Communicable E62: POET
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Emily: Hello, everyone, and welcome back to Communicable, the podcast brought to you by CMI Communications, ESCMID's open access journal covering infectious diseases and clinical microbiology. I am Emily McDonald. I'm a physician in general internal medicine, infectious disease trialist and scientist at McGill University in Montreal, Canada, and associate editor at CMI Communications.

So, the POET trial, partial oral intravenous, antibiotic treatment of endocarditis, was published in August 2018 in the New England Journal of Medicine. And the study found that in patients with endocarditis on the left side of the heart who were in stable condition, changing to oral antibiotic treatment was non-inferior to continuing intravenous antibiotic treatment.

And even more so, the five-year long-term data published in February 2022 showed that the oral switch strategy was statistically superior to continuing long-term IV therapy. So while the initial six-month study only looked to [00:01:00] prove that oral pills were just as good or non-inferior, the five-year data proved that patients who switched oral antibiotics actually fared significantly better over time

, And so with that, I'm delighted to be co-hosting today's episode with Josh Davis, fellow editor at CMI Communications, looking at oral, switch for endocarditis.

Josh: Hi, great to be back and, um, I'm really excited to be talking about the POET trial today, particularly given that the senior author of the trial, Henning Bundgaard, is here with us.

one reason I'm excited is I was reflecting on this and thinking it's one of the trials we talk about in my workplace all the time. we allude to the POET trial. What would they have done in the POET trial? Could we apply the POET trial to this patient, et cetera. So it's nice, to be able to sit down and talk through it.

So we're, excited to have two guests with us today. One I already mentioned, Professor Henning Bundgaard, um, who's the senior author of the POET trial and a clinical professor in the Department of Cardiology at the Heart Center at [00:02:00] Copenhagen University Hospital in Denmark. and our other guest is Sami El-Delati, who Emily will introduce in a moment.

and Sami has published studies looking at the uptake of oral antibiotics for endocarditis after the publication of the POET trial.

Emily: Yes. thanks Josh. Sammy is clinical associate professor of infectious diseases and director of the endocarditis program at the University of Kentucky. Sammy and I have worked together online, on, endocarditis publication, specifically a guideline for endocarditis, and we've also corresponded over the years on different strategies to treat endocarditis.

So very happy to have you here today, to speak about oral switch for endocarditis.

As our regular listeners know, and our new listeners are about to find out, we always start the podcast with an icebreaker.

So today's icebreaker has to do with poetry for the poet trial. When we were younger, many of us had to learn poems in school, so I'm wondering, if my co-host and guests, if you can recall a [00:03:00] poem that you had to memorize when you were younger and that to this day you still recall some lines of. Bonus if you can share some lines.

okay, because it's a tough question, I'll go first. So for me, the poem that immediately came to mind when I was thinking about this question was called "Lizzie's Lion" by Dennis Lee. and I remember my dad said he would give me $5 if I memorized it, which in the early '90s was basically like a million dollars, and I will tell you some lines.

Emily: So it's about a girl, Lizzie, who had a lion. So Lizzie had a lion with a big, bad roar, and she kept him in her bedroom by her closet cupboard door. And Lizzie's lion wasn't friendly, Lizzie's lion wasn't tame, not unless you learned to call him by his secret lion's name. Then one night, a rotten robber with a rotten robber mask snuck into her bedroom, and he didn't even ask.

And Lizzie's lion ends up giving the robber, an experimental chew, which I always thought was a funny line, and the robber, is not able to guess the lion's name, which as it turns out is [00:04:00] Lion. Josh, you're up next.

Yeah, I love this question because, I don't remember being forced to memorize poems at school, but I actually, memorized poems anyway 'cause I love doing it. And, I could, torture you with like the whole "Rime of the Ancient Mariner", but that would take up the whole, podcast.

Josh: But I was trying to think of a short one I know. The short one is, The Eagle" by Alfred Lord Tennyson. It's just a few lines. He clasps the crag with crooked hands, Close to the sun in lonely lands, ringed by the azure world, he stands. The wrinkled sea beneath him crawls; he watches from his mountain halls, and like a thunderbolt he falls."

Emily: I like it. Very powerful.

Josh: It's supposed to be funny, but as in that wasn't funny, but I like it. Henning, have you got a poem you can tell us about?

Henning: Yeah, I've been thinking about this, but, you know, that would be in Danish, and that would probably not be suitable for the audience. So I think that here my [00:05:00] contribution is gonna be a poet trial.

Josh: Oh, nice. Nice segue. And I, didn't even think about that. How rude of us to ask you to a poem in English. I would have loved to hear one in Danish, actually.

Emily: Yeah.

We would, we would definitely accept a poem in Danish.

Henning: Okay. you can have one in Danish.

Emily: Okay.

It's great how even in another language you can hear the kind of lyricism of the words in a poem. Can you tell us what's the subject of it?

Henning: It is basically that when you are young, trees are trees, [00:06:00] mountain mountains, and, valleys are valleys. When you have studied and become smart, these are not the way anymore.

But when you have turned wise Again, trees are trees, rivers are rivers, forests are forests

Josh: Wow, that's deep

Emily: Thank you

Josh: And Sammy, have you got a poem to share?

Yes. It's a tough act to follow, but, the one that came to mind, getting this question is, The Road Not Taken" by Robert Frost.

I don't have it memorized. the last couple lines are, two roads diverged in a wood, and I, I took the one less traveled by, and that has made all the difference." That's always been one that resonated with me.

Emily: I think it's a perfect introduction to try and convince people to use oral switch, in fact.

Sami: I thought,

Emily: I thought that

Sami: as well. So thank you for that.

Emily: Okay, we can, get into the meat of the podcast then.

Josh: let's start with the history of the POET trial. So Henning, can you tell us a little bit about, why you [00:07:00] ran and designed this trial in the first place, and what were some of the challenges you faced in getting this trial up and running?

Henning: That is a very good question because it illustrates how clinical research is actually developed. I have been in charge for handling patients with endocarditis for, several years in our hospital. And, before the POET Trial, we sometimes experienced young people coming in with endocarditis and when told that they had to stay in hospital for up to six weeks, they considered it like getting a prison sentence.

They couldn't stand staying in hospital for that period of time. You know, often young people with small kids at home, or a lot of other things to take care of. And we had, some who said, " We don't care. We are going to leave. I won't accept, to stay in hospital." And then we discussed with the clinical microbiologist saying at least we could give them, tablets.

And we didn't like it, but we did. And [00:08:00] to, cover, in case of fast metabolizers, we always, in these still few cases, offer them two different types of antibiotics for tablets to go home with. And as it turned out, it worked. these cases were in stable conditions, or they would not have, been in the position to ask to go home.

but it worked. And we published it with a small, case series of, 12 cases. And that was basically the idea saying, "Hang on. If this works in these cases, then we could expand this idea, and then, do a randomized trial to show, that it works." We got a lot of pushback, not least because we consider, endocarditis to be a disease with a very high mortality and no room for major mistakes and especially not, mistakes regarding antibiotic treatments.

and to get around this, we, did several things. First of all, we tried to use the ideas [00:09:00] of precision medicine, just saying we are not blunt, just doing it in all cases. But we were looking for, patients who were stable, and we defined what we mean by stable. Basically, it's a matter of responding to treatment, getting afebrile, the infectious parameters to be, normalized or close to be normalized, and then echocardiography to show that, it seems stable, that you are not in need of, surgery anytime soon.

Uh, that was one thing. Then also we did, measurements of, antibiotics in the blood, pharmacokinetics. that was a bit tricky. That was difficult. you can wonder why this is not, commonly used in, treatment of, infections. It's key that you have the right, levels of antibiotics. but we had to do so to make sure that if there was fast metabolizers or people who are not absorbing, the antibiotics, then we could put them back on, IV treatment.

Still, I remember that I [00:10:00] was sitting at a dinner, soon after we started the trial, sitting with a, major, person from the United States, in endocarditis and told him about the trial, and he said this was a stupid trial. This was unresponsible. We would kill people. He felt uncomfortable

Henning: later on, actually last year, at a major conference, he came back to us saying he really, recognized what we did, and he also recalled what he said before, and he said we did it the way we should, and also taking the precautions, and it was certainly the way to move research ahead.

But he was not the only one. Others, considered it the same way, and I think that, you know, when we have been stuck with concepts for, like, since the '50s, it is hard when anyone challenges, this. and basically we have been joking saying, " Yes, but

this just a matter of, are bacteria dying [00:11:00] more if they meet antibiotics coming in through the, intravenous route as compared to the oral route?"

it's of course a matter of, antibiotic levels, but that was ensured, and we could do that.

Josh: people turn that phrase around by the bacteria don't care how, the antibiotics got into the person's body.

Henning: Yeah. Yeah.

Josh: I love that little anecdote about the opinion leader in the United States, you know, eating his hat or- Yeah.

Mm-hmm ... changing his view, because it's, it's just a really good example of why randomized trials are so important. Like, we often find something that we didn't expect to find or that challenges dogma and changes practice, and, oh, it's such a good example of that. you've given us the background.

Can you give us just a brief summary of what the actual results of the trial were?

Henning: Yeah. You know, we, were screening a total of 2,000 participants and included 400, and they were randomized one to one. they were randomized after an average of 17 [00:12:00] days on IV antibiotics, and then the remaining part, that was, roughly 16 days, was then on, either continued or, conventional IV antibiotics or on oral.

And if on oral, the participants were allowed to leave the hospital and , treated as outpatient, and that was used in 80% of the cases. and we think that this may be The main driver of the difference, not least long-term, to get people out of hospital. When we have elderly people in hospital, not least, elderly comorbid, patients in hospitals, the decline in mental and physical capacity, is certainly, being reduced, and I think that means a lot, long term.

Henning: so just getting back to your, own pot plants, your own food, your own bed, your own habits, and the family means more than we [00:13:00] can imagine, I guess.

Josh: based on your primary outcome, the oral switch was not inferior, correct, to continued IV?

Henning: Yeah, of course. that was the key point that there was no difference, after six months.

it was a non-inferiority trial. the difference was three point four percent. That was in favor of, the, oral switch. so it was as good as. And then as you, alluded to, Emily, in the beginning, after five years, it was actually better

Emily: Yeah, I'm wondering if we can talk a little bit more about the five-year results and whether, you're surprised or, we're surprised that it ended up looking better for these patients.

Henning: Yeah, we were indeed surprised. and it was even a difference in mortality we saw. And the only way we can explain it, we cannot prove it, but try to explain it, and that is that if you have these comorbid or elderly people, in hospital, then if they have a further reduction by staying in [00:14:00] hospital, then it may be a matter of getting out of hospital in the IV group with a walker as compared with the oral group getting out before, maybe just with a walking stick.

And most of us know that if old, fragile people are getting home with a walker, they are bound to the living room. They cannot get out exercising. They cannot get out, being as social as before, meaning that they are probably getting even more fragile, meaning that when they are hit by the next pneumonia or the next cancer They haven't got the same capacity, as compared to others, and they die from it.

So when we are comparing the causes of death between those in the oral and those in the IV group, the causes of death were the same, but the numbers were just higher in those who stayed in the hospital for, 16 more days.

Emily: Yeah. It certainly makes me think about, you know, for example, [00:15:00] the hip fracture literature, where, when an older person breaks their hip, if you look at their one-year mortality, it can be extremely high, even up to 50% in some circumstances.

That's not necessarily the immediate mortality in the hospital. That's when you look over a year because it can be so, deadly to lose your autonomy and lose your mobility. even if it's something that we can fix in the first, you know, three or four weeks after it happening, that, event persists.

Henning: Totally agree, and I think we have a number of, uh, similar cases in other areas of, medicine. And I think that modern hospital, management of patients are looking more and more and be- getting more and more aware of this, and not least, as you say, Emily, the autonomy of the patients means so much.

Emily: Absolutely. let's talk a little bit about, maybe some of the limitations of the trial. Many people who've read the trial have a tendency, for example, to stick to the [00:16:00] exact specifications of the trial. Now, I, think it really helps to hear the backstory of, your designing the study, which was that you had, the potential for people to critique, trying to switch people to oral antibiotics.

And so it had to be extremely rigorously conducted in so much as you really had to define who would be eligible, what it meant for them to be stable. You had to have very, you know, specific recipes for antibiotics, including two antibiotics to be sure that, the person was well treated if they were switched over to oral antibiotics.

so people have a tendency to, look at those criteria for the trial, and some people hesitate to extend the results or maybe to drop some of the parameters of the trial when it comes to, quote-unquote, real life. so, as an example from another trial, we had a trial in infectious diseases that found that, pip-tazo was not non-inferior for [00:17:00] meropenem for, bloodstream infections with extended-spectrum beta-lactamases.

Emily: And since that trial, we were comfortable in some cases taking those results and applying them to less serious infections. So for example, applying them to urine infections. so in some sense, clinicians, and guideline makers are comfortable taking a trial and extending it to a different population.

Whereas for POET, it seems, people wanna stick to the exact recipes. They're nervous about applying, uh, the concept to bacteria maybe that were underrepresented in the study. And I'm wondering just as a group if we can discuss this.

This is a very interesting and key point when going from randomized studies to clinical practice.

Henning: Because in randomized studies, not least when you're doing something that is really different from what we're used to like we did, then we are putting a lot of, safety nets around the trial. And all [00:18:00] these safety nets, if they are taken into clinical use, then we have a challenge. When I was on the stage and, going to present, uh, the POET trial at the ESC conference, then the discussant, a guy from England, said, "It's a fantastic study.

I'm really looking forward to hear about it, but we'll never use it in the UK." I said, "Why not?" " Oh," he said, " obviously, because you say that a stabilization criteria is that the, patient has got a transesophageal echocardiography, and our scarcity to that, examination tool is terrible, so we'll never get it.

We can never make the cardiologist do it, so we can't include the patients." and that is in the guidelines as well, and we have discussed many, many times. Wasn't that just a matter of our safety concerns that we would pick up any minor things that could be harmful, but we could as well have used transthoracic, echocardiography, which would not be a problem at all.

in [00:19:00] the New England Journal of Medicine paper, we were very clear that we did not consider that the future should be with pharmacokinetics, because that would have been the death of POET, criteria or of, handling these patients.

So going from trials with safety concerns to real life, I think it's, quite often the same in the pharma industry, where they have set up a number of, safety, measurements. now in cardiology, we have some, new drugs, uh, that may reduce, the pump function of the heart, and we started having, echocardiography every three months in all patients.

Now data is coming saying that is not necessary. so how are we going to change that in endocarditis? And it's interesting because we came from no evidence but just history and observational studies, and then getting into something that is a lot more, evidence-based, and then we take it in a very, very [00:20:00] exact way rather than trying to say, "Yeah, hang on.

Henning: if it works in left-sided, then probably also works in, right-sided. If it works in these bacteria, then this probably also works in these other bacteria."

Emily: when we stick to those exact parameters of the trial, I think we understand why things were set up a certain way for safety in order to pioneer something new.

but at some point it almost seems like it's getting to a point where when your sports team is winning and, like, the person isn't changing their socks anymore because, you know, like they were wearing those socks and that's the way the team won, and so now we always have to do that. Exactly. Yeah. Yeah.

Um, so yeah, we have to use a little bit of logic too.

Henning: Yeah.

Emily: It's possible that you don't need a transesophageal echo for every case in order to include that the patient has clinical stability. Sammy, what do you think?

Sami: Yes, I completely agree. I think, as you've alluded to, a number of the parameters were done for safety concerns as you're doing, performing a randomized control trial.

and so I, you know, personally have seen, kind of the two groups that might [00:21:00] benefit, the most from being switched to oral antibiotics, patients, who inject drugs, which was a very small component of the original study. I hear people say all the time, "Well, those patients really weren't in the study.

How can we apply this data to them?" Well, I mean, they take oral antibiotics just like anybody else does. There's no reason to think, you know, that, the medication wouldn't work in them. it's been very interesting to see, as I've submitted my own work around this, there's, a lot of the reviewer comments really focus on how did you ensure that the patients were actually taking the medication?

which is very interesting because almost any trial that involves a patient taking an oral medication, you could make the same claim. And I, you know, whether it's a, a study looking at, you know, taking a beta blocker after an MI or something like that. And I don't think those studies get held to the same rigor standards of is the patient actually taking the medication.

And so it's just interesting. in that population, I think there's some existing stigma that comes into play and, that contributes to people, maybe not being as willing [00:22:00] to extrapolate the data to them. and then the right-sided endocarditis, as, Henning alluded to, I mean, if that's a disease that has a much lower mortality than left-sided endocarditis.

So if you're ever gonna feel comfortable extrapolating the results, from POET, that would be a population I would probably feel most comfortable with. But at the same time, I see a lot of, peoples, reluctant to make that change. and I think it, ties back into what we've discussed is that it's a big paradigm shift.

People have been practicing a certain way really ever since antibiotics were introduced. And so, even though they're, I think it's important to highlight that, you know, the six weeks of IV antibiotics for endocarditis, that's not really based on any concrete studies that show that that's the best way to treat this disease.

so even though it's mostly anecdote and just, practice that was developed in the absence of data, people have been reluctant to apply this new information that we have. So that, that's been a struggle, for me as well as I've, tried to get, this practice more widely accepted in my institution and, in the United States in [00:23:00] general.

Yeah, that's really interesting, Samin. And Henning, to reflect on what the state of knowledge and opinion was when you started the POET trial, it's quite different today, right? So if you were designing the POET trial today, you know, POET 4, I know there is already a POET 3 or, or two or something.

Josh: But like doing the POET again with what people know now, do you think the safety guardrails could be a bit more relaxed?

most certainly. the most tricky thing was the pharmacokinetics, and I think I'm not aware of a lot of literature, referring to our findings here, but I think that was a real study thing to do. also, you know, if we had failed, then we could say, " Was that due to, too low doses or was it due to, reduced uptake?"

Henning: You know, we did pharmacokinetics after day one and day five. So we could have, identified that. but with the echocardiography is one thing. Another thing that is quite important is that we were seeing patients in the outpatient [00:24:00] clinic two to three times a week That's far too often.

You know, we ask them to, measure the temperature at home, every morning and contact us if the temperature is above uh, 37. Now we are in Celsius. Or if they feel uncomfortable in any way. So if we see them just once a week, that would be fine.

then maybe a phone call, we, quite often use that, rather than coming to hospital. but that has also been taken to the, guidelines How often you, are going to see them. and that is actually also a bit of the discussion with the OPAT regimens. so what is the most tricky thing is that to have outpatient visits twice a week, three times a week maybe, or home visits, on a daily basis or maybe, several times a day.

I think that it would have been possible also to, reduce the number of outpatient clinics, visits.

Josh: Can I just jump on a s-small tangent there? I hadn't quite realized it before I heard you talking about this, Henning, that it sounds [00:25:00] like, hospital in the home or OPAT for intravenous antibiotic therapy maybe wasn't a commonly practiced thing in your setting at the time of the POET trial because you said that intravenous committed someone to being in hospital for four or six weeks.

Is that true?

Henning: Yeah. Yeah. has not really been used in Denmark for treatment of endocarditis.

Josh: Right.

Henning: So that was not an opportunity, to use, in our setting.

Josh: So I wonder if, th-those five-year results where there was a mortality benefit we talked about that might be about earlier discharge, I wonder if that difference would not be seen if it was early discharge to hospital in the home versus discharge to oral antibiotics.

Henning: Yeah. that is a key thing because what you're alluding to here, is this a matter of autonomy and, the reduction in mental and physical capacity by being in hospital, or is this related to antibiotics? It could also be related to the amount of antibiotics. And maybe, uh, [00:26:00] that's a question for you, Sami.

Do we have any knowledge about, the level of dosages, and long-term effects? Or is it unlikely that these findings in POET may be related somehow to the, antibiotic treatment differences?

Yeah, it's a good question, and I was, wondering that as well, Josh, as you were mentioning about, is there a role for, you know, for OPAT and, and doing IV antibiotics at home? you know, would we still see the same differences? I think what I found, I should provide some context.

Sami: So Kentucky has been, a state that's been particularly hard hit by the effects of the opioid epidemic in the United States. so we saw a massive increase in, drug use-related endocarditis between, 2010 and 2018, almost an elevenfold increase in the amount of drug use-related endocarditis. So we went from seeing about, maybe thirty cases, a year to, approximately two hundred and fifty cases of endocarditis a year at our institution just over that kinda eight-year time period.

And [00:27:00] the challenge with that population has been, that even if the institution does offer OPAT, it's often not offered to those patients because of concerns that, they may, tamper with their PICC line or inject substances through it, even though, there's not clear evidence to suggest that that, that will happen.

So, so similar to what Henning was describing, many of those patients are in the same situation. They have to stay in the hospital for four to six weeks, which is just not feasible. So that, that was a, kind of the big opportunity for us, to try to make an impact in that population. with respect to the dosing of the antibiotics, it's a good question.

I think the regimens that we've applied have been very similar to what was done in POET. I think we tried to, use the evidence that existed. we've extrapolated slightly. what we found was, you know, a number of the regimens used, for example, d-dicloxacillin was used at, at high doses, and I found when, when trying to do that, that patients had a really hard time tolerating it.

So we substituted [00:28:00] for our MSSA cases, cefidroxol for dicloxacillin, and we used that with linezolid. and our results have been very encouraging with that. In that regimen, we use a gram twice a day of cefidroxol. People seem to be able to tolerate that relatively well. The dosing is easier and then we've used a lot of levofloxacin as a substitute for moxifloxacin for cost reasons.

insurance in the United States often would not cover moxifloxacin. some pharmacies didn't stock it. Levofloxacin was much more readily available. so we know we made some kind of slight tweaks and we haven't really seen any significant downsides to doing that. we don't have the ability to do pharmacokinetics for a lot of these antibiotics at our institution.

So, we don't have the option to kind of see where the drug level's at, which is unfortunate. I think that's maybe coming in the next five to 10 years, but, but it's just not an option right now. So we follow the patients with some regularity, but again, as Henning alluded to, seeing [00:29:00] patients two to three times a week is, is really hard to do practically.

So we make a point of trying to see everybody within two weeks of discharge, at least for one visit. we might have them do lab work locally because our patients come from three to four hours away from us potentially. So we'll have them go get labs at their local lab or hospital and fax the results to us.

So that's kind of how we've worked around some of these concerns about dosing and super therapeutic levels is we just monitor the lab work and we try to stay in touch with the patients as best we can.

Henning: I think that makes a lot of sense what you're saying. Ha-have you in, in any systematic way been assessing the outcomes in, those, switched to oral?

Sami: Yes. Yes. so we, just published actually last, fall, our results with ninety-three patients that we had switched to oral antibiotics. we had a, a control group of IV patients that were one hundred and thirty-six. we looked at ninety-day, mortality, relapsed [00:30:00] infection, and a composite of both and found, no difference between IV versus, uh, PO, in terms of the composite outcome, mortality, relapse infection.

So, the results were very encouraging, and over fifty percent of the patients had a history of substance use. almost fifty percent had right-sided endocarditis. So, those findings were particularly, I thought, notable from our group. And we're still continuing to track, so we're probably over, a hundred and twenty, over a hundred and thirty patients now that we've, switched to PO and, it continues to go, fairly well in, , in our experience.

Henning: Yeah. And it's striking, how happy the patients are to be switched. it is like getting released, getting out of the change, in our hospitals.

Sami: it's really a great point. I think it really helps build a therapeutic relationship with the patient because you're kinda working with them to, craft a solution.

Whereas I think sometimes it feels like when you're recommending these six weeks of antibiotics and they stay in hospital, that you're kinda dictating to them [00:31:00] what they can and can't do, and that, I think can sometimes fracture the relationship a little bit. so I think talking with the patient, we try to explore all the options with them.

You know, we can do OPAT at home. We can do oral antibiotics. You can stay. some of our patients, , they need to go to either physical rehabilitation or substance use treatment, so we talk about those options. So we try to make it as patient-centered as possible. I think that's been lacking from, a lot of the discussions, at least in the United States, about, how to best treat endocarditis.

putting on my Martha Stewart hat, can we get into the recipes? a lot of, course regimens that are published use two antibiotics, and I'm wondering whether we can talk a little bit about are there cases where we can use one antibiotic? , We use one antibiotic for osteomyelitis, which is also arguably, , a deep-seated infection maybe with not a lot of blood flow.

Emily: It could be hard for the antibiotic [00:32:00] to be delivered to the site. But the, OVIVA trial, for example, used one antibiotic. POET trial used two. Are we comfortable, starting to use one antibiotic? And maybe another concept to pair with this is a lot of the observational data shows that the switch happens quite late in the regimen in the real world, so maybe not around day 10 to 14, but sometimes around day 25 or day 30.

maybe that should also be factored in if we are switching later. are two antibiotics necessary at that point? Are they necessary for the whole regimen? So yeah, op- open question to whoever wants to comment.

Yeah, maybe I may start. Our pharmacokinetic, study, in the POET showed that we had seven cases where one of the drugs was at a s-suboptimal level.

Henning: But in all cases, the other drug was at a sufficient level. So if we use these [00:33:00] datas, seven out of 200 cases had a, it was not a, a zero level, but it was, suboptimal. that may give the indication maybe of the size of the problem going to one drug only. I think that can be used as a starting point maybe.

I'm sure, Sammy has a lot more insight compared to me as a cardiologist here.

Emily: That is helpful though, 'cause that does give us a sense of how many people are we treating with two to prevent, very few cases of a suboptimal dosing of one of the two antibiotics. So as you said, seven out of 200.

It's fairly small, and I think even more important to consider is whether that suboptimal dosing of that drug we will never know, but would that have led to an actual clinical failure? That's, laboratory data too.

Josh: Yeah. Yeah. That, that's my main thought about that, is that so much, not just what we're talking about today, but so much antibiotic research is driven by pharmacokinetic [00:34:00] considerations, theoretical considerations and what levels you're achieving, and not by actual observed clinical outcomes.

and when we really try and look for, a difference in clinical outcomes based on drug levels, we usually don't find it. and I think one of the reasons we don't find it is because once you're at week three or four of treatment, it doesn't really matter that much what antibiotic you're using and what level, as in it's a lot more forgiving.

You know, in the first week or two, the patient's bacteremic, you definitely need high blood levels. But to week three or four, you're just really mopping up. and f- that's the reason why, in the SNAP trial, which is a staph aureus bacteremia trial, that does include patients with endocarditis, although it's probably only about 10% of people.

we're doing an, oral switch part of that. and when people with staph aureus bacteremia switch to an oral antibiotic in that trial, we're just using a single antibiotic at, re-relatively high dose and an antibiotic with [00:35:00] high oral bioavailability, but just a single antibiotic. but ask me in a couple of years if that worked or not.

Sami: I guess too, one question I have for the group is, do you feel like the adoption of POET would be more widespread if the recommendation was to only use a single agent compared to two? Do you think that is sort of a hang-up for people, is using that second agent?

Emily: it might be a mental hang-up. Right. I don't know that it's necessarily-- There is a little bit of, "Oh, what's the, you know, maybe I have to use linezolid or rifampin, and maybe I'm not so familiar with those antibiotics."

And so that's like a little bit of a hurdle. But then it's also, it's almost labeled it with this concept that there is a higher risk of failure because you need to use twice as much, and so maybe that makes you a little bit more nervous. So I, think it's twofold.

Josh: I also think it's the regimens seem weird to us because they're not combinations we'd normally use in other contexts.

So for example, if the regimen was rifampicin plus ciprofloxacin, [00:36:00] that's a fairly commonly used thing in, bone and joint infection. But the regimens dicloxacillin plus rifampicin, I don't think I've ever used that combination. Um, moxi plus moxi, rifampicin plus linezolid. So they're uncommon combos, so therefore they seem foreign and strange, and I think that makes people uncomfortable with them.

Sami: I could certainly, see that. And I think going back to the original point of, extrapolating a little bit, can be helpful. And I think one of the nice things about the POET trial is that there were a number of different regimens used. So, you know, not every regimen requires rifampin, and so we've, generally tried to stay away from the use of rifampin.

Just we, we run into a lot of drug-drug interactions, which I'm sure that comes up for other people when trying to consider the use, and especially again, the substance use population. Many of them are on methadone, and that, can be a big interaction, methadone and rifampin. So you have to get a little bit creative, but it, it really helps to have that evidence to fall back on from the [00:37:00] study.

and with respect to the earlier com-comment about kind of single agents, I agree. There's, is a, time and a place. So in our study, we did include patients with, methicillin-resistant Staph aureus, which I know is not a group included in POET. you know, a lot of times it was a practical thing as, the patients with substance use.

and so our median switch, in, terms of IV lead-in time was twenty-four days in those patients compared to eighteen in other, non-MRSA patients. And again, we found no difference between PO and IV even using linezolid monotherapy in those MRSA cases. So I think as you were saying, as you get closer to that three to four-week mark, you know, that's when I start to feel comfortable, okay, maybe we can just use one agent.

so we, we often call it our like four plus two regimen where we'll do maybe four weeks IV for MRSA and then switch to PO for the last two. But, honestly we could probably be looking at making those switches sooner. but similar to what Henning has described, you know, you have to kind of start [00:38:00] somewhere.

and so we try to be a little on the more conservative side as, we're figuring out what the right time to switch is

I've got quite a few comments from other sides, not least, Southern Europe, where, you know, in Scandinavia, we have a quite tough, antibiotic stewardship.

Henning: in Southern Europe, they are more liberal. and I have had the comments saying that, yes, but finding two old drugs that you, have a resistant pattern for that is suitable is an issue. And that would then be an issue to make the shift or the switch, if you can't find two. But do you see it quite often? I guess you are also fairly liberal in the United States.

Yeah, I would say it's rare that we can't find, two agents. we do see some with our strep species. We do see some penicillin, intermediate strains or resistant strains.

Sami: But most of the time, if we wanna use a fluoroquinolone, they will be susceptible, so we [00:39:00] could still use kind of linezolid and a fluoroquinolone. and then if it's methicillin su-susceptible, they're generally all susceptible to linezolid, and then we can use cefidroxil with that. I would say the organism where it can be hard to find a second agent is sometimes MRSA.

But again, many times when we're switching those patients, it's late in the course, so we don't feel quite as strongly about using a second one. I haven't really run into too many instances where we can't find a second option

Yeah, sometimes I do find myself convincing people that, you know, if you're switching over week two or three and linezolid is your second agent, it's okay if maybe they stop tolerating it at week four and you finish up with one agent for the last two weeks. 'Cause I see that sometimes as a barrier that people hesitate to switch someone over to linezolid.

Emily: although in practice it is actually fairly well tolerated. so you could switch at week two, include one of those, trickier antibiotics, so to speak, around then and if you end up finishing with one antibiotic for [00:40:00] the last two weeks, like that's probably okay. I don't think you're gonna be stuck bringing the person back into the hospital to put them back on IV.

In most cases, you're gonna be able to find a regimen to finish the six weeks with.

what's uptake like in Australia, Josh, for oral switch?

Yeah, it's-- I mean, this is anecdotal. I'm not aware of systematic data, but it's pretty slow, for endocarditis. I know that some people, some centers are doing it, but no centers are really doing it in a large proportion of patients.

Josh: I think it's been helped by there's been a large swing towards shorter IV and early oral switch in general with severe infections over the last few years because of the bone and joint infection data, the OVIVA trial you mentioned, Emily. and in my particular, hospital, because we're now much more comfortable doing that for bone and joint infections, and we, we've actually set up a program on our hospital in the home where we have supervised oral [00:41:00] antibiotics for early switch.

We're now leveraging that to start to do it for endocarditis as well. but it's still really the minority of endocarditis patients who, who get this switch because, not everyone's comfortable with it. But yeah, look, it's evolving. I think the uptake is much smaller than it should be at this stage.

Yeah, I think having a program in place can really help, just so that it's protocolized and that can help make things, more accepted locally. That's sort of what you've done, Sammy, is it not?

Sami: It is, yeah. So one of the, kind of the unique things we did is we, created a cardiovascular infections consult service or team.

so just because of the, volume of consults we have at our institution, we have five, infectious disease consults teams. So usually it's, one physician on each team. and we have a, transplant infectious disease team, which I think that as a subspecialty within infectious disease has been broadly accepted for many years.

but for whatever reason, I think there's been this feeling [00:42:00] that cardiovascular infections, any ID physician should be able to manage, which, I think in an ideal world that, that would be great. But as, as we know, medicine is becoming more and more complex. There's more, data out there every single day.

So it's just a lot for any one person to try to master. So, I think the sub-specialization for these cardiac infections, they're diseases that have, very high mortality. And then additionally, there's a lot of non-compliance with guideline recommendations, at least in the United States, particularly around, cardiac implantable electronic device infection.

so we really push to have that dedicated team. I think the other advantage of that is rather than, you know, maybe a large university might have twenty to thirty infectious disease faculty that could be seeing all the endocarditis patients by having one team, it's really just three or four of us that would, rotate through that service.

So now you're standardizing practice amongst three or four people instead of twenty or thirty people, which becomes much easier to do. then it's also you can kind of have a consistent message [00:43:00] to the primary teams in the hospital that are taking care of the patient as you're communicating the recommendations.

So, I think the ability to have that dedicated, consult service really has helped tremendously with the uptake and tracking the outcomes. And then we did some other strategic things to try to, improve the implementation. we did some grand rounds talks, where we presented the data from, POET.

and then we presented along the way as we were building our own cohort of patients, we presented the outcomes from those patients. So we published a smaller series of thirty-two patients. We presented that as a grand rounds. and then we presented the ninety-three patients that we published on more, more recently.

So it was sort of a, graded approach and you had to, have a little bit of propaganda, for your, for yourselves as you were doing it. but I think that was, really the key, was having the ability to, have a separate service, a small group of physicians, much easier to standardize practice, in that way than throughout an entire department.

I think that is, a [00:44:00] great job you're doing there, and I think we should all, not only in endocarditis but also in ma-many other, aspects of medicine, really, really be aware of the implementation gap, of new knowledge. It took us seven years to, uh, run the POET trial, six or seven years.

Henning: and then now it's seven or eight years since we published, so it's 15 years s-since we started. and still some of our colleagues are hesitant to use it, even though now you have some, evidence, not least our five-year, outcome data. And I think it is a matter of being very specific when we are making our, guidelines, being even more handheld, being very, very precise.

Sometimes even in our hospital, some of my colleagues say, "Yes, but for safety, for safety reasons, maybe we should stay on IV." Then I say, "We have actually shown that that is dangerous practice. [00:45:00] You reduce your patient's survival by this." "Oh, yeah. Ooh." Yeah. So, so you know, how, are we getting the dogmas we are sitting with in our bones as physicians out of the bones?

Henning: And we have it, all of us, all of us, of course. But how do we drag that idea of dogmas, what I learned in med school is still the right thing, that feeling, that sense, and say, "Okay, I will be, following, guidelines, the most recent evidence"?

Yeah. Well, we have four countries represented on the podcast today.

Emily: We heard about taking the road less traveled, so join us. it sounds like, you know, there are a lot of different options for timing of switch and different regimens. I'll put a call out for our journal, CMI Communications. If you do have some successful recipes for your early oral switch for endocarditis, we'd be interested in taking a look at those and publishing them.

I think it [00:46:00] does help to show, as you did, Sammy, that we used, cefadroxil as an oral switch, in these, cases and that these were the outcomes. So it really does help to start to publish some of the literature on alternate regimens and timing so people can see others' experience with that and we can become more comfortable.

Before we end, any other thoughts on, things we need to improve in terms of uptake? where do we go from here?

I think, there's oft-quoted implementation science research that suggests that on average it takes about seven years for a change in practice to happen after evidence is published. And it's interesting, Henning, that you said we're now at that roughly seven-year mark since POET was published, so maybe this is the time, right?

Josh: This is the time where we really need to push the uptake and because people are ready for it. and I think the other thing that's helping change attitudes is that, I mentioned the SNAP trial, but there's also other trials that looking at, oral [00:47:00] switch of antibiotics for bacteremia, both gram-positive and gram-negative.

And so we're all getting more and more comfortable with this, and there's more and more evidence emerging.

Yeah, I think a couple of points too around uptake in, the United States at least. I think, one thing is that, the guidelines, in North America have really not been updated since twenty fifteen. And that's obviously predates the POET trial. So the American Heart Association, Infectious Disease Society of America kind of joint guideline is, is eleven years now, out of date.

Sami: I hear that a lot with, physicians, and especially if you're in a maybe a non-academic or non-research setting, you know, you're gonna rely on those guidelines as you're trying to make decisions. And, I know the European guidelines were updated to include oral antibiotics, but, you know, the United States people aren't necessarily going to be looking to that.

So I, I think that is something that would really help tremendously is if we could get an updated guideline that included, the recommendation for oral antibiotics. I think that would [00:48:00] go a very long way here, with adoption. I think it's great too that you guys are calling for these papers, to highlight people's experience because, you know, one thing that was very interesting was we had a, lot of difficulty getting our work published.

it's sort of an interesting dichotomy because-- I had to write rebuttal letters, to a couple of journals to even get them to review the paper. and their perspective was, well, the data already exists. and so what, what are you adding to the literature by doing this? And so I, found that very interesting when there's this-- as we talked about this sizable gap between what's happening in the literature and what's happening in practice.

So, so I think the more people publish, I think that will help too. and then the third point in the US, that you can kind of use to your advantage, there's this interesting dichotomy between maybe what the clinicians, are recommending and what the hospital might want. So, the hospital in many cases is very motivated, for these oral switches because it, it reduces length of stay and increases bed capacity.

we're very financially driven in some of our [00:49:00] healthcare decisions here, for good and bad, unfortunately. but it's an opportunity, I think sometimes to partner with the hospital, potentially get a little bit of funding to develop a program, as a way to implement this because there's benefits to the healthcare system by getting these patients home.

Obviously, the, primary benefit is to the patient, but you can sort of use that language to potentially partner with the hospital, get some support for the work you're doing, to get the patients out faster.

I'm also happy that Henning, you mentioned, that this is extremely patient-centered and that patients prefer this approach. so when it's safe to do so, I think if you choose to switch someone over to oral, you're also, picking an intervention that most patients will really appreciate if it's safe to do so.

Henning: Yes, and may- maybe I can expand a bit of what you're saying there. We are based on Danish, numbers and Danish, financial costs. we have looked into the potential savings, of using the POET, regimen [00:50:00] in the EU, and that is for beds, outpatients, and, drugs. It is half a billion, a half a billion euros per year just using this, and that is based on we, we did the same as you did, Sami, doing a phase four study of does POET work in Denmark.

And we showed what was the uptake, and it was 55% of all cases. if we use that in general in Europe, and that may, of course, there may be differences, but just to say this is not only for the patients, but that's also for the healthcare systems. There are other interests here, that we are also as physicians obliged to take into account, and that is resources.

Emily: So patients like it, it saves lives, and you have the nice side effect of it also saving money for the healthcare system.

Any final thoughts, Josh?

Josh: No, I don't think so. like I said, now is the time for this to really percolate out into clinical practice.

Emily: Thank you so much to our [00:51:00] guests, Henning and Sammy, and to my co-host, Josh, for this incredibly interesting discussion on POET uptake and how we can move this practice forward.

Before we hit that classic, it takes, seven to 10 years to go from a trial to incorporating evidence into practice. We've arrived at that timeline. So think about what you can do locally to help implement early oral switch in your hospital. Thanks for listening to Communicable, the CMI Comms podcast.

This episode was hosted by Josh Davis and me, Emily McDonald, editors at CMI Comms, ESCMID's open access journal. It was edited by Katie Hostettler. Theme music was composed and conducted by Joseph McDade. The executive producer of Communicable is Angela Huttner.

Any published literature we've discussed today can be found in the show notes, and you can subscribe to Communicable wherever you get your podcasts, or you can find it on ESCMID's website for the CMI Comms Journal. Thanks for listening and helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along.

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