Persistent candidaemia, why does it happen; and a new Meningoencephalitis reference guide

In this episode we discuss a study looking at persistent candidaemia (based on the Candida III study), as well a new quick reference guide on Meningoencephalitis.

The Candida III sub-analysis study can be accessed here

Read more about Candida IV here

The IQRG meningitis/encephalitis article is here

A higher resolution copy here

And other IQRGs can be accessed on the BIA’s website

UK SMI B27 for investigation of CSF

Cochrane meta-analysis for steroids is here

And Dr Fiona McGill's previous guidelines on meningitis from 2016 is here

And the UK 2017 audit of the guidelines mentioned is worth a read here

Plus the DexEnceph study of steroids in HSV Encephalitis is on the Lancet website 

Thanks for listening to MIC! Feedback is appreciated, email us at journalpodcast@britishinfection.org

Our logo was kindly created by Gabriella Petruso; check out her website at www.gabriellapetruso.com

Transcript

Intro

Amy 0:07

Welcome to MIC. More Infection Chat, the podcast for the BIA highlighting articles from the Journal of Infection and Clinical Infection in practice with me, Dr. Amy Bellfield.

Michael 0:19

And me, Dr. Michael Blank, and we're both infection trainees in the uk.

Candida III sub-analysis

0:24

We've now been running this podcast for over six months and we are very keen to hear your feedback. You can do this by emailing Journal podcast@britishinfection.org, which is also, in the show notes. Or you can leave a comment, below the show notes. We'd love to hear from you and we're always looking to improve our podcast. After the recent MenB outbreak in the uk, optimal treatment of meningitis is a really hot topic. And so we're excited to have on the podcast today, two authors of a recent guideline that was published in the Clinical Infection in Practice Journal. And we also have a. Look at the Candida three study specifically at the reasons why people develop persistent candidemia and the appropriate treatment for them. So first the candidate three study.

Michael 1:24

I very excited to introduce Sarah Sadik and Professor Martin who are the authors on the paper in the Journal of Infection Risk Factors for Persistent Candidemia and Prognostic Implications, results from the E CMM Candidate three study. Welcome to the podcast.

Martin Hoenigl 1:46

Thanks. Having us.

Sarah 1:48

Thanks so much for the invitation and it's great to brand new today.

Michael 1:53

I thought we start off by talking about the background. What is the background to you performing the study?

Sarah 1:59

The original Canada three study, gave us a really important big overview of how Kemia is managed across Europe. And it showed quite clearly that when clinicians follow guideline recommended care, patients are more likely to survive. And, what the study didn't really explore, however, was what happens after the diagnosis is made. So in particular, it didn't answer why some patients failed to clear Canada from the bloodstream even after treatment has started or how often that actually happens. And that unanswered, question was the main motivation for this sub-analysis. So we wanted to understand how common persistent candidemia is, what factors are linked to it, and whether persist persistence itself carries prognostic significance. Especially when accounting for methodological issues like Al time bias.

Michael 3:05

Great, and we'll come to a mortal time bias a bit later I think. I wonder if you could say a bit persistent candidemia and why is it clinically important?

Sarah 3:14

So persistent candidemia is a signal that something isn't going right. First, it tells us that the fungus isn't being cleared from the bloodstream despite treatment that often points to the problem like suboptimal, antifungal therapy delayed, or in upper drug choice, in adequate source control or poor adherence to guideline recommended care. Second, it acts as a real biomarker for treatment failure. While a single positive blood culture tells us, Canada is present. Our ongoing positive tells us that current strategy isn't working well enough. Third and most importantly, it has prognostic meaning. So persistent emia, especially OID five days, is strongly associated with higher mortality independent of other risk factories like ICU admission. So it's not just a lab abnormality, it's a warning sign for worse outcomes. So in short, resistant Candidemia tells us who. Is at high highest risk, who may be, untreated, undertreated, and who needs urgent reassessment, not just that Canada is present in the bloodstream.

Martin Hoenigl 4:41

Angle on that, I mean you can just imagine if you have candida in the blood for a long time, the risk is that candida is going, going to sit and infect some other organs, right? It can infect the heart wells, it can infect other organs. It could can go even to the brain, the longer you have candida in your bloodstream, the risk of these complications that are often then at the end deadly are increasing. And basically our study showed that actually there is this direct association if there is longer candida in the blood, then. As we thought mortality is higher due to these complications.

5:14

So it's a symptom or a downstream effect of other things. It would be useful to talk about what you actually did in this sub-analysis and how did it differ from the original candidate three study I.

Sarah 5:31

So in the original Canada three study. The focus was on the overall quality of care, so how can was managed across Europe, as mentioned before, and it clearly showed that sticking to the recommended guidelines improve survival. What it didn't really look at, however, was how the infection actually evolved over time, specifically whether patients cleared the infection from the bloodstream or whether candidemia persisted. Despite treatment. So in our sub-analysis, we went back to the same large, multinational, multinational dataset, but asked a different clinical question. So we focused, on patients who had follow up blood cultures and looked at how often canid persisted, what factors we are as well as associated with that persistence and what it means for. Outcomes. And a key part of this work was being careful for methodologically, especially addressing immortal time bias. So we could probably understand the link between persistent kemia and mortality.

Michael 6:49

Great. The data is clearly very granular.

6:53

What were the key findings?

Sarah 6:54

We have a few key findings. First persistent candidemia is more common than many people think about. One in five patients still had candida in their bloodstream on follow-up blood cultures, and when clearance was delayed, outcomes were clearly worse. Second guideline adherence really matters. So patients who received less guideline recommended care reflected by lower equal CANIDA scores were much more likely to develop persistent bloodstream infection. The third key finding, getting the initial antifungal choice right, is critical. Patients who were not started on an ent, mean as first line therapy were more likely to have ongoing candidemia. Fourth, resistance is not just a laboratory finding. It's approach, prognostic warning signal. So when Cantina lasted five days or more, the risk of death was roughly doubled even after accounting for. Other risk factors. And finally, this all reinforces a simple but powerful message. So early guideline adherent management, including culture, practice, prompt, ethnic and immune therapy, and close follow up really can save lives.

Michael 8:33

That's refreshing, finding really, isn't it? I thought comment first on, one result I thought was interesting was the association between persistent candidemia and blood culture volumes that were below 40 milliliters. speculate why that was, why, a lower blood culture volume would've resulted in a persistent candidemia?

Martin Hoenigl 8:57

Yes, of course. I mean, I think there's not likely a one shot answer to that may most likely. It's a, it's a combination of different mechanisms. first of all, we know if you draw. Less blood, right? If your, your blood culture volume is below 40 milliliters, your sensitivity is lower, so you are not able to detect candidemia at an early stage, but more likely you will detect late stage candidemias, which means you already have a lot of fungal burden in your blood when your blood culture still becomes positive despite your drawing, only a low volume. that's basically one indicator that potentially these cases that were still positive despite the low volume, had higher burden of candidemia. In, in, in the first diagnosis. And then of course, also a higher likelihood of positive follow-up blood cultures along the road. The second explanation, of course, is that, this may also be a surrogate marker, right? So if you don't adhere to guidelines when it comes to draw or drawing volume of blood cultures, you may also not adhere to guidelines when it comes to, you know, appropriate first line treatment. Rolling out complications. For example, doing an echocardiography of the heart or looking into the eye, basically to look into eye infections, et cetera, et cetera. So it may also be a surrogate marker for, you know, not optimal care, and thereby also contribute, as a surrogate marker to, the higher likelihood of having positive, follow-up blood cultures along the road.

10:24

I think it would be useful to talk about the equal candida scores. Your study showed that low equal scores were an independent predictor of persistent candidemia. Could you tell us a bit more, and is it just a research tool or does it have clinical usage as well?

Sarah 10:41

That's a great, question. So the equal candidate score is essentially a quality checklist for clinicians managing patient with is in the bloodstream. What's important is that it doesn't measure how sick the patient is or their underlying risk factors. Instead, it focuses on the quality of care that is delivered. So the equal candidate score assign points for. Evidence based steps correctly. These include, taking enough blood for blood cultures more than 14 millimeters, identifying, the exact candida ps starting the recommended first line treatment, which is usually an acne canine checking the heart and e and the. Eyes to look for spread of infection and, removing potentially infected intravenous lines. So the equal candida score was so powerfully predictive because persistent often isn't about resistance or bad luck, but raised to or delayed steps in care. So when these core elements are not applied consistently clearing the infection from the bloodstream becomes much more. Because.

Michael 12:00

In the places that you or in your experience, who is implementing the equal scoring system? Is it the infection doctor? Is it the intensivist?

Martin Hoenigl 12:11

Yeah, it's a clinical score that's not necessarily always used in clinical routine, right? So if it's basically implemented or calculated in routine, it would most likely be an infectious disease specialist who is aware of the score. But when you ask about what the score summarizes, it really summarizes the whole care, right? Just does not only summarize what the IT specialist is doing, who is recommending some of the stuff that's depicted in the score, of course, because these are the guideline recommendations, but it's also summarizing, you know, it, it's especially, a reflective of the actual doctors who took care of the patients, whether this is in the ICU, the ICU doc or on a general ward, right? Better, for example, one component is that you take daily follow up blood cultures until. Infection tears. Right. Until it becomes negative. And that's one point, of course, you know, the ID specialist won't do that, right? So it comes back to the care team actually to match the guideline recommendations and that adhere to the guideline recommendations and do what they were told. But I think it's still an interesting question because one of the components, we looked in our study. But also whether a consult by a specialist, infectious diseases or microbiology, made a difference. And generally we saw trends that, you know, if there was an ID doc involved or a microbiologist and there was a consult consulting in these patients involved, then actually the equals scores were higher. So it definitely shows that, you know, experience helps here, and, helps to achieve better, care actually, in these patients.

Immortal Time bias

13:44

Great. Let's talk a bit more about immortal time bias. For those listening who are not familiar with immortal time bias, what is it and how do you control for it in your study? I.

Martin Hoenigl 13:57

I think it's a very important point, that many studies control for and some still do not, and that, that may be a problem. So basically, immortal time bias means, by default that some people who fulfill an outcome can't basically, fulfill certain, variables that may predict an outcome because of time. Right. Practically speaking, if a patient is dying, for example, within one day of Candidemia. This patient can't have, treatment for candidemia for 14 days, or this patient very often can't have an a echocardiography of oscopy because this is done mostly after seven days, after initial diagnosis. And there's multiple other factors of course, that just not feasible just because the patient has died early. And the wrong conclusion would be just to say. This patient has died early because this patient did not get an cartography right? This would be the wrong conclusion. The right conclusion is because of immortal time bias, the patient did not live long enough to even get this intervention right. So in reality, there is no association between those, and that's something that's important to control and in our study. We had the control for this to some extent with the equal candida score because as Sarah mentioned, the equal candida score combines multiple variables, not only at the time of diagnosis, but only during care of candidemia, which is, you know, for example, for our blood cultures that I mentioned before, which is, examination of the heart and the eyes, which also is duration of antifungal treatment after the blood culture are negative, right? So in patients who really die early. After diagnosis, they will naturally have a lower equal Candida score, and that's why it's important to control for it and that. we did in the past by excluding sometimes patients who died early. And here in this particular study, we tried to implement a second model where we really looked into baseline predictors rather than follow up predictors that come along along the road and excluded, therefore the equal Canada score, the second model. And indeed, we found in that model that persistent candidemia was a major predictor of mortality in these patients.

16:13

Thank you for explaining that in a very clear way for the non epidemiologists among us. It would be useful to talk now about whether there are anything that came outta the study that you were not expecting, particularly with regards to the results.

Martin Hoenigl 16:31

So I think the main thing I was surprised by is probably. Initial antifungal treatment. I mean we, it was a multicenter European study right across European countries, so it was not a worldwide study, and we'd have very clear guidelines recommending OCHIN as first line treatment. Nevertheless, we found that 40% in the persistent candidemia arm and. 20% in the, non persistent can arm. Did not receive a canid as first line treatment, but still received mostly fluconazole, which was really an old recommendation, more than 50 to 20 years back to be used as first line. and this shows us that in reality, right, it's always great to have kind of like new guidelines, new drugs available, new evidence that some treatments are better than others. For real life and patient care, we have to acknowledge that. You know, sometimes it takes surprisingly long until this new care practices are really implemented innovation care, and I think this delay is something that's enlightening, you know, telling us maybe we need to do more. Kind of like talk even more about things that are very clear to us, because for us it seems clear to use Asian cans, but we still need to emphasize this maybe more and talk more about this. And, potentially find strategies in the future how we can kind of like shorten this gap between kind of like new drugs, evidence for superior treatment and actual implementation into clinical care. So I think that's. Something that really strikes me because we also saw in our study that this was one of the factors that predicted resistant emia and bad outcomes, and I think that's the most surprising finding, of our study.

Michael 18:12

behavioral change is really complicated, isn't it's not just do we have the, facts.

Martin Hoenigl 18:18

Yeah,

18:19

And what are the limitations of your study?

Sarah 18:23

There are a few limitations people should know about. First of all this was a real world study, so care wasn't standardized. The diagnostic strategies and treatment approaches were across hospitals, which could have influenced how quickly candidemia was detected and managed. Second, some patients died very early, which means they didn't have the opportunity to undergo complete diagnostic workup or receive full treatment, and that could affect some of the results. Also, the main finding state the same even after accounting for this. And the third point is follow up. Blood cultures were not performed. All patients for all patients, and were not done at the same time. So measuring how quickly the infection cleared wasn't perfectly consistent. And finally, most patients were from Europe while resource hospitals. So they results. So the results may not fully apply to settings with limited resources. So overall the findings are important. They, but they should be interpreted with these limits in mind.

Michael 19:40

And I guess, the data is in a sense, in the past. So if we were to do this study again now, we might different findings, which brings me onto a question about candida, zy, Aris, or previously known as candidate. Because obviously we know that in Europe in the last. 5, 4, 6 years, this has really taken off. And the numbers of it were relatively low in your study, presumably just because of the time period studied. so I'm curious what your thoughts are about how can we extrapolate the data in your study into Canada Zy Aris patients, whether we might expect to see some differences in the future in this group.

Martin Hoenigl 20:31

Question, I think, and you're absolutely right. So I think when you look in the study period, this was 20 19, 20 20, right? So at this time there was, Canada S was not as big a problem in Europe as now. So it was still a representative basically sample that we drew back then. But if we would do this again. Nowadays, of course, in certain countries in Europe, we would have very high rates of Canada, ours, and of course the results may change to some extent. I mean, it's all. Hypothetical of course, but I would assume that, considering the higher rates of resistance of antifungal drug resistance in CanDos I would expect that we would have even higher rates of persistent candidemia nowadays. Compared. Do back then five years ago. So this would be one factor because obviously we don't get it right initially. You know, usually we start treating when we have the organism, but we don't have the resistance profile at the time point, right? So we sometimes just get the treatment wrong because of resistance rates. Not only, I have to say in Canada, Summa hours. We also shouldn't forget Canada Aosis, which. Still existing, but now has developed more resistance against fluconazole in many South European countries and is by some considered a similarly broad, large problem than cans. So definitely it's something, you know, it's always, I think we can draw a lot of conclusions about the implications of persistent candidemia. But the rate of persistent candidemia may nowadays even be higher than it has been five years ago. And. We are not sleeping. Right. So it's basically something the ECMM also addresses, right? So we are currently, this is, these were results from the E CM candidate free study. But we are, as we speak now, we are performing and coming to the final months of the ECMM Candida four study, which is specifically looking into non alcan candida species, including candida, Summa S, but also osis, gabra, et cetera. So the former Candida species and. are analyzing there basically better things have changed. We are also looking a little bit more into the isolates and kind of like wanna adequately analyze the isolates, not only in terms of resistance, but also in terms of antifungal tolerance. So it's something we hope we can address with this ongoing study within the next few years when we start analyzing it and getting all the results in.

Michael 22:56

into sort of future directions. What are the research gaps? What still needs to be addressed apart from the things you've already mentioned?

Martin Hoenigl 23:10

Yes. I think what we really need to address, one of the issues we are facing with emia is that, we are still having very high mortality rates, right? So if you look on overall mortality, we are still above 40% in patients who develop candida candidemia. And this has not significantly changed over the last two to three decades. Some people argue this is to the course that people who now develop candidemia are more sick than they were before, and thereby, you know, more likely to die of the underlying diseases. But we still did also some analysis of e cmm, candida Free, where we showed attributable mortality just because of candidemia is still 20% and above. I think that's really the main. Target for research in the future to find ways to reduce this attributable mortality of candidemia and base that could help is obviously, you know, maybe looking into new treatments. Potentially also looking into combination treatments. So there's also welcome, trust funded trials that are about to start, about combination treatment for candidemia, for uncomplicated candidemia with. old established drugs that we have available. So all of these, I think, are, you know, key components. And last but not least, as I mentioned before, pretty well about identifying resistance in Candida and Cando Zuma, which we, you know. More and more see and and really they care when we choose our drug. But there's also another thing called antifungal tolerance, which means more, it's not classical resistant. So if you test them on the Petri dish, they will be susceptible, but still in the presence of antifungals, they won't die. They will still persist basically, and tolerate the antifungal drugs. In real life, in the human body and then cause breakthrough infections. And that's basically also I think, a big area of research to find better ways to identify tolerance. Because this may really be one of the predictors of therapeutic failure and, you know, and how to implement then these results into clinical care. So that's in part something we are addressing with ECMM Candida for.

Michael 25:19

Are all awaiting the results with trepidation. Sounds like a really interesting study. And what are you both doing next? What's your, what are your future research directions?

Martin Hoenigl 25:30

As mentioned, I mean, we are both really busy with E cm, candida four, which is now coming to its final stages, and you know, we are kind of like wrapping up collecting isolates. This is a worldwide study by the way, so it's. You know, adds complex compared to E Canada free, because it's really study worldwide with centers worldwide. And we also have another project also multicentric ongoing about something else, another fungus aspas about influenza associated pulmonary aspergillosis. I don't know what the rates of influenza currently in the uk, but in Austria we have a huge influenza wave with, you know, lots of hospitalizations. All the ICUs are full with influenza patients and we are also pro prospectively enrolling there nation national wide. So that's also something that keeps us busy in parallel. But this is as palos, this is a different fungal pathogen, but that's also something we are working on.

Michael 26:22

That's a really interesting interaction between two very different pathogens, isn't it? It'll be interesting to see results. Thank you both for coming

Martin Hoenigl 26:32

Thank you.

Michael 26:33

today and you've really enlightened us the world of candidemia treatment. So thank you very much.

Sarah 26:41

Thank you for the opportunity.

Martin Hoenigl 26:43

our pleasure.

26:44

This is just a quick reminder that the B'S spring meeting will be in Birmingham this year on the 19th and the 20th of May.

Meningoencephalitis IQRG

Michael 26:54

Today on the podcast we have a really interesting paper from the Clinical Infection Practice Journal entitled The BIA Meningitis and Encephalitis Infection Quick Reference Guide.

27:07

And today I am joined by both authors on the paper, Dr. Christina Fernandez and Dr. Fiona McGill. So welcome to the podcast.

fiona mcgill 27:15

Hi Michael Thank you Nice to be here

Cristina 27:17

Thanks.

Michael 27:21

I have to admit, I hadn't heard of an IQRG before I read your paper. So could you start by telling us a little bit about what an IQRG is and why was it created?

fiona mcgill 27:32

So the I Qrg are infection quick reference guides I think and these started coming into being a few years ago maybe three four years ago something like that And they are the brainchild if you like of the British Infection Association who wanted to have a resource where the people who are seeing a lot of infections at the front door so a and e acute medicine et cetera could quickly look at something that is evidence-based Obviously we are talking about meningitis or encephalitis but there are other topics as well

Cristina 28:08

They focus on adult patients particularly or. As a resource for frontline clinicians to support them in, investigating and management

Michael 28:25

would you expect infectious disease doctors to use them as a resource or to help make guidelines or they'd be less useful for that group?

fiona mcgill 28:40

Certainly the one that we've done it all the information there has stemmed from other guidelines So whether that be NICE guidelines or BIA guidelines and I think as I say it's like a distillation of All those other sources of information So I think even for infection doctors they are useful cause they can see where those guidelines have come from So they're not gonna make guidelines from the IQRG but they can go back and look at the original source and enhance their knowledge that way And also infection doctors will sometimes be that person seeing the patient at the front door as well

Cristina 29:12

Yeah. I think it depends on the setting where you work. If you as an infection team, you're seeing patients at the front door presenting with infections be that pneumonia, skin and soft tissue they're a great reference tool to just. Go back and make sure that you've, you know, done all the appropriate tests and instigated appropriate management for the first, you know, 1224 hours. I, think they're a very useful guide for, for anyone dealing with patients with infection.

Michael 29:42

Let's get down into the details of what it says. So broad strokes. What are the, headlines from the IQRG?

Cristina 29:54

As I mentioned earlier, really having a, a clear definition, of when you would consider meningitis, when you would consider encephalitis. And then although meningococcal sepsis is not covered in this guideline, and it's covered in the sepsis IQIG just to. patients that might present with a sepsis syndrome and a rash. Classically as we, as we all know, kind of particular rash to think about meningococcal sepsis and manage these patients appropriately with the sepsis IQIG I think that was, one thing that we really wanted to, to kind of highlight. This guideline is, is it doesn't cover sort brain abscesses. And then as I mentioned, the importance of doing a lumbar puncture and key to maybe think when a, lumbar puncture is not indicated within that first hour. And then criteria for, for critical care reviews. So patients are kind of escalated appropriately when level two or level three care is necessary. I think those were the three things that we really wanted to put across. And then early liaison within with your kind of local infection service was another factor that I think occurs through, through the IQIG as to, you know, what cohorts of patients you, you really might want to be calling your, your local infection service on. Those were patients that were immunocompromised. Those were, that had recent trouble. We talked about a little, there's a little reference to membrane to consider TB and listeria which are sometimes not thought about a different door.

fiona mcgill 31:37

I think one of the things to bear in mind again that these IQs are meant to be It's about what the initial management is But it's those initial tests What do we test initially and what do we give empirically as our first line treatment it's not about what do we do two weeks down the line et cetera

Michael 31:55

I should say, obviously for listeners, they can't necessarily see it, but it is a very easy to read guideline. Bright colors, flow charts. You could imagine being a clinician in the front door, you know the information is easy to access quickly.

fiona mcgill 32:13

I think one thing I would just even sitting here now thinking about it is you know these are published in clip which is an infection journal and we are talking on an infection podcast So I think if anybody's listening to this they're probably an infection specialist Please forward this to your acute MITs and colleagues to your ED colleagues And that's what I'm gonna do straight after this podcast is forward it to our acute medicine colleagues cause as you say you want it printed out You want it in the doctor's office where people can see it

Michael 32:42

We'll also put the link to the PDF into the show notes so people can access it and forward it if necessary. I want to talk a little bit more about some of the detail that you've mentioned. So, one hour, to a lumbar puncture is certainly in the guideline, but I think we all know that sometimes the feasibility of this is challenging. I wonder if you could maybe share your own experience about this and, how could we improve on getting to that one hour?

fiona mcgill 33:14

I think the first thing to say is we do get a lot of people questioning that and I accept that this one hour has been in iterations of British Infection Association guidelines for decades now actually and when we wrote prior to the NICE guidelines there was the British Infection Association guidelines and when we wrote that the feeling was that we should aim for what we believe is best practice than what actually happens if you like and so that's where the one hour comes from It is something to aim for even though we accept that in a busy ed It doesn't always happen and the bottom line is the sooner the better interestingly we are recording this at the end of March 2026 and There's a lot in the news at the moment about meningitis and we've seen an increase in people coming in with suspected meningitis cause people are hearing about it and they're worried and probably an increase in people needing lumbar puncture I've had a conversation recently with our acute medicine physicians about how we try and get those to happen quicker certainly where I am there there's quite a good Pathway now which didn't exist several years ago where patients go straight from ED to Estec and get their lumbar puncture there So They don't have to wait For the next morning These are for the sort of low risk ones where you actually you you suspect it's going to be negative but you need to do it to rule out Obviously sick patient septic patients would be being admitted anyway So I think that's one way of trying to get it quicker to speak to your Emergency medicine colleagues and try and come up with pathways get people trained on doing lumbar punctures is another way And again that's something that our acute medicine colleagues are working on acps probably do the most lumbar puncture in our ec and training up our resident doctors to be able to do them as well helps increase the pool of people that can do them so that's one thing I think is helpful I dunno about you Christina What happens in Manchester

Cristina 35:10

Reflecting that actually that pathway would work well locally, but it doesn't exist at the moment. We've done quite a bit of work around making sure that availability is there, because that's one of the real frustrations that. There just isn't all the kit that you need readily available for when you need to do these particularly outta hours. Also using IT systems. I know that this is something that's happened in Manchester, not no credit to me but using your IT systems to, to really. Create kind of order sets so that all the investigations that are required are actually requested because that's, I guess, one of the challenges that even when that lumbar puncture is performed, if you, do not collect enough CSF or don't consider the kind of other, tests that you would need to do as, for example, your PCOS from blood or your blood cultures, et cetera. So, using the, the pathways, but also the tools that you've got to really kind of maximize the availability and the poss to do that Lum puncture and then doing the appropriate tests at the appropriate.

Michael 36:23

Which brings us on quite nicely to the actual tests that you recommend in the, iQRG you are very specific about the volumes of CSF, and I wonder if you could explain a little bit why it matters. Where do those volumes come from and, and why does it matter that the clinician takes the right volume?

Cristina 36:45

That was actually I guess it's a bit of a bug of mine that we just don't take enough. And I think if you're an infection doctor, you're used to taking quite a lot of CSF. know, we do a lot of LPs for We send off cytology at times. So I spent quite a lot of time looking at SMI and our laboratory handbooks and emailing. My labor colleagues locally to see what the minimum required volume would be, just so that that clinician, looking at that IQ ig who's considered,, the differentials that they might want to be testing for actually takes correct amount of csf. What you really don't want do is have to repeat it because you've not taken enough csf

Michael 37:39

Specifically with regards to tuberculosis testing the high volume is about improving. Sensitivity, is that right?

Cristina 37:47

improving your yield.

fiona mcgill 37:51

And I think just one of the things I was always taught was that you make CSF at the same rate that you make urine so people worry about taking too much CSF off but actually you will accumulate that CSF very quickly And I think the it's the old TB guidelines that give a guidance on how much CSF we can take and I think they say up to 17 mils or something like that 15 to 17 mils we don't need to be too cautious Although there is always the risk that if you use a black needle like I do you'll be there for half an hour waiting for it all to come out

Michael 38:26

In terms of the treatment, ceftriaxone is a pretty standard treatment across the board. But, I wonder if you could say something a little bit about the steroid inclusion in the, immediate treatment. Where does this come from and, although you don't mention when we would stop treatment, I, I wonder if we could just briefly talk about the times when the steroids would not be indicated.

fiona mcgill 38:53

I can talk about that steroids have been a little bit of a controversy in meningitis in years gone by and they first showed their worth in pediatrics with hemophilus type B Probably well over 20 years ago now they were shown to be beneficial in reducing hearing loss in in that group of people So then obviously people started to look at in other conditions and there was a European study led by a Dutch group looking at steroids in adults With meningitis and they showed a particular benefit in terms of mortality in patients which was mainly driven by pneumococcal meningitis had a significant decrease in mortality if they were given steroids and that was with or before the first dose of steroids So that's when it started to become a little bit more Thought of that we steroids were probably maybe beneficial in adults with meningitis and so then there few papers after that There was a couple of papers one in Sub-Saharan Africa and one in Vietnam that tried to replicate this but unfortunately actually didn't manage to replicate this So then there was a bit of a should we give steroids or should we not So then there's been a couple of Individual patient data analysis and eventually a Cochrane metaanalysis as well the bottom line is that They probably are beneficial in resource rich settings and that's what the Cochrane Review says in terms of mortality and hearing loss they've not been shown to be beneficial in other settings where maybe pneumococcal isn't the most common cause of meningitis and maybe where you've got more HIV more tb more cryptococcal that kind of thing and so we recommend it based on That Cochran review And they've also importantly in the Cochran review not been shown to do any harm so there wasn't an increase in bleeding there wasn't really an increase in other opportunity infections There was a slight increase in length of fever but really any harm So that is where the sort of rationale comes for including it in that they are certainly beneficial in pneumococcal disease and they don't do any harm in other forms of disease

Michael 41:07

Do you think non infection clinicians are currently giving steroids without an infection discussion? What's your experience locally?

fiona mcgill 41:16

So interestingly in Leeds which is where I work I have absolutely seen an increase in people doing this over the last A few years and maybe that's because I work here and I bang on about it I don't know But there has like it would almost never have been done before and it is routine now and it might be and I have to say I don't work in the front door so I dunno But it might be that when you go to click ketone on your drug shot and you say meningitis something pops up and says please give steroids as well but certainly it's given a lot more often now than it was without having to speak to an infection specialist and I think it would be really interesting We did a national audit almost 10 years ago now when the NICE guidelines just came out looking at that and it was still steroids weren't given that often so it would be nice to re-look at that I dunno Christina what you think in Manchester Is that your experience or not

Cristina 42:09

We, locally where I work we as an infection service do take patients from the front door. So I'd like to think that we think. Steroids and prescribed steroids early. but I guess my reflection would be that a lot of patients referred for med have correctly been identified as possibly having meningitis and they get given antibiotics and it's when that secondary care. Be that your, your medical team or your specific infection team sees them as the admitting doctors that then go on and, and think about the steroids is probably my reflection.

Michael 42:56

So I think we'll, we'll continue down the IQRG into the additional considerations box which I, creates some interesting talking points. One of them as an infection doctor I'm interested in is you mentioned in listeria that you could consider Cotrimoxazole as a second agent. I wonder if one of you could talk a little bit more about that.

Cristina 43:20

I can maybe say why we put that in. And it's essentially because the new NICE meningitis guidelines were published at the time that we were creating the IQIG. I know that in the past infection guidelines had suggested Gentamycin as the second agent and. Ole is what nice recommends. And so we included that there. Saying that I, I think this in practice would be done after a discussion with an, with an infection specialist.

fiona mcgill 43:52

I mean I think what people certainly maybe older people might be thinking is traditionally we've given Gentamycin as a second agent in Listeria and there was always a little bit of again controversy either whether that was needed or not And in our in the previous guidelines it suggested gentle medicine as a second agent if you wanted something and I think that's where the difference is now They seem to be recommending Coach Mox Instead of Gentamycin Nobody's done a randomized control trial to compare the two but I suspect it's something around benefits and harms and nephrotoxicity et cetera so yeah as Christina said we put it in because we obviously don't want to be contradicting national guidelines in these I qrg

Cristina 44:40

I think if you had, you know, 12 hours in if you've got someone who you think has lister probably you should be discussing that with your local infection.

Michael 44:53

And another digital consideration you, you talk about is tuberculosis. And sort of trying to risk stratify the patient in front of you to decide whether or not they might be at risk. Do you, do you think if someone suspects tb, that that's an automatic flag to talk to? Id, what, would normally happen?

Cristina 45:14

I think lo I can only talk about what local practice is in Manchester. That would be the expectation that anyone where a team is suspecting CNS tb should be discussed within, with the infection. I.

fiona mcgill 45:30

I guess the only Caveat I might put on that is like Christina and I are both coming from centers that are tertiary centers that have an infectious diseases department and probably have a reasonably high instance of TB as well obviously patients with suspected meningitis will present anywhere and you know they might present a very small DGH and weather It's on somebody's radar there to discuss with the local ID team or the microbiologist or whatever I'm not so sure so we might have a slightly skewed view of what happens in reality hopefully as you say with the that's one of the things that these IQs are supposed to help across the board where maybe you don't have that

Cristina 46:11

And another thing that's in the IQ IG is just thinking about or inquiring about recent foreign travel. So incentives where, TB incidents might be low or you might not have a, a tertiary ID service. This IQIG should hopefully highlight. Issues early on, and, and then those clinicians can contact their,

Michael 46:36

with regards to travel, you've put some in useful information about where clinicians can find a bit more information about certain viruses and, and, based on where the person has, has been.

Cristina 46:48

Yeah, it's not a comprehensive list. But it just does highlight that there is a wider differential in patients that, that have traveled. And the, there's also a recommendation to do a malaria film in anyone presenting with kind of meningitis or encephalitis symptoms. 12 months of, of, of foreign travel. So, a again, it, it just is there to guide clinicians at the front door to, to consider differentials that just might not be that common or with a lower incidence in, in the area where they live.

Michael 47:27

And maybe we could talk a little bit more about the patient isolation precautions, which you touch on in the IQRG. It was discussed a little bit earlier that, the recent meningitis outbreak has, has made a lot of people concerned about spread of meningitis. What are the infection implications in terms of spread of, of meningitis and what should we be doing to reduce the spread?

fiona mcgill 47:54

So I guess the concern is meningococcal disease is the

Michael 47:57

I.

fiona mcgill 47:58

concern in terms of acute meningitis And so we say that until somebody has had 24 hours of effective antibiotics then there should be a fluid resistant surgical mask apron and gloves and aerosol generating procedures You should have an FFP three mask The thing about Meningococcus is it's exquisite exquisitely sensitive to antibiotics usually which is why within 24 hours you can generally step that day

Michael 48:32

So, one thing that came up a little bit earlier was about previous national audits. Looking at, how well we, adhere to the guidelines. Do you think you could use the IKRG to audit practice or would you, you think a more broader guideline, like the nice guideline would be a better way

fiona mcgill 48:51

I mean to be fair I think actually the IQRG would be a useful tool to audit cause as I say all the information there comes from the NICE guidelines guidelines has a lot more information in it And if you wanted to focus on you know the key elements of immediate management then yes I think the IQRG would be a useful place to start for your audit You know it's all consistent with what's in the nice guidelines but got all the sort of extra stuff that maybe you're not so interested in equipment and or whatever

Michael 49:29

and because it is a bit more condensed, you could probably find some quick wins about how you could improve things. I imagine.

Cristina 49:37

yeah, definitely. You know, time to number pump antibiotics at the front door. Whether, the different diagnostics are done, in the first kind of 12 to 24 hours. They're very easy standards to identify towards your, your practice against.

Michael 50:01

That leads me on to asking about what gaps you identified when you were doing this. We've already talked about a number of controversies, but when you were making the IQRG, did you find something that maybe had not very much evidence

fiona mcgill 50:17

One of the things again that was a little bit of a gap of modern evidence Base is what you do in your penicillin allergic patient so I think we've just put in the IQRD contact infectious diseases or microbiology and national guidance still states to use chlorine clinical which is based on evidence from 30 40 years ago something like that But a lot of places struggle to get chlorine yl cause it's not really a drug we use that often and there are potentially alternatives like quinolones or carbapenems et cetera So again that might be an area that would be worth Looking at and trying to create maybe a more modern if you like evidence base or something that's more readily available to recommend At the moment we've put in discuss with your infection specialist because of it will be different probably in different sites as to what they use but that might be an area to look up

Cristina 51:09

The other thing that just reflecting on the now and recent published evidence. Trial results that have essentially shown that whilst steroids not proven to improve outcomes in patients with her simplex and encephalitis they do no harm. I think, historically been a degree of concern around giving steroids in patients with potential HSV encephalitis and whether that would. Lead to uncontrolled viral replication and and adverse outcomes. And that's really not borne out in, in the study. So I guess, it just provides a bit more assurance around the, recommendations there which is that, you know, patients with encephalitis, steroids are recommended. If.

Michael 52:00

Thank you very much. That was a excellent whistle stop tour of the IQRG and I would encourage you to go and have a look at it because as I said, it is wonderfully laid out and, a really useful tool, at the front door. So thank you both very much for creating this resource, and thank you for coming on the podcast.

fiona mcgill 52:19

You