97. FIS 2024 part 3: Fungi, NTM, quinolones and others

 HO HO HO, MERRY FISMAS!!!

On the Third & Final Pod of FISmas these ID:IOTS have for you… 6 golden topics! Listen to hear about:
1. Personalised approach to invasive fungal infection
2. Agricultural anti-fungals and One Health
3. Candida auris
4. NTM standards of care
5. Narrative reporting
6. Fluoroquinolones and the MHRA warnings
 

Jame and Callum attended the Federation of Infection Societies 2024 annual meeting in  Liverpool; here they share their reflections on the sessions  they attended on:  a wide mix of topics

We hope these episodes have been ADVENTatious to your learning.

Notes for this episode here 

Transcript

Jame: 0:18

Okay, back with our fungal section, Callum. Do you want to start?

Callum: 0:24

So no, no introduction, no pun, nothing. You don't think, if we did a really good joke, we could make the mold, we could be very candid with how we're talking about things So yeah, but we're back to this

Jame: 0:37

all right onto fungal.

Callum: 0:39

on defungal. Yes. This may be a separate episode.

Jame: 0:41

if it is welcome back,

Callum: 0:42

yeah. Yeah.

Jame: 0:44

Right, so did you go to this one Callum? Invasive Fungal disease Personalised Approach?

Callum: 0:48

yeah. So this is very first talk on the very first day. We were, you're not

Jame: 0:50

Oh! This one, yes I was. This was a brilliant talk to have on day one. And this was really interesting and engaging and funny. This lady is evidently very famous but I have never heard of her. Do you know about Professor Rosemary Barnes from Cardiff, Callum?

Callum: 1:09

I've heard her name, and, she's a very established researcher in the field of, mycology, and has come to the end of her career, and I really have been invited, I think, to give an overview of, the last 30 years, I think, the title of her talk, Invasive Fungal Disease, and where we've been, and where we're going next. It was a really broad bunch. I think there was a lot to talk about from there, but a couple of things I thought would be worth, highlighting, and, we'll be coming on to fungal diseases in more detail, soon, but essentially just, highlighting that this is a problem that we're all going to have to deal with more and more as more of our patients are, at higher risk of fungal disease, either from sort of therapeutics or from, comorbidities. And. her takeaway really for me was that we need to be personalizing our approach, the risk assessment. So we know that a lot of patients that have invasive fungal disease have delayed, treatment, because the diagnostics are tricky and it's maybe not thought about in the differential earlier on. So she was proposing an approach where I use bioinformatics, so things like functional genetics, biomarkers, or for example, BDD glucan or others, and a host response And, use those to, determine which patients are at high or low risks and then start treatment earlier empirically, or consider prophylaxis. So that was that one. Next one you went to, I think,

Jame: 2:28

I'm not sure how much practical application this is, but I thought it was a really good example of how One Health is more complex than you might think it is. So One Health is the idea that, antimicrobial resistance respects no barriers between humans and animals. And so antimicrobial use in animals can be reduced. drive antimicrobial resistance in the human population. And we've already seen this with azole resistance driven by the use of farming fungicides to increase crop yield or to reduce disease in animals. And there's, one example that you gave with Voriconazole resistance being associated with Imazalyl use in farming, which is an agricultural azole, and the mutation there is a CYP51A SNP, in Aspergillus fumigatus, but that also creates cross resistance with other antifungal drug classes and some isolates, and that implies that Anti fungal use in agriculture is driving multi drug resistance in fungi. and he then pointed to the anti fungal drug discovery pipeline and We've seen these kind of oddly named new agents like ibrexifungirp, razofungin, olorofilm, and then he focused a little bit on olorofilm, to highlight that at the same time that allorafilm was being developed, a drug manufacturer had already Developed a new antifungal called ipfluflenoquine, which is an alloraphilm like antifungal that is approved for agricultural use. And the remainder of the talk demonstrated the cross resistance between ipfluflenoquine and alloraphilm, and highlighting that the use of this agriculturally will drive resistance to a lot of film. Now, this is a drug which has barely got its license in humans, and there doesn't seem to be any sort of fitness defect compared to wild type. So some resistance mechanisms will cost the bacteria or the fungi in terms of its fitness as you're well aware Callum, so thinking particularly of the beta latinase hyperproduction. But if you're in a environment where those drugs are being used, it will confer a selection advantage, and if you aren't in that environment, then the wild type will dominate. Well, that doesn't seem to be happening here. So the. Ip, flu, flenoquin, resistance mechanism, whatever it is, which also converts resistance to a lot of film, is stable, compared, compared to the wild type population. So that was reasonably terrifying. And the issue there, I think, is that you don't know what's going to have a license. generally speaking, when you have a drug, your first thought will be as a drug company will be, can I use this in humans? And if it doesn't pass phase one testing or even animal testing, your next thought will be, can I use this in animals? And if it doesn't pass that, your last, Commercial application will be, can I use it in plants? Can I use this as a pesticide or a fungicide? And that's what the makers of this ipfluflenoquin, did. And in their defense, they didn't know that a lot of film was going to be developed. A lot of film was developed. Actually, the presenter made it sound after, ipfluflenoquin was going through, testing. And so the. The idea that we can just tell people stop developing these, drugs, the kind of flaw in that logic is that they don't know what drugs they're going to develop and you don't know what drugs you're going to develop for use in humans in the future anyway. At the time that it was being developed, it looked like it was completely unique. And now that's not the case. So what do you do? Do you prioritize agricultural food production or do you prioritize human health? I don't have an answer. So let's move on.

Callum: 6:23

the podcast for answering that wide ranging question. huge challenge. And I guess, trying to avoid use of drugs at all in agriculture and, animal husbandry we're not there yet, but maybe that's what we need to be aiming for. so yeah, there was quite a, there was a lot, a large amount of mycology, content and there was a whole session on mycology, hosted by the British society of medical mycology more on them later. but, yeah, I think some of the other sort of highlight talks and we're obviously just flying through talks and we've missed off a lot of things. It was really about candida auris, which is, really puts the, Hackles up of any infection specialists when you hear those words, something that we've been worried about a lot in terms of outbreaks, particularly in the ICU settings, and this talk was an update on the epidemiology. Now, we won't go into this in too much detail because we'll be talking about Candida auris in the not too distant future in a few episodes, but essentially the things I took away from it was, about the different clades. So like how it's evolved and, historically we've been looking at this sort of four clades, but actually we're seeing more clades emerging, and some of them are the most linked with the larger outbreaks. and, other sort of takeaways was that most people that are colonizers. In the skin and the groin, and that can be even normal skin and groin, areas, but that some patients seem to be high shedders that have high concentrations of the organism, and they transcendently colonize the surrounding environment. So the Canada can then go into your environment and start form fomites and be on equipment and so on. And the patients can actually harbor multiple strains, which can make, difficult when you're dealing with an outbreak. If you're typing your strains, that can make it quite tricky. and the colonization of people can be transient. So a lot of things that we're introducing wrinkles for when they're trying to investigate, like, where it's come from, where it's going. And these longer term outbreaks, really quite hard to just put a stop to them and figure out exactly how they're happening. And one thing that was really key is that we often screen people for candida RS based on travel history, but actually in the most recent outbreak there was no foreign travel in patients histories. So, having a high level of vigilance for Candida auris, and you're probably going to be seeing that in your lab, soon there's more screening for this. and then I guess the final thing was there was some discussion about, taxonomy and the sort of re branding of a lot of Candida, so it's going to be renamed Candidozyma. Yeah.

Jame: 8:46

Yeah, the Candida genius contains 13 genera which the only similarity really is that they exist in the cellular form at mammalian temperatures and apart from that they, they're phylogenetically very different, so that's brought about this, horrific, speciation of the candida into, Pitchia species and Nacassia mices, et cetera, et cetera.

Callum: 9:11

yeah, that talk was by Andrew Borman from the UK National Mycology Reference Lab. And actually he was really advocating for renaming them and making the point that they are extremely different organisms. So you know, I guess there's arguments to and for, So, that's the fungus, so moving on to non fungal, so in the world of mycobacteria, there was an update session all about non tuberculous mycobacteria, There was a couple of really, useful resources that were highlighted. so the, NTM Network, have recently published a standard of care document, which really sits beside and supplements the, joint treatment of non NTM, pulmonary disease guidelines, which I think has quite a few offers, including the IDSA. And also the British Thoracic Society guidelines, all of which are linked in the show notes. And essentially, a lot of the talks were focusing on the standards of care and saying, what are we doing, currently in the UK, what variation of care there is. So a lot of patients aren't getting that, care. basic standard of care you might expect, such as entity input and patient resources being provided as some examples. so it writes down, what level care people should expect to get, and some standards that you can audit. and I thought it was really useful for if you're thinking about your national, your sort of local delivery of services, it gives you like really useful standards and how to measure them, to make sure that You're providing an adequate standard of care and following on from that. There was another talk about what experience the National Reference Lab have and what sort of samples are getting and how they're testing them, which again, fed into the standards of care to talk about, susceptibility testing and treatment guidelines. And we won't go into the detail of that because you can go and read it yourself. But just to highlight that resource is something that's recently been published and I didn't go to this next section. So Jane. Can you tell us a bit more about narrative reporting?

Jame: 11:03

Yeah, this was by a guy called Mike Simmons who works out of southern Wales and he was talking about their use of narrative reporting in microbiology to try and improve their stewardship, diagnostic stewardship. He also called it clinically aware authorization and they have also published a Paper titled How to Manipulate Friends and Influence Practice, the link of which we've got in the prep notes, and the idea was that they were trying to reduce the automated or fast thinking of the end user and relegating sensitivities down to the bottom of the page was one way that they did it. And they include a little narrative of their interpretation of the results between the organism ident and the user. And the sensitivity so that the end user is not just going straight to the sensitivities and they would comment on things like, apparently he's not allowed to do this anymore, but he would say things like, it's a shame that no clinical details were put because this influences our interpretation of the result, the re emphasized the. asymptomatic bacteria doesn't need treatment, that cath drives patients, colonization does not imply infection, etc, etc. And they've rolled this out between 2014 and now, and impressively, the number of negative urines have almost halved. So that's 2, 000 fewer MSUs a month, and the level of positive urines have stayed static, i. e. the ratio of positive to negative has changed. And therefore, there's still Detecting the same amount of pathogens, but their negative urines and therefore the processing time and costs, et cetera, et cetera, has gone down significantly, and they've rolled this out in northern wares as well and got the same result. And they ended with. Or did he start with? I can't remember. Antibiotic reuse in the rules, which I thought was really, really good way of thinking about antibiotics for early years trainees. Which is rule one, by default, antibiotics cause harm. Rule two, prescribe when benefits outweigh those harms. Rule three, if you use the wrong antibiotic, you will only get harm. And, I thought that was a really good, way to end. Thank you. a good, few points to end on, if indeed he did end on it. I think he started on it actually.

Callum: 13:35

Yeah,

Jame: 13:35

then the last thing that we're going to talk about is, did you go to this one Callum?

Callum: 13:40

yeah, I did. I was sitting just in front of

Jame: 13:41

Oh yeah, so you were.

Callum: 13:43

so Quinolone. a lot of attention recently to the MHRA alert. So if you're not UK based, the medical medicines, health. Regulatory agency and they put on alert and talking about quinolones and saying that we shouldn't prescribe them unless we have no other option and that's led to some questions about, what that data is, what that advice is based on, like what the data underlying is and why we've got a warning for that, but not for other things. So this was by, Chavda, who's one of the senior lead pharmacists at Imperial London. And essentially gave a bit of an overview about what the, drug analysis profile is from NHRA for ciprofloxacin and a number of reports. On, the toxicity. And I think, nobody's saying that there isn't a link between quinolones and, musculoskeletal issues like tendinopathy, but particularly worried about, large vessel, aneurysms or dissection. but the problem is that, if we just say that, that precludes its use, it is a very useful drug. Cipro is the only available oral agent for Pseudomonas at the moment. and it has a lot of indications where it is useful. And that balance of risk versus benefits is the key for any sort of drug decision making.

Jame: 14:55

Yeah, I get that. I think seeing as antimicrobial resistance is so tightly linked to beta lactams and quinolones that are use of those two drug classes should be restricted. On those grounds alone, side effects be damned. And I think that the side effect profile of quinolones are, is serious enough that that risk benefit has a different balance compared to other drug classes. But the number one reason I want to stop using them is because they are the only agent for, oral agent for Pseudomonas, and they are, the, Antimicrobial resistance to quinolones is a significant, issue and if I've got a bad gram negative infection and I can't take a beta latam for whatever reason, the next drug class I want is a quinolone, so they should be reserved for those patients. Uh, yeah,

Callum: 15:45

Yeah, We need to think carefully about using these drugs. But, I guess it was just trying to support. clinicians and making decisions by digging into the data a bit more and providing some information. In the show notes, there's quite a lot of, notes that James made, about the different side effects. But one thing I guess is they are to dissection that people worry about. So the 60 day risk after a course of equinolone Was found to be 1. 2 per 1000 patient years, and that base is a sort of control. If you look at amoxicillin, it's about 0. 7, so it's clearly a base rate, and I think that take the takeaway I had was that, it is a real risk. It seems to be reported in the data, and it's a rare risk, and so if it is the if it is the right drug to use, you have to be. Weighing up the benefits, against the risks and there's a load of other sort of stuff about C def and side effects and so on. if you're interested, you can go to the show notes and see a bit more about that. Um,

Jame: 16:39

one. So the sort of risk for tendon rupture in general is 2. 9 per thousand patients per year. And for Achilles tendon rupture is 2. 1. But if you use steroids, that goes up to 10. 9 and 4. 9 respectively. So steroid use is particularly associated with Quinlones and, tendon rupture.

Callum: 17:00

yeah, that was a really good point. So you've got your patient on, acute steroid course. And then you might be thinking, oh, I'll give them a separate focus and course to treat this infection. And it's not a good option. I think really tough to think quite carefully about that.

Jame: 17:12

or to see if they can, you can avoid using them concurrently and apparently the risk of tendon rupture is greatest about a month after exposure to the quinolone. So the antibiotic course is finished and then, the rupture happens down the line. So that, that was interesting too.

Callum: 17:28

Yeah.

Jame: 17:29

but yeah, and then they finished off by talking a little bit about how they were trying to comply with the MHRA. Safety alert. And so apparently the NICE guidance, Quinlan's are first line only for prostatitis. And so they've been stripping it out of the other guidance or making a second or even third line. BASH have it as first line for gonorrhea, but they're reviewing that. And for the UK HSA, for meningitis, prophylaxis of exposed contacts, they say that one dose is unlikely to come to harm, which I think I agree with. And so they're not changing their guidance. So a one off should be okay. And then for other things, for alternatives, conditions that you would normally use ciprofloxacin for, say for SBP prophylaxis, you might use cotrim instead. For traveler's diarrhea, you would use azithromycin. a lot of places are. using azithromycin up front anyway because of resistance to quinolones in areas where people are getting the traveler's diarrhea regardless. And then just shortening the course in general. so shortening the course of antibiotics just reduces the amount of times your gut microbiome is exposed to that antibiotic and means that the evolution of resistance strains is unlikely to happen. So they made that point as well that even if you do use quinolones, using them with the minimum duration possible is still in your patient's best interest. And that Callum, is that?

Callum: 18:57

Yeah, we've flown through a small amount of what was at Fizz.

Jame: 19:01

Yeah, this isn't even a quarter of what was presented there,

Callum: 19:04

Yeah, and not even everything that we went to. There's so much interesting stuff that we didn't have time to talk about. But I guess, if you can get to Fizz, then we'd highly recommend it. And obviously, huge thanks to all the people that worked so hard to make that conference a success, and all the people that presented their research and findings there.

Jame: 19:23

Absolutely. All right. Until next time.