129. Penicillin allergy 3: CEPH FAST

AKA Penicillin Allergy 3: Delabel Hard With A Vengeance

A departure from our semi-annual penicillin allergy episode: one on cephalosporin allergy! 

Jame and Callum are joined by Fionnuala Cox to discuss Cephalosporin allergy in general, and the CEPH-FAST risk assessment tool in particular. 

Ever wanted to know how to deal with cephalosporin allergy? Listen on! 

Paper here: 

Cox F, Vogrin S, Sullivan RP, Stone C, Koo G, Phillips E, et al. Development and validation of a cephalosporin allergy clinical decision rule. Journal of Infection. 2025 June 1;90(6). Available from: https://www.journalofinfection.com/article/S0163-4453(25)00089-1/fulltext

https://doi.org/10.1016/j.jinf.2025.106495

(It's open access, don't worry)

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Sign up for the BIA Dilemmas Day on Critical Care Infections here! 

Transcript

0:18

Hi everyone. Welcome to the Idiots Podcast. That's infectious disease insight of two specialists. I'm Ja. That's Callum, and we're going to tell you everything you need to know about infectious disease. Soon may the editing, editing come to discontinue the Tazo sun. One day when the CRP done will take our leave and go.

Callum & Jame: 0:37

Callum, before we start,, I need something to help me write something down. I need a pencil pronto. I need a crayon rapid. I need a pen fast. And what a coincidence that is.'cause Who are we talking to today, Callum? Well, today we are honored to be joined. We've done two episodes before on penicillin allergy. But we are not allergists, we are not immunologists, but we are honored to be joined by a real life, uh, allergist. Dr. Fionnuala Cox, and Dr. Cox is a consultant immunologist based in Beaumont Hospital Dublin. She's undertaken a clinical research fellowship focusing on drug allergy in Melbourne, Australia. I guess you could call that an international center of excellence in this field. And now her day-to-day work includes complex allergy and inpatient allergy labeling. Alongside all that very complicated immunology that, I don't understand. Ula, welcome to the show.

Fionnuala: 1:34

Thank you very much. Thank you very much for having me. I've listened before and that, phone was pretty good. I'm gonna say it's up there.

Callum & Jame: 1:42

Kalan does have some humdingers, but, we shall continue.

Fionnuala: 1:46

Guys, I understand you've spoken before about pen fasts and you've had podcasts about penicillin, allergy and de labeling. Your audience, I presume from that, will know, I guess first time listeners, what is Pen fast and why do we care about it? So, pen fast, from my point of view is a point of care risk stratification tool that any doctor and any healthcare professional can use when they first meet a patient. And I understand you are using it, in your clinics or on the wards at the moment. Is that right? Can you tell me a bit about how you've. Implementing it. And what do you understand Pen? Fast to be because I, I, I know all about

Callum & Jame: 2:29

yeah, yeah.

Fionnuala: 2:30

it, to be?

Callum & Jame: 2:30

You can tell us

Fionnuala: 2:32

I can, I can quote you the

Callum & Jame: 2:33

to inform the loyal listeners at f has just finished, that fellowship that we mentioned with Jason Triano, grand Master of the Pen, FAST score, and other scores related. I mean, I guess I can, we can see how my experience with it. Yeah. So I guess Jae and I trained together in NDOs, Royal Infirmary North, and, Jae started the journey along with others, to introduce penicillin allergy to labeling. And often when I give toxin this, I think like back to when I first was around infection and we really weren't challenging anybody or there was rarely people going to skin allergy testing and then came along this idea of actually one, we can actually challenge it and consider whether people truly have an allergy. And that's where Pen Fast came in for us locally, was this really simple, Tool to remember, to risk stratify patients to say, who are these low risk penicillin allergy patients? Who are the people that might be suitable for a direct oral challenge rather than, skin testing. And, locally. Our guidelines are based on evidence around, how this can be used and trying to just hone down the usability of it as a guideline. But we're still essentially getting people to do a pen fast score along with our more extended penicillin allergy history. And then at the end of it, giving them some way to assess it. But, the more I read about it, the more like sort of side complexities there are. Yeah. Like different side chains of cephalosporin. There's just so many of them. So that's been, yeah, I guess locally what we've been doing. And then James being off. Evangelizing it elsewhere? Elsewhere? Elsewhere. Yeah. Nado South. So I, I got a job in Nado, northern firmly southern wing, which is several hundred miles away from the northern wing. And, they're, at the time we were actually doing a trial on pharmacist laid, delayed. And we had some money for that. And, pharmacists would go around the labeling and it was very successful. And it was published and then the money stopped'cause the trial stopped. And so then that service was withdrawn and people were like, oh, what to do? And I said, well, pharmacists can do it. The juniors in NADOs, Royal Firming North can do it. That means that everyone can do it. So I developed De Novo Penicillin. Guidance that was obviously fairly strongly based on what I'd already done in Nado, Raleigh from me north and what Klum had been improving on. The thing I quite like about FFAs, we've said this in previous episodes, is that it is a. Easy structured assessment plan that gives you some decent advice about what to do with, a score of zero, one or two. And then above that it says this is beyond you. You can either send them to an allergy clinic, which of which there are scant few or you just can't de label them and you have to continue avoiding penicillins or kelo sporin. Or do you ula because what have you just published in?

Fionnuala: 5:27

This is a big, yeah. Yeah. So we have a pen fast score. And just to, so everybody's on the same, I guess on the same, grounding here, fa what FAST stands for is, so it's the idea of the tool is at point of care. So when you meet a patient for the first time, you don't have medical records, but what the patient can tell you in their own words, did the allergy happen within the last five years? Or can they remember how long ago it was? And then the A is, did they have anaphylaxis or angioedema? So very specific, was it anaphylaxis? And symptoms of that. So being able to use the pen fast score means being able to take a history. Of knowing what anaphylaxis is and what angioedema is. So not just generalized swelling, but actual angioedema. And then the next one, s is scar. So severe cutaneous adverse reaction. Do they have anything that sounded like a blistering rash, a rash that brought them into hospital, had systemic symptoms with it, or fever, or if they're mucosal involvement in the rash. So a nasty rash. And then t is treatment. Did they require any treatment? They don't have to remember what the treatment was. Anything, a tablet? Did they like an injection? Often patients don't know what they took or did they take anything?

Callum & Jame: 6:45

but I mean,

Fionnuala: 6:46

and that

Callum & Jame: 6:47

of cetirizine equals a point. You know? It can be,

Fionnuala: 6:50

it does equal a point. It does equal a point. However, if they had supposed, anaphylaxis and didn't take any treatment for it, you're, wasn't really anaphylaxis., so this is where, the scoring system comes from, and it's clinically validated, in penicillin. And that was done a number of years ago. And then we did a lovely, well, I wasn't part of it, but some of my colleagues from Melbourne who are a great bunch, did a randomized control trial in inpatients to see whether it worked versus the standard of care at the time, which was to do skin testing with everybody. So if you get a low score on the pen fast under three,

Callum & Jame: 7:31

what each point is. The five years or less anaphylaxis, anema, or scar. They were all two points. And then the, treatment required is one. So the maximum possible is five points. And then if they score zero, one or two, they would be amenable to an oral challenge and three plus it's generally recommended to avoid. And that's got a good, positive and negative predictive values for actually having a reaction. What I find really useful is when you do the score, you're able to then quote a percentage chance of them having a true allergy.'cause I find that most of the people that I'm de labeling have a pen fast score of zero And it's really powerful. The patient's a little bit on the fence about having a de labeling or they're uncertain about how safe it is. And you can turn and be like, there's less than 1% chance that you've got a true penicillin allergy That's pretty powerful. And I think there's a randomized control trial that you mentioned there is at the palace trial.

Fionnuala: 8:25

Yeah, the palace trials. Yeah, so that was undertaken actually a number of centers in Australia, Melbourne being the main one, and then also in North America, So standard of care before this Move towards direct oral challenge was to do skin testing on everyone e even our low risk people. So they randomized people, took history, used the pen fast tool people who were low risk, they did standard of care, which was skin testing, and then if that was negative, a direct, subsequent oral challenge. And then the other people, who are randomized into the intervention group just got a direct oral challenge and they demonstrated that they were equal. And I think there was zero point, 0.5% positive rate on both groups. And it was done over with over 400 patients. So it's very, yeah. Takes away the need to do the skin testing and also demonstrate it's actually quite safe to challenge these patients.

Callum & Jame: 9:18

And just to labor the point, skin testing is actually pretty difficult to come by in the uk and particularly in Scotland actually, where we have a dearth of immunologists. We're not flush with immunologists like Dublin is.

Fionnuala: 9:31

Yeah. Well,

Callum & Jame: 9:32

Um, so you're, you're nearest allergy

Fionnuala: 9:34

a hub Of, of the all of Ireland. Also, skin testing is. A specialty service that has, so it has to be done by a clinical immunologist or someone who works with the immunology team. And it's, it takes time and it's resource intensive and it can be painful

Callum & Jame: 9:49

yeah. And there's a very low predictability as well. Like if it was a, I I kind of think that skin testing and, IgE and all these other things that, that immunologists do, if they, if that was a new test being rolled out today, nobody would approve it. It wouldn't be given the time of day. It was just grandfathered in from yester year.

Fionnuala: 10:07

It, it was a bit grandfathered in. Yeah. But it's what we rely on, we do it, we still do it, and we do it for all our allergens. We do it for. It works very well for food and for our aero allergens, drugs, bit hit or miss of all of them. Penicillin is probably the best one to do skin testing. That's the one that has been validated for. But the other ones also, you have to use non irritant concentration. And then as an immunologist, if you're doing it on something you haven't tested before, you have to do it on yourself to make sure it's not just, causing irritation to the skin,

Callum & Jame: 10:38

So Jane mentioned IgE, so I guess we've got. Immunoglobulins. But actually what I often find is that people talk about the types of allergy that people are having without really maybe having an understanding of the types of allergy now I think I have a basic understanding in my head, but given that whether you take this serious, well, no, I don't want,

Fionnuala: 11:01

Yeah.

Callum & Jame: 11:02

An immunologist with us. I was wondering Could you briefly take us through the different types of hypersensitivity reaction and what differs that from a side effect?

Fionnuala: 11:14

Okay, so both side effects and allergic reactions are adverse events. So you, we don't want either of them happening, but it an allergic reaction. What makes it different to a side effect? Is it the adverse reaction is immune mediated and we can demonstrate it's immune mediated. Versus a side effect might be something that, although unpleasant could be a known mechanism of action of the drug, that only happens to some people. And, allergy has to be from, an exogenous agent to the body. So it has to be something you've either ingested or become exposed to in the environment. So when it comes to allergy, we then sub divide this into the gel and coons classifications that we probably all know from or forget from medical school, and that was described in the, in this fifties and sixties, and essentially divided up your hypersensitivity reactions into four different types of immune mediated reactions. So they're all adverse reactions, but they're all immune mediated. And this is where we get our first one, which is your IgE mediated. So you're thinking anaphylaxis and it's acute onset. And that's the thing that most people are actually really worried about, that if I give somebody penicillin, they're gonna have an anaphylaxis in front of me and we won't be able to manage that or control that. The other two that. We don't really talk so much about our, your type two, which is almost like a direct cytotoxic action on the there. It's antibody mediated, but it's where a, the medication can cause like a hemolytic anemia, so it's directly, acting on the cell. The next type three is where the drug or penicillin or whatever it is, can form immune complexes and then that can get into the small vasculature and cause renal injury or, pain in the joints. And that's almost like a serum sickness, but two and three people don't really think about so much. And as immunologists, we don't manage as frequently. And then type four is the one that I'm scared about most, and that's your severe cutaneous adverse reactions. So that's your dress and your SJS or your Steven Johnson syndrome and your TEN and your age E. So that's what gel and K says however. In recent times, EAACI, so the European Academy of Allergy and Clinical Immunology, who just held their meeting in the very salubrious city of Glasgow, have launched a new way of describing allergy. And they've put nine times

Callum & Jame: 13:47

they've not, they've

Fionnuala: 13:48

Yeah. They really, no, no, no. They've

Callum & Jame: 13:50

Okay. I hate this instantly,

Fionnuala: 13:52

oh yeah. So I won't explain all nine of them, but generally they're the same. But subdivided and from a clinical point of view, it doesn't really matter. Which, subdivision it is, but from a mechanistic point of view, it's kind of important because it will allow us to, figure out, how to target these reactions. And so I guess the gel and coombs is very much a phenotype description of the allergy. Like, what happened, was it an anaphylaxis, was it a rash, was it anemia? Versus the, this more specialized is more an endotype explanation. So it's explaining what chemicals and what, exact, cytokines are behind it.

Callum & Jame: 14:33

I guess as far as the pain fast score goes and your risk assessment analogy, what we are worried about is the severe adverse reactions, which are divided into your type fours. Your, your scar, and your anaphylaxis angioedema, which are your type ones, IgE mediated, and everything else would be considered non-severe, including everything that's actually just a side effect and would be, scoring low on the pen fast score.'cause if it's not anaphylaxis, angema scar, the most they can get is three if it's five years or less. And treatment was required for whatever the side effect was.

Fionnuala: 15:07

Yeah. yeah,

Callum & Jame: 15:08

It's difficult to score higher than that. Which is part of, it's like the setup of it is, it's why I like the pen fast score so much is that it simplifies things a lot into a fairly easy to manage number.

Fionnuala: 15:22

yeah. And the data was taken from real clinical history. So much data was collected on what do people say when you ask them about their allergy? And what are the key words that come out that really demonstrate it was a true allergy? So other things that, people describe. So sometimes people might say, during childhood, I had a rash, but all, we all know about that could be like a viral exam anthem, but it could you know, a scar rash. So then you have to do, you do have to know a little bit about taking history to be able to pull out was it blistering? Was it, what type of rash was it? And if you can, pull from it that it was a benign rash, then they're not getting a point. So there's lots of things that patients will say, you're taking the history, but if it's not me, just over kind of thousands and thousands of histories taking, we find these are the key words that really will signify that it's a true allergy.

Callum & Jame: 16:14

Yeah, I think that the, what I find about Pen Fast is as simple as easy to use as it is. There's still a need to be able to take a history and when we've rewritten our local guidance, we've taken a lot of time to just con, consider how we lay out the history and make that really simple for people that maybe aren't used to taking those sort of, detailed histories all the time yeah. Yeah. And actually our local guidance in Nado South starts with, here's how to take a penicillin allergy history. Yes, exactly. And then says, okay, here's how to do the assessment and then leads on to the labeling. In that order for that reason. Yeah. Yeah. Talked a lot about penicillin allergy and pen fFast and antibiotic allergy in general, and I think Jamie and I can't quite remember what we said before. I'm sure it was good, but we did an episode on penicillin analogy. We said only could do the same thing for spor analogy. I think we did say something like that. So we know that penicillin allergy matters for a variety of pieces. I can go back and listen to that. So why, what about cephalosporin allergy? Why does that matter? Spor, penicillin's smide and kelo sporin is 90% of all allergies.

Fionnuala: 17:48

It is 91%. Yeah.

Callum & Jame: 17:51

Precision is key. So yeah, that's why I guess two, something like that.

Fionnuala: 17:57

Yeah, you do, actually. Most people are, it is penicillin, but the fear is actually people with penicillin allergy labels then get a dual label of sporin allergy. So people say, oh, you best avoid the kelos born and then suddenly gets written and then they keep that as well. So what we do know about Kelos born allergy, those allergy labels are on the rise and they're, the actually kelos borns are the number one cause of, seeking medical advice for a rash, which is often a benign rash. So after, penicillins, telos ones are the number one, allergy label that people have now, it's nowhere near the 10% that is quoted, for hospitalized patients, for having penicillin allergy labels is probably closer to between three to 5%, but depending on where you're practicing. So, the reason it's important is because cephalosporins are often our number one in hospital, and particularly at times when people have severe infections like. Bacteremias and query meningitis. So at times you really want to get a good antibiotic and a first line antibiotic in quick. If somebody has a cephalosporin allergy label, you're you might be on the back foot with a second line agent, especially, because the urgency of needing to get it in and the fact that it's a more, critical, infect in like infection, history.

Callum & Jame: 19:23

Well, and, and ke sporin are experiencing something of a resurgence, not least because of the SNAP trial, which you also mentioned in your paper. Another Australian trial, if it's, multi network net international adaptive platform trial can be said to be Australian. But the, cefazolin Is maybe and already is in some parts becoming the standard of care for staph Orus Breia. So if we're going to be throwing cefazolin at everything with gram of Cockeye in his blood Kelo Sporin analogy is, labels are going to become an increasing problem. And as we use more cephalosporin, I presume there'll be more labels. I guess that the fact that penicillin allergy is so highly labeled is because we use so many penicillins. You mentioned there about the risk of cross reactivity. So when I was first training, people used to quote me, 10% cross reactivity between penicillin and kelo, sporin allergy, and 1%, I think with carbopenem, and as I've learned more, I think that doesn't make sense. What, and I also think it's quite hard to put a number to that, but I'm gonna ask you anyway. What is, if someone was to say, what's the rate of cross reactivity, and I think I know what you're gonna say, but I'm gonna ask you anyway, what would you say to that question?

Fionnuala: 20:36

what would I say? Well, can I do a bit of a history lesson? So the lore that I am, have been thought is the cross activity between penicillin and cephalosporin That 10% came from, essentially when the first generation kelos borns were being developed and manufactured. They were manufactured in the same site as penicillin. So a lot of the early cephalosporins were actually contaminated with benzo penicillin. And also benzo penicillin back then was a different beast to what it is now,

Callum & Jame: 21:07

with coming from the same fungal cultures or similar. Yeah.

Fionnuala: 21:11

Yeah. So, having, allergic reactions to benzo, penicillin probably was more prevalent in the past. And then particularly if then your cephalosporin had a bit of. A pinch of pen, pen. In it, those same pe people would be, would have allergic reaction. So when the company were releasing the first generation Catalyst warrants, I think that they felt that the cross reactivity rate or was like seven to 8%, but they just rounded it up to 10 for ease for the patient, leaflet. So that's where that 10% came from. So it probably wasn't a true cross reactivity to begin with. It was more contamination. But what we do know now is between pen penicillin and cephalosporins, they're both beta-lactams. In the past, people thought it was the big beta-lactam ring that people were allergic to

Callum & Jame: 22:02

That's what the BNF says. Actually, if you go into the B and you look at the allergy section on. Beta latum in general penicillins, it says that, the reaction is due to the beta latum ring.

Fionnuala: 22:13

So I guess if you have a penicillin allergy, it could technically be to the fetal lactam ring, but even at that, it doesn't cross react to the lactam ring of, the Keli Sporin,

Callum & Jame: 22:24

No.'cause they are different. the

Fionnuala: 22:27

mm,

Callum & Jame: 22:27

km ring and the beta-lactam ring are actually differently structured. They just share a beetle latam bit. Yeah, So is it, um, our understanding is it's more the side chains that are important.

Fionnuala: 22:40

side chain. Yeah, it is. The, R one. So, when our later penicillins were developed, or amino penicillins, like our, amoxicillin is probably the most prevalent one that we use. They, added some chop side chains exa essentially to, to the ring An AM immuno chain. So that's the oral one side chain. So what we find now and our allergy knowledge has developed so much in recent years that people are more likely reacting to. The side chain and not the ring structure. And it's all about, if you wanna get into the weeds of immunology, it's all about haptens and how the body sees, the structure and how it's broken down in the body and how the immune system processes and is So it's a way a protein can be banned and shown to T cells. So essentially we think that people are more reactive to side chains than to the main structure. So when it comes to kelos borns, some kelos borns,, share, say share side chains with some of the penicillins. So I guess when you're treating patients, you probably think of kelos borns in different generations, and that's how you treat, patients. But as an allergist, we think of them more and what side chains are associated. So your cefalexin and your cefaclor have a similar side chain. And then when you get onto your ceftriaxone, that has a different side chain. And that's, that's similar to your ceftazidime and cefuroxime. And then Zolin again has a, a different side chain

Callum & Jame: 24:10

Yeah. And, but side chains completely unique, isn't it? So it doesn't cross anything. So you can't just think the first gens cross, right. With each other. The third gens cross. It doesn't work like that.

Fionnuala: 24:20

It doesn't work like that. You need a table. You need a table,

Callum & Jame: 24:23

and we have a table, don't we? Yeah. So are we going to point to the Dutch swab table

Fionnuala: 24:28

The Dutch one is good. The Dutch one is good. However, I will say, so I think most, like most allergists would know, the ones that we commonly use and which cross react with each other. However, some of the tables that you see for cross activity with cephalosporins, there are some differences. So again, I think it's EYE are going to publish A, consistent one. That is, yeah, with a heat map. The cross reactivity. So some of the tables will have show cross reactivity. What you're really looking at is the OR one, but Catalyst Warrens have an OR two, which is less immunogenic.

Callum & Jame: 25:08

Hmm.

Fionnuala: 25:10

So,

Callum & Jame: 25:10

Yeah, you mentioned that in your paper actually. And the Dutch swab table has a different color coding for R two compared to R one, and I never really know what to do with that. I know R one's important. I know Penicillin, moty allergy is is important. I don't know about R two, so it's reassuring that you say that it's less of a immunogenic

Fionnuala: 25:31

it is less immunogenic. Yeah. So when we look at these tables, people I think focus on the antibiotics, you know, and use a, there's a lot of, SSPORs use on, on the continent and in North America and in Australia that we don't use in Ireland on, and from what I know from my knowledge in the UK either. So I think it's more that some of those more niche ones, there might be disparity between the tables, but when it comes to, Keflex and Kelo, they're joint together. And then your Keone Keine, that's joint and your keone in a separate. And then when it comes to cross reactivity, that's where the R one, some people, not everybody, but some people who have a, an anaphylaxis to an amino penicillin like amoxicillin can also have the same immediate reaction to, an amino Keli points, or your Keflex and your

Callum & Jame: 26:25

Mm.

Fionnuala: 26:27

But that's, it's not everybody. And also all of the data is coming from Australia and North America, some from Europe and some from the uk. So there's, even in those different gene pools, we see different, percentages of people who have this cross reactivity. It's said to be about like 1%, but

Callum & Jame: 26:47

yeah. I think we've said two previously on the show, less than 2% for sounds and first gen, because I find it like I've got this amazing table from the Dutch guidelines, which we'll put in the show notes outside the table that's more specific to ke SSPORs. From your paper. But I struggle sometimes to implement that locally because there's still this lingering reluctance to use cephalosporins even if there is no side chain homology. In patients that have reported a penicillin allergy and often our patients end up on a carbapenem because that's viewed as a sort of safer option despite all the sort of obvious, obvious negative impacts as the microbiome and other risks that go with that, not let alone a stewardship angle. So I guess I wish there was some way that I could make an assessment of someone of a careful spor allergy, maybe some sort of thing, a bit like pen fast. Oh, this is a link that canand that can be used. Oh, I understand. To know what's going on, to try and dela these patients that be useful, say up Callum, and what a coincidence that is. Pula, do you want to tell us about your paper now that we've done this?

Fionnuala: 27:49

Yeah,

Callum & Jame: 27:50

pre

Fionnuala: 27:51

that

Callum & Jame: 27:52

Keep it, keep it quick.

Fionnuala: 27:53

Keep it fast. Keep it fast.

Callum & Jame: 27:56

Yes. Hardly

Fionnuala: 28:00

And so the, it's called Kfa and it's joining the trilogy of Fast so that we've pen fast. So fast kfa, Sofast is a similar scoring system to pen fFast. You'll have to read the paper. It was, published in a journal of infection there recently. And I'm sure we can link it in. I think it's a free access.

Callum & Jame: 28:19

Into the show notes, got the pdf, and yeah,

Fionnuala: 28:22

amazing. Okay, great. Everybody should read it. To have a good understanding of what's going on. But in a nutshell, essentially it's the same five years, angioedema, anaphylaxis, scar and treatment, slightly different scoring system. But, very similar two points for angioedema and scar and one for five years are treatment.

Callum & Jame: 28:42

The questions are different, but the interpretation varies subtly, doesn't it? Because in pen fast, the answer is unknown, you get a point. But I know from FFA that if it's unknown, then you don't. Give a point. Do you want to explain briefly why that's the case?

Fionnuala: 28:59

So Our wonderful statistician, Sarah Roran, who works with us on many of the papers, has demonstrated that having unknown is similar to no and has had the same negative, predictive outcome. So that's why it wasn't scored, for the CFAs score.

Callum & Jame: 29:21

Okay. So it's really simple because it's essentially we're doing this same thing.'cause I always wonder that with pen pass, just oh, I'm just gonna slightly sle over and use this on my kelo, sporin allergy labeled patient. But it's really reassuring to have the data now to back up what, in a way just feels like common sense. I don't dunno if that's fair to say or not. I guess you can't assume things about having them proven, but Yeah. But I guess it means that with Kfa it's yes answers only that give you the points, but with pain fast, it's still unknown or yes, answers that would give you the points. And so you can't combine them into into an all fast

Fionnuala: 29:59

Yeah, but I guess it's the same pneumonic and the same

Callum & Jame: 30:02

And the same questions to ask, which is beautiful.

Fionnuala: 30:23

the same questions. So that's like creating a different tool. It is just not as applicable and not as usable for the point of care setting, having separate tools. So that's why and I guess people are more likely to, use it when they, have the familiarity with how to take a history in that format.

Callum & Jame: 30:44

Absolutely. And in fact, I've done it for Keli Spor analogies even before the publication of this paper, which is probably quite naughty. But if you assess somebody with a K Ffis full analogy, and their pen FFAs score is zero, or K FFAs score is zero,, as I would now call it, that is reassuring to the patient. I wouldn't, I didn't tell them the numbers, but I would just say this is low risk. And how does it perform? Because obviously we know the percentages. From reading the paper, it seemed like it wasn't quite as good in a negative predictive value of the low scores.

Fionnuala: 31:15

yeah, it's still strong though. It's still, so the low ca fast score will give you, a 5.7% chance of a positive test, so it's still. A low for direct oral challenge. However, I do understand it's not as low as the pen fast, but it still gives reassurance to the person, particularly if you have a score of zero. In the paper goes through which the percentages for each score level. Also it talks a bit about the cross reactivity and like safety of giving non or one cross-reactive kelos borns and how, you know that can be used.

Callum & Jame: 31:54

Oh, that's right. I wanted to ask you what's the nomenclature that you use when you test the actual Keo sporin compared to just testing one that shares the R one

Fionnuala: 32:03

Oh Yeah, so, it's like RR one identical and R one cross reactive.

Callum & Jame: 32:08

right. Okay. Yes.

Fionnuala: 32:10

Yeah. Yeah.

Callum & Jame: 32:11

So do you want to describe what you mean by that?

Fionnuala: 32:15

so, or one identical is when you use the index cephalosporin and then a cross reactive one will be one that theoretically you would cross react with because it has the same or one side chain. And the reason why that's important, again, for making clinical decisions,, if somebody has a capital sporin allergy label and you really wanna stay away from it using a non cross-reactive hormone, one side chain, you're definitely in a safer ball pool, then you are using one with a cross-reactive sighting. But when it comes to allergy testing, we, not all of them are in formulas that we can do skin testing too. So sometimes, when you know your RAC is to the wall and you're doing skin testing, you'll pick one that you can do skin testing too, and is most similar to the index one that the person has a label to. One thing that I didn't mention earlier actually, is. When it comes to all this cross-reactive data, it's all pretty much, based on IgE mediated, so your anaphylaxis reactions, and we don't know so much about scar. So although some data has been published that if you have a, like a dress or a severe cutaneous adverse reaction to a kes one, people haven't really tried it with the disparate side chains or the similar side chains because people don't really want, to try that. So, so we really, we know it for the IgE mediated the anaphylaxis people, but if somebody's had a bad Steven Johnson syndrome, you definitely want allergy input before you try them on another cephalosporin, even if it is of, for.

Callum & Jame: 33:59

Yeah, I guess the. I'm thinking about the patient that we had in Nado, Roland firmly north, they had dressed to Meropenem, and we told them that you can basically never have a carbapenem ever again, as in total avoidance. And I wonder at the time how evidence-based that was, but we were too scared to suggest anything else. And so treated them with other stuff. Yeah. But it's interesting that you say that the evidence behind that's, variable because it, it sometimes feels to me like, or nomenclature hasn't really caught up with the science yet because patients are often given a label of quote unquote penicillin allergy, which ends up translating to all beta lactams, or I guess even now you're talking about all the side genes, I feel like I need to be better. Instead of saying, Kelo spor allergy, saying Ctra allergy, and then caveating that with the type of allergy. So Keft Rx analogy, anaphylaxis is very different from ctra allergy scar. I think there's some work going on about getting some sort of healthcare data labels applied for this.

Fionnuala: 34:58

Yeah. However, it's a, it is definitely a more recent thing that Ketra or Kef sporin isn't just a blanket allergy, like you are getting it a bit more niche territory. So be very impressed if kind of general physicians were, de labeling. To that extent, I think we really need to focus on, the penicillins first and then the kelo ones. As, picking at your low risk people and just even at the low hanging fruit, and I am a big fan of, the beauty of the directly label. So just getting a good history and was never allergy to begin with. I think that's really where people can start

Callum & Jame: 35:35

We've said before all the negative consequences of a pen allergy, label, half of the papers that we point to you, you're probably one of the authors on anyway. So we will not bela the point anymore. There's the previous episode for people to, go to, but these allergies do harm, let's just say.

Fionnuala: 35:53

Yeah, so Kimberly Blumenthal and her group, published a recent meta-analysis that looked at 56 studies, over 9,000 participants, and they showed in that meta-analysis that with over 9,000 directoral challenges, that there was an extremely low risk of somebody having an adverse reaction. I would think it was like, 3.5%. And of that, it describes reach like how many and what their reactions were. So the kind of take home from that is sometimes it's more dangerous to carry a label than to challenge the label

Callum & Jame: 36:25

Yeah.

Fionnuala: 36:26

and, but, but saying it is extremely low risk, you still need consent and you still need written consent. And that's really important because a patient has a label and they believe they're allergic. You can't just do label them without telling them. So they still need consent and they need written consent. If you're gonna, what you say, challenge them. And if you find that's not an allergic, if you take a history and you can do a directly label where it just wasn't consistent with allergy to begin with, it was like thrush or GI upset in isolation, you can directly dela them and take away their penicillin allergy label, but you still have to tell them. And it's good to tell them that in writing as well, because they will just come back.

Callum & Jame: 37:05

We've recently rewritten our guidelines to have that, the first step as James had on is the history. Then it's suitability for, direct directly labeling, and then say what the histories are, and then it's suitability for oral challenge, and then it, you basically do the challenge and the outcome., And that's really powerful because obviously you don't need to, but I do find that sometimes people want that extra reassurance of having a OR challenge, which is fine, even if it's like a side effect.

Fionnuala: 37:32

And, to be honest, actually the, there's a good B-S-A-C-I guideline that's a, that is focused on non allergists doing challenges and testing. So if somebody doesn't have an allergy history, but they're just very concerned, it's not necessarily a challenge, but a supervised dose is reasonable if it means that they'll be more comfortable to take it a reintroduction.

Callum & Jame: 37:56

You're talking about the besa. Guidance. I, remember the old guidance in 2014 was very much all tied to the man who tries to dela a patient. And then the guidance 10 years later is a complete sea change and is very positive and is really good actually. Yeah, it's really

Fionnuala: 38:15

yeah, it's nice. It's a

Callum & Jame: 38:16

I've used that guideline and one thing that's confused me is that every time I read a trial, I'm really interested in what they put as a contraindications to the labeling, on an oral challenge. So the Oracle trial, which was mentioned earlier on in the Palace trial, obviously the Bsna guidance, and each of them gives a slightly different list of contraindications, which usually includes variations on pregnant. Plus or minus breastfeeding, severe asthma, severe disease, severe cardiac disease, clinically unstable or for this, and it'll include things like, any history of certain medical conditions. And then one that's been recently added as, omalizumab, which is this anti drug. So recently trying to get my head around that., So I, my assumption is just that, people are in contraindicate'cause they're not included in the trials in which we base the guidelines and the evidence.

Fionnuala: 39:13

Yeah. So the article is a good example. So traditionally people wouldn't challenge antibiotic allergies while patients were in ICU because they might be on inotropes and steroids and things that could mask an allergic reaction. So the Oracle study demonstrated that people, while they were in ICU, they had to be all off inotropes and they had to be at a certain steroid level. But if you did a low risk penicillin, direct oral challenge in the ICU, and then these patients would have the same challenge when they got to the ward a couple of days later and demonstrated that people who had the negative challenge in ICU while on those medications also would have a negative challenge on the ward after. so traditionally icu, PA ICU patients weren't, were challenged, because of those reasons. Then other contraindications such as pregnancy, we don't like to do anything in pregnancy that, that doesn't have to be done. But I mean, if you're gonna have, if you're syphilis or you

Callum & Jame: 40:17

Well, that's a bit of a joke, isn't it? If you're wanting to treat syphilis in a pregnant lady, you might do a desensitization program, but a direct oral challenge because they got nauseous on MCL one time 10 years ago, is considered high risk. Well, that they would get to be directly labeled.

Fionnuala: 40:32

The actual original study where desensitization came from was a group of pregnant women infected with syphilis, and they, I think it was 11 women and they desensitized them all. But looking at today's criteria, and there's a nice little paper on this that I can link you in with. They, looking at today's criteria, most of'em would be suitable for a direct oral challenge. And then the best bit is of the 11 patients that went under a desensitization, for penicillin, seven of them subsequently had penicillin within the study period, thus demonstrating they weren't allergic to begin with. Because the idea of desensitization is you give small amounts and you build it up until somebody tolerates the dose. And then once a couple of half-lifes of that medication have gone. So after stopping the medication, after a few days, you regain your sensitization. So a lot of the desensitization data has actually been, superseded

Callum & Jame: 41:28

So just going back to the congen indications thing. So, I guess the way that I've taken it is that there's two reasons to, to avoid oral challenges or that is conjugated. One is acutely on well patients where if the unlikely event they had a reaction, you would tip them over into a point of no return in critical illness. That makes sense to me. And it seems like every paper slightly redefines what that risk is, but ultimately the way I've written it is just basically, clinically unstable patients not suitable for charge. And that includes things like severe asthma where they may not respond very well to Ana to anaphylaxis treatments. And then the other one is the patient may have a mass, immune response to the challenge. So you might not see a positive. You mean like people that are on beta blockers and stuff? Yes. I don't know if beta blockers really needs to be on the list. From what I've seen, it's dropped out of exclusion. Oh, has it? People that are on antihistamines high dose steroids or am omalizumab, which I'll say differently every time.

Fionnuala: 42:26

omalizumab. Yeah. So the beta blocker thing is that adrenaline doesn't work as well because, and you might need to give glucagon, but however, if you're doing a low risk al challenge and someone who's on a beta blocker, what is recommended now is that you just hold the morning dose and give it to them after the ch do the challenge of the morning, give it to them after. And by no means would you want them to have unstable cardiac disease if you are doing a challenge. But if they're on a regular beta blocker, you can definitely, similar for ace inhibitors as well.

Callum & Jame: 42:55

I find it very hard because everybody seems to use slightly different

Fionnuala: 42:59

slightly be different I think. Very reasonable. If somebody is clinically unstable, just don't challenge them, wait until they're stable. And then when it comes to the, something masking a response, I guess you, if a patient needs a penicillin and they're on a regular antihistamine for their hay fever, just give them the penicillin and. A single antihistamine will not mask an anaphylaxis.

Callum & Jame: 43:24

that's true. I was just thinking actually,'cause if it did, then what we do, we would just give everyone an antihistamine and then give them penicillin.

Fionnuala: 43:31

yeah, yeah, yeah. If that was the thing, if that was the answer, if like food allergy wouldn't be a

Callum & Jame: 43:36

Yeah, that's a great point. I actually hadn't thought about it that way round, which, no, I wondered if it was like the people were worried it was gonna mask the rash as if cetirizine the second you're on cetirizine or Loraine, all your urticaria disappears and you get to skip out of the office. Oh, chronic urticaria must be very easy to manage that. Ah, well, isn't it? Just tell about that. Sure. For another

Fionnuala: 43:56

passion. But I will say if I, ideally they wouldn't be on an antihistamine because what you're say, what you could be saying is you could mask early signs of an anaphylaxis. However, if you're challenging people who are low risk. Oftentimes there isn't a history of anaphylaxis. There's usually a history of a delayed, benign rash.

Callum & Jame: 44:19

When you say delayed benign rash, that's type four

Fionnuala: 44:24

like a macular papular ex exam anthem. Yeah,

Callum & Jame: 44:27

as well,

Fionnuala: 44:28

it's, yeah. So this is where the new Iki nine types come into play because it,

Callum & Jame: 44:34

I? Yeah, I always find that confusing. People were worried about type four, and I was like, in the old classification, type four included like a benign macular papular rash. That's my understanding.

Fionnuala: 44:42

Yeah. But was the benign macular papular rash a viral example? Or was it to do with the drug to begin with? So that's, yeah. Yeah. And omalizumab again, technically you could mask a reaction, because it's actually now being used for allergy

Callum & Jame: 45:02

okay. I, guess what you're saying is if they're on any of the stuff, if they are very low risk, it's probably fine. Which most patients that usually, so they're more relative than absolute contraindications. And I guess it depends on, as of all things in medicine, balancing the risks then they should be called cautions,

Fionnuala: 45:18

And in a research study, you would repeat it after, like you would repeat the challenge. I had someone recently and they took it while on an antihistamine, so we brought them to our day ward, and we just gave them the penicillin without the antihistamine to demonstrate that they were

Callum & Jame: 45:31

okay that. leads into my other selfish question, which was, delayed reactions. So we are very well set up for inpatient, well, not very well, but we were set up for inpatient de labeling episodes where the patient's given antibiotic in hospital monitored closely. But what we fail to have is some,'cause we don't really have a allergy service, so, we don't really have a good way, if someone three days later develops a rash to like.

Fionnuala: 45:55

Mm.

Callum & Jame: 45:56

well, the, this sort of delayed reaction area, are, is there any ways that we can figure out who those people are going to be? And, are, is there any value in doing things like sequential, like you do multiple challenges over the three day challenge or something? Does that improve your pickup of that?

Fionnuala: 46:13

Watch this space. there will be a trial, coming out. So.

Callum & Jame: 46:17

oh.

Fionnuala: 46:18

So essentially again, all the meta-analysis and the data, so far haven't demonstrated whether you should do a single dose, allergy challenge or whether you should do it for a few days. And whether that's three days or five days, and again, as you mentioned, particularly in childhood, a lot of times the reaction or the rash can happen on day two, the day three. So by giving them a single dose, are you really demonstrating do they have the rash again? And these are not severe rashes, they're what we call our macular papular exams. They're a bit itchy and then they go away after a day. And usually when you stop the antibiotic. So was it due to the antibiotic or was it a different external factor? Occurring at that time as well. So generally people give a single dose, however. Sometimes, and I do it too if it's a more recent, event. So in the last I'd say five years and the rash was a benign rash and it happened on day two or three, I would usually give them a single dose in the clinic. And then send them home on a course of like, if this is ammoxicillin BD for the next three days, but the single dose, they would take it that day and then wake up the next day, check if they have any rash, and then after that, for the three days, take it. So sometimes what we find is somebody after the single dose, they may not have a rash immediately, but may wake up in the morning the next day with a rash and then they won't take it. Or they might be on it for a few days and the a rash might occur. The vast majority of people are ab absolutely

Callum & Jame: 47:51

What percentage do you had to put a number on it?

Fionnuala: 47:56

So these are usually our low risk. And prolonged allergy challenges, I would say like over 90% are actually fine and they don't have anything. And this is where the beauty of the trial will come in. So, people are given the direct oral challenge, low risk, and if they have an unknown or a delayed benign rash, they're given both of them given their amoxicillin. And then one set are sent home with a five day course of amoxicillin to take from the following day. And the other set are sent home on a five day course of placebo to take. And that will really show us whether, that one dose can cause that allergic reaction, but in a delayed phenotype, or whether you need a few doses to really bring out that rash It is pretty exciting. It's the first time it's been

Callum & Jame: 48:47

Yeah. Yeah. Well, That's Well, that's, my question. I had, and you've, you not maybe not told me the exact answer, but you've told me that you're gonna answer it, which is I guess the next bit.

Fionnuala: 48:55

we are going to, but we don't know the answer, but we will answer it. I have a feeling there's a percentage of people out there who have a delayed rash after one tablet,

Callum & Jame: 49:04

Yeah, I think, I think so too. But yeah, it'll be really interesting to see the answer, so I'm glad that people are doing all this important research while we just record podcasts. No, not us. We are very much just living on the coattails of the real scientists.

Fionnuala: 49:16

Can I, can I give a plug up for a study? Can I mention a study that I didn't put in and I should have

Callum & Jame: 49:23

yes, yes.

Fionnuala: 49:24

a study? So think palace. So Kelos Born the Castle trial is coming where we'll do similar randomized control with, low risk kelos born, whether standard of care, which is your skin testing or direct oral challenge. So that will really show us how well calf fast works in the fields. And I think that will answer more questions for you and also, provide clarity on your side chain reactivity

Callum & Jame: 49:52

That's a fantastic name. So you've gone from the palace to the castle. So what next is there gonna be Fortress and or Bastion? Could be another one. I think there's quite a few different sort of, it has to have a scene. It doesn't, if it's car, I guess, but hang on. Like what, uh, what does So in the ca, in the capital trial, how do you get around what you mentioned earlier on, which is obviously there's quite a few ke SSPORs that don't have oral formulations available.

Fionnuala: 50:18

so it'll be oral or iv. It'll be, a lot of them will be in inpatient. So you can do an IV challenge

Callum & Jame: 50:25

okay. Yeah. For some reason I never have done that, but I guess that makes sense.

Fionnuala: 50:28

Yeah, so an allergy and also it's becoming, or I am given I am dose. And a lot of our high risk kely, sporin allergies are actually coming from the perioperative clinic. And that, that's mentioned in the paper a lot. So I think it's, if somebody has a high risk, and it's coming from, like zolin is the number one cause of perioperative anaphylaxis,

Callum & Jame: 50:50

Yeah, there, there was a paper out of America that you've probably seen, but was all they did was in pre-op clinic? Not all they did, but they did quite a few interventions. But in the pre-op clinic, they had a sort of Keli SPO side chain, cross reactivity table and able to show that even without de labeling, Kelo, Sporin allergies, just educating people and putting up this cross reactivity, they were able to reduce the rates of more toxic and higher risk side effect drugs like Tyco, plana and other glycopeptides significantly, and use their sort of kelo sporin more readily just by, using ones of different side gene homology. So there was like, there was a lot of.

Fionnuala: 51:25

That's a lovely study. Although another thing is like, carrying cappi allergy label or indeed penicillin allergy label, you're a much greater risk of having post-op surgical site infections. And that's just from missing that one first line, prophylactic dose, you know? So it is really impactful. yeah,

Callum & Jame: 51:44

So we've covered a huge amount of stuff there in this, the third and the trilogy, which I think most people will probably agree is the best. so we introduced again, penicillin, allergy and pen fast and the importance of allergy. We heard a little bit briefly about the different types of allergy, the gel cos and the unnamed, nine rings. What is there a name for that new system? I dunno.

Fionnuala: 52:09

I dunno if there's anything catchy. It's very European.

Callum & Jame: 52:12

Yeah. And then we talked about the rates of cross reactivity of careful sporin allergy, what the historical context was of that. We talked about cross reactivity, a different kind, sporin, the side chain homology. I moved forward into Cfat building on the foundation of pen fast. I asked him questions about contraindications to allergy de labeling, which is very educational for me. Thank you very much. And also about delayed reactions and, the potential use of prolonged challenges to bring out those delayed reaction. And we, ended on, highlighting the upcoming trials, which is really exciting, the Castle trial, which would be the, randomized control trial for Kelo Sporin allergies. So yeah, that's what we've covered.

Fionnuala: 53:02

Oh, one last thing before we say thank you. Do you know the Immuno tea podcast?

Callum & Jame: 53:07

oh yes. We're well aware of our bro dogs over at the Immuno Tea Podcast. Oh, Jason Triano was on episode four, five.

Fionnuala: 53:15

Yeah. So that's my mate, Laura Dungan and Vian Denberg. And they'd,

Callum & Jame: 53:20

we I'd love do a collaboration with them, at some

Fionnuala: 53:23

Can we give them a little shout out?

Callum & Jame: 53:24

Yes, by all means, if you are interested in matters immunological, then Immuno Tea is Europe's Premier immunology, podcast as we are the UK's premier Infectious disease podcast. Asterisk, asterisk. Yes, you should definitely, dunk into the Immuno Tea podcast. I'm not sure that's why our surname is Duncan dunk. Oh, actually it wasn't even, I was talking about teabag Oh, right, okay. I just assumed. I just assumed. Absolutely. God awful. Pun and subtly insulting fan's. Friend, no fan. Thanks for coming on the show.

Fionnuala: 54:02

it's been a pleasure, a joy. Thank you very much for having me.

Callum & Jame: 54:05

so much for coming on.

Fionnuala: 54:07

Thank you.

54:09

Thank you for listening to the Idiots Podcast, the UK's Premier Infectious Disease Podcast. We are supported by the British Infection Association, but they do not have creative control over the episode content, so please don't blame them if we get something wrong. Questions, comments, suggestions. Why don't you send them into Idiots podcasting@gmail.com. Have a five star review in your pocket at call, and I would love to have it. Please drop it in your podcast player of choice. We tweet at Idiots Pod and if you want to donate to support the show, there's a link to do so in the description. But until next time, I'm Jane. I'm Callum. See you now. Now that the episode's done, we hope you learn, had lots of fun. So go forth and treat people with some of what you now know.