145. POETry in Motion

The POET trial was the biggest endocarditis trial in some time, and since 2019 has changed how we manage these patients. But how to implement oral regimens for Endocarditis? 

Jame speaks to Nik Rae, Consultant Physician, on how they implemented the use of oral antibiotics for endocarditis patients in Ninewells Hospital, and how you can too! (in your own hospital, not Ninewells, the're already doing it). 

Transcript

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Jame 0:00

Hi everyone. Welcome to the Idiots Podcast. There's infectious disease insight of two specialists. I'm Jane, that's Nick, and we're going to tell you everything you need to know about infectious disease.

Speaker 2 0:08

Soon may the IT team come to discontinue the Tazo sun. One day when the CRP's done, we'll take our leave and go.

Jame 0:17

Nick, how you doing?

Nik 0:18

I'm good. Thanks. How are you?

Jame 0:19

There's normally a pun at the beginning of this episode. Do you have anything to hand?

Nik 0:23

No, but you might.

Jame 0:24

I dunno what you're talking about, but I'm sure this episode will go smoothly. You could almost say it'll be like poetry in motion. Which leads me to ask the question, Nick, what talk did you give at the BSAC OAT Conference last year?

Nik 0:38

I was sharing the experiences that we've had around use of oral antimicrobial therapy in infective endocarditis applying it to the real world setting in our teaching hospital up in Scotland.

Jame 0:49

And this is in Dundee, where you work as one of the infectious disease consultants. Is that right?

Nik 0:54

Yes. Yeah. I'm based in Namos Hospital in Dundee in the ID unit

Jame 0:57

Okay. Nine Wells, completely famous in Scotland. Probably a little less famous outside of the country. I suppose it's big claim to Famous that BSAC was founded there in Dundee.

Nik 1:07

That's true. Yes. We've got di and the origins of bsac and indeed some, strong oat credentials, stretch

Jame 1:15

But this is more CoPath than Notepad. So let's talk about what you've been doing with the endocarditis patients in Dundee.

Nik 1:24

Since 2022, we kinda moved towards using oral antibiotics in endocarditis in. Carefully selected patients given the weight of the evidence that was being produced on the subject. Historically we had used, a lot of OPAC treatment with ketra. So, And for strep and daptomycin or tyin on O Pac for a staphylococci. But the evidence was clearly shifting towards supporting use of oral antibiotics in endocarditis. And so we had started using that and all discussed to our endocarditis, MDT, which is run in conjunction really between. Cardiology, including our imaging cardiologists ID physicians, and we've got a cardiothoracic surgeon from our local cardiothoracic center in Edinburgh that dials in who also provides some advice regarding surgical cases. And we made this move really towards just treating all the organisms that the evidence was based on. And that is, streptococcus. So oral streptococcal in particular, staphylococci and Enterococci.

Jame 2:29

I'm going to ask you later on about has x, but no gram-negatives. For now, we're just talking about the gram-positives. Are you

Nik 2:35

No, generally,

Jame 2:36

Or both sided endocarditis.

Nik 2:37

both sides. Both sides. We would treat both sides. Clearly a lot of the big randomized controlled trial published in 2019 poet was mainly looking at left heart endocarditis. For us, we've used it in all patient groups and including patients with device infections.

Jame 2:51

And before you started on this project, you were using IVs entirely, but you were still using oat regimens

Nik 2:59

Yeah. AB absolutely. We use a lot of oats for endocarditis. And like I said, very much probably it similar to I think the most of the uk, the rest of the UK U Ceftriaxone daily for. Sensitive or streptococcal, endocarditis and daptomycin normally at very high doses, so eight to 10 milligrams per kilogram for mainly staph aureus. Although sometimes using Tyin as well.

Jame 3:21

Okay. And. You mentioned the preponderance of the evidence base, but you also say that you started this in 2022 before the ESC 2023 guidance came out. So apart from poets, are you thinking of any other studies or trials in particular?

Nik 3:36

Yeah there is quite, when you look back, the earliest evidence is actually in 1991. So it, it goes back for, quite some time and Okay. Some of the studies were quite small, but, there is. Evidence supporting oral use in endocarditis. In 1991 there was a study comparing, four weeks of ceftriaxone versus two weeks of ceftriaxone, followed by oral high-dose amoxicillin and sensitive streptococci. Uhf two weeks and two weeks respectively. Obviously in 1996 that mainly look at right heart endocarditis. There was a kind of. Helman study with Cipro and R compared with conventional anti staphylococcal treatment for right heart end, and people who inject drugs.

Jame 4:14

was all from the beginning.

Nik 4:16

That was no lead in whatsoever. Which I think is, it gives quite a lot of weight to, the, there's a lot of debate about lead in, and lead in times in what is required. 'cause clearly the big randomized controlled trial poets that we all know about, used a minimum of 10 days of treatment or seven days post surgical intervention before oral switch was considered. A lot of people get hung up on that. The specificities around this the lead in time. You've got studies like that where actually you can use oral treatment from the get go. And outcomes are equivalent. And obviously these are drugs that are highly bioavailable. That kind of lends itself to that, I think the only other study other than poet, is the French study comparing it's not a true randomized controlled trial, but as a before and after study, looking at standard anti staphylococcal therapy. Versus the combination of high dose of Cotrimoxazole and Clindamycin for a week and then phasing on to oral Cotrimoxazole thereafter.

Jame 5:14

That's interesting cause I don't really think of Cori as an end kind of drug.

Nik 5:18

No, it's, and it's interesting, there are a couple of studies looking at cotrimoxazole compared with comparators, upfront in serious staph aureus infections. I think it was a randomized controlled trial from Israel that really did show it performed poorly in comparison to Vancomycin particularly in those patients that were bacter remic. So although it's not a drug that we would necessarily use upfront, I think a step down treatment, it certainly is something that can be used. I think the other thing to note about that study is the dose they use was extremely high. And so it's basically works out. It's about three it's basically six double strength tablets a day, which is much. More than we would use in routine practice. And there was quite a high rate of intolerance in that study. So I think the Wiki guidelines on endocarditis do discuss some of the points around that and that some authors on that consensus guideline did suggest that using a slightly lower dose, for example, two double strength tablets twice daily, maybe a kind of compromise.

Jame 6:20

Yeah. Interesting. It almost sounds like they were trying to use PCP dosing. Or cd bacterial infection. And I'm not really convinced that massively overdosing somebody on quota ole is valid even for PCP actually. But anyway, to be continued listeners. Fine. So you had the evidence at your back. You didn't have an ESE update? At the time. So we were still going on the 2015 guidance or the BSAT 2012 guidance, and they all say just give. IVs, they don't really mention orals at all from memory. So how did you take that to the endocarditis team and persuade them that you weren't doing something horrifically dangerous?

Nik 6:59

I think we as a group, we get on very well between I, ID and cardiology. We have a very good working relationship with our cardiologists and they're very relaxed and pragmatic and are willing to let us make, and, a lot of the decisions around antimicrobial therapy. And especially when we discussed the evidence, I think you have to start relatively small, like when Aviva came along and we, went from prescribing protracted course of IV therapy, to then having the evidence that the bulk of bone and joint infection can be treated with oral agents. You have to probably make incremental, progression towards the end goal. You're not gonna all of a sudden go from treating somebody, with six weeks of IV therapy to then doing, 10 days and straight out the door. You might end up going for a kind of half and half or four weeks and two weeks kind of

Jame 7:49

is that how you did it? You walked them back from so like the last week was oral and then the last two and then et cetera, et cetera.

Nik 7:55

I think for some patients, that definitely helps. And I think even within the ID department, I think we all have had different levels of comfort with if you like, moving away from what has been a really established practice. Not based on good evidence, many of us we've trained will remember our mentors and bosses saying. IV therapy, for endocarditis, and that's drilled into you. So I think it, everyone is different in terms of their risk acceptance and some of us are more willing to dive in and do it.

Jame 8:26

Fine. So when you did start to use orals, you've talked about the bugs, talk to me about the drugs. What drugs did you start to use and what did you present at the OPAC conference?

Nik 8:37

a big chunk of our prescribing in endocarditis was linezolid. And I think that was what we initially got used to using. And it was actually linezolid monotherapy, which is at odds with the poet study,

Jame 8:51

And the ESC 2023, Guidance, if I remember rightly, but not Wiki guidelines, which we'll come onto in a minute. That's the second mention. Brad, I hope you're happy.

Nik 8:59

Yeah. So yeah, I think one of the things that we'd looked at was actually using, for example, SLI with rifampicin, given the drug interaction with rifampicin and sli, we've. I had thought, actually the zolin levels may be compromised by the rifampicin. And if you can give linin rifampicin together and it still works, why would Ezzo on its own not be just as good, if not maybe better. And again, avoiding the other drug interactions. And there is decent observational data from other kind of. Other non-randomized studies where monotherapy with N is frequently used. So that was probably the agent that we started using initially, particularly for staphylococcal infections and for Enterococci. And I said, and I think that we even then started to use it in some of the streptococci. Just because we had good experience with it. And because it's a very convenient dosing, twice a day. As time has progressed, we've expanded into using things like amoxicillin often with rifampicin streptococcal endocarditis, which is similar to poet, but it's amoxicillin dosed four times daily rather than three times daily. And

Jame 10:05

the maximum that you could give and still have them absorb it because of the absorption kinetics and stuff. So you're topping that out and then you're adding a second agent in.

Nik 10:15

Yeah.

Jame 10:16

Have you ever used a mono?

Nik 10:17

although yes, we have, and and again, the data for that goes back to that kinda early study that I was talking about in 1991, which did use amoxil monotherapy in very sensitive streptococci. So we would use that with native valves with patients who've got very sensitive streptococci with low MIC. So normally below 0.12 we have used monotherapy in a, in a few patients. It's, and it's gone. It's gone well. The other drugs that we have used a bit, just touching on what you were saying about Cori Ole previously we've used Cori Oxil a few times often when there's been issues with intolerance with zolin and staphylococcal endocarditis, but also in a couple of other patients. We have used it as a kind of oral switch. And Lynette, when EZ has not been straight prescribing has not been straightforward. And again, opting for that to double strength tablets twice daily,

Jame 11:06

So that would be 1,920 milligrams twice daily. So much double the dose that you would normally give for

Nik 11:13

yeah.

Jame 11:13

or

Nik 11:14

That's, yeah, that's the dose that we would normally use. And again, I think I would not. Use Cotrimoxazole in, upfront. But certainly when you look at that French study, the before and after study it seemed it performed well in, when it was used as a kind of monotherapy, a step down after the intensive kind of very high dose with clindamycin were given

Jame 11:38

what do you remember what dose of clinda they were giving with it?

Nik 11:40

It was a very high dose. I can't remember off the top of my head, but it was a very high dose in, in three. Three different

Jame 11:46

Gotcha. Because that's another drug that I wouldn't consider friend.

Nik 11:49

No, absolutely not. And I, and again, it's, it was a very, it's a very unusual study. 'cause it, the regimen on the face of it is not what you would choose. And I think it's interesting that it seemed to perform well in patients with neo staph aureus, endocarditis.

Jame 12:04

Okay, so those are the kind of agents that you've used, so mostly esli, and that's the data that you presented at the OPAC conference, but you've also done high dose Cori, and you've done a mos usually in combination with Rifampin. Any o, any other combinations? Any other potty combinations or anything that was in the ESC supplementary table?

Nik 12:24

So yeah. Certainly Quinolone and Rifampicin, you does have good evidence.

Jame 12:30

Just Annie Quinlan or specifically Moie.

Nik 12:33

Mo say and rif generally for strep and End and Enterococci and Levo and RIF for staff. And we don't, we use very little in the way of quinolone in our unit and always have done, we've steered away from using them. But we would use them if we had to. But those are certainly, those are agents that certainly have good evidence and,

Jame 12:53

fine.

Nik 12:54

Is highly bioavailable and and they're very attractive in many ways because they're once daily agents. So for, from a compliance perspective, they may be easiest to

Jame 13:02

Yeah. Okay, fine. So that's what you give. Let's talk about what you need to do before you can give it. And I will just jump straight to the to the question. Do you give a pre oral switch? Transesophageal echo to every single patient?

Nik 13:19

No abs. Absolutely not. And in fact, we, that was one of the things that we really found difficult to understand was from the ESC guidelines, was the suggestion that you need to perform a, repeat the transesophageal echo prior to. Oral switch?

Jame 13:34

You're not the only one.

Nik 13:35

know, No I think it has been inferred from essentially the poet trial protocol. For me it just seems to fly in the face of logic because we used to put people out on you. OAT Kft and daptomycin whatever for their endocarditis. And we never used to perform a T OE prior to putting them out onto oat. So why is this any

Jame 13:59

And, And these are drugs, which according to the poet, five year follow on. Observations are performing worse than their oral equivalents for, and all those patients in the post study, they did have a TOE, whether or not they were going to get switched, if I remember rightly.

Nik 14:15

So yeah, I think it's difficult to justify and from, for an argument, most of the time patients get a TOE probably in the region of five to seven days into their, hospital admission anyway. So it's not, the first few days. So it, that already does add an element of delay and it's just, it seems like it's not an adequate use of resources to be

Jame 14:35

Yeah. And so you decided not to implement, people can go to the ESC and they can look up that pre oral switch flowchart. There's a bit that says do TOE even if you've already done a TOE and you just don't do that bit.

Nik 14:49

We, I think viewed it as highly impractical in the real world. And it and if you were to follow that strictly, then I think that would be a major, that's a major barrier to implementation of

Jame 15:00

yeah. We do two ue locally in nato, Royal Infirmary West once a week. So we would have one opportunity a week, and that list is invariably full. So in reality the delay would be like another fortnight from whenever you consider them appropriate for oral therapy. So that all of a sudden you're halfway through a six week course or almost at the end of a four week course.

Nik 15:22

yeah,

Jame 15:22

yeah, I this, not doing a TOE on everybody is music to my ears. And presumably also music to the cardiologist's ears 'cause they're the ones who actually have to do it.

Nik 15:31

For sure. It's, it reduces their workload. And again, I think it's, it in the NHS setting, we're always trying to, add value and use resources wisely. And I just don't think this is a good use of resource.

Jame 15:44

you, can't add value by saying you need to do this expensive, time consuming thing, which is not risk free either. People get aspiration and consequences because of that. So let me ask you then, what, when you're thinking about the endocarditis guidelines, what guidelines are you referring to? Are you referring to ESD or Wiki guidelines or some other Heather two undiscussed guideline

Nik 16:06

we would we have generally in our more, more recent endocarditis policy updates referred to the Wiki guidelines because we find that pragmatic and straightforward, particularly around the use of oral agents. I think that they give very good evidence appraisal about what there is evidence for and what there isn't. They're very straightforward guidelines and I think are very applicable wherever you practice they, they are, very honest and upfront about what we know and what we don't know. And I think that is one of the issues that we have sometimes with guidelines is that there's a standard of care that is enforced upon us often in consent by consensus statements, which has limited evidence, and is just a feeling of, that is exhibited by experts. I.

Jame 16:51

Yeah, and the overturning of that consensus requires vastly more evidence than it should, as evidenced by the fact that a bunch of places still aren't doing oral therapy for, otitis or bone joint infection for that matter, and that there's resistance there. Yeah. This will be music to the Wiki guidelines, authors, ears, one hopes. The one thing I thought when I was reading the Endocarditis Wiki guidelines was that I said this in the our previous episode on this as well, that they didn't really recommend anything 'cause they were just like, there's not enough evidence for this. There's not enough evidence. The only thing they hard recommended was the oral therapy for endocarditis. But my God, the evidence base in, I think one of the supplemental tables, binder, or the main document was an absolute masterclass in how to summarize the evidence base in something. And by the time you get to the end of it, the evidence is so overwhelming that oral therapy is non-inferior to IV or superior. But there's no way it's going to be inferior as long as you pick the right patient, you know they got an untrained abscess, you shouldn't be switching them to pills. That's fine. I understand that.

Nik 17:55

And I think that's the thing is that, for, I think all the arguments against oral use, there is still no study that has suggested that IV therapy Is better. There is still the, there are all these concerns, but equally and these, and there are quibbles with, certain studies and methodology concerns. But actually, the evidence we have, is still evidence and we don't have evidence to support IV being better than oral.

Jame 18:19

Fine. Nick. One, one more thing I wanted to ask. Have you expand this beyond the Gram-positive space. Do you have any evidence in either gram-negatives, has X or the old Klebsiella and Pseudomonas, or dare I ask fungi?

Nik 18:34

Yeah we have had very few EC in recent years. We have pragmatically used Oxil in one patient with Ella. But these would be very off off piece. And without really good evidence, I would say that it would be very much an individualized decision. And it would require quite careful thought. Clearly there is some evidence for quinolone in some of the hatch checks and where, whereas conventional therapy has often been centered around things like Kef track. But,

Jame 19:02

Yeah, I suppose the good thing about Ceftriaxone is it's fairly easy to give in an outpatient setting, but

Nik 19:07

yes. That

Jame 19:08

are almost advised against because the guide, and certainly BSAC does, and I think ESC still assess this. They advise to give an IV.

Nik 19:17

yeah, I think there still is a kind of caution A against that, but I think that, I mean that you say cef traction is, we can give it out. We can give it as an outpatient, but there is still. All of the considerations around having a long-term catheter in and the risk associated with that, be it, thrombosis and, infections from the the

Jame 19:37

Yeah, absolutely. Nick, thanks very much for taking us through that. To finish off, if you had a young vigorous infectious disease consultant who's just got his first substantive job in a Nado Royal Infirmary unspecified, and he wanted to take on the ization of endocarditis therapy in his local area or her local area. What would be your advice to do this? How do you win the hearts and minds to get this implemented?

Nik 20:07

I think you, the evidence is pretty stark. And I think you have to lead with the evidence. And also discussing it again, a lot of cardiologists and cardiothoracic surgeons are bound in that dogma of we give IV therapy for everything. But actually when we discussed openly with our cardiologists, a lot of them are very open. And you discuss the evidence with them and say, actually. This probably is something we should be looking to implement. And I think especially when you look at the outcomes are equivalent and often, it reduces, we know that you can get people home faster, you have reduced length of stay and there's less complications from IV lines and a lot of patients prefer it 'cause it's less. Either, traipsing back and forth to, healthcare settings to get their injection or self-administering. If they are, it's a lot less constraining taking a few tablets a day than even a once daily iv. So I think we should be discussing it openly with patients as well, because I think a lot of patients, if they were confronted with the option, would far rather take some tablets,

Jame 21:08

As long as they know it's safe. Yeah. I kinda, I tell my patients this when I'm discussing this in other settings as well. I say that what I'm about to put you on is what I would put my mom on if she had this condition. And that tends to reassure them that I'm not completely insane for suggesting that, pills are as, as good as iv, or as you said, even better.

Nik 21:31

yep.

Jame 21:31

thanks for coming on the show.

Nik 21:32

At all. Thank you.