92. What is resistance anyway? (S/I/R)

Have you ever looked at your microbiology lab report and wondered "What does resistant mean anyway?"

We're sure you have (and if you haven't you should have)! And conveniently we've recorded this podcast episode to explain how it all works! We talk through the definition of S, I & R, plus some explanation on the science behind these letters.

Show notes for this episode here.

Transcript

Jame: 0:18

Callum, how you doing?

Callum: 0:19

Well I'm doing excellent, good, sir. Which you might spell S I R.

Jame: 0:26

I would. I just wanted to apologise for calling you a big dumb idiot who doesn't know anything about infectious disease the other day. I know that your feelings were hurt.

Callum: 0:36

Well, I, would have been hurt if I was sensitive, but actually, I'm not susceptible to your nonsense anymore, so

Jame: 0:44

Oh, fantastic stuff, Callum, and what a coincidence that is, because what are we talking about today?

Callum: 0:50

resistant to shame. You know, If you get exposed to something enough, eventually you might just pick up resistance. So yeah we're talking about what resistance is anyway.

Jame: 1:05

Indeed we are. So, this is a talk that I've actually just given today to the infectious disease trainees that are in ADOS Royal Infirmary's southern wing, a shout out to Mel and the crew. And this is, I, I think this is something that, ID trainees certainly don't particularly understand well. Certainly nobody in the room seem to understand it particularly well. When I was explaining it, and I get a lot of blank looks when I talk about this to people. And so I think it's just worth going through, when we say sensitive and resistant and other categories, therein exactly what we're talking about, and then we're going to give a brief sort of pressy on how breakpoints, bug drug breakpoints get determined the sort of UCAST way.

Callum: 1:58

Yeah, I think this is essential learning for anybody working in infection and in bacteriology, but I guess in other things like mycology as well. And as you say, quite poorly understood, I guess you go from that position of being the FY1 or I guess even much more senior members of teams, if you don't work in infection of you see the report on your system and it says sensitive or resistant or other things which will come to and that's it. And there's just no understanding of how that process is reached. And actually the more I learn about it, the more I'm like this science is really quite complicated and to make that cutoff is, isn't straightforward a lot of the time. And I think recently and make open secret that on this podcast we have. Maybe moaned is the right word, but you cast in the past and some of the sort of on maybe perceived as unhelpful positions they've taken in not providing guidance and stuff. But I have to say recently I've been very impressed with their approach to giving sort of pragmatic advice to people trying to interpret bug drug combinations.

Jame: 3:11

I don't know what you're talking about there, Calum. Some of my best friends are uCAST. Now I will preface this by saying that if you are interested in this kind of bug drug breakpoint setting stuff, we have to get a little tip of the cap to the breakpoints podcast run through the Society of Infectious Disease Pharmacists by the inimicable Erin McCreary and the even more inimicable Julianne Justo and Jason Pogue. And they have a mini series called Breakpoints Talks Breakpoints, and I've put a link to that at the bottom of the show notes, where they, on their new Breakpoints podcast website, they've got those episodes listed, and it starts with a couple of guys that are involved with CLSI, and I think USCAST, and they talk about how CLSI, and this will also apply to UCAST as well, go about the business of setting a breakpoint. And so if you want more detail than what we're about to do, because we're not going to be as comprehensive as that, but we're going to try and break it down for early years clinical trainees in infection, then that miniseries of the Breakpoints podcast is a brilliant place to start. And there's a few other links and references that I've got in the prep notes as well.

Callum: 4:26

Yeah, very cool. I've heard that break points had a really good guest on recently, actually

Jame: 4:32

No, no, I think you may have misheard that Callum.

Callum: 4:35

Really? Oh, okay. Well, you can go for their back catalog and see what we're talking about.

Jame: 4:39

absolutely. But maybe stop at episode 101 or whatever one I was on anyway. Okay, let's start. Let's start with some definitions, Calum. What is sensitive?

Callum: 4:49

sensitive? is susceptible.

Jame: 4:51

Excellent. And what is susceptible?

Callum: 4:56

Angry emails, cute. Susceptible

Jame: 4:59

we better explain this actually for people that don't know what we're talking about. There is a growing war between infection doctors as to if the S stands for sensitive or susceptible. Newcastle have taken the point of view that it stands for susceptible to the antibiotic. And people argue that sensitive doesn't make a lot of sense. But, that's like the more common or colloquial use. I have to say, I do not care

Callum: 5:23

no, I don't care either.

Jame: 5:24

Oh,

Callum: 5:24

so what actually is it? So UCAS define it as susceptible or sensitive as high likelihood of therapeutic success using a standard dosing regimen of the agent.

Jame: 5:39

And what about resistant?

Callum: 5:40

And resistant? is non susceptible so likelihood of therapeutic failure even when there is increased exposure.

Jame: 5:49

Increased exposure, Callum. Whatever do you mean?

Callum: 5:52

that leads on to what used to be called Intermediate and now is termed as susceptible increased exposure or sensitive at higher doses, etc. And that is defined as high likelihood of therapeutic success because exposure to the agent is increased by adjusting the dosing regimen or by its concentration at the site of infection. So, what we mean by increased exposure is giving more drug or a site of infection where you get a concentration of the drug. So, classic example being Coamoxiclav. So, the standard dosing in the UK would be 625 milligrams, 8 hourly. But there's formulations available in other countries and in the UK that are Increased dosing would be, you give the comoxaclav plus amoxicillin 500mg three times a day. So then you're giving a gram of amox and 125mg of clavulanic acid. And because

Jame: 7:00

and in other countries you would be giving the Colmox Clav 1 gram pill, which is 1 2 5 of clavulanate and 8 7 5 of amoxicillin. But like I say, we don't have that in the UK, so we are fudging it by using Colmox plus Amox. We call this the boosted regimen in Nadosh Royal Infirmary. It's probably got other names elsewhere, or maybe it doesn't have an aim.

Callum: 7:22

So that increasing exposure either means you're giving a higher dose of the drug or it means in urinary tract infections, when we talked in our episode about antibiotics for UTI, we talked about how a lot of antibodies are excreted via the urinary tract because they're concentrated there. You, you obtain these higher doses.

Jame: 7:43

Yeah, and you, yeah, and you do that sort of naturally, but the sensitive at higher doses the point to make is that you can still use the drug. You just need to make sure you get an adequate penetrance of the drug to the target and this, do you, do you know why this? changed Cal? Because it changed relatively recently. I can explain it if you

Callum: 8:04

Well, do you, I know, but do you know,

Jame: 8:07

Yes so just to prove that I know Callum so we used to have sensitive intermediate and resistant, and the idea behind intermediate was that you were still able to use the drug, you just had to use the higher dosage. And that didn't happen, because what did happen was intermediate was interpreted as low level resistance, and I count myself in this as well. I remember having MDTs where we were you know, studiously trying to avoid the use of an intermediate drug, I think it'd be Lactam, which on reflection would have probably been the best thing for the patient, but because it was listed as I, we didn't think of that as sensitive at higher doses. We thought, Ooh, that's a bit resistant. I better steer clear of that. And defaults you onto using You know, more and more toxic therapies, last line therapies, colistin, that kind of thing particularly in the ITU population when you're dealing with DTR, gram negative infection, so the UCAS realized that this was a problem. And so they said, okay, we're going to change this and instead of having a. susceptible and two sort of resistant categories. We're going to flip it. We're going to have one resistant category and two susceptible categories. They renamed I a susceptible increased exposure, as in increased exposure to the drug. But actually nobody uses that nomenclature because I don't think that makes a lot of sense to the end user. So we say sensitive at higher doses in NADOS South. I forget what you use up in NADOS Royal and Firmly North. Thank

Callum: 9:42

we use sensitive increased exposure, I think, but it's a real headache to, it's been a huge change in terms of how the laboratory interface works, how the reports are set up and, and educating clinicians has been really challenging.

Jame: 9:57

Yeah. And I know that there are lots of other places where they're still using I as well, just because the, their lab management system has not been updated to, to reflect the

Callum: 10:05

And the other thing has changed is that a lot of things that were previously just called susceptible, but then you knew to give the higher dosings, are now moved into that category. So you see that UCAS now they're setting a lot of breakpoints, as we'll come on to the explanation of what that is, at a very low level. So basically, no matter how susceptible it is, it's in that category. So we're looking at, Pseudomonas and ciprothoxacin as a classic example.

Jame: 10:26

Okay, so those are our categories. How are we going to determine the bug drug breakpoints? Well, you're not going to, UCAST is going to, and CLSI is going to. But what. Is the process for doing that and to understand that you need a rough understanding of the MIC and the MIC 90 in particular. E comps, and then clinical breakpoints. So I think we should just talk about those sort of in that order, I think. So, Calum, do you remember what the MIC is?

Callum: 10:58

MIC stands for minimum inhibitory concentration.

Jame: 11:02

Well done! That's right, Calum! Oh, very good! That CCT can't come soon enough. And what is that? Is that a marker of stasis or sidality of the drug?

Callum: 11:13

that's a measure of bacterial stasis.

Jame: 11:15

Well done! You do So well,

Callum: 11:17

are being, I don't know what's wrong

Jame: 11:21

ha ha!

Callum: 11:24

Yes, measure which basically that's a concentration which a visible growth of the pathogen is inhibited at 24 hours. So that's the measure that we actually do.

Jame: 11:33

Exactly, and the nBC,

Callum: 11:35

the minimum bactericidal concentration.

Jame: 11:38

so that's the true marker of sodality, so that's the concentration at which a 3 log 10 or a thousand fold or 99. 9 percent reduction of pathogen in your sample is detectable again at 24

Callum: 11:54

That's much harder to measure because it's not something that you can do easily. It's possible, but it's not easy to do. I did a whole episode on bacteriostatic versus bactericidal as a measure of antibiotic success and myth busted the, idea really matters. So MEC doesn't, it's not really something that is important to know that much about. You're better concentrating on the MIC. And what's

Jame: 12:16

yeah, it's commonly used in the the research setting to determine the sort of toxicity of the drug, and it's important to know it for. It helps with determining dosages that you're going to be giving to the patient, and that has to be offset against toxicity. But like you say, when we're actually detecting susceptibility, we use the MIC, because it's easier to detect an absence of growth than quantify a percentage reduction of pathogen load, particularly in an agar place. You might be able to do it with broth microdilution, but anyway, fine. So we'll, let's talk about the MIC. The MIC has another couple of subclassifications. There's the MIC50 and the MIC90. I want the loyal listener to imagine a series of samples of wild type population of a pathogen.

Callum: 13:08

What's wild type?

Jame: 13:09

Wild type is the sample of the pathogen that don't have any acquired resistance mechanisms in the context of antimicrobial

Callum: 13:17

Oh, you get a gold star, James. Well done.

Jame: 13:19

Oh, thank you. Oh, well, it's nice that it goes both ways. And so you've got, say a hundred samples. They won't all have the same MIC to the drug that you're testing them against. There'll be a variation. Think about a think about a bell curve of response. And so the MIC. 50 will be the MIC at which growth is inhibited by 50 percent of the pathogens in your sample. And the MIC 90 is the MIC at which 90 percent of isolates will have had inhibited growth in your sample. And if you want to figure out what your population of wild type strep pneumo say is, then it's very easy. You get a bunch of different wild type sample sets from a bunch of different sources and people send them in to UCAST over the years. And a bunch of samples are historical and some are more recent. But mic. ucast. org. I forget the name of the WEGLINK has all this data accessible for use by researchers, but the important thing is that the MIC 90 is what we think of when we think about the MIC, and that's what was used to then go on and help set the the clinical breakpoint. And the last sort of definition before we need to get into the process of doing a breakpoint, clinical breakpoint setting is we need to talk about e coughs. Sorry, Callum.

Callum: 14:50

Yeah, I'm gonna Oh, sorry, that was an E, cough. This is the epidemiological cutoff, or as CLSI caught it call it an ECV, or epidemiological cutoff value.

Jame: 15:03

Yeah, which I prefer. And by the way, CLSI also calls susceptible increased exposure SDD, which is susceptible dose dependent, and I also like that better than UCAS thing. But anyway, over to you. So an ECOV is the European nomenclature, an ECV is CLSIs. So what

Callum: 15:22

Yeah, so that's the MIC above which bacterial isolates have phenotypically detectable acquired resistance. So Jane mentioned earlier on wild type. So if your MIC is below the ECOF, then you would say that's a wild type. And if it's above the ECOF, then you would say it's got some sort of phenotypically detectable acquired resistance. And that's.

Jame: 15:48

And, and you do have to check if you do get something that's above that ECOV, that there's not been some sort of screw up with your process. the the antibody hasn't. Just diffuse into the agar or there's been some sort of error. But once you exclude all that, then you've got phenotypically acquired resistance confirmed. Then you can use that set your

Callum: 16:12

Yeah, so it's quite a useful thing, the ideal is you grow an organism and then you test against antibiotic and then they've defined a breakpoint uh, MIC at which you think that you're going to have success. Ideally, you don't have that in ECOF can be useful. Because If your MIC is very low and it is below the EC o, then you can be pretty confident that there isn't resistance there.

Jame: 16:36

Yeah, although the. still like to have clinical data of success. And that's the last bit that's required in order to set a clinical break point is that you need to have all this M. I. C. stuff and you need to have your sort of ECOF and you need to be able to tell between the Wild type and resistant populations, but you also then need clinical data to say, actually, yes, when you use this and you're hitting all these targets, in a susceptible population, you then get clinical cure. And so that's why some stuff doesn't have a breakpoint. But it's got all the rest of it. It just doesn't have a clinical breakpoint set because they don't have enough of that clinical data.

Callum: 17:18

And I guess part of the difficulty of all this, very complex science, but you're basically dichotomizing variation in organisms. And there will be some organisms that have a resistance mechanism. So looking at things like Oxy 48, which is the carbapenemase, they quite often have a low MIC. to the carbapenems, even though they have a resistance mechanism that's detectable. there's going to be, as Jane mentioned on a bell curve of wild type population, some of the wild type population will have. Relatively higher M. I. C. S. And organisms that aren't well said that have resistance will have lower M. I. C. S. And it's like, where do you draw the line between those two things? You're trying to set a point where you can confidently say this is going to work. This is what you know it has to be reliable. And

Jame: 18:05

yeah, totally,

Callum: 18:07

I think historically, the break points are a bit more arbitrary and it wasn't as much science behind them.

Jame: 18:12

Well, we will come on to that.

Callum: 18:14

We will come onto that.

Jame: 18:16

So, let's talk about how we determine an SR breakpoint. So step one we've mentioned already, get N samples of your wild type bug, and incubate them with various concentrations of whatever drug you want to test against. So strep pneumo against amoxicillin, pseudomonas against pericillin, staphylococcus against cifrofloxacin, etc, etc, etc. You then go ahead and determine the concentration at which 90 percent of your sample has inhibited growth, and that is your MIC90 for your population. And the bigger your sample, the more likely it is to reflect the wild type population of that of that bug in general. But the MIC 90 just tells you about growth inhibition of your sample in vitro. There's lots of other stuff that's going to affect how it's going to perform in the real world. So nitrofurantoin will kill bugs plenty good on an agar plate, but if you've got an E. coli bacteremia, with abscess formation in your spine or your one of your spinal discs. Nitroferantone is not the drug of choice because that has low plasma levels and gets virtually instantly excreted in the urine. So we're not mentioning all that PD stuff. We're just talking about the breakpoint determination here. It's step three is get a load of samples with acquired resistance and repeat the experiment. And then you'll have a bunch of wild type mices, and you'll also have a bunch of resistant organism MICs because if you give the drug in high enough concentrations, you'll probably still get a bit of kill unless that resistance mechanism is completely insurmountable. And there are some thinking about efflux pumps or porin losses and things like that for the drug just at any concentration will just no longer get in to the the pathogen and high enough to kill. The next step after that is that you will plot all this data on an MIC distribution, and that can be either in table form, and I've included a little sample here, which I've picked up from the UCAST website. You can name either the drug, and it will list all the bug MICs, or you can set it by the bug and it will list all the drug MICs and that's the sample that I've given here. And if you do that and you click on one of the drugs, it takes you to a nice little graph which has the bug drug MICs in bar chart form for you to have a look at. And what it usually does is it bisects the susceptible and the resistant population into blue and red. For you, and it lets you know at the bottom what the ECOF is. So again, I've got an example here. It says strep pneumo to amoxicillin and the ECOF is 0. 06 So that's how good penicillins are at killing streptococci and all of the MICs for streps are really really low I often think about that sensitive at higher doses where they just set the SR breakpoint at 0. 001 and 0. 06 is not that close to 0. 001, but it's like very low, very low indeed. And yeah, they've stated the ECOF there as to what they think the wild type population stops at 0. 06 and anything above that is colored red and that's your resistant population. Step 5 is determine the ECOV by making that determination of what the wild type population is. And I think at this point we just need to say a little bit about ECOFs and what they're useful for because it's not immediately apparent when you're comparing it to an MIC why you would bother doing this. So I've included a little sort of toggle list of what we use them for. Now the first thing, which is probably maybe the most famous thing that they would be used for, is when you are setting a breakpoint in the modern times, not historically, is that you have to make sure that your clinical breakpoint isn't going to bisect the wild type distribution. And There's very I mean, it's not famous, but like this, it's an example that still smarts Callum, which is the gentamicin pseudomonas breakpoint. So the gentamicin breakpoints were very historical and based on experimental data from decades ago and US cast. Decided that they were going to take a look at that with a modern eye, and they got the MIC distribution of the wild type of resistance. And at the time, the GENT pseudo breakpoint was 2. And. Because Gentamicin has a concentration dependent kill, its PD target was a C max of 10 times over the MIC. So if your bug drug breakpoint is 2, you want to get to 20 in the plasma after a dose. And with the 7 dose, about 90 percent of patients will get there. That is fine, as long as that breakpoint remains at 2. But when they actually had a look at the MIC distribution of the wild type population, they were getting MICs of up to about 8. And so clearly, the ECOF, if you're setting the ECOF at 8, there's a bunch of samples which are being classed as resistant, but actually they're part of the wild type population. And if you set the ECOF if it's at 8, that's like the lowest limit of what you're, you could set your clinical breakpoint at. So if you set your breakpoint at 8 you're going to get a P plasma level of about 20 in, in most people. So that's going to be 2. 5 times the MIC. That's nowhere near the PD target that we've got currently of 10 times over the MIC. So you can't hit it in plasma. And if you're not hitting it in plasma, you're definitely not going to be hitting it in lung and other tissues as well. And so they presented this data and both CLSI and UCAS said, well, okay, we can't have a Jentsuno breakpoint. And so it's been removed. I would argue Callum, that you could have retained a urine breakpoint. Because Gentamicin, the urine levels are something like 100 times your plasma level. So if you're getting a plasma level of 20, you're getting a urine level of 200 to 2, 000, and that is enough to kill any Pseudomonas. But You know, uh, UCAS don't really like to send urine specific breakpoints, at least not yet. And so they haven't done that, they've just removed it entirely. In their defense, if you do want to use namnoglycoside to treat pseudomonas, you've still got TOBRA, whose SR breakpoint is still 2, and you've got amikacin as well. So it's not like there's no other

Callum: 25:19

Yeah. I think they just, in their ucast break points table, they just say insufficient evidence, which then directs you towards the table, which is what to do and there's no break points, which is really useful. And I think it comes back to saying okay, yeah, fair enough. You can't say that Gentamycin work for all, but often when treating pseudomonas, you've cultured it and you've got MIC. So I think if you test it against Gentamycin and the MIC is relatively low, and I would be very happy using it.

Jame: 25:46

I guess, but are you still, will you still be happy when the GENT pseudobreakpoint is no longer reported by your lab?

Callum: 25:52

Well, I think, I think we're moving away from a position where we say that we can only use drugs that we've got breakpoints for and we can say are SIRR, because actually there's so many things that we don't have breakpoints for and we have to use a level of interpretation. And I guess I said earlier on that you cast have done something really helpful that paper that they've released, which is when there are no breakpoints. I would love to do another episode on when there are no breakpoints.

Jame: 26:19

Fine. We can do that next. But the other uses for an ECOF, you can occasionally use them as a surrogate breakpoint for when PKPD data are incomplete and clinical data pertain only to wild type organisms. You can screen for resistance. So cafoxazine ECOF can be used to detect MRSA and oxacillin can be used to detect all penicillin resistance in strep pneumoniae. You can use it for AMR surveillance and lastly, you can use it to exclude resistance. The example they've given here is a perfloxacin 5 microgram disc to exclude all quinolone resistance in Salmonella enterica, Yeah, so EcoIFs are useful for other stuff, but the good thing that they're useful for doing is making sure that your breakpoint is not bisecting the wild type population, as some historical breakpoints have done, and a lot of them are being revised by UCAS. And then we get to the last bit that we do. Which is we actually determine the clinical break point. We've got the MIC 90 for the wild type distribution. We've got the ECOF to determine what the resistant population is. And then that's our target for our PK PD stuff. What we then need is a load of PK PD data that correlates with positive clinical outcomes. And it's up to researchers and people to submit that. Now, if you've got a new drug, like Kefidericol, the Trojan horse, or Keftazidamababactam, or Aztrinamababactam, or various other combinations thereof that we're, that are coming to market, then no problem, because you've got your phase one, your phase two, and your phase three data, and you can just smoosh all that together and say, here's how well it's working in clinical trials, and UCAS on CLSI will take all that and say, okay, fine, here's our breakpoint. It's a bit more difficult with older things, particularly older drugs and neglected tropical diseases. And the example I've got in my head is Burkholderia pseudomallei. So we've done a Melioid episode relatively recently, and we commented at the time that UCAST have a bunch of breakpoints for Melioid. How did they get that? Well, they didn't go out and get all that data themselves. Bart Curry and all his chums in Darwin and all the guys in Thailand got together and got a lot of PK, PD, and hard outcome data and sent it to UCAST and said, I think you should have a Brochodarius pseudomallei breakpoints for these things. Moxasol, etc. And UCAST said, fine. And that's why we've got a breakpoint for Melioidosis, a disease which does not occur in Europe. But UCAS is not just for Europe, it's used in lots of other places, including parts of Australia. So yeah, the last part is that you do all that sort of lab works and then you correlate it with clinical outcome data. And UCAS do a lot of sort of work about PK PD outcomes and sort of Monte Carlo simulation to determine what they think the optimal dosage is because before UCAS there was a bunch of different bug drug setting. breakpoint setting organizations for the individual countries. BSAC was the UK's bug drug breakpoint setting organization. And when they all amalgamated, they all were recommending sort of different doses for stuff and UCAS had to determine what they were going to standardize to. So that's a sort of overview of how, or at least my understanding of how a bug drug breakpoint gets created. Anything to add, Cal?

Callum: 30:03

No, I, I think you've put some good show notes together, which are linked in the episode description. So I recommend having a look at that. There's a couple of images that might help people grasp this. I don't think it's particularly straightforward.

Jame: 30:17

No, but actually the picture says a thousand words and the show notes are mercifully brief. So they won't take very long to go through and they've got links to a couple of documents, one covering ECOFs and one covering MICs, which I thought were really useful. And they're relatively recent as well, like 2021. And that kind of thing. So they would if you want a little bit more detail from people that know a little bit more what they're talking about. You could just go out in the street and ask anyone really, but those two papers in particular would be worth the squares as with the breakpoints. Many CDs as with the UCAS website, which we actually haven't mentioned before now, but you cast does put out some pretty decent stuff. So I've linked to the clinical breakpoints page. And I've linked to the, yeah. Mic. ucas. org, which is their big list of all the bug drug MICs. And then they've got a short three page explainer document that they released when they changed SINR to susceptible, susceptible increased exposure and resistant to explain what they were doing. They've also released a 40 minute video lecture, but I didn't feel that I had the time or inclination, Callum to do that

Callum: 31:31

40 minutes is far too long to listen to something, James. I can't imagine anybody would listen to something that is 40 minutes long.

Jame: 31:38

We better wrap this up. Okay then. So just a little final point on sort of the breakpoint. So you've been through this big rigmarole and you've got A breakpoint for something. Now some drugs just have an SR. Breakpoint at the same MIC. So your SR breakpoint are like four. So if you are,

Callum: 31:59

If you're less than four, then it's susceptible, and if it's greater than four, then it's resistant, or usually greater than or equal to four.

Jame: 32:07

yeah, something like that.

Callum: 32:08

So some drugs will have the S and the R breakpoints are different. So, for example the S breakpoint might be less than 0. 001. And then the R breakpoint might be greater than 8 milligrams per litre.

Jame: 32:23

But Callum, what happens if you've got an MIC That's between the S and the R breakpoint.

Callum: 32:28

That's where this I, so our susceptible at increased exposure comes in so the bit between S and R is susceptible at increased exposure essentially an area where you will likely achieve therapeutic success, but you have to have that increased exposure. I

Jame: 32:47

But Callum, if I go to the clinical breakpoints document, I'll see a bunch of bug drug combinations, just picking one at random in the document here, where the S breakpoint so I've got for Pseudomonas here for all of the Penicillins, Pepericillin, Peptaz, and Tisarcillin clavulanic acid, the aspirate point set at 0. 001. I can't possibly get that level in my patient. What is going on?

Callum: 33:21

this is a little bit of a forcing function from UCAST because what they've done is that they've set this S breakpoint so low that all you're going to get is susceptible increasing exposure or resistant. And that is deliberate because there's some bug drug combinations where you're just always going to have to use that higher dose.

Jame: 33:41

The higher dose, so say for Peptaz, instead of it 3 times a day, you would want it 4 times a day.

Callum: 33:47

Which I think used to be, like, quite a common thing that you would do as an infection specialist. And they were like, oh, you're treating Pseudomonas, you should give the Tazosin four times a day. And you keep saying that again and again.

Jame: 33:57

I think the, the real cause of confusion will be with clinical teams where it's a sensitive at higher doses, because I, I get called a lot by people who are saying, I've got a pseudomonas, it looks really resistant and I look up the sample and it's wild type,

Callum: 34:13

I had someone who's labeled as having MDR organisms was transferred from their health board that was in a side room with contact precautions for four weeks.

Jame: 34:22

Oh my

Callum: 34:22

And I came to see them and I was like, What's this data? I went back to the source. And yeah, it was just normal pseudomonas. So that communication piece is going to be really key.

Jame: 34:32

Yeah

Callum: 34:33

It is confusing. So good luck. So just to summarize what we've talked about today. So Jane has taken us through what the definitions for susceptible, susceptible increased exposure and resistant are, talked about MICs, MIC90s, ECoVs, clinical breakpoints and how we just set that. And. Once again, recommend, go to the show notes, have a bit of a read there. Look at the UCAST website, familiarize yourself with what they're recommending. Because I think for anybody working in infection, this is really critical to understand particularly now that we're going to be seeing more reports that don't say sensitive or susceptible or resistant. We're going to have this eye category more, and we're also going to have reports which say there is no breakpoint but here's an interpretation.