so, the takeaway was, sure, we can use oral antibiotics for very uncomplicated staph aureus bacteremia and that type of patient is extremely rare. And when you find them, you were probably comfortable using oral anyway, although great having that RCT data available. I will say more so than oral antibiotics for serious infections, which is a paradigm shift indeed.
Speaker 3:These are data that we eagerly awaited. At least I can speak for the United States. I will tell you right now, UPMC is a 35 focus for every institution is getting patients out of the hospital, and decreasing nursing burden which is true of inpatient and outpatient. So, the way we structure our outpatient parenteral antimicrobial therapy here is that patients either have to go to a skilled nursing facility if they have to continue to receive IV antibiotics and they don't have insurance coverage, or they don't have access to home health at home, which is common. A lot of patients don't have that type of coverage.
Speaker 3:Or if they have that type of coverage, you still need some kind of nurse to go into the home or they have to be able to do this themselves, which a lot of these patients with multiple comorbidities and, you know, they may be of advanced age. They may not be comfortable administering multiple daily doses of vancomycin at home or even once daily daptomycin. And so the ability to get patients out of the hospital faster by 1, operationally not having to coordinate all of that care because you don't have an outpatient plan. You just get one dose and you go home, and then you have to come back. I think it's day 1 and day 8.
Speaker 3:So, come back, you know, a week later and get your second dose to an infusion center. That is so much easier. And and a lot of times, patients aren't sitting in the hospital at the end of their care because they clinically aren't ready to go home. It's because we operationally and logistically are having trouble getting them out with a commercial health system. So I know that's gonna be different around the world, but at least here, it's these are really impactful data, and we've been doing this.
Speaker 3:So, I love Mark's comment of, you know, would I apply this to my patient? Does this change my practice? I think this actually reinforces practice that's been happening off label because of this need, because of these patients that we can't get out because they don't have this coverage or they're not safe at home. And so we actually already have a a what we call a dalbavansin discharge pathway, wherein patients with these complex staph infections or osteomyelitis, things like this, they end up, which I think was a good chunk of the patients in this trial, were patients with osteoarticular infections. I think only about 10 patients had right sided endocarditis.
Speaker 3:We have a pathway wherein we discharge them same day from the ward to an infusion center. They get their first dose and then they just have to come back for their appointment. Another thing to point out about this trial that's relevant is I think 13% in the Doblavance and arm and and oh, sorry. 13% in standard care and 16% in the double Vinson arm were persons who inject drugs. It's really great to include these patients and to have data in this population.
Speaker 3:Again, from a operational standpoint, is really, really a good choice in these in these patient often cannot get PICC lines and who may not be reliable taking oral medications. And the dosing scheme they used to I'll put my pharmacist's head on the 1500 milligrams, at these two doses. This came out of osteomyelitis trials and some early data, but it is a dosing scheme we've used because it seemed to work for osteo, and so why not apply it to other drugs? So it's great to have RCT data showing this is this is a this is a reasonable dosing scheme. These are really important data.
Speaker 3:I'm actually presenting these to what we call our system stewardship collaborative in 2 days from now. So I came back from ECCMID. I was emailing on the plane, like, you guys, I have something to present at this meeting. I think our physicians and pharmacists need to know about this sooner other than later. I know they're not peer reviewed yet.
Speaker 3:I know things are subject to change. We need more details like we discussed, but I think these are things people should be aware of and and honestly, I think should change your practice. I think this is a very patient centered way to use this drug And I think this is where care is shifting. Drug companies are starting to think about this. Look at what we've done with HIV and the long acting injectables, and then raise a fungen in the antifungal space instead of having to get a daily at Canikandin, how about a weekly?
Speaker 3:Can you get away with 2 or 3 doses to finish a course? And I think this is quite meaningful for patients. And so, I'll end with that. Sorry, I rambled. I guess related to that though, I love the door.
Speaker 3:I love how idea shifting to door analyses because it is patient and these are outcomes we care about. And ordinal scales are complex because going from intubated to dead is very different than we talked about this in COVID. Right? I'll just use that as an example. Going from 6 liters of oxygen to 10 liters of oxygen may be the same one point on an ordinal scale as going from intubated to dead, but you certainly care more about one of those moves.
Speaker 3:Right? Even though they're both worth one point. And so a door is a much more holistic and meaningful way to evaluate these nuances and outcome.
Speaker 1:Mark, do you fully agree?
Speaker 2:Yes. I do. I do. And I'm I'm I'm not aware, and I don't know in to what extent this approach is already used in Europe. But if I were already using DelVal for such patients off label, as currently is practiced a lot in the United States, I would be very reassured by these, by these findings, and I would certainly not change practice.
Speaker 2:If I were not, I think this study would provide sufficient evidence to to start using it in this patient population. And that is the group of patients in which, let's say, with the definition of complicated staph aureus bacteremia with good clearance of the first, let's say, initiation treatment. Yeah. If I were a clinician with a mission, an academic clinician, then I would try to convince the SNAP leadership to reproduce the results in a in a trial that is ongoing, a platform trial, to build up the evidence base for this approach for for all patients and maybe even to extent the inclusion, diagnosis, for the pipe the population in the study.
Speaker 1:So, Ira, I have a question because, honestly, in Switzerland, we do not have these long acting antonystaphylococcus, not quite yet. We just got DABA. In the states, you seem to have had them, have access to them for quite a while, not the thing that sort of scares me still is this long half life. Is there in real life, a real worry about, you know, not being able to deal with the bad side effect? Have there been any really awful situations where you've given somebody a drug that's gonna last all week and they're having a terrible reaction to it?
Speaker 3:Yeah. It's a it's a great question because, admittedly, I think that was something that held this drug back a little bit. Anything new is is scary and change is hard. So we've had these drugs since 2014 in the United States. And like all ID things, I think it takes about 10 years to adopt them into practice, which is exactly what we're seeing.
Speaker 3:Because I would say now they're used relatively commonly or at least people know about them. And when these drugs first came out, dalbavanssen and aritavanssen, they were studied for skin and soft tissue infections either failed either failed orals or you can't take orals or maybe it's just a deeper infection, but they don't really they're not really sick enough to need to sit on a ward, but that's what we would do. Right? They get admitted for a couple days of vanco and they go home in 2, 3 days, and it just seemed like a waste. And so they said, instead of admitting them, give them a dose of dalbavanser in the emergency department and send them home.
Speaker 3:Is gonna change the game. Right? This is gonna keep people outpatient. And I will tell you that was a very slow uptake for a million reasons, but largely because of cough and then this long acting. So if I give this to them and they have anaphylaxis, is that gonna happen for 7 days?
Speaker 3:Do they need to be on high dose steroids and get epi continuously for this drug to completely wash out of their system? Who knows, right? Allergists were scared. We had no idea what to do with patients that had vanco hypersensitivity reactions, vancohistamine release and infusions, daptomycin adverse events, so we generally avoided it in those patients. I would say clinically now that we've used it a lot, allergy and anaphylaxis remain extremely rare and if they have anaphylaxis, it seems you treat it like you would in anaphylactic reaction and then it doesn't persist.
Speaker 3:In terms of resistance development, so this was another thing. I think the authors talked about it when they presented. So one dose, this 1500 milligram dose of dalblavanserin maintains your exposures over the average MIC 90 of staph aureus for about 40 to 50 days,
Speaker 1:Despite the fact that we give
Speaker 3:a second dose, right? So that's why you only need 2 doses. So we say a week, but really this lasts for months. And, and so there are some really good scientists, Brian Wirth in particular out at the University of Washington in in Seattle. He's looked at this and like this low as you get to this tail end, these low level exposures, is that breeding resistance across the lipoic, like, opeptide class to staph aureus, enterococcus?
Speaker 3:Think we don't know the answer yet, but I think it is interesting data when, you know, looking at at this tail end, and and we have more to learn in that space. But by and large, those concerns are are interesting hypotheses, but they would not preclude me from using this drug, especially as Mark said in light of these data. I like the way you framed it, Mark. And I do actually think the SNAP platform is looking to build in these agents. They're trying to look for drug, I think.
Speaker 3:And I'd have to check their website. They keep a really nice website. So this arm may even be up and running. But last, I actually Tom and and Steve Tong and I actually had a call trying to see if we could do this in the states specific in persons who inject drugs, and it's just extremely challenging to get to get trials up and running in the United States because of the cost per patient enrollment, which is so unfortunate. You guys you guys do such a better job at enrolling in these rapid adaptive platforms in Europe, Australia, and in parts of Asia.
Speaker 3:If they haven't built it in already, I know it was on their radar.
Speaker 1:Just speaking of Australians doing great clinical trial. Erin, can you tell us about Game changer?
Speaker 3:Yeah. I'd love to. I mean, truly, where would we be without the Australians even when they moved to Singapore? So David Patterson, near and dear to my heart because he was actually at Pittsburgh. He started the stewardship program here in Australia.
Speaker 1:Chris, I did not know.
Speaker 3:No worries. He, he was here in with Yohei Dort or twenty 12, I think. I didn't come till 2018, so I missed missed the David Patterson area, but he was at Pitt for a good bit. And so the game changer trial was an investigator driven multicenter, randomized, non inferiority, open label trial which compared cifidiracol or cifidercol as the Australians would say. Cifidercol as we say in Switzerland.
Speaker 3:Cifidercol. I know. Right? Cifidercol. I'm gonna have, like, give Fidderick a call because I wanna feel cooler Australia.
Speaker 3:Than my American self. So they compared it with standard care antibiotics for gram negative bloodstream infections that were hospital acquired or healthcare associated. I think that's actually an interesting point because later we'll find out they also screened a lot of patients. Actually, one of the main reasons patients were excluded is they had community associated infections, which from a world AMR standpoint, we continually talk about how we're finding mittauer beta lactamase producing infections in patients with seemingly no risk factors in the community. And that is a that is a thing.
Speaker 3:Right? We're seeing that a lot of patients were rolled out because they weren't hospital acquired or healthcare associated. It's like we said, David Patterson presented this. This trial enrolled in Australia, Malaysia, Singapore, Taiwan, Thailand, and Turkey. They did have partial funding by Shionogi and Shionogi supplied the cephitra call, but there were no other additional funding sources for this study.
Speaker 3:This was adults only. They had to have a positive blood culture with 1 gram at least one gram negative organism from at least one blood draw, and they had to be enrolled within 48 hours from the time of positivity. So a tight enrollment window. They're randomized 1 to 1. So ifitercal was given at 2 grams intravenously over a 3 hour infusion per its package insert.
Speaker 3:You're allowed to go up to a, every 8 hours. You're allowed to go up to every 6 hours if you have augmented renal clearance, and then they could dose down for decreased renal dysfunction. All patients received antibiotics for at least 5 days and no more than 14 days. So that inherently rules out any complex endocarditis osteomyelitis kind of infection. Standard care was any antibiotic per the treating team and they could give up to 3 gram negative agents.
Speaker 3:They also could adjust standard care throughout the treatment course according to susceptibility testing results or the patient's clinical condition. The main exclusion criteria is where if the investigator said the patient was unlikely to survive for more than a week, they were excluded. If they had a concomitant gram positive bloodstream infection, they were excluded. But notably, they could have other infections or concern for other things. So patients could receive any gram positive anaerobic or antifungal in align with their gram negative infection.
Speaker 3:They just couldn't have a gram positive bloodstream infection. Pregnant patients were excluded and patients on peritoneal dialysis were excluded. The primary outcome was a 14 day all cause mortality. Day 1 was considered the day the patient was randomized. So, not necessarily the day of the positive blood culture, the day of randomization.
Speaker 3:And they hypothesized that Safitter recall would be non inferior to standard care with a non inferiority margin of 10%. And they had predetermined that if they met the non inferiority margin, they would continue to do a superiority analysis. Again, kind of looking through our consort, all the patients that were randomized were included in the analysis except for patients who ultimately didn't grow an organism. So these would be patients that maybe had a positive gram stain, got randomized, but then nothing grew on culture. They were out.
Speaker 3:They didn't get any dose of study drug or they withdrew before day 14. So they assessed 9,144 patients throughout this, and they ended up excluding 8,631. So to our point earlier, it's hard to enroll in some of these complex drug resistant trials. And and again, the main reasons patients didn't get enrolled is because they didn't have a hospital acquired infection or it was more than 48 hours since enrollment. I do think it's challenging to enroll really, really sick patients in that time frame.
Speaker 3:Often, you have to find their family, whatnot. And then there were 734 patients that weren't expected to survive, which again speaks to how sick some of these patients are. So ultimately, they ended up with 256 patients, the phenterichol group, 257 patients in the standard care group. About 30% of those infections were e coli, 30% klebsiella, 8% enterobacter, about 10% give or take Pseudomonas, 10% give or take of carbapenem resistant Acinetobacter, only 1% steno. And if you look at totality of organisms, there's more than a 100% because they were allowed to include patients that had polymicrobial gram negatives.
Speaker 3:20% UTI source, which is actually lower than we'd anticipate. So usually these studies are kind of heavy with UTI. So interesting is 20% UTI, about 20% intra abdominal, 20% line, and about 12 give or take percent pneumonia, And then 20% unknown, which is interesting. I feel like gram negative infections are typically easier to classify than than gram positives, but 20% unknown. These patients were sick.
Speaker 3:Median Charles and comorbidity score of 5, baseline SOPHAS score of 4, 20% were in the ICU. What we care about is the results. So moving into the results. So day 14, all cause mortality was 8% in the cepidoccal group versus 6.7% in standard care. Non inferiority was met.
Speaker 3:Superiority, however, was not achieved. When we move out to day 90, those numbers evened out a little bit, so 20 9.2% versus 29.5%. There are no adverse events directly related to study drug that were associated with death. Then they looked at this, predefined subgroup of carbapenem resistant organisms, which this is a group we care about. Right?
Speaker 3:This is the group we're gonna use these agents in. And they define this by the 2024 UCAS definitions. They had all these organisms done in a central laboratory in Australia. So they ended up with 57 carbapenem resistant organisms in the cifidiracol group and 60 in standard care. 14 day all cause mortality in this subpopulation was 18% cepheidiracol, 12% standard care.
Speaker 3:By day 90, that those numbers became 49% 52%. So these are very, very small numbers, but at least numerically, greater mortality in the cifidrechol group. In the cifidrechol group, so of those 57 patients, 42 were treated with monotherapy and 15% with combo therapy. No analysis based on that because the numbers are too small. And so even in the carbapenem resistant, their conclusion was non inferior.
Speaker 3:But I think all in all, this is another trial with cifidical. So now we add these data on top of Credible, on top of some of the other cifidical data, even Apex MP looking at pneumonia, which compared to meropenem. We continue to see with cifidricol somewhat disappointing the in vitro potency of this drug. It's spectrum and it's a it's a cephalosporin and, you know, just not what we wanted to see. But I don't know.
Speaker 3:Mark, what are your thoughts?
Speaker 2:I was also puzzled by the difference of this these results of the carbapenem resistant bacteria with the analysis of the CREDIBLE study, the CREDIBLE 2 study, I think it was, because the effect size point in this in a different direction, but the message here is these are still small numbers. And I don't think we really can draw conclusions on the 14 day mortality. Definitely, if the 1990 mortality is no longer different with small numbers of patients. And then this result and the game changer, the other result in the credible study, which only, let's say, underlines that that we needed a larger study to really define, quantify the effects of these antibiotics and also of the the different components of the standard of care treatment.
Speaker 1:I think I just wanna throw something out there because I agree with you that when when things even out at 90 days, then you, you know, you should normally be able to say, okay, No difference. Right? But I wonder whether with this population, they are so sick. Right? They are so sick on day 1 That by 90 days, you know, maybe they're all gonna die of different things, you know?
Speaker 1:And and I know normally we don't talk like that. Right? But in this case, given the severity, these people are very comorbid. I don't know if you can give this much weight to a time point that is so far out for this particular population. Just throwing that out there.
Speaker 3:I I agree with that. I agree too. I I struggle with the 90 day endpoint for acute infections, although it's a common endpoint. I mean, BLING3 use 90 day mortality as their primary primary endpoint. And, you know, we eagerly await those data in a in an ICU population.
Speaker 3:So Mark had mentioned, you know, what standard care was given in and so in these about 60 patients with these carbapenem resistant organisms, 21 got polymyxin based therapies, 14 got ceftazav, 9 got either pip tazo or meropenem, which is interesting. Are they on inactive therapy or is it a different kind of CR? Was it only ertopenem resistant? Who knows? And then 7 got tigecyclin or minocyclin and 9 others.
Speaker 3:And so as with Tango 2 and the septazav studies and what we've seen when we compare novel agents to standard of care. Standard of care is like a big bucket of nothingness, including polymyxins, which are all not fun agents to give. Minus septazav now. Right? But what we don't know is we don't know the more nitty gritty on what these infections were.
Speaker 3:How many NDMs? How many oxa? Oxa? How many KPC? How many non carbapenemase producing, carbapenem resistant organisms?
Speaker 3:So we don't know that other than we know the Acinetobacter in there is gonna be complex. We don't know how long patients got antibiotics for in each group, and if there was a difference. We just know 5. They had to get between 5 14 days. We don't know how often patients in standard care were changing therapies, because that was allowed.
Speaker 3:So how often were patients escalated? Did that make a difference? Did that matter? At the end of the day, though, we have another trial comparing cepitiracol to essentially polymyxin based combinations, showing that in its most positive interpretation, it's no different than polymyxins, which just is not what people want to hear. Right?
Speaker 3:There's a huge cognitive dissonance here because it's a cephalosporin, and we want it to be super effective.
Speaker 2:That brings us to a very philosophical question of what is the attributable mortality of these infections in this patient population, and to what extent can that mortality be influenced with our standard of care and with any new therapy? And, actually, the answer can only be given by a very effective treat. If we have a treatment that is very, very effective that significantly reduces this mortality, then we know that it's attributable mortality. The observational studies will not tell us. They can give hints.
Speaker 2:Yes. There probably was a terrible mortality, but they can never prove it. So I think we need to continue all our efforts to bring better treatment to these patients, but it must be in randomized, well designed, large scaled randomized trials. And the standard of care will always be a a mixed bag of treatments.
Speaker 1:Yeah.
Speaker 2:So, hopefully, next year, we will have a little more information on this difficult topic. But I think the game changer study was really an exceptional study also for the way that it was designed in in difficult settings with so many patients and also so many patients screened.
Speaker 3:I do wanna commend Shionogi and the and the investigators for for doing these studies still. Right? They're really trying to her to help patients with the with, patients that really have very limited antibiotic options, and they're really doing these complex studies in these complex patient populations. And it's a team of really strong scientists. Yeah.
Speaker 1:No. I fully agree. I mean, this is harpulean, extremely complex. Sometimes a very simple question, but extremely complex to carry out.
Speaker 2:So this game changer study was really in the area of the adult patients, very sick, very severe disease, and very high exposure to antibiotics. Now let's move to the other study that studied severe infection respiratory infections in children, where they tried to reduce the antibiotic exposure, and that was the pedicap study. Angela, can you please tell us about that study?
Speaker 1:I would love to because I have to say I love this study. And so they're already, you know, full disclosure. I I didn't know about this study before, but before I'm even gonna tell you about it, I'm just gonna tell you I think it's a fantastic study. So Victor Musimae of Uganda presented the results of this, what I find to be highly relevant investigator initiated trial that was run-in 13 hospitals in Sub Saharan Africa. The PI of the trial was Mike Scharland, and the study was supported by the clinical trials unit of the University College of London, but fully took place in these countries in Sub Saharan Africa.
Speaker 2:Mhmm.
Speaker 1:So this study had 3 questions. Number 1, for severe pneumonia in children, WHO recommends 5 days of IV antibiotics. You can imagine that this is not practical. So first question, is early step down to oral therapy safe and non inferior to those recommendations by WHO. Number 2.
Speaker 1:Is there superiority if you step down to amoxiclav versus amoxicillin alone? Question number 3. What is the optimal length of total antibiotic therapy in these patients? In other words, can you shorten IV therapy and hospital stay without increasing clinical failure or relapse in these patients? So they had 3 hugely relevant questions, and I think they managed to answer all of them in a very elegant study.
Speaker 1:This was an open label, parallel group, 2 by 5 factorial plus 1 IV ole arm, randomized trial, and I'll explain what all that means. The old children were 2 months old to 6 years old. They had to have severe community acquired pneumonia with, a CRT over 10, and they had to have received less than 24 hours of antibiotics before being included. Main exclusion criteria were nosocomial pneumonia, need for invasive ventilation, or suspicious viral pneumonia. So these were children with severe pneumonia, but not so severe that they needed be inspated.
Speaker 1:And the study recruited during COVID times from December 2020 to August 2023. So this is the way this factorial design works. These children were first randomized to 1 of 3 treatment modalities. So there was that WHO IV arm where they just remained on injectable IV therapy for 5 days fixed, according to current WHO guidelines. This can be seen as the control group's standard of care, and this group had a 100 patients.
Speaker 1:They could have also been randomized to step down therapy with oral amoxicillin alone whenever the child could take oral medication, and this group had 500 patients. Or, thirdly, they could be randomized to step down oral amoxicillin plus the clavulone whenever oral intake became possible. This group also had 500 patients. And, just be aware that in this study, the ratio of amoxicillin to clavulonegazet was 7 to 1, which is pretty standard. But by the way, this study has, like, so many moving parts.
Speaker 1:They actually, have a substudy a PK substudy where they're actually looking at different ratios of amoxy of amoxicillin to clavulanic acid. Those two groups of children who were randomized to step down therapy were then further randomized to different durations of amoxicillin or amoxiclav on a spectrum from 4 days to 8 days. So that's where you get this, 2 by 5 factorial design. So in each of these step down groups, 100 children were randomized to 4 days, a 100 children were raised to 5 days, and so on up to 8 days. So follow-up, once these kids were randomized was 28 days.
Speaker 1:Primary outcome was all cause hospital readmission or death in that time period. And they set the non inferiority margin at 10%, which is pretty standard. Outcome, there were some secondary. There are a lot of secondary outcomes. They also looked at, community acquired pneumonia related preadmission, death, length of stay, antibiotic exposure, serious adverse events, emergence of AMR.
Speaker 1:We'll get those results later, I think. So they screened around 22100 patients for the 11001 included. This is a nice ratio, speaking of, included to to screened ratios. So on top of that, they had really good follow-up. They lost and this is in sub Saharan Africa, where it's not always easy to get your kid to the hospital.
Speaker 1:They only had a 4% loss to follow-up. Mean age of the children was 19 months old. 1% of these kids were known to have HIV. 91% had at least one pneumococcal vaccine. And in terms of severity of the pneumonia, it wasn't it was pretty severe.
Speaker 1:62% of these children were on oxygen at baseline. So how did they do? First of all, the timing of the step down to oral therapy was similar in both groups. 68% of kids stepped down on day 1 to 3 therapy, though 80% actually never ended up stepping down to oral therapy at all. They received totally IV.
Speaker 1:And these, you can imagine, were the kids who were randomized to the shortest durations, 4 days, 5 days. And how do they do in terms of clinical outcomes? Well, the primary outcome, all cause hospital readmission or mortality had an event rate that was essentially the same in all arms. 6% in the IV only arm, 6% in the Amoxic only arm, and 7% in the Amoxiclav arm. When looking by treatment duration, results were also similar.
Speaker 1:Primary outcome event rates were low. At 4 days, only 4 percent. At 5 days, only 5%. And they weren't different than those in the 8 day group, also 5%. So all of these findings were well within the 10% non inferiority margin.
Speaker 1:The length of stay was longer in the IV arm as expected, but by only one day. There was no difference in serious adverse events, and there were really no differences in the other secondary outcomes that they reported. So, overall, this study, really the first RCT in children to question, to to put out some evidence, on whether or not you treat children for 5 days with IV therapy in settings where it's very difficult to do that, these are the first data that essentially say no, that is not
Speaker 3:necessary. Yeah. I love this trial too. This is one of those moments you remember when I I wasn't aware of this trial was enrolling dots and game changer I knew about. I knew the data were gonna be presented here.
Speaker 3:When this trial came up, they did a fabulous job presenting it, and I I love when I learn new things, and I'm like, that's gonna to me, this is gonna change practice quite significantly for the better, for patients all over the world. But particularly looking at where and how they did the study is just really, really amazing work by the investigators. And I love how they designed this to look at 4, 5, 6, 7, 8 days because we always ask that question. Right? We're always like, well, it's and I love that they looked at even numbered days of the MP.
Speaker 3:I feel like it's always 5, 7. Right? So 4, 6, 8. I love it. I love it.
Speaker 3:Sometimes when I might get chaotic on rounds, I recommend 6 days just to have people stare at me. Odd. So I love this. Yeah.
Speaker 1:I love that they move this
Speaker 3:needle to 4 days. We know in a in the adult space, 5 days is pretty much standard now for CAP and accepted for CAP, but that's only if they're clinically well, you know, and they and they rapidly improve. These are sick patients like you said, 60% or more on oxygen at baseline.
Speaker 1:Well, yeah. No. I love it as well. I love this this granularity of of durations. You know?
Speaker 1:Like you say, we're so it's like this dogma among ID people that we have to give, you know, either days of the week. We're on, like, this lunar calendar. You know? Either Saturdays or 14 days or, And here, yeah, why not why not go for 4 days? But I think it's really, really great that they that they went to this level of granularity.
Speaker 1:So now we all will feel better, basically, when giving 4 days. So, yeah. So I agree with you, Erin. I think this should absolutely change practice. Disclaimer, I am not a pediatrician, but I think the data, you know, in and of themselves are very, very strong.
Speaker 1:That being said, this trial obviously has some limitations, the biggest ones being that it was open label and that clinicians chose when to step down. That wasn't dictated by the the trial protocol. It was clinicians looking at these patients and making that decision. But that open label limitation is mitigated by the the child's use of hard endpoints. Right?
Speaker 1:So when you have, an open label study, you should not use subjective primary outcomes, and they didn't. They had a very objective primary outcome of all cause mortality or all cause readmission. And then the clinician's involvement in the choice to step down, I wouldn't say that's part of real life. You know, you probably don't want that decision being made by a blind algorithm. And it was a risk, but it looks like from the data that physician bias didn't really tie a cake rules.
Speaker 1:The ultimate timing of oral statin was similar in both groups. So, yeah, I mean, overall, this data are just super intriguing to me. I love that amoxicillin alone without the beta lactamase inhibitor is just fine for follow on therapy of severe pneumonia in these children. We don't yet have the microbiologic data, but, you mean, you'd have to assume that pneumococcus and hemophilus are at the top of list. But still, I think it will be interesting to see how children did by pathogen because for certain infections and certain pathogens, I really wonder whether follow on oral therapy is really just detail.
Speaker 1:Whether it might just be an extra step that makes us doctors happy and reassured, but, it kind of gets there only after the battles are even won. But, anyway, we'll find out. So that was those were our 3 very big trials that we're all very excited about. And now to the trials that we won't describe in as much detail, but from each of which there's definitely something similar. So, Erin, can you tell us about the study that looked to reduce e coli transmission in Burkina Faso?
Speaker 1:Yes. I'd love to.
Speaker 3:So this was presented by Esther Van Cleef on behalf of the CABUEICO study group. This was very preliminary data. I think she said they got the data, like, 2 days before the presentation. So they are still doing a lot of intensive analyses, but kudos on them on getting this together. The protocol for this study is published in trials if you want to read more about it.
Speaker 3:But essentially what they did was they looked at the effect of a behavioral intervention bundle on antibiotic use, quality of care, and then specifically, if that would reduce household transmission of ESPL producing E coli in rural Burkina Faso. So, they targeted a lot of different interventions. They held very her slides are beautiful. They held these community engagements where they got the community out. They did theater plays.
Speaker 3:They visited schools. They did a lot of education about antibiotic use, about hand washing. They talked locally in the villages to people who dispensed antibiotics. They so that was a provider side and then they talked about the supply side targeting antibiotic use. They talked about sanitation standards across the villages and they did a particular focus on health literacy.
Speaker 3:And they did this community engagement around antibiotic resistance practices and antibiotic dispensing for about 6 months, and that's where we talk through their theater demonstrations to school, things like that. And I think this is really neat because we mentioned this earlier in the podcast, but we know that community transmission is what really is driving AMR. And we don't have a good perspective on this in low middle income countries, particularly in the absence of good infection prevention and control efforts or without any antimicrobial stewardship in place when the community is the access to antibiotics. And so E. Coli was their proxy for the burden of antibiotic resistance in this, in this community.
Speaker 3:So the intervention lasted about 9 months in total. They went through 3 different rounds of different layers of interventions. They said during each round, they would visit these villages for 4 days with these structured antibiotic use at the community level. They did household surveys. They simulated patient visits.
Speaker 3:I mean, this was a lot of work that went into this. They said they had 22 village clusters. Twelve households were included in each cluster, and they were allowed to sample specimens from up to 7 members per household. Remember, these are communities in which many, many folks live in these households so that it's stool sampling to check for E. Coli screening and transmission.
Speaker 3:And what they found the punchline is they found very, very high prevalence rates of E. Coli at baseline. And so ultimately, they did not see a difference in their intervention pre post. They're doing, again, a really rigorous analysis to look at all these different factors in the different village clusters and things like that. But at at least that front, it didn't seem like this intervention made a difference probably because prevalence was so high already and also because it it they didn't go after structural drivers of change here, which is access to clean water, indoor plumbing, things like this.
Speaker 3:And and structurally, those probably are going to make more of an impact than any any education or antibiotic use would do in these communities at this point in time, but I think it's nice to have these data that that show that. And I think it's really just tremendous tremendous work by the by the author group and a nice presentation. Another study yes.
Speaker 1:I can. Another study out of Australia. So this was an investigator initiated trial, and it asked the question of whether the cleaning of shared medical equipment actually leads to a reduction in health care associated infections. So infection is not just colonization. This was a step wedge trial that cluster random has 10 wards in one hospital, making 5 clusters to either intensive cleaning or standard cleaning.
Speaker 1:So intensive cleaning was definitely that. The intervention consisted of 3 hours of extra cleaning every weekday by dedicated staff with fortnightly audits. Equipment was anything from wheelchairs to blood pressure monitors. It looks like essentially was anything that touched a patient. So the primary outcome was the portion of inpatients with any health care associated infection.
Speaker 1:And they measured these health care associated infections by fortnightly point prevalence studies done on all patients in these wards. In total, in the end, 5,000 patients were included. So the results. In adjusted analyses, the prevalence of health care associated infections in the control arm was 15% and 10% in the intervention arm. So the absolute difference was 5%, and the relative difference was 35%, which is big.
Speaker 1:So it is. It's a very big effect size considering that many health care associated infections would normally result from endogenous infection, as was noted by Stefan Habart, my former boss who was in the audience, when this trial was presented. So Brett Mitchell, who presented the results, he responded by saying that it really might have to do with the very high baseline of of HAI in this hospital. So whereas you're saying in Burkina Faso, that a high baseline of E. Coli may have been a reason for not seeing a difference.
Speaker 1:I find very interesting. Here, Brett Mitchell, the Australians are saying, well, actually, we had a very high baseline of these infections. So maybe that's why we saw a bigger difference. And the other thing he noted was there was a pretty low standard of cleaning at baseline. So he gives the example that some IV pumps were not being cleaned at all.
Speaker 1:So it the intervention had a big boost right there. So the single center hospital may tell a different story than someone else's hospital might. We don't know. And there's also a major issue of feasibility. This also came out in the discussion after the actual trial presentation.
Speaker 1:That's why it's always really nice to be in the room. It came up that there was a huge human resources question, direct quote from the presenter. Patient care cleaners found it tedious to do this job. They didn't like doing it. They had to pay more money.
Speaker 1:The team had to pay more money to get people into the study to clean. Apparently now, they're working on a cost effectiveness analysis to see if they can even maintain this kind of intervention. So we'll see we'll see on that. And, Mark, do you wanna tell us about the CAMERA 2 follow on in vitro analysis study?
Speaker 2:Yeah. Sure. So this was a, indeed, a follow-up study of the CAMERA 2 study, though. The CAMERA 2 study was a randomized controlled trial of patients with MRSA MRSA bacteremia, in which they compared treatments at vancomycin or deptomycin with or without an antisteflacoccal beta lactam. So the addition of the antistephelcoccal beta lactam was the intervention in that study.
Speaker 2:That study was stopped because there was no effect or no benefit demonstrated at day 90 mortality rates, but more importantly, they found an increased risk of acute kidney failure in the patients in the combination group. Now they had a preplanned postdoc analysis to determine whether in vitro interactions between vancomycin or deptomycin and the combination therapy with the isolates would predict the treatment effect in the combination therapy. Now they took 150 isolates that were available from the patients that have been randomized in the combination therapy arm, and they determined in vitro where there was evidence for either synergy or additivity or indifference or antagonism and looked then at the outcome. So they took this arm of the study, of a randomized study, turned it into an observational analysis in which the isolates and the patients where the isolates came from divided on the group that had synergy or additivity in the lab or the group that did not have it. There were only 4 isolates of patients that were treated with deptomycin.
Speaker 2:So this mainly was an analysis of vancomycin and the synergy with the antiseptococcal beta lactam antibiotics. Now the group was divided in 2, there were 47 isolates in which there was indifference or antagonism, and 103 had synergy or additivity. And these two groups were then compared among the many comparisons that were made for day 14 mortality. There was a significant difference that the patients with Synergy had less mortality in that group. However, there were only 9 patients with the endpoint of day 14 mortality with an even distribution between the two groups.
Speaker 2:And if for none of the other endpoints, that difference was maintained. The difference was 3% versus 13%, but the difference did not persist for any other endpoint or for day 42 and day 90 mortality. So what we can learn from this study is actually what the presenter, Andurielle Honquoi, also mentioned that, and she mentioned it very clearly, that we should interpret these data with great caution and use them for hypothesis generation. And that hypothesis then would be that, indeed, that there is a possibility that in vitro determination of synergy could help us in the future in deciding whether to add an antisteflococcal beta lactam therapy to, for example, vancomycin or deptomycin. But for that, we first would need a trial to really demonstrate that that has a clinical relevance.
Speaker 1:So something to look forward to. And, Mark, can you tell us about one last study, the French multicap study?
Speaker 2:Sure. This was a very interesting multicenter study done in 20 ICUs in France, trying to do an intervention to reduce antibiotic exposure in patients that have hospitalized with severe community acquired pneumonia. And the intervention here was twofold. 1st, to do a multiplex PCR testing at the time of admission, and the second part was to do repetitive procalcitonin measurements. With the results of of these tests was an algorithm.
Speaker 2:And if there were no bacteria demonstrated with the multiplex PCR test, the suggestion to clinicians was to stop antibiotics and based on PCT measurements also to stop antibiotics earlier than in the control group. The primary endpoint was days alive without antibiotic exposure at day 28. The multiplex PCR that they used was the BioFire providing very fast results about a lot of bacterial and viral respiratory pathogens. As mentioned, that PCR was done in the first day that patients were randomized, and the PCT was done at several days, but also on the first day. The execution of the study, I found was quite remarkable.
Speaker 2:Within a median of 4 and a half hours, the patients were enrolled in the study between hospital and ICU admission. That's very fast. And then the tests were done within a median time of 9 hours. In total, 385 patients were analyzed, 188 in the intervention group, and 197 in the standard care group. Now the results, and they were quite disappointing.
Speaker 2:Testing with the multiplex PCR actually led to more bacteria documented. That's a good thing. It was an 81% of the patient versus 55% of the patients that had used standard of care diagnostic. And as a result, almost all patients in both groups started with antibiotics, and the intervention with the repetitive procalcitonin measurements did not reduce antibiotic exposure. Both groups had a median of 19 days of life without antibiotics at day 28, and also all secondary endpoints that they measured were similar in both groups.
Speaker 2:And in the discussion of the presentation, it became clear that there was not a very active way of having the physicians treating the patients following the results of the tests. There was an algorithm. The algorithm was provided at the beginning of the study, but there was not a daily follow-up. And for such a study as did, you need both physicians that use the test, but you also need a patient population in which the test can influence antibiotic use. And both of these aspects are sometimes overlooked.
Speaker 2:In fact, a patient in which the physician will prescribe or withhold antibiotics regardless of the test results should better not be eligible for such a trial. There should be equipoise. Including patients in which such a test result cannot make a difference. It uses the trial capability to demonstrate any effects. And this was an ICU population.
Speaker 2:Patients hospitalized with severe CAP, and I wonder whether physicians will, and actually, I also wonder whether they should withhold antibiotics as a rapid test may not disclose bacteria, but may also not be 100% sensitive, and you're dealing with a very sick patient in the ICU. Almost all patients in this study started with antibiotics, as in most us using the world's indication, I presume. And I think that the proportion of patients in which a rapid test could really make a difference in such a population is low unless it's during COVID 19 as we have seen. But now there is a myriad of pathogens that can be involved. The observation that the repeated procalcitonin measurements did not produce antibiotic exposure was not discussed in detail, but deviates a little bit from other studies that did find that effect.
Speaker 2:So it will be important to see what data will be shown on that measurement. I want to end with one remark on on these kind of interventions because we all want to reduce antibiotic exposure to patients. Because we all think it's wrong that we give them so many antibiotics. But what we learn as a physician is also something that we should not forget when we do trials. The first thing is do no harm.
Speaker 2:There is a certain standard of care that includes antibiotics. And just to quote Bruce Lathin, antibiotics do more than causing resistance. They actually help patients survive if they have a severe infection. And in all these studies, we have a certain standard of care that has evolved over the years with the antibiotics that we use. So if we think of trials that test an intervention to reduce that antibiotic exposure, the first thing to make sure is that we're not harming patients so that our level of care remains intact.
Speaker 2:That's a safety issue. So we have written a white paper a few years ago in which we argue that such studies should be designed as a combination of a non inferiority trial for patient outcome and a superiority trial of antibiotic exposure. And then the goal of the study would be first to demonstrate that the antibiotic steroid intervention that you use, that you do no harm to patients, that it is safe for patients and remain safe, so that there is non inferiority for a clinically relevant endpoint such as survival. And then you can demonstrate or hopefully can demonstrate that with less antibiotic use, the same safety of patients can be guaranteed. And I think future studies should hopefully focus on that, but it has a price to pay because that will definitely have an impact on the patient sample size that you will need to demonstrate non inferiority or better to demonstrate the safety of the patients if you give them less antibiotics.
Speaker 3:I think that's beautifully stated, Mark. And I think it's really important when we look at the diagnostic literature in totality, because procalcitonin is, is, is a very controversial test, at least in my center. It seems like a test we send a lot. I can tell you we spend anywhere from we spend 1,000,000 of dollars on procalcitonin across my 35 hospital system. And I'm not sure how often it actually changes care because exactly what you said.
Speaker 3:Some patients are gonna get antibiotics no matter what. In some patients, we may be able to stop them earlier, but the with the old Cochrane review from a couple years ago looking at ProCal, you have to be careful when you interpret just the just the abstract. Right? So those patients were getting when it said it reduced antibiotics, it was when we were going from like 9 days to 7 days for pneumonia. Now, 7 days is pretty standard for even VAP and HAP and really 5, maybe even down to 3 days for community acquired pneumonia.
Speaker 3:And so, the PROACT trial that was done out of Pitt looking at procalcitonin in the EDs that found no difference. It's because patients in both arms got 4 days of antibiotics. So, So the test isn't gonna reduce it when your physician's already saying I'm good with with short course. And so, that needs to be looked at too. So I think we're evaluating procalcitonin.
Speaker 3:I think the investigators did a
Speaker 1:interesting trials. These are some of the most beloved sessions of Escondido Global, and always lots and lots to think about. We thank you for listening to Communicable, the CMI and comms podcast. This episode was hosted by myself, Angela Huttner, Mark Longton, and Aaron McCreery, all editors at CMI Coms, which is Smed's new open access journal. This episode was produced by Angela Haft, edited by Monica Balestaros, and peer reviewed by doctor Hugh Streicheravi.
Speaker 1:The theme music was composed and conducted by Joseph M. Dade. The executive producer of Communicable is Angela Huttner. You can subscribe to Communicable on Apple Podcast, Google Play, or Spotify, or you can find it on Esket's website for the CMI Comms journal. Thanks for listening and helping CMI Comps and ESKMID move the conversation in infectious diseases and clinical microbiology further along.