86. Legionella and pontiac fever

Jame and Callum are joined by Lee John and Ella for this episode around the arch-villain of atypical pneumonia and the bogeyman of every spa. Yes Legionella pneumophila (and friends) are addressed in depth whilst this podcast is aerosolised around the world.

Show notes for this episode here

Transcript

Jame: 0:18

Callum, how are you doing?

Callum: 0:20

I'm good. I actually was just meeting up with three of my very good friends the other day.

Jame: 0:28

Huh, what are their names, Callum?

Callum: 0:33

together. And there was a lot of air conditioning there. It was lovely. I've got a bit of a cough now though. So today what's our names? So it's Lee, John, Ella.

Jame: 0:48

And what a coincidence that is, Callum, because what are we talking about today?

Callum: 0:52

We're talking about my good friend's Legionella. I was

Jame: 0:58

That is the worst one for a long time. I'm very disappointed in you.

Callum: 1:02

thinking about like making a Roman Empire reference, but there's all this stuff on social media about that's all the men think about, and I don't want to further that stereotype, although it may be true.

Jame: 1:10

Yes, Legionella a cause of atypical pneumonia, but atypical in a different way to how I, I suspect most people think about it. Why don't you take us through the genus

Callum: 1:25

legionella species, the genus which is in the family legionellaceae which is in the order legionelli alleles, legionella

Jame: 1:36

Enterobacterialis.

Callum: 1:38

Legion Anies which also includes things like Rickettsia coxiella.

Jame: 1:44

we're in the really weird bit of the Gram negative tree. It's getting really funky down here. So

Callum: 1:50

Yeah. They're like, where are these tiny little bacteria live inside the cell? You're like, can you really, bacteria? It's just such a big chunky box, isn't it? So yeah, there's of 52 species that we know about, but more than 70 serogroups. So typing used to be done by serogroups. But the clinical disease is called legionnaires disease. There's a whole load of them. Most of the time we're thinking about Legionella Pneumophila when we're talking about this. And Legionnaire's disease, 90 percent are caused by Legionella Pneumophila and 84 percent of the cases of all the Legionnaire's disease, 84 percent are caused by Legionella Pneumophila sero group one.

Jame: 2:34

Which is of interest because that's the one that we've got a urine antigen test against.

Callum: 2:40

Yeah, exactly. It's, that's a key takeaway, we talk about Legionella species, now, historically, that was the only one really knew about. But over the last 10, 20 years is like their diagnostics have become more widely spread. We're picking up a lot more Legionella species that would cause human disease. So I certainly remember early on hearing about Legionella Longbechiae, which was the one first reported in New Zealand and it's linked to soil and compost.

Jame: 3:10

Yeah.

Callum: 3:10

So yeah, we've got a long list of legionella species

Jame: 3:14

Are we going to do a classic Jame and Callum list that alternating species names and bore everyone to death?

Callum: 3:19

Yeah. Some people say that they need something to fall to sleep too. So

Jame: 3:23

Fantastic. so the legionelle pneumophila subspecies, there are three of them,

Callum: 3:29

Legionella Pneumophila Fraseri,

Jame: 3:31

Legionelle Pneumophila. pasculii, and the non pneumophila species, anissa,

Callum: 3:41

Birmingham Anensis.

Jame: 3:43

cardiac,

Callum: 3:45

Cherry Eye.

Jame: 3:46

cincinnatiensis, gratiana

Callum: 3:50

Kelly

Jame: 3:52

jordanus.

Callum: 3:54

Lansing.

Jame: 3:55

Long Beachie. Nagasakiensis.

Callum: 4:00

Oakridge Ansys,

Jame: 4:01

Quinlivanii.

Callum: 4:03

Saint Lenza.

Jame: 4:05

Santicrucis.

Callum: 4:06

Steel Eye,

Jame: 4:08

Tusonensis.

Callum: 4:10

Wadsworth Fi.

Jame: 4:12

And that's all the species. And no, you don't need to know them. I barely knew any of these before we did this episode.

Callum: 4:18

I like Birmingham. Ansys.

Jame: 4:19

Yeah, me too.

Callum: 4:21

Yeah.

Jame: 4:22

Why don't you go live there then? So let me tell you a little bit about the history, Callum, as if you hadn't prepped this episode and not me. So initially the this was identified at an outbreak at the annual convention of the American Legion in 1976 in Philadelphia. There were 182 people, 29 of them died. Yeah, and then they identified the organism the following year by culture and was named Legionella, after the American legion, pneumophila, because it was causing a pneumonia. And the source was identified as, and people that have sat the MRCP or their medical exams will no doubt know. Recognize this as a stem, the air conditioning system and the air conditioning system was infected with Legionella and aerosolized it through infected water. There was actually another outbreak previous to that in 1968, which was termed Pontiac Fever because it happened in the Pontiac region. Town in Michigan, and that was retrospectively identified as being caused by Legionella Pneumophila through sampling once it had been identified in the 70s.

Callum: 5:34

when you come across Legionella clinically, it's like, Ooh, Legionella, severe. But obviously there is a spectrum of clinical disease because there is Pontiac fever. I always find it a bit weird because people say you can either have Pontiac fever or Legionnaire's disease. And I feel like it, there's a spectrum of disease severity.

Jame: 5:52

Yeah, people say that about, Staph

Callum: 5:54

selection bias, isn't it

Jame: 5:55

There, there's no such thing as, yeah, there's no such thing as non severe, infection with this disease. Thing. And, a lot of infectious diseases can cause a spectrum, of infection. Some people get hardly any symptoms with the flu, and some people get a life threatening pneumonitis. And with Legionella, it is the same. It depends on the host, it depends on the environment, it depends on the initial inoculum etc.

Callum: 6:21

The that's about the history. So where, Legionella is all around us. It's an environmental organism. It's found naturally in fresh water. And it likes to live at 20 to 42 degrees C, which I would say is quite a nice thing for a human actually. 42 is getting a bit hot,

Jame: 6:39

It is, but if you think about freshwater sources, like in the UK, there's not a lot of them that will actually sit at 20 degrees normally. So this is much more a disease of the Mediterranean and other kind of, hot bits of the of the planet, which I suppose, now that I think about it, is most of the planet. But compared to compared to Scotland and to a lesser extent, England. But yes, you're right, it is. And what is it doing when it is in that freshwater system,

Callum: 7:05

loves it. Hanging out intracellularly. In the human host, it is an intracellular pathogen. In the environment, it is an intracellular pathogen. It loves living in those free living amoeba. Which I always feel like it makes the amoeba sound like they're having a great time. They're just free living. So it parasitizes things like Acanthamoeba, Naeglerii, and lots of other

Jame: 7:27

Another protozoa. So it's a parasite, basically, of eukaryotic single celled organisms. And when it gets into a human, we'll come to it in a sec, it tries to target the thing that looks most like an amoeba. Which goes around all day finding things to gobble up, and that's a macrophage, because macrophages go around all day trying to find things to gobble up. Fair enough.

Callum: 7:48

The main problem is, obviously, in the natural environment, that doesn't really cause us a bother. But human made water systems quite often set at a bit of a warmer temperature. And they can be colonized by amoeba and protozoa. Then legionnaires are found there as well. And they are able to form biofilms and surfaces and form these sort of like polymicrobial biofilms. So they can be really hard to get rid of once they're colonizing a water system. And I'm just going to say this now, there's so much talk about legionella infection control and built environment wise. And I think that is a whole separate episode in itself. Hopefully at some point in the future, we'll come back to infection control and built environment stuff. But Have you watched that space? We're not going to dwell on that this episode.

Jame: 8:35

fine. There are other infection prevention podcasts which may have mentioned it or may be going to mention it, so do you want to give a shout out to them?

Callum: 8:43

Yeah yeah there's Infection Control Matters and there's also Infection Prevention and Conversation. James, what are the risk factors? Obviously this is probably pretty widespread in some parts of the world. Why is not everyone just dropping down a legionella?

Jame: 8:58

It's, it'll be partially lack of exposure, but also, most Legionnaires not particularly wanting to get into humans. It's perfectly happy living in water systems, killing Ecanth, Amoeba and things like that. You are more likely to get it, say if you've got certain risk factors, so increasing age, if you're a smoker or you've got some sort of lung disease, so pre existing lung damage predisposes you to colonization, or you're immunosuppressed, and then there are Things which increase your risk of exposure. So if you work in construction or you're working, water systems or you're traveling to kind of foreign claims, maybe staying in hotels, maybe hotels, which don't have water systems that are up to scratch, things like that. And then there are more specific risk factors in some parts of the world Legionelle Lombice is, uh, parasiting gardeners because gardeners are the ones who are getting their hands into the soil and that's where their legionelle is living.

Callum: 9:59

Yeah, I was thinking about that when I opened a bag of compost, I don't like stick my head in it and take a deep breath in to really get that compost smell anymore.

Jame: 10:07

Now you're telling me, Calum, because I just shove my head right in there all the time whenever I'm buying compost which I do every week.

Callum: 10:14

It's really fancy. You do ask your patients, like sniffing any compost

Jame: 10:20

Yeah.

Callum: 10:20

and then what's wrong with you? Which I guess is just being an ID dog, isn't

Jame: 10:24

and then, in terms of what it does once it gets into the the target site, which is the lung here, is that it will find The thing that looks the most an amoeba which is a macrophage in our cases, and then it will enter that through, it will get phagocytosed basically, but it's got a bunch of evasion mechanism, which means that basically when it's in the lysosome, and being exposed to lysozyme, Nothing happens. It's got ways of neutralizing it, and it's got ways of getting it out. And then there's a couple of other sort of pathogenic factors. One is it's got a type four secretion system called dot ICM, and what that does is that delivers proteins from the bacteria into the host cell that stop the phagosome combining with the lysozyme and therefore it's not exposed to as much lysozyme and then the cell can proliferate unhindered within the phagosome and it can escape it. And then it will feed off the host cell, and then once the nutrients are exhausted it will the flagellae of the lead genel will release something called caspase 1, which you probably will recognize if you know anything about apoptosis as something which triggers apoptosis in in eukaryotic cells. And then the cell will die. Undergo programmed cell death and then the Legionella will be released into the environment to infect other cells. And that's very effective. And that leads to what we know as Legionnaire's disease. So what's, what is the clinical syndrome of Legionnaire's disease, Cal?

Callum: 12:01

Yeah, so you're obviously wiping out that immune response, so I think that's a, like a classic pathological feature, if you get lung samples from patients that have Legionnaire's disease, and then in contrast to other types, other bacterial causes, pneumonia, you see a sparsity of macrophage. Types of the cell. That's my understanding. Not that we often do that. So yeah, really the clinical syndrome is a severe, atypical, community acquired pneumonia. And that's generally speaking, when we say atypical there's a sort of whole area around that. We talked in a previous episode about atypical pneumonia more generally, and we'll link back to that in the notion notes. But the, this, the presentation, you've got this prodrome before you get real pneumonia. So you're starting with fatigue, fever, myalgia, headache, and then that's followed by the cough and the shortness of breath. In contrast to how you usually think about a more usual bacterial pneumonia, say your strep pneumo, where your respiratory symptoms are quite early on, although it's a bit difficult to unpick because, say a strep pneumo bacteremia. A major risk for that could be having something like flu. So sometimes it's a bit hard to unpick did they have a viral infection and then develop subsequent bacterial pneumonia and it's a typical infection? Or was that preceding quote unquote flu like illness actually the beginning of their atypical pneumonia? And that's a real puzzle to unpick, that's when you start thinking about a typical pneumonia from the history is that sort of prodrome and the incubation between exposure to Legionella and clinical diseases is reported to be about two to 10 days. And then obviously once you've got the cough and the shortness of breath, then you would see signs on chest x ray Typically bilateral, patchy, or diffuse infiltrates.

Jame: 13:43

So not the focal low bar pneumonia of a typical,

Callum: 13:47

not typically,

Jame: 13:48

Of a typical pneumonia like a strep pathogen or haemophilus or something like that.

Callum: 13:52

And the other thing that are reported as quite common, and certainly this correlates with my experience seeing these people, is that you often have reporting nausea, vomiting, and confusion. I definitely remember one case I saw who was, like, a fever and returning traveller. I saw them in clinic. They were very odd and very confused, and didn't really have any respiratory symptoms to speak about. And I was like, this is encephalitis, The lumbar puncture, all that stuff. And then, I don't really remember, I think it was just one of those things I was, like, quite junior, and just got caught up in the investigation of encephalitis. And then we did a chest x ray and he had a big pneumonia. And I was like, oh, and the lumbar puncture was just like champagne tap, like no white cells or anything. And the eventual diagnosis of Legionella. And he was pretty sick with it, he had all the classic stuff. He was he had this sort of initial prodrome. He didn't have that many respiratory symptoms, but it did develop later on. I think we got him quite early. He had nausea and the other things on investigation is hyponatremia. So that's like a real exam question.

Jame: 14:57

Yeah. Do you remember the mechanism for that, Cal?

Callum: 14:59

I don't know actually, I was wondering that. Do you know what the mechanism is?

Jame: 15:02

Yeah, so the hyponatremia has been commonly attributed to SIDH. But There's a more recent study that I'm just reading here has tested that and found that ADH or vasopressin levels were not significantly elevated, but ADH precursors were in response to severe disease. So it's all due to the severity of disease, not due to anything that the bug is doing.

Callum: 15:26

Yeah, and the other thing that you quite often see is a transaminitis so elevation of a LT and or other markers of hepatocyte damage. And overall the case fatality rate is reported to be about 10%. Now I think they can, you can do like estimates to see what the. The general like prevalence is, as I say, we'll come on to the diagnostics. I'm going to be talking about that a bit more there, but there's maybe a bit of skew in that because we only really. We're only really testing, Paul, if that's severe atypical pneumonia for Legionella, so whether we're missing the less severe end of the spectrum. Anyway so yeah, that's the clinical syndrome. I think I guess it's not common, but it's certainly not rare. Like you do see it from time to time.

Jame: 16:09

You see it occasionally. It's not like you're seeing it all the time,

Callum: 16:12

Yeah, I've read that most cases are sporadic from environmental exposure. Now obviously if you're seeing I think in Adarsh North there was an outbreak in 2012. Do see time to time outbreaks and there's obviously a big public health concern and often it's traced back to like water cooler towers or, external air handling units, things that have water stored and maybe the checks haven't been done. So public health get really involved with this because, you need to have building codes and standards for maintenance. These are things to stop it because, people are sick and go to ICU pneumonia, you need to stop that, it becomes something of big importance. So yeah, that's the sort of a whole other. discussion itself. So what about the lab diagnostics?

Jame: 16:57

The gold standard way of identifying it, and there's what everybody actually does. So let's talk about the gold standard first. So the gold standard does microscopy and culture and if you go ahead and do that, you will see that it's a pleomorphic gram negative. The can appear as coccobacilli in tissue and secretions. And then they can also appear filamentous in culture. They're pretty small, about three to five micrometers. And so that makes it difficult to visualize on the gram stain. In terms of culture, you would have to use specific agars. So there's Buffered Charcoal Yeast Extract, or BCYE Agar supplemented with a couple of unpronounceable nutrients, and you could grow that for 10 days in a moist atmosphere at 35 to 37 degrees. it won't grow on Blood Agar, and it won't grow on Maconkey, so that means that you have to use this funny stuff. And then the, there's another Selective Agar

Callum: 17:54

so you, so yeah, the BCYE is like a enriched media, which means that you're more likely to go to legionella. And then there's a elective media, which is BMPA Alpha. So buffered ke Mandel, poly mixen and CIN alpha, ketoglutarate medium.

Jame: 18:13

Thank god you said that, not me.

Callum: 18:15

Yeah, I don't know if I've ever said that before, but yeah, so in the standards for microbiological investigation, the SMI UK there's basically the two different media that you can use. And when you're trying to grow it, my understanding is, not that I've ever done this that you're, mainly looking for growth on this buffered charcoal yeast actor, the BCYE. And the Legionella's dependence, it's growth is dependent on L cysteine and then soluble iron supports it's growth as well. So what you do is if you grow it on there, you then set it up on BCYE without the L cysteine. And if it still grows on that, you can immediately know it's not Legionella, which

Jame: 18:54

I see, yeah. So you use one then the other. Yeah, fine.

Callum: 18:57

And and you also set it up again on the supplemented agar to make sure it's still alive, and it's quite slow growing, so say that it should grow, but it might have like early growth at 72 hours. But it can be very hard to ID, up to 5 percent CO2 can improve the growth of some legionella species. It doesn't grow in a usual agar, so you'd have to set up the AGO that you're looking for initially. You're not doing that very often. Like often in pneumonia early on you don't get respiratory samples. I think of all the cases I've seen and actually, often they didn't actually have a productive cough.

Jame: 19:30

No, but I suppose some of these, pastes will end up in the unit and then getting a bronchial vulva or lavage will

Callum: 19:36

But yeah, it's not clinically that useful because it's like, what, you wait till they're in ICU and then they get tubed and then you get the BAL and then you put it out for culture and then it takes three

Jame: 19:47

All right. You don't need to persuade me. Let's skip down to the good bit then. Let's talk about the antigen. You happy

Callum: 19:52

let's finish the culture. So you grow it, right? What happens, what does it look like? So the colonies, they're pretty small, flat. They're over time, if you let them grow, they're reported to come smooth convex. iridescent and opal if you do them long enough. And if you put a loop into the colony, it's got a fixed string, which sounds pretty cool. Yeah, you need like a low power microscope to look at them if you wanted to look at them earlier than that. Sometimes they have A green or pinkish color. Lots of shades. It's something quite interesting. I've linked in the show notes to a website called Microbe Canvas, which we've mentioned before on some revision episodes. Thanks. And honestly look at that. They've got great grammar. I've not stolen their pictures because they don't have rights to do it, but just go to the link. And they've got pictures of the organism growing on the charcoal agar. And it's got like a pinky green color, I would say. And then they've got pictures of the microscope of the colonies looking like perils. Really nice pictures, so you'll remember if you look at that. And then biochemical test wise, so it's catalase positive and oxidase is reportedly variable. So you know, it's an aerobic organism. So we talked before about catalase and oxidase being things that organisms have to survive in oxygen. Reason we're talking about this is that I guess it's done in reference labs and you can, that's how you do it. And. Antimicrobial susceptibility testing and typing, et cetera. We're not going to talk about that anymore because what do we actually do, Jim?

Jame: 21:21

In, depending on where you are, you may still do this Legionella urinary antigen, which as you've said, only works for Pneumofla C R1, but seeing as that causes 85 percent of all the Legionella, in the UK at least, that's worth doing in some cases. It's detecting the LPS. of that particular seed of R. It is 99 percent specific. And there are some lateral flow devices which can be done. So I think in nadoschrona and Fermi North, we were using a lateral flow device, On urine. And so you can get a result very fast. I suppose the downside of it is that And I was certainly guilty of this before becoming an ID doctor, is that if somebody had a bog standard pneumonia, I would, send off for urine antigens for both pneumococcal and legionella, regardless of severity, and so that's just a cost to the trust, that confers no benefit, because outside of severe disease, who cares, frankly.

Callum: 22:28

I was wondering who was doing that and it was you all along.

Jame: 22:31

When I turned up in Enbrun in Nadosh Royal Infirmary North in 2014 to start training, they'd already canned it. Yeah. So if you are going to do this, I would probably reserve it as, diagnostics stewardship for people that actually have severe pneumonia, severe clinical syndrome. Yeah. Cause otherwise your yield will essentially be nil. What about PCR, Callum?

Callum: 22:56

Yeah. So molecular tests. So PCR is really the mainstay of diagnosis. So if you read some of the review articles, they talk a lot more. They're like the, with the recent introduction of molecular tests, but this is now widespread, particularly in the sort of post COVID era where there's been a big upsurge in the molecular diagnostics that's been done. The PCRs, you get the diagnosis so quickly. It's very specific. Ideally, you want to do this on deep respiratory samples. So like sputum, juice sputum bronchoalveolar lavage is ideal, really. Whatever you can get, but, it can't just be a throat swab. And, people have looked at doing it on blood or urine, but it doesn't really have much sensitivity it's not really done. And, yeah, there's not much more to say. It's a PCR test. You can do PCR certainly, in Nadosh Norf, we've got PCR for Legionella pneumophila. And then another one for Legionella species. One thing to be aware of that I've certainly seen is that we know that Legionella species, not Nymophila generally, are pretty widespread within water systems. And so it's possible for some of your lab reagents to become contaminated with the molecular material from dead Legionella species, which can lead to low level false positives. for joining us. The context I've seen that in isn't like pathology samples, like post mortem. If there's been like water in the environment or some, like the lab reagent. You get these sort of low level false positives. Which can be difficult to get rid of. When we say it's got high, specificity, but yeah, that's the hallmark of diagnosis really. And it's surprising in some ways reading the SMI to see that culture is the gold standard. I guess it's not what you compare it to, but

Jame: 24:43

Yeah. Yeah.

Callum: 24:45

things have moved on a bit. I think that SMI is from 2015, so maybe a wee bit older now. Okay, let's jump to treatment now, Jim. How do you treat it?

Jame: 24:54

As an intracellular organism, you need things with good intracellular penetrance, and as luck would have it, we have a bunch of those, don't we? We've got, the macrolides, we've got tetracyclines, and we've got the quinolones. And those are the main drug classes that we would use to treat this if we had confirmed it. A note on early treatment, though. There is pretty good evidence that treatment delay in Legionella is associated with increased mortality. And it's for this reason, really, that as you go up your pneumonia severity in Legionella, It doesn't matter what you're using, SmartComp, PSI, CURB 65, the atypicals cover gets introduced. You're unlikely to die because of a short delay to antibiotics if you are infected with Mycoplasma or Chlamydophila. But that is a real risk if you've got Legionella. So for severe pneumonia, that's why we're introducing atypicals cover. And that generally starts to kick in at a CURB score of about two to three once it's three, basically everybody's including Atypical's cover, and at two it varies. Yeah.

Callum: 26:03

I think there's pros and cons to that approach and in episode 34, arguing about oedipals, I think we had a little bit of a moan about the propensity oedipal cover when it maybe wasn't needed. So you can go back to a bit more of a Discussion on that.

Jame: 26:18

But and we'll link to this too antimicrobial susceptibility testing for Legionella is difficult to do and almost never done because you almost never culture it anyway. You're usually using the antigen test or a PCR for diagnostics. And so the sensitivity testing is really performed. And so what options are there? Do we have and do we have any evidence as to their efficacy? Yes, we do. And you've linked to a meta analysis here in the subject matter. And it was a pooled comparison of the quinolones, either Cipro or Levo or the macrolides, predominantly clarithromycin and azithromycin. And azithromycin was the one that was mostly used. And the macrolides. Mortality rates quinolone versus macrolide was 6. 9 versus 7. 4 percent, odds ratio of 0. 94, crossing one, non significant between the two. And there was no difference in time to aperexia, length of stay, occurrence of complications. And so to all intents and purposes, the macrolides and the quinolones are equally effective for treatment of Legionella, which I think is worth looking at. emphasizing, I think that when we think about these things for treating pneumonia, people have a tendency to think of macrolides as like a weak antibiotic, certainly compared to the quinolones, which, Levol will cover atypicals, but it'll also cover strep, like it must be more powerful than all the rest. It doesn't work that way. Macrolides are concentrated intracellularly. Extremely well, and are very good at their job, which is killing intercellular pathogens.

Callum: 27:59

And I think that we did an episode called Escalation Emancipation, where we talked about this idea of an antibiotic ladder and one thing being stronger than the other and how, we think that's pretty nonsense. And that's demonstrated here, because I think in a lot of situations you would be like, Oh, quinolone, it's probably a more reliable cover than a macrolide for a lot of other things. But in a certain sense, They're non inferior. There's issues with the evidence base. Nobody's really done any randomized controlled trials in treatment of Legionella with a decent number of people. So we aren't in quite a, there's a low volume and low quality of evidence in this area. So it'd be important to stress that.

Jame: 28:38

but the evidence is best for these two groups

Callum: 28:41

Yeah, and for everything else, I didn't really find anything. Like we talked about doxycycline, so that was mentioned in the Sanford guide as a possibility. I really couldn't find anything anywhere to say what that's based on, other than I guess in vitro susceptibility data. And there's some other studies where they look at like adding in rifampicin. for cold therapy and didn't really find that it helped. I guess the idea being rifampicin gets intracellular pretty well. And the other thing that's reported is that cotrimoxazone might be another treatment option. So I guess it's worth, when there's no evidence, being aware what the other options are, like someone who's got a severe allergy to quinolones and their QTC 600 and you can't use macrolide, I don't know. It'd be a bit of a niche case. So yeah, really a lack of evidence here.

Jame: 29:26

you can think of other reasons why maybe they would, like allergy or something like that, where maybe the top two options are not, options. And then I suppose doxycycline would be in the running, or it would be what you would use next. Certainly all the review articles that we looked at for this. prep, they all, mentioned quinolones and macrolides and variably or not at all mentioned doxycycline.

Callum: 29:51

Macrolides or quinolones, everything else you'd be looking at if you really had to. And it's interesting because my experience is as soon as we suspect or confirm legionella straight on levofloxacin, and I really thought I would go and read through the literature and be like, ah, this makes sense. But I don't know. And now I'm like, is, obviously when there's not much evidence, you can lean back on clinical experience, actually, someone's improving and they're on azithromycin or clarifromycin. I'm like I'm not going to change them. I don't think. And there is a real pressure to change people to leave with loxacin. I'm like, with all the concerns that are noted about quinolones. Is that the right thing to do? I don't know.

Jame: 30:31

What about resistance mechanisms, Callum?

Callum: 30:36

the end because it's not very much antimicrobial susceptibility testing

Jame: 30:40

No.

Callum: 30:41

as Jane mentioned, it's.

Jame: 30:43

found, yeah.

Callum: 30:44

Yeah, so EUCAST don't provide breakpoints. They've got like a guidance document which talks you through the two methods. So essentially e tests or microbroth dilution and give a wild type distribution for different antibiotics and say, you can report as likely susceptible to Based on that the wild type. And then I guess what we're looking for is any resistance mechanism. It's worth just saying why do other agents not work? Things like beta lactams, aminoglycosides, Legionella is intrinsically resistant to them mainly because they just don't get into the cell well enough. They don't concentrate there to get over the MIC. So although if we could test those in the laboratory, if you can do that, they actually work pretty well in vitro. I guess it's a good example of why, clinical data is key. And EUCAST are really focused on correlating in vitro data with in vivo data because of stuff like this and why PKPD is so important. That's the intrinsic resistance, acquired resistance GYRA for ciprofloxacin, so single point mutation. We've talked about that with lots of other organisms. It's cropping up here again that's been reported as a potential cause of resistance and certainly been described. And then the other thing is, For Macrolides. So for Azithromycin, you've got your LPE AB eFlex pump. And so that's been reported be responsible for elevated mics for azithromycin. So you know, there is. Reports in small numbers of resistance it's thought to be rare people have looked at this in a sort of surveillance point of view, but it's not really not something that we seem to talk about much clinically and yeah, I guess the clinical significance of these resistance mechanisms, although they're described in the literature, isn't particularly clear efflux pump, who knows if it actually means that you're unlikely to respond to zephromycin. One thing that's been suggested is that erythromycin, so it often be like inferior sensitivities from other things. And erythromycin might be a poor predictor of macrolide decreased susceptibility just because the efflux pump, I don't think, is so good against erythromycin is my understanding.

Jame: 33:01

we're not, but the presence of that pump's not, also not being correlated with reduced efficacy to a Zithro either. No,

Callum: 33:08

little bit of, I think my takeaway for the resistance mechanisms is yeah, potential. We don't routinely test for, or at least not in a timeframe that's clinically useful. So I guess if you put the patient on a Mac ride or quinolone and you've got confirmed or highly probable legionella and they're not getting better, and then you could maybe think about switching to the other one. Might be a way to look at it, but it's far more likely they're just not responding because they're severely unwell with pneumonia in ICU and they're vulnerable hosts because they've got chronic lung disease, they're over 50, they're a smoker, and they're immunocompromised, because those are the people that get legionella. Anything else to say?

Jame: 33:48

I think so. Thanks for taking me through that, Cal.

Callum: 33:50

You're welcome. Yeah, a rare Callum Prep episode. It's it's not easy. Anyway I guess to take away we ran you through a load of different names of Legionella. Why is it called Legionnaires disease? What even Pontiac fever is? The sites, the risk factors, the pathogenic mechanisms, clinical syndrome lab diagnostics, probably more than you wanted to know about culture. And then touched on treatment just a little bit there. I

Jame: 34:17

Lovely. See you next Fortnite.

Callum: 34:20

See you next time