102. AST: When there are NO breakpoints- how to use the EUCAST guidance document

So now, Loyal Listener, you know all about Susceptible, Sensitive at higher doses, Resistant, MICs, ECOFFs/ECVs and how to use the EUCAST breakpoints table....

But what about the wild-west of bug-drug combos where there are no breakpoints?

Well in this episode, Jame and Callum talk through the EUCAST approach to this situation.

Show notes for this episode here

Transcript

Jame: 0:19

So, Callum, do you have a terrible breakpoint based pun for us this week? Or are we being given a reprieve?

Callum: 0:27

I played this really great game of badminton with my brother the other day.

Jame: 0:32

It's the same pun?!

Callum: 0:33

I absolutely destroyed him. It was like 21. 5, so there was no breakpoint.

Jame: 0:39

I don't know badminton, so I don't even know if that's a good score or not. Anyway, and what a coincidence that is, Callum, because what are we discussing this week?

Callum: 0:45

Well, last time we took you through where there are breakpoints in the UCAS guidelines, which is not as straightforward as you might hope.

Jame: 0:54

I know, but at least I knew what to do when there was a breakpoint. If only there was some guidance on what to do when there aren't any breakpoints.

Callum: 1:00

Yes, which there is, but thank

Jame: 1:04

ha, huh?

Callum: 1:04

Thankfully it's even more complicated than when there is a breakpoint.

Jame: 1:08

oh, for God's sake. Okay, then. So is this, Cam, you were telling me, offline just before we started, this has sort of replaced the PKPD breakpoints, which used to be a tab in the breakpoints, Excel spreadsheet. Is that right?

Callum: 1:23

Yeah, I don't exactly know when that disappeared. I feel like it wasn't that long ago. I'm thinking like UCAS

Jame: 1:30

Yeah.

Callum: 1:31

Was the last time that was in. So it used to just say PKPD breakpoint, so essentially UCAS lay out that, if there's a breakpoint, as we said before, that's great. If you have, an organism and either there isn't a breakpoint for the specific drug you want to use or if it's just a really rare organism and it's not on the table at all. What you used to do was go to this other tab and it was called PK PD breakpoints pharmacokinetic pharmacodynamics and essentially it would just have a list of all the different antibiotics you might want to use and it would have a number. And it would say, if it's less than this, it's probably sensitive, and if it's more than this, it's probably resistant. And it was super straightforward.

Jame: 2:10

was number specific, but not organism specific because it's a generic breakpoint. So it's just saying if you get this level of plasma or whatever, then you're probably good to go.

Callum: 2:19

Yeah, I guess it was based off, as you say, PKPD data saying, this is an achievable number that you might reach in serum with this drug. So if your MIC is lower than this number, you'll probably get enough. Of the drug there to kill the bug.

Jame: 2:35

Yeah.

Callum: 2:36

Simple. Yeah. Great. I think, I don't know. I'm not, I don't know affiliation of UCAS. in their minds, but it always seemed a bit too good to be true. And I think with the move to a more scientifically robust method of determining break points based off a combination of ECOS and clinical data, this didn't really sit with that and I almost flew in the face of they were trying to do. So whilst I can't deny I was aghast when it was removed. I can understand now, why that happened. Following that, there was this period of time where we were suddenly not really sure what we were meant to do. And, there was a lot of still using the PK PD What they did release last year was a document says when there are no breakpoints, which I really recommend you just go away and read.

Jame: 3:33

All right. The, what to do when there are no breakpoints document, when does it apply?

Callum: 3:37

Yeah, so I guess if you were going to define when there are no breakpoints, there's a couple of scenarios in which there, this might be the case. So, option one, either your organism isn't in any of the table, sheets, it's just a rare organism, or the agent isn't mentioned, so it's a really old antimicrobial, or rarely used, or something that's dead. So that's option one, just not there. Option two is that there isn't a numerical breakpoint, there's this IE, Insufficient Evidence, which we talked about in the last episode. So that's probably the clearest one for this. Next option, there's no breakpoint, there's a dash. Now UCAS are basically saying, Don't use it if there's a dash. That's quite straightforward. Again, there isn't a break point. They're just saying don't use it.

Jame: 4:19

yeah, yeah.

Callum: 4:19

or the other option is that the species or the agent is listed of guidance and either they're expert rules or expected phenotypes. Expected phenotypes. So this is. Another guidance document, which basically replaces the term intrinsic resistance. And divides up things up into expected resistant phenotypes or expected susceptible phenotypes., And allows you to. Just to report things without testing, if that makes sense. So they have this big long table in there which talks for your expected resistant phenotypes, so things that you can just report as are without doing any further testing.

Jame: 4:58

All right.

Callum: 4:59

Expert rules are, expert knowledge and interpretive rules, which should be applied to reduce the number of testing. For example, in inter batch rallies, they have some rules saying, basically, if X, then Y.

Jame: 5:15

yeah, I'll give you an example, Cal. So for streptococci, if you're testing macrolides and clindamycin, if your isolate was resistant to erythro, but susceptible to clinda, then they would advise testing for inducible mlsb resistance. But if negative, then you would report clinda. Susceptible, and then if positive, then report clindamycin resistance. So that's, you're checking whether or not the agent has inducible resistance to clindamycin.

Callum: 5:49

I think this is, again, quite complicated, there's lots of different documents in there,

Jame: 5:53

Hmm.

Callum: 5:54

It will mostly be baked into the standard lab practice. I used to always think of beta lactams, for example, as a ladder, like you went broader and therefore you cover more things. So if it's susceptible to penicillin and all the other beta lactams would work against it, but it isn't like that. You know, we've talked about penicillin binding protein, before you've talked about, and I listened and, it, the expert rules is really saying That So you know if it was susceptible to this, what can I? What else can I expect it to be susceptible to? Or if it's resistant to this, what else can I expect to be resistant to?

Jame: 6:30

yeah, definitely.

Callum: 6:31

So you know, more documents which are helpful, but it's complicated to go through. So I think now we just focus in on this, i. e. the insufficient evidence area, because that's. That's really what the when there are no breakpoints and document is around, or the species and agent aren't in the specific mentioned table. So those first

Jame: 6:49

Yeah, the first two. so you don't have any data or it's IE and you're thinking, oh, can I use it? so you've got a nice wee flowchart here, which you have pinched, no doubt, from the document in question. why don't you take us through it?

Callum: 7:01

Yeah, they have recommended approach, which I think is quite useful that for odd reason, the flow chart is at the bottom of the document, which is I think they should just have at the top.

Jame: 7:10

In their defense, you've put it at the bottom of this document.

Callum: 7:12

Oh, yeah, whatever. So, okay. So you identified your organism, probably on a molotov, and it is possible to search the relevant literature. first you have to say, is, am I actually worried about this organism in this situation? is it clinically relevant? Is it important? because there's a lot of Malditov specials out there and sometimes it's actually not, they're not relevant, they're environmental contaminants or whatnot. and then you might have looked at the literature to decide, okay, so what antimicrobial agents, might we want to use

Jame: 7:43

Has it been tested against in the past? Yeah, yeah, yeah, yeah,

Callum: 7:45

And sometimes there's really great review articles, which will point that out to you. Sometimes there's not, and obviously if you cast off in their table, got the bug drug combination and they listed as IE essentially they're saying to you, okay, you can potentially use this here, but we've not gonna give you a break point., And then you also need to decide, what's the most appropriate medium for testing? What type of egg are you gonna to use it on? Which is usually, either Mul Hinton, Muller Hinton, Sidious, or Sidious anaerobic agar. that's key. and then you're gonna determine an MIC. So essentially you are either gonna do something like, an e test or a micrograph dilution. And then you,

Jame: 8:24

not disk testing?

Callum: 8:25

You won't, this testing doesn't give you an MIC so this testing will give you a zone size, which then correlates to MIC. You're not really gonna be used this testing in this situation. so you then get an MSEU number. And what they then recommend doing is that you compare this to the known MIC distributions. And those are contained on a website that EUCAST host, which is a DA database of mics and then that you can search either by organism or by agent. And it essentially is all the data that's been submitted to EUCAST, about this. And you gave a good example before about Burkholderia pseudomallei. Remember you were saying that UCAST didn't have break points for that. And then a lot of people. went off and submitted a load of data and then they made us some breakpoints.

Jame: 9:10

Yeah, yeah,

Callum: 9:11

Yeah, so that's a good example of where, EUCAST got the data and it was, enabled them to provide supportive, breakpoints.

Jame: 9:19

but these tables on the right hand side of them, there are ECOFs, for the wild type distribution, which is usually also highlighted in blue, in the table. And and so if you go there and the MIC is above the ECOF, then you would call that resistant because it is by definition in the resistant range for that pathogen. And you would just say, I can't use it. What if the,

Callum: 9:42

simple, that's a simple, that's, you obviously don't want it to be resistant, but sometimes it is a lot easier when you get the high MIC and you're like, clearly it's resistant, and then you're done. Now, you can't

Jame: 9:53

MIC is below or at the ECOF then?

Callum: 9:55

Yeah, or if there just isn't, if you go into that database and there is no data,

Jame: 9:59

Yeah.

Callum: 9:59

that's the other option. So yeah, either it's below the ECOF, and not all organisms will have ECOFs listed for different drugs, and, sometimes there just won't be data on that database, or there's not enough MIC distribution data for them to have defined an ECOF. So then they say, okay, take that MIC, and they've given us some tables in the document, which is a list of MICs, where they're, it's essentially very similar to what the old PK, PD, breakpoints were. So a list of numbers which are based on the pharmacokinetics of the drug. They divide it up into, aerobic, and then within aerobic gram positive and negative, and then anaerobic. Organisms and essentially you've got your M. I. C. data from your bug drone combination and then you're going to compare it to this number, but it's still not straightforward because again, it's not going to tell you something sensitive or resistant because you just don't have a break point. So even if you've got a super low M. I. C. and it's below the ECOF and you look at this number and it's below that number there, you still can't say it's sensitive because it's not, you don't have a clinical break point. Does that make sense? Okay.

Jame: 11:06

Yeah. Yeah.

Callum: 11:07

and essentially they give you, some advice on how they think we should be reporting this. so they say don't use SIR, use these options. So either you couldn't get an MIC, so maybe the organism didn't grow or there was some issue technically. And so basically you're just going to be going with best guess based on the literature. Or you could get the MIC, if the MIC was higher than that number in the table, then they say formal categorizing of the susceptibility of this organism is not possible. The MIC suggests that the agent should not be used for therapy. So you're not saying it's resistant unless it's way over the ECOF or, like the MIC is something like over 128. you can just call it resistance. People will understand what you mean. And my experience is that these comments are really hard for people to understand. And so you usually need to have a direct conversation to explain it. If the MIC is low and it's lower than number in the table. Then they suggest saying a formal categorization of the susceptibility of the organism is not possible. A cautious interpretation suggests that the agent may be considered for therapy. And then they say the MIC value is additive appropriate. So it's a really, softly, softly, you know, it's not possible. Cautious interpretation may

Jame: 12:28

It's too wordy. does UCAS think that we've got endless amounts of time to go about reading screeds of data? Don't we have patients to see?

Callum: 12:36

Well, I think it's scientifically correct. I think that's, okay. Yeah, it's quite complicated for a user to understand and I, but I think these organisms, you're going to have a conversation from clinician anyway, because they're often organisms that nobody's ever heard of. And so I think it's not unreasonable to expect to have to phone. And so this just gives us a text and basically I just have the saved and I copy and paste it in to the report when I use it. and I found that relatively straightforward and, Before we had this document, it was just, make up as you go along. There wasn't really a clear way of doing it. So, love it or hate it. The, approach that they're giving is at least an approach that you can use

Jame: 13:20

Yeah. Fair

Callum: 13:21

I guess that's how I approach it. and my understanding of it, I find it really complicated using the EUCAST stuff because there's often a lot of cross referencing different documents, and it's not straightforward to get your head around. and explaining that even on here, I find quite difficult as well.

Jame: 13:45

Yeah, but explain that you have Callum, and thanks for taking us through it.

Callum: 13:49

Do you understand it, james?

Jame: 13:51

Uh, better than I did at the beginning.

Callum: 13:54

Well, that's what we were aiming for.

Jame: 13:56

Oh, thanks. Thanks for the little lesson in education, Callum.