110. The yeasts: Candida part 3, C. auris and Candida resistance

The conclusion of the Candida trilogy focuses on the rise of the Lord of the Candida resistance mechanisms: C. auris.

Alyssa and Callum are joined by returning guest Professor Tihana Bicanic to discuss the rise of C. auris. Here we highlight some resources for managing this difficult to treat Candida including the recent UKHSA updated guidelines. 

We also discuss anti-fungal resistance mechanisms in Candida in general.

Although this concludes the Candidal section, there are more yeasts yet to come!

Show notes for this episode here: https://idiots.notion.site/108-110-Yeasts-Candida-0eb5f9271f654312b59458d39f8de603?pvs=74 

Chapters

• 0:00 Candida auris and candida resistance

Transcript

0:00

Hi everyone, welcome to the Idiot's Podcast, that's infectious disease insights of these specialists. I'm Callum, and that's Alyssa, and we're going to tell you everything you need to know about fungal infection. Soon may the editing come to discontinue the tazos, son. One day when the CRP's done, we'll take our leave and go.

Alyssa: 0:23

Hi Callum!

Callum: 0:24

Hi Tihana

Tihana: 0:26

hello. Hello.

Callum: 0:27

Welcome back. Thank you for agreeing to return. we're privileged, to be joined again by, professor Tihana Bicanic, who's a professor of infectious disease and mycology at St. George university, London. And if you haven't listened to it already, then please now go back. pause this episode and come back to it later. But go and listen to our invasive candidiasis episode, because this is really a continuation on from that. But if you're not listening to me, then, we, are honoured to be joined again, to talk about, Candida auris and Candida resistance in general, which is obviously very topical as we're recording here in early 2025.

Tihana: 1:10

Would you like me to tell you a little bit about auris and why I think it's important?

Callum: 1:15

uh, would love that because I think everybody listening will be, reading about this and it's obviously, really. Topical and relevant issue for infection trainees in UK, but infection specialists globally at the moment. So, if you were able to give us a brief, overview, I feel like we should have done a pun, but we haven't done one.

Tihana: 1:36

I think we should call this, podcast episode Candida auris coming soon to a hospital near you. So, yeah, Candida auris. So, auris, as you know, is, of the ear, and, it's one of the newest species of Candida that was first identified in 2009, but in retrospect, I think, has been shown to be around for longer than that. But it was identified from a Japanese scientist. person's ear, hence auris, but since that time, it has spread globally, across, really all the continents, and there are Six clades. of which the first one is the South Asian clade, and then the second East Asian, then African, South American, Iranian. The sixth clade was described only end of last year from Singapore, which are widespread globally. For whatever reason, and some postulate that it's due to climate change, these clades seem to evolve simultaneously on all these different continents. And, Candida auris, compared to other Candidas, is very, thermo tolerant, so it tolerates higher temperatures, as well as, tolerates higher salt concentrations and one of the theories is that climate change has contributed towards its evolution, but there's still gaps in our understanding of whether this was an environmental organism that colonized humans. But nevertheless, there are several concerning aspects about this yeast. first of all, is that it's very adept, probably even more adept than other candida, species at, colonizing patient's skin. And, it Persists once it colonizes the skin and it's very adapted. It has a virulence factor called adhesion surface colonization factor, which allow it to adhere to the skin. It also can enter deeper layers. And therefore, once a patient is colonized, particularly patients who are long term dwellers, either in hospitals or ICU or long term ventilatory facilities, nursing homes, it persists. and we do not have a reliable decolonization regimen, unlike with MRSA. Unlike other candidates, it's not so much a gut commensal, it's more skin, particularly nose, axilla, groin. It also is spread, into the environment around the patient in terms of equipment, biofilm former, Once again on the surfaces, it's transmitted between patients on the hands of healthcare workers and through shared equipment such as thermometers or other equipment like blood pressure cuffs. and it's very resistant in that environment to cleaning with standard ammonium based compounds. So that's another worrying thing. It persists on the skin, it persists in the environment, we're not very good at eradicating it from the skin, and you have to switch to chlorine based cleaning to eradicate it from the skin. Um, the environment and or to single use equipment. And then the third thing why it's concerning and probably I think the most concerning clinically is that almost all the clades are resistant to fluconazole, which as you all know, I'm sure, is the oral and step down agent for treatment of invasive candidiasis as we discussed in the last episode. And echinocandins are the recommended first line treatment as we discussed, but around five percent of patients have primary resistance to echinocandins. However, there are increasing reports of resistance evolving to echinocandins during treatment. and certainly in the U. S., resistance rates have doubled in recent years. So that is a concern. And Amphotericin B, there's also around a third resistance, although again we can discuss what that means because there's only a tentative break point as they are for most drugs and isolates cluster around that. But so our three main classes, if you like, Azoles, Echinocandins and the polyenes Amphotericin B. This is, if you like, the first MDR candida that we have, with some cases also being reported as pan resistant now, coming from the United States. So, we are now entering 2025, where we're seeing some outbreaks of candida auris, including in a hospital in London, and also in Southampton and would spill over to other hospitals in London, and therefore it's a very topical time to be discussing auris.

Alyssa: 6:55

Fantastic, thanks so much for that, for that introduction and an overview to Candida, Candida auris. One thing I wanted to ask is, it's interesting clades, isn't it? And, do you know which clade we predominantly see in the UK or do we, are we really a melting pot of these?

Tihana: 7:14

I think we mainly see clade 1, the South Asian, but I think we also have some of the other clades as well, but particularly in London, obviously we have patients from all over, but my understanding is that our current UK outbreaks are largely clade 1. the South Asian clade.

Alyssa: 7:34

And I guess just for listeners, part of why that's important is that, resistance tends to be, resistance patterns are quite clade specific. So clade, I think, is it clade 2 is intrinsically resistant to fluconazole, whereas the other clades are commonly resistant to fluconazole, but that's an acquired resistance so some might be susceptible.

Tihana: 7:57

Yeah, I think there are, I think the South American clade is the one that's more often susceptible to, fluconazole. Whereas the vast majority of the other clades, my understanding is that they are, resistant to azoles. and really I would not recommend in our setting, trying to use azoles unless you're You know, forced into an oral step down and you've got confirmed susceptibility to one of the non fluconazole azoles. But I would not be using fluconazole. In fact, the use of fluconazole for prophylaxis or treatment in places like South Africa, where candida auris is now the second most common cause of candidemia, is, has been associated with auris colonization and infection. So. We know that in addition to the other risk factors for invasive candidiasis, auris tends to affect patients who are heavily both antibiotic and probably antifungal pre exposed, paving the way for even selecting this organism. And these are often patients who've been in hospitals a long time and certainly in my experience and in the published literature have often had for example, resistant gram negatives associated, isolated as well. So these are a group that almost are, there's a successive selection of, treatments, both antibiotics and antifungals, as well as being in an environment where You're more vulnerable to transmission and colonization with these organisms. So, my view is that we have to take it as seriously as we do resistant Gram negatives, and we have MRSA in the past, and we have a unique opportunity now in the UK to take this seriously and act, on a national level before it becomes, endemic in our hospitals, which is the risk and which is what has happened in places like India and South Africa. and that's why I think you all need to be, on alert for it in your own centres.

Callum: 10:19

So I guess we're saying take action. what action can be taken? Because it certainly sounds like we've got this opportunity to act now. So, say I was, a microbiologist working in a, hospital in the UK and we didn't yet have Candida auris. What steps can be taken or should we be taking at this point in time, do you think?

Tihana: 10:45

Yeah. So, what I would do, is I would review. So the, health security agency is about to release its updated guidance on auris, including everything from screening and surveillance diagnosis. and treatment and I would look at that guidance and audit what is currently happening in your practice. So let's talk for example about screening. So in theory certainly we should be from the intensive care units and any high risk wards such as infectious diseases, renal transplant, bone marrow transplant. Any candida should be identified to species level. That is not that you report a candida in sputum as candida spp., which in my experience still does happen in some cases, but it is speciated and If you have MALDI TOF, which I think most labs have, then there isn't such a concern about misidentification. So, that's one thing we can do, is ensure we're speciating candida from at risk patients. From April, this year, Candida auris is going to become, a notifiable organism, even cases of colonization, which can be reported through the laboratory system. so we have an idea of what the burden is both locally and nationally. The other thing is to review, whom we screen, because at the moment, or certainly in the past, it's been recommended to just screen certain high risk patients coming from abroad. I would argue that probably inter hospital transfers need to be screened. Now this depends of course where you are. For us in London it probably makes sense to do that even from now. If you're in Wales or Scotland or a region where there've been hardly any reported cases, you might just consider and look at hopefully the national data in due course, look at your own area and think about whom you need to screen. And then also think about how you are currently screening. For example, here where I work at St. George's, they say they are screening with a chromogenic type agar. Certainly that is what is recommended. Some other places may just be screening with a sabro dextrose agar, and as you know on sabro dextrose agar, all yeasts and candida will look quite similar, and there may be multiple species of candida on the skin. So if you're not using a chromogenic agar, for example, the one that's recommended is called, chromogenic agar plus, I think it's called,, and in that you can readily distinguish, even if you have a few colonies amongst a lawn of, say, albicans or glabrata, which you may have, you will pick it up because it has a distinctive whitish pinkish Colonial appearance and then you can MALDI-ToF the individual colony again from a lab implementation point of view Certainly, it's important to make this as cost effective and efficient as possible So looking at for example doing composite of nose axilla groin Then you need to think about if you are finding auris at what stage you do a point prevalence survey in your high risk units to look at whether you have all risks. So these are some things that you can do both in the lab to review policies and also look at your local epidemiology. and then the third thing is just to look at whether you've got local treatment guidelines for invasive candidiasis and just think about what you might do. And again, I don't know that the HSA guidance will have that much details, but look at The latest ECMM candida guidelines in Lancet Infectious Diseases. Look at that guidance for any more detail and just think about if you do get a candida auris candidemia. what you would do or would you do anything differently? Because one of the concerns is it's fine if you have a straightforward line related candidemia, which many cases will be, you pull the line, you do your standard treatment, you clear it, but this organism is far more likely to cause breakthrough infection on treatment or even relapse after treatment. Why? Because it has this propensity to evolve resistance to echinocandins at standard doses, particularly during prolonged treatment. So in terms of echinocandins and where they penetrate, we know they don't penetrate well into the urine. We know they don't penetrate well into the abdominal cavity. And in the case of, neonates the brain. So if you do have an infection at those sites, and indeed it's not a coincidence that the vast majority of pan resistant isolates are reported from things like urine, it could just be colonizing. Or, from, abdominal sites, Echinocandon resistance, that's a sort of sentinel site, if you like. So if you have somebody on weeks and weeks of Echinocandons, especially empiric treatment for colonization, this is probably going to be a, quite a risky strategy. And you may, My personal clinical recommendation, and this is not based on any evidences yet, but it's something we're looking at in the research setting, would be, certainly it is recommended clinically if people are, persistently candidemic to switch to ambazone. the latest New England Journal of Medicine paper, which has just been, published, and I would. urge you to read it. It's a very good review published in November Anuradha Choudhury, but they say after five days, I mean, my view would be if somebody's candidemic, even by day three, I would consider switching to Ambizome with or without Flucitazine. So some sort of combination therapy, depending on whether you have MICs by then, you can strategize. If your Ambizome MIC is somewhere on the border, I would say use combination therapy. And equally for patients requiring prolonged therapy to these sanctuary sites. because we have so few classes when it comes to antifungals, really, we just have echinocandins, azoles, which are out in this case, amphotericin B, and then flucitazine, which you must never use. on its own because it has a very low genetic barrier to resistance. Do not add flu cytosine as a single drug to a failing regimen So if you're going to use them, really think about how to use them. Consult with your local ID teams or even, national, expert groups. We're going to have a clinical expertise groups as part of the national incident. with the HSA. So contact us because all guidelines will say when it gets to difficult cases is contact an infectious disease specialist. Well, we are the infection specialists. You're going to be contacted. So you need to get informed and think about what are you going to do? How are you going to individualize therapy where there's an absence of evidence and you need to think strategically.

Callum: 18:49

Real call to arms there on so many issues. But the thing that struck me there was that just like we've seen in resistant Gram negatives that are antifungal stewardship is going to play a key role here. And, I guess previously we've not had so much of a worry about that. Or maybe there hasn't been as much focus on it as there should be. I had two questions. there from that. One was, so you've got someone on an Echinocandon and they're not improving,

Tihana: 19:19

yeah, I mean, if they're breaking through on a kind of candens, I guess you've got several options. I personally don't have, we've had a few colonizations here at George's and only a few candidemias, although I just hear, having come back from New Year, that we've got somebody who's candidemic. I had a patient who, for example, was on ICU and despite line removal, this was a few years ago, remained persistently candidemic. So, what I did was I initially doubled the dose of echinocandon, when they were still growing on blood cultures from day two and three. of course, you're doing all this delayed because by the time the blood culture flags positive, you might be a few days down the line. When they seem to be still candidemic, I then switch to ambazome with flucitazine. Now, No guideline recommends at the moment using combination therapy, so I say this is just from my knowledge and understanding of resistance mechanisms, but we have yet to determine if this is more efficacious. And indeed, we are going to be doing a clinical trial in South Africa starting next year. Hopefully early next year that's been funded by the welcome, where we're going to be adding Flut, Toine to either Akin canine or AmBisome a standard of care to see if combination therapy clears any quicker. So that, that remains, I can't say I would recommend that, as a general, always treat or is candidemia. We don't know that for sure, but I certainly think. I would add Amazone. I certainly would never just add, if they then fail Flucitazine, because that's the worry, or, as some cases, Panresistance, or let's say add an Azole, then they fail Amazone, then you add an Azole, like Voriconazole, or something that it seems to be sensitive to, or stop that drug, add another one. So, My view would be, I think it's okay to switch to a polyene. Consider increasing doses of echinocandins and depending on where your site of infection is and the relative tissue penetration of the drug, I think it's okay to use monotherapy. with either Ambizome or Echinocandins, particularly at higher doses. However, if you start failing on that, then you really do need your MIC results. And based on that, you should consider a combination regimen. We don't have data in humans, like I said, in combinations, but some of the Certainly in vitro work and preliminary, very preliminary, the odd animal experiment, and there's very little out there, suggests that maybe either combinations of Echinocandins and Ambazone might be, one to explore. So these are all drugs that we have available. or combinations with Flucitazine, particularly Amphotericin B with Flucitazine and maybe Echinocandins with Flucitazine. So. These are some of the combinations that have been shown to be have some either synergy or additive value, but I must stress that this is mainly based on in vitro checkerboard type data, and we don't know yet how this translates, but that would be a rational selection at the moment. is to think about some combination of the drugs we have available. So let's say a patient is failing echinocandin therapy, but you get an MIC and it still remains susceptible, then I don't think it would be unreasonable to use a combination, let's say, of echinocandins with amphotericin. again, I gather anecdotally that's been sometimes used during the latest outbreak. And just remember that invasive infection is quite rare and at the moment, fortunately, because in the UK we have got fairly good infection control and Lyme care, etc. Even in the ongoing outbreaks, there have been few invasive infections. But my concern is that if we don't act now to prevent colonization and this organism becoming an MRSA style endemic organism in our hospitals, we will get into a situation of having more tip of the iceberg invasive infection, particularly in our high risk patients, as we talked about in our invasive candidiasis and in our ICUs. And in that situation, this could have consequences both for the individual patient and also for potentially onward transmission of more resistant organism to other patients.

Callum: 24:18

So the treatment sounds, very challenging. I guess another question was say we've got our patient. They've had an invasive candida or a disease. And they've been treated or say it's someone who's just colonized. You mentioned that we don't have a specific decolonization, regimen at the moment. So does that mean that these patients are then labeled with this for life and how is that sort of managed from a, from an infection control point of view

Tihana: 24:49

yeah, I think this becomes a really challenging and probably I'm not the best. I don't have the best expertise not having handled an outbreak yet myself. But my understanding is both from the literature and talking to people that. And I think the HSA guidance will allude to this, that once a patient is colonized, the question is there any point rescreening them or just should they assumed while they're in that healthcare facility or even in future to be persistently colonized? People have tried. Chlorhexidine and Chlorhexidine certainly is what's used because we don't have other good options. And I think these are important research questions and we do need a lot more data on alternative, skin decolonizing, agents. One of the challenges, again, this is anecdotal, is that chlorine, of course dries the skin out. And a bit like with. Staph aureus, maybe if it increases skin shedding, it could in theory potentially even increase the risk of transmission. However, that is what is recommended as is and has been used in outbreak settings as have been chlorhexidine discs. The difficulty is that, of course, once you have a certain number of patients in a ward affected, then it becomes about not having enough side rooms. in theory, you should have dedicated nursing staff, dedicated single use equipment for these patients. So it becomes very difficult logistically, especially in the NHS. as it is to manage this. So I think it will become about cohort thing and just enhancing infection control throughout changing cleaning. and for the individual patient, I guess they became, they stay labeled as potentially colonized for the entire duration of their inpatient stay. And if they're in a long term facility, one can't assume that they will be, free of it, but perhaps that's less risky than whilst in hospital undergoing invasive procedures.

Alyssa: 27:01

I guess we've highlighted is that, candida is generally gut commensal, but auris is different in that respect, isn't it? And that it's predominantly a skin colonizer.

Tihana: 27:12

I initially thought that maybe an approach to candida or a screening would be just to piggyback it onto your gram negative resistance screen and just add another plate. Clearly, that would be cost effective. However, the challenge is that unlike other candida, Auris is less, frequent in the gut, although through my study we have found it through some mouth, we do mouth and perianal swabs, but in general it's more the skin areas, the nares, the axilla and groin, so it's difficult to, Piggyback the screening onto the resistant gram negative screen, which hospitals will do routinely.

Callum: 27:54

Could you piggyback it onto your MRSA screening? Or do you need to use a different swab transport media? Because I guess locally we would screen anybody for MRSA that's been admitted to a healthcare facility in England. sorry, England, but, or anywhere else in the world or have other specific risk factors. Would that be an approach That could be adopted. you take the swab and you put It out to two agar plates or does it?

Tihana: 28:18

It could be, except I think the patient risk groups being screened for MRSA may be not all the same. I mean, maybe you're screening transfers, but if you think about it, it's patients coming in for elective surgery. I mean, we've stopped screening everyone in the past. We used to screen all admissions, didn't we? But most places aren't doing that. So the question is looking at which risk groups you are screening and if there's overlap, so obviously not elective surgery, but if there is overlap in those groups, then absolutely those are similar sites. So you could just take an additional mob or just plate that out onto chromogenic agar.

Callum: 29:00

Interesting. Okay. When I go back to work tomorrow, I'll be emailing my boss, suggesting something like that.

Alyssa: 29:07

And just to make there are some UK HSA guidelines the consultations closed on them and we've put a link to those in episode notes

Tihana: 29:14

Yeah, so this will be released and certainly one should refer to them as best as possible. But the fact is that none of us know, I mean, one of the major challenges is once it's embedded in your hospital, and that's the other thing, is that literally these outbreaks can cost millions of pounds, particularly if they do, as they have necessitated in the past. the first publicized outbreak, the Brompton, I think it was in 2014 or 15, but they had to close and refurbish their ICU. At St. Thomas's they've also closed and refurbished one ward, but it was already too late. It had spilled over. So ward closures, again, I'm not an expert in infection control. I always a last resort thing and certainly for deep cleaning. There's some evidence, I think, that UV irradiation may also help in areas that where there's been a high condensation burden, but this then becomes logistically and practically very difficult for hospitals, which is another reason why we want to try and act on this now in the UK and really try to prevent once we do have a case onward transmission so it doesn't become endemic in our hospitals. And we don't face these very, very challenging questions operationally.

Alyssa: 30:43

so it sounds yeah, really proactive approaches needed, particularly in hospitals where, we're not seeing cancer diarists at the moment to make sure that we're not missing cases, either locally or being transferred into the hospital. And I guess one of the key things is making sure we're speciating as many Candidas as possible, particularly invasive, from invasive sites or from, critical care patients or, patients that, that have been transferred in. and, that we're screening in the right way. And it sounds like, using the chromogenic agar, you're not going to miss your candida auris then. Whereas if you screen with the SABC, you're only then, you might only mold it off,

Tihana: 31:32

one colony

Alyssa: 31:33

and you've got mixed, yeah, organisms.

Tihana: 31:36

So again, it might be a bit more costly to do it that way initially, but it may prove, especially in, I would say in hospitals in London and with patients coming back out from London, it may be worth it. that initial investment to save later costs of dealing with it when you didn't realize it was there. And then it's only there when you start detecting invasive infections, which is clearly what's going to happen in a lot of places. labs are overwhelmed. There's a lot of demands on their time. They're reluctant to increase, their workload, but I think we as infection specialists can see the bigger picture and should really argue that it's worth that initial investment to try and see if there is a problem. And again, my personal view is, and not everyone might share it, but if you even see a few colonizations, you should call an outbreak meeting early, because then you have your infection control plan. Nurses on board and your DIPC and the lab and everyone's thinking what to do before it gets out of hand, because I think one of the reasons why some of the outbreaks have been out of hand is by the time you recognize you've got a problem, it's already spilled over into multiple wards and then it's much harder to contain.

Callum: 33:02

so Candida Auras? We've talked about the detection and screening, we've talked about treatment, and we've talked a little bit about the infection control aspect. Although, as Jayme and I have said many times, this isn't an infection control podcast, so we're not going to delve into that, too deeply. But, there are other sort of resources available, on that if you want to. But, you mentioned earlier on. the resistance mechanisms and your treatment, your thinking around how you would treat a patient with Candida auris invasive disease was based on that. So maybe now we could spend some time talking about resistance mechanisms and Candida species in general.

Tihana: 33:41

absolutely. absolutely. So I think, Candida auris is nicely illustrate some of the principles around antifungal resistance, certainly in Candida. we mentioned about And as you know, azoles are the most widely used antifungal drug class because they're the main one that's available orally. And they're used for both maintenance, treatment, after an infection, as well as prophylaxis and sometimes also empirically, although mainly not empirically for candidiasis. And of course we know a lot of our high risk patients. patients are on azole prophylaxis, either mold active or, fluconazole, so that's active only against yeast. Because of their widespread use, then, including in agriculture for crop spraying against certain molds, there's been widespread reports of azole resistance, particularly in both candida and aspergillus. So just focusing on candida. In candida, obviously, as we said before, candida is a gut commensal and although it may be present in the environment, really the main selective driver in humans is azole use. Probably it's possible that some of the agricultural spraying contributes, but it's mainly clinical use. and azoles, as you may recall, block the final step of synthesis of ergosterol, which is a key component of insulin. fungal cell membranes. So our cell membranes have cholesterol, theirs have ergosterol. They, target an enzyme called 14 alpha demethylase, which is encoded in candida by the ERG gene for ergosterol., So If you have resistance in fungi, and this is true for candida to azoles, usually it's in one of two ways, either you can have a mutation in the ERG gene itself, ERG11 is one, common one and other ERG genes. or you can have a pump, an efflux pump that pumps the drug out of the cells. So, these are transmembrane pumps. So CDR1, so that's one of the pumps that pumps fluconazole out. And, this is usually mediated through increased transcription of, the gene. So it's mutations in the promoters or transcription factors. So TAC1 is one that's sometimes can happen in candida or UPC is another one. So these are, transcription mediated upregulation in efflux. So candida auris and other candidas, these are some of the resistance mechanisms. And as we said in auris, this is almost universal for most clades. Whereas In albicans, it can evolve on treatment, or prophylaxis, and for example, Labrata., Has a greater propensity to develop the flx pump mediated fluconazole resistance, which is why you may recall that in Glabrata you would never report a glabrata as fluconazole susceptible. Regardless of MIC, it's always reported as either intermediate or resistant and if fluconazole is to be used for treating glabrata infections, then higher doses are usually recommended. glabrata is another candida in parallel with auris that's evolving multi drug resistance. So if you like, it's enemy number two when it comes to MDR candida, because the next thing that goes after fluconazole in glabrata are the echinocandins. So what about echinocandins? So most antifungals, and as we've mentioned before, the disadvantage compared to bacteria is really we have three main drug classes we use. So most echinocandins act on the cell membrane or the cell wall. So echinocandins, inhibit beta glucan synthase, which is synthesized by the gene FKS and there's two subunits FKS1 and 2 and the main mechanisms, although there have been some other mechanisms and mechanisms of adaptations, but the main mechanisms that have been described in auris and other candidates are mutations, in FKS1 or more rarely, I think, in Glabrata FKS2. But for ORIS, it's mainly the FKS1 subunit. so, a single mutation can be associated with, A resistant M. I. C. And then finally, Ambizome, or Amphotericin B in the polyenes, where resistance generally occurs very rarely in Candida and fungi in general, but there are again Erg gene based mutations. Erg 6, I think, is one of them, and that can, alter the content of a ergosterol in the cell membrane and perhaps make the drug less liable because it has to bind and also cross the cell membrane to be effective. So again, it's an erg mutation based selection. I mentioned earlier that one of the challenges with AmBisome is that most candidate auris isolates cluster around MIC of either two or four, and four is the tentative breakpoint. So I've been hearing again in London that some of the. isolates of auris that people have been testing in the lab. And I'm told again, that it's quite challenging. And I would always confirm any e test based MIC. Apparently they're quite unreliable, send it to the reference lab and get them to use broth micro dilution because. You may be seeing if you have an MIC of four, you're going to report out of your lab that isolators resistance, which of course then gives a signal to the clinicians not to use that drug. I think we need to understand a bit more what that means and whether you could potentially still use it in combination. But I think from a clinical practical point of view. If you are doing e tests locally, and again, a lot of people are not, and maybe with this advent of auris, we need to review in general whether we do in house susceptibility testing, and if so, on what candidates and for which drugs. There is now e tests available, both for echinocandins and e test strips for kynokandins, fluconazole, as well as amphotericin but again, it requires in house expertise, which labs have lost in recent years. But we have to remember that the reference lab is not necessarily getting any further resources to deal with increasing number of isolates that are likely to be sent their way, both for susceptibility and sequencing. So I think we need to understand We still need to understand a bit more how MIC relates to treatment response, but in the meantime, we should look at this in, in, in the laboratory. So yeah, these are the main things. And then for flu citabine, as I mentioned, again, it's a genetic, it's a mutation in the F1 or FCY genes, which are the genes that encode. So flu citabine, it inhibits DNA and RNA synthesis. So it. It's the only drug or the main one that has a site of action in the nucleus rather than on the cell wall or cell membrane. And, this mutation, if used in monotherapy or, for example, flucitazine is added to, an already resistant or failing drug on its own, then that is a challenge because resistance will evolve quite quickly. And indeed in the literature where it's been described pan resistance to all three classes, plus flucitazine is when these drugs were all added in succession, including flucitazine to a patient, albeit there's a single case report. This was an, gut, combined pancreas, liver, gut transplant, you know, heavily immunosuppressed. So, again, one has to think of the setting, and if you're then using a kynokandin prophylaxis, as some centers now do for high risk transplant patients. You're already setting up the auris, if it breaks through that and is colonizing somebody, it's already adapted to the echinocandins, so your options are going to be fewer and you really need to think about the patients. And as you mentioned, actually, I wanted to mention earlier Callum, that what you mentioned about stewardship is we know, as we discussed, I think in the last episode, that a lot of echinocandin use in our hospitals is empiric. particularly on the ICU. So another thing that I think potentially this auris increasing reports in the UK is we need to look at our diagnostics locally because that goes hand in hand with empiric prescribing. If we send away all our diagnostics, let's say we start a patient on empiric echinocandins for fever, not responding. We talked about the candida risk score and when you might start it in the last episode. If we won't get our beta D glucan result, or, and we don't have Candida PCR, which most labs don't, if we don't have that on site, likely is that the drug will be continued for longer. And let's say that patient happens to be colonized with Candida auris, we are then giving them longer courses and potentially driving resistance. So, targeted treatment is really the tip of the iceberg for invasive infection. And auris will really make us rethink how we use echinocandins, because that's our main drug class for treating invasive candidiasis, and we need to protect it. and once a patient evolves resistance, of course, there's the danger then that these genetic mutations are spread in the isolates to other patients, say, on the unit around them. So it's a useful framework to think about. candida resistance in general.

Callum: 44:39

There was two things I wanted to. Add, you mentioned that the reference lab are having more requests, and we have to make sure not to overwhelm them, and recently we found that some isolates that we would previously have sent to the reference lab for things like additional susceptibility testing or speciation, we're now getting a reply saying that they're no longer providing that service,

Tihana: 44:59

Are you

Callum: 45:00

they're,

Tihana: 45:01

locally? Wow.

Callum: 45:03

and I guess that comes down to, if there's no additional funding for extra work, then, you have to ration your resources and say, what are the key priorities that we will do? We used to have B2B Google Clan. Available locally and we lost it because of funding issues and, it just shows that, if we can't have those diagnostics closer to the patient and then be able to deescalate or stop these empiric therapies, then we're going to be in a situation where stewardship is really hard to action because we can't just, if you've started something, it's quite hard to stop it, isn't it?

Tihana: 45:35

Yeah, absolutely. And again, anecdotally, I'm told that the workload in terms of the candida speciation in England for the mycology reference lab has doubled in recent years. And that's, without Extra staff. I mean, everybody is working late, and there comes a point where I think the local labs do, you know, it seems crazy that we identify bacteria and do susceptibility testing in house as far as I'm concerned, I understand with the molds that takes expertise and maybe That's more of a reference, but unfortunately, in the era of automation in microbiology labs, anything that actually requires you know, set up and human expertise. Some of the skills have been lost, the sort of higher skill levels because you don't need a skilled person to load something on a machine that will then do this sort of downstream processing and analysis. And I think that is a bit short termist to think of it just in terms of course, labs are receiving more and more samples, so they have to cut corners somewhere, but as far as I'm concerned, Candida is an honorary bacterium in that regard. We know it's the most common cause of fungal sepsis, and I believe it's Something like the fifth most common cause of bloodstream infection in patients on critical care, certainly from some American studies. So, it's so common, we can't afford not to be, doing more detailed diagnostic and susceptibility testing, at least some testing, on site, rather than sending it away.

Alyssa: 47:21

it feels like, speciation certainly should be achievable for most local laboratories you have multitask. I think the database is very reliable and for yeasts. I guess, performing B2D glucan locally is going to be, will be very challenging for most labs because it's. It's quite involved and I think it's put up on a 96 well plate, isn't it? So unless you've got, several samples to test that day, then you would not have enough

Callum: 47:49

so no. Okay.

Tihana: 47:50

there are now kits that are single use or smaller use where you can break off until

Alyssa: 47:57

Okay.

Tihana: 47:58

yeah, there's Waco and Fuji, but yeah, performing, yeah, the stand, the Fungitel was, I think, more challenging, but I think even Fungitel beta de glucan test now allows for, smaller numbers of samples because it is about volume, isn't it?

Callum: 48:15

One question I had was in terms of resistance where would we direct people if they wanted to learn more about those resistance mechanisms that you'd mentioned?

Tihana: 48:23

Yeah, there are. Let me just find because there are other papers specifically. I mean, resistance is covered. So if you look in the section on and there's a section on antifungal resistance and obviously that will have references. So it talks about 11 mutations. You know what I mentioned talks about FKS one. And it talks about amphotericin being six. So there's a whole section on it. And then there are other references, but the. There are also reviews on resistance. Do you want me to dig one

Callum: 48:56

that'd be great. I don't think everybody will want, but I'm sure there'll be some people listening, probably jane, that. want to read more on it, and, are real resistance nerds. So we can direct them to that paper. That'd be great. Glad that people like you are working on the, on the clinical trials to tell us what to do in the situation and certainly hats off to

Tihana: 49:17

we won't have the answer to that for about five years, but anyway, at least we've got welcome funding, on, because on candidate resistance in South Africa. So my colleague Ray Wake has just gone out to start getting that set up in Johannesburg.

Callum: 49:31

I'm sure we'll have bated breath. Maybe I'll just take a five year sabbatical and come

Alyssa: 49:34

I

Callum: 49:35

we've solved it. So.

Tihana: 49:37

Actually, we have funding for, if you want to work on the trial in South Africa, if anyone's interested, we have funding for a clinical fellow. If you want to be at the cutting edge of the research into this pathogen, we are going to be advertising for clinical fellows to help run the study in South Africa, probably with, with local PR. Thank you.

Callum: 49:59

ever likely to come out?

Tihana: 50:02

Probably in the next, yeah, after, just after you screen this podcast, maybe in three to six months.

Callum: 50:09

So sometime spring 2025.

Tihana: 50:11

Yeah. Yes. Maybe summer.

Callum: 50:13

link for that in the show notes when it's live. So we've had a great overview there of candida auris and resistance mechanisms, and we've heard about candida auris epidemiology within the UK and globally, about the sort of screening, for this, the importance of this. As well as a little bit about the infection prevention control aspects of candida auris. and then we've talked quite a lot about the treatment and the treatment challenges and how those relate to antifungal stewardship in general, both for candida auris and candida In general, really. And then finally, we talked about resistance mechanisms in Candida in general, and talked about, some of the challenges of that, particularly in Candida auris going forward. And, as always, there's, links to the papers and guidelines discussed in the show notes, which have been prepared by Alyssa. So thanks, as always, for doing that. I heartily recommend having a look at them because I think it's a really great resource. and there's lots of, useful guidance, particularly the UK HSA guidance, which are recently updated at that NEJM, website. So I'll just pass over and ask if you've got any closing statements for our listeners.

Tihana: 51:34

so because of the global increase in candida resistance, candida auris was added a few years ago to the WHO Fungal Priority Pathogen list, on which, candida auris is a critical priority pathogen in terms of both. research and development of new drugs because of this propensity to cause outbreaks and develop resistance. But note that out of 11 critical and high priority pathogens, 11 different fungal species, candida forms six of those. So albicans and glabrata are higher on that list as well. So another useful reference to look at is the WHO fungal priority pathogen list. And we're fortunate in the UK in that so far, we have only a few percent of echinocandin resistance in our, candidemia isolates that are sent to the reference lab, but this could change over time, and our fluconazole resistance rates, particularly for glabrata. have been increasing. so there is increased global, azole resistance in places that don't have as good stewardship and infection control as we do. And again, this is a useful model, if you like, for where we infection specialists need to work. tightly with infection control, and, stewardship and think holistically about how we approach it because it's all tied in together, the lab, the infection control teams. the ward clinicians to strengthen, best practices, really.

Callum: 53:23

So I guess all that remains to say is, again, thank you for coming on and sharing your expertise and giving up your, time, to talk to us about this. And I'm sure as things go forward, this is a rapidly emerging field, so there'll be new information. So, as we're recording this in early 2025, but there will be, there'll be more to come. I'm sure. Hopefully good news.

Tihana: 53:45

Absolutely. And I hope that in the UK we can mobilize efforts and be world leading in our generation of good clinical research and data like we did in COVID.

53:57

This mycology series has been supported by the British Society for Medical Mycology. The BSMM aim to bring together clinicians and academic researchers in the field of medical mycology. For more information, you can find the link to their website in our show notes on Notion. Please consider joining up to become a member. Thank you for listening to The Idiot's Podcast, the UK's premier infectious disease podcast. Questions, comments, suggestions, why don't you send them in to idiotspodcasting at gmail. com. Have a five star review in your pocket? Calum and I would love to have it. Please drop it in your podcast player of choice. 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 Jay. I'm Calum. See you then. Now that the episode's done, we hope you learned and had lots of fun. So go forth and treat people with some of what you now know.