101. AST: When there ARE breakpoints - how to use the EUCAST clinical breakpoints table

BREAKPOINTS. We all love them. S breakpoints... R breakpoints... dash, IE, NA...

Wait, dash, IA, NA, Brackets?!

LISTEN ON (and read the accompanying prep notes), and soon you'll know! In this episode Jame and Callum talk through the EUCAST breakpoints table and how to interpret it

Show notes for this episode here

Transcript

Callum: 0:18

Hello, Jame.

Jame: 0:20

Hello Callum. How are you doing?

Callum: 0:22

I'm doing great. I was, I was having a really good game of badminton with my brother the other day,

Jame: 0:29

Uh huh.

Callum: 0:30

and it was really close actually, it was a break point.

Jame: 0:34

Oh, and what a coincidence that is, Callum, because what are we discussing today? Okay, so this is, another, part of our How to EUCASTT mini series that we've started with, what is susceptibility, anyway. And we're going to talk about how to interpret or use break points, are we, Callum?

Callum: 0:54

I like that you changed the title from what is resistance anyway to what is susceptibility anyway. We have 2025, James, he's got a more positive spin. It used to be what is resistance anyway, but he's now flipped it around to what is sensitivity anyway.

Jame: 1:08

Did you deliberately say sensitivity the second time that you mentioned that instead of susceptibilities that you could annoy absolutely everybody? As if so, well done. So today Callum, you're going to take us through what to do when there are breakpoints and what to do when there are not breakpoints. And we're going to start with what to do when there are breakpoints. Is that right?

Callum: 1:31

Yes,

Jame: 1:32

So the difficult business that we covered in the previous episode about defining what's sensitive, what's sensitive at higher doses, and what's resistant, all that breakpoint setting has been done by the lab And now it's been published on the EUCASTT website. Some of that will run in a fairly automated fashion, and sometimes you will need to look stuff up in order to aid interpretation to the end clinician, and that's what this first episode is going to be about. Okay.

Callum: 2:03

Exactly. Very succinctly put. And, in the UK, laboratories are using the EUCASTT, uh, breakpoints. Obviously the major other, Breakpoint setter internationally is CLSI in America, and there are some others. So for EUCAST, which is what we're going to focus on, that data is contained in their breakpoint table, which is updated on the 1st of January every year. And it's always the most exciting part at the beginning of the year for me. The EUCAST table, EUCAST 15 we're on now. It's, the number is the year after 2010, which is when they had EUCAST 1. You can just Google it. So if you just go online, Google EUCAST 15, it, you'll find it. So anybody can Google this data. It's there. And the MIC data isn't behind a password either. So I guess if you're interested, go and just read through it. I guess not anybody can understand and interpret it and I thought that was why it was a good idea to talk about this on the pod because I think that when you first come into microbiology or if you're working say in an infection service or just clinically and you're having these difficult situations it's worth, and I quite often use the EUCAST table when I'm thinking about what treatment options I might be able to use. And that's not really what it's for, but, if I've got an organism ID and don't yet have susceptibility data, it can be quite a useful thing to go into the table and be like, well, these are the agents that there are breakpoints. This is probably the sort of things we might be using. And, essentially on the table, there's different sheets and it talks about different, groups of bacteria. Essentially, there's Three main options when you look at a table. So you're looking at a drug versus the bug. The most straightforward is, as we talked about last episode, there's a breakpoint. there's a bit of nuance in that one. Or there's a dash, or sometimes there's something that says IE,

Jame: 3:55

Hmm. Okay.

Callum: 3:56

insufficient evidence. I'm going to just walk through those with some examples.

Jame: 4:02

All right, so let's start, and so that the loyal listener can follow us along, we've, we will have released prep notes to go alongside this episode, and there's a link in it to the EUCAST breakpoint tables. I think everybody who has worked in the lab in Europe will know how to find these breakpoint tables, but we've linked directly to it regardless. And they are. You can open them as either an Excel, which is a bit easier to navigate on the computer, or as a PDF, which is a bit easier to navigate on your phone. And if you want to go to the section for Acinetobacter and then scroll down to the section on Quinolone testing, then you will see what we are about to talk about now. So Callum, take me through what I'm looking at here for Ciprofloxacin. Here we have breakpoints that are listed.

Callum: 4:51

So we used this example because I think it covers all the different options in the table. So your first option, ciprofloxacin, it's listed as s, is less, than, or eco to 0.001. This is a sort of made up rate point, and the idea is, as we talked about before, that this bug drug combination will always be reported as susceptible, dose dependent or increased dose. And that's a sort of. work around that EUCAST are using essentially to force you to use higher doses. that's straightforward. And most of the time when there is a separate point as the sort of clinician, you won't really get involved with that because there's a lab protocol and they'll just follow that

Jame: 5:28

Yeah, and so the R breakpoint is one. So if you get an MIC 125, it, all that will be reported as sensitive, dose dependent. fine. And then anything one or above will be resistant and you will be directed not to use the, uh, Levo?

Callum: 5:49

So leave a slightly different because it's got a S. breakpoint or less than or equal to 0. 5. So there you might get a report saying either sensed, uh, sensitive or sensitive at increased dose or resistant. So it's got the three different option that, that's straightforward. There's a breakpoint and boy, I wish that every bug drug combination had a breakpoint, but it is not so simple.

Jame: 6:13

well let's go on to the next example. So here let's talk about Moxifloxacin, Norfloxacin, and Ofloxacin. So they don't have anything, they've just got a little hyphen or a dash in the middle of their SNR points. cells. what does that mean?

Callum: 6:30

So you cast pretty clear that if they've put a dash, What they mean to say is that they think that the agent is unsuitable for treatment of infections caused by that organism and to avoid clinical use and even testing. And if you need to report it, they say just report it as resistant without doing any prior testing.

Jame: 6:49

I wonder why you would need to report it if they know it doesn't work. Do you know what I mean?

Callum: 6:54

I guess there might be a rare circumstance in which case you want to report it as resistant. people might have, use that or, in the past. I think this is a sort of catchall term. There is a sort of note section on the guidance which explains all this stuff, which is where we've got this from,

Jame: 7:08

Oh yeah. Okay.

Callum: 7:08

and they walk through their sort of rationale for it. So I think where there's a break point and where's a dash is fairly straightforward,

Jame: 7:16

Yeah. Okay. Well, let's make it not very straightforward, Callum. Let's talk about delafloxacin. here it says IE in both the S and R, breakpoint cells. so what does IE mean?

Callum: 7:28

so it means insufficient evidence and essentially they're suggesting that in their opinion, the organism, or group probably is a good target for therapy with the agent. But there's not clinical data to support its use. So often there'll be an ECOF, an environmental cutoff, or epidemiological cutoff value, which we talked about in the last episode in Defined. But they don't have that clinical data to support its use. So they've not set a breakpoint, but they're sort of gently saying that you could use it if you wanted to.

Jame: 8:01

Yeah. If your back was against the wall. So I guess we, we talked about this in the, SIR episode that it's not enough just to get an ec cough. You need and say, if your MIC is below that, then it's a susceptible organism. You need to actually have clinical data showing good outcomes when you use that in that circumstance. And so the IE is like a sort of halfway house to that. Okay, fine. And what about N A for nalodixic acid?

Callum: 8:28

no, NA stands for, actually I didn't notice that it stood for an addict, see I said, NA stands for not applicable, so that just means it doesn't, you've done that deliberately, just to troll me, so, it just means not applicable, so sometimes there's, things like screens, which can be used in certain circumstances and when they can't be used, they just put any. I think that's pretty obvious. Um,

Jame: 8:49

okay.

Callum: 8:50

and if they can, if you can use a screen, for example, Foxitin is used as a screen in Stafford Cochai. to screen for, resistance. It usually, it will have a number, it will just say note. And then in the note section on the right, it will explain what it means. And in general, notes are, are really, where something's too complicated, you just put it into the section. so if you see note, there's a bit on the right hand side. A good example being, Kefiderikal.

Jame: 9:16

The Trojan horse.

Callum: 9:17

Thank you. against Acinetobacter, for that, they don't set a breakpoint. They have some notes, which explains it. Quite complicated, not going to go through here.

Jame: 9:27

Yeah, you've actually put it in the prep notes though, haven't you? So we've jumped down to the notes section here.

Callum: 9:32

So, straightforward. That's only Oh God, what's this? Bracketed breakpoints? What does that mean?

Jame: 9:39

bracketed three points are a scourge on the UCA breakpoint document column. Much you know, my feelings on bracketed break points, it's'cause they went for the am gly sites first when they bracketed. Aye, it's because they came for the aminoglycides first, Callum. But, yeah, tell me all about bracketed breakpoints. And there's a guidance document on this as well, by the way, which we've also linked to.

Callum: 9:59

so bracketed breakpoints is where there is a number, so they've set breakpoints for S or R, but they've got little brackets around them What they suggest for these agents is that clinical evidence as monotherapy is usually lacking, but they can still be used for specific indications or in combination with another active agent. So for, aminoglycosides for systemic infection, against, enterobacterioles, They have bracketed breakpoints and they're saying that, um, that you shouldn't use them for monotherapy. and essentially they're e coughs that distinguish between isolates with or without required, acquired resistance. So it's somewhere between, in my mind, an actual breakpoint and something that says IE, because I suspect put into this position because For example, the glycosides against enterobacterioles, it's a very established treatment, and if they went and just took away the break points, that would be, very challenging to a lot of people. So I guess it's them trying to be helpful. Um they often, Represent a best fit e cough, and, one of the things that you can do, so if there's a bracketed breakpoint and you've got specific organism in mind against an agent, you can go and look up the precise e cough for that drug combination. and for a bracketed breakpoint, just like you can with a normal breakpoint, something with an MIC above the, this bracketed breakpoint, you can report it as resistance. However, what they recommend doing is if the MIC is below that bracketed breakpoint, you should avoid reporting it as S or M. susceptible dose dependent. and, if you are going to report it, you should report it with some sort of adjunctive measure. for example, EUCAST recommend combination therapy, although they also states that specific countries may choose their own approach, which is a bit of a get out of jail card for, some certain small Northern European countries that use a

Jame: 11:58

Can you think of any in particular, Callum, that have an extensive use of gentamicin as their gram negative backbone for the coverage of sepsis and have never had a problem with treatment failure? Can you callum?

Callum: 12:10

But yeah, I, I think, um, There's a lot of experience and they're nodding to that, but also to give them credit, like there isn't that data there, but they've looked for it, they've not found it, so it's kind of on us to prove that point, isn't it?

Jame: 12:24

Yeah, I mean, I guess. I mean, I would argue that there's actually decades of use of, aminoglycides not only for infections originating from the urinary tract, but other systemic infections and quite a lot of that was. with monotherapy

Callum: 12:41

Yeah, I guess, love it or hate it, EUCAST have an approach and the, whatever data is out there hasn't met the criteria for them to say that it's a set breakpoint. So maybe I challenged all the megalocoside nerds out there to convince EUCAST, but that's where we're at. So, Bracketed breakpoints are another little wrinkle in the hat. So we've gone through when they're breakpoints, a dash, an IE, an NEA, notes, bracketed paypoints. They're all sending to different guidance documents. And then to make it more complicated, there are sometimes breakpoints where it divides it up by indication. So for example, again,

Jame: 13:18

Yeah, but this is, is it relatively new or is it just that this year they've included endocarditis

Callum: 13:24

new. The big change this year in 2025 is that one of the clinical conditions that they've set, separate break points for as infective endocarditis. Now, I guess there's PK reasons why I might want to do that is it's a endovascular infection. And we were used to using higher doses, but given that EUCAST have started giving dosing recommendations, kind of make Sense, but it is more and more complexity into something that was already quite complicated. So the specific indications you might see in the table are things like uncomplicated UTI, which is variably defined, but EUCAST have their own definition, which is in the table, they then have infections originating from the urinary tract and they have a definition for that. So basically it's what you might call complicated UTI, but they've been a bit more defined of that. They've also ones for meningitis and infective endocarditis, and they have a whole other document on. breakpoints for infective endocarditis. And all these definitions are contained within the notes section of the clinical breakpoints table. So, you hope that you go in and you see a number and you just do it. But, it is a table that, when you're looking for something outside of that box, it's quite often you sending you to different documents and having to look things up. And when you're busy, that can be quite complicated. So it's definitely an essential thing to be familiar with for an infection trainee. Infection specialists. Cover your exams.

Jame: 14:50

Yeah, I think so. And so that's a brilliant introduction to what to do when there are breakpoints. If only there was some guidance on what to do when there weren't any breakpoints, Callum. But I'm afraid that's something we shall never know.

Callum: 15:07

Ha ha ha! Okay.