71.Nobbling the Nonfermentors: Burkholderia pseudomallei - Melioidosis

In this penultimate episode in the Nobbling the Nonfermentors mini-series, Jame and Callum discuss the regionally important neglected tropical disease Melioidosis, caused by Burkholderia pseudomallei.

This episode was based disproportionately on the following article, and we extend our thanks to the authors for thoughfully publishing it so close to us wanting to do a podcast episode on Melioid!

Meumann, E.M., Limmathurotsakul, D., Dunachie, S.J. et al. Burkholderia pseudomallei and melioidosis. Nat Rev Microbiol (2023).

https://www.melioidosis.info/

Link to prep notes here.

Transcript

Callum: 0:18

Callum, how you doing? I am good. Although I'm up in Scotland and it's wintry, so it's pretty cold up here.

Jame: 0:29

Is this another bur cold here? Yeah.

Callum: 0:31

per.

Jame: 0:34

That really got me last time, but you have to do a new one.

Callum: 0:37

Oh,

Jame: 0:38

Do you I am not sure I get along with these hues and all these protein shakes. They're, they're not really like a full meal. They're they seem to me to be quite meite.

Callum: 0:49

that's good. Yeah.

Jame: 0:52

You can have that for free if you like much.

Callum: 0:53

It took me quite a long time to realize that the, the ending o on something means like it.

Jame: 1:01

Yeah,

Callum: 1:02

Shank is like a Shanker.

Jame: 1:04

Like a Shanker. Yeah. Yeah.

Callum: 1:05

Yeah. That's another example. Dip Oid. It's like diptheria, but it's not diptheria. Soran cranial bacteria often described as dip OID on a gram.

Jame: 1:16

yeah.

Callum: 1:16

yeah, I love I, once I learned that, I was like, oh, this makes things so much easier to remember.

Jame: 1:22

Well, this, this is just giving everybody the idea that you didn't learn Greek at school.

Callum: 1:26

I did not learn at school.

Jame: 1:29

So what are we talking about today?

Callum: 1:30

outed. We're talking about Balaria pseudo malai.

Jame: 1:36

Indeed we are. So this is the cause of agent of OID and Meiosis was first described in 1912 by somebody called Alfred Whitmore. He was a pathologist working in Ranon, Burma who published a paper on a gland like illness. So gland is the thing that Berk Didi causes and he. You know, observed an illness that was similar to gland Earth, but in Southeast Asia where Ardi Deer and Mallis wasn't considered to be traditionally found.

Callum: 2:05

You can find the original paper, which is. interesting read. It was published along with somebody called I think Presume Dr. Krish Ash Whamy, and yeah, I had a, I had a Skimm read through the article and it's just always interesting reading articles from that long ago and how things are described.

Jame: 2:23

And yeah, so the, for a while its alternative name is Whitmore Disease, also known as the Vietnam time bomb because Vietnam vets would come back. To the US and then be diagnosed with a meite, sometimes decades after their last known exposure to, to Ardi Psdo. So it's a really interesting disease. And one which I've had personal experience of treating when I was working in Darwin, in in the Northern Territory. This is a real big problem, particularly in, in indigenous Australians as we're going to talk about shortly. But as a, a brief reminder to the Alder genus, Callum There are 79 Berk dairy species. We've talked about Berk Dairy Cacia Complex, and that's about 20 to 22 species Within that complex of the remainder, there are three. That are kinda worthy of mention, I suppose, and alde a gladioli, which is very non-pathogenic, but occasionally turns up in CF sputum. And people are not even sure if this is actually pathogenic or not or if it can cause disease in humans, but it's sometimes observed in culture. Rkl de edi, the thing that causes glands and brood didia, pseudo the cause of agent of myosis, and. To differentiate between the two, you can use the three, you can use an oxidase test. Pseudo is ox positive. Malli and gladioli are ox negative, and the cacia complexes is variable depending on what species you're talking about.

Callum: 3:53

That would make a good exam question. I think if you wanted to ask people You would get a scenario of someone that had traveled or, or lived in an area endemic for these diseases with symptoms and as we'll come to there, there's some overlap. So, you know, you would grow the gram negative bacillus and they would give the oxidase result and I think if you knew that, then that could be a good aid.

Jame: 4:12

I, yeah. So Colin, where do you get Al de Psal ai?

Callum: 4:19

Yeah, so I guess as with all epi epidemiological data, we are we, there's some areas where you, you have reliable data collection and some areas where it's not possible to do that. Usually to do with just resource I guess. And so the areas that we know it definitely is Southeast Asia, along with, as James has mentioned, the, so in Indonesia and Northern Australia, in the show notes, James found a good graphic, which that lays out like how certain you are about other places. So we're certain it's in those places we're less certain about its presence in other tropical parts of the world. So this pretty good evidence, consensus that MEO is presence in areas of central and south America. So Mexico, you know, Brazil. Peru, Venezuela, et cetera. There's good evidence consensus there, and then there's, there's not consensus on whether it truly is in Africa or not. I remember reading a paper a while back, which was looking at soil samples and people were able to grow ur like the cause of organism was found in. Of I think there was West Africa, that paper,

Jame: 5:34

Yeah

Callum: 5:34

when I was doing the DTM and

Jame: 5:35

but, but is it causing disease in humans?

Callum: 5:38

well, yeah, exactly. And you know, the, the access to the, you know, so call to the diagnostics, but the access to those tests is not universal.

Jame: 5:47

Hmm.

Callum: 5:47

So it is difficult to know and a lot of places are using certain you do syndromic treatment. So we just don't know. But I think that's a nice way of laying out, which is, how certain we are. And then I guess on the other end of the spectrum we're we've got good evidence that is not present in places. Like North America, Europe, China.

Jame: 6:10

Uh, you see that Kum actually, but there is endemic spread in the southern USA recently been documented. There was a couple of people that had Amelio

Callum: 6:20

oh. That's the, that's the little state that's notched into the us

Jame: 6:23

And they had not left the state in, you

Callum: 6:26

I

Jame: 6:26

ages and they'd never been to Amelio area. And so they went looking around the kind of homes of these people. I think they were farmers by trade. That's the high risk. Group there, and they found pseudo mal growing in the soil. So it's more widespread than we think, but certainly the lion's share of meiosis is in south, is, is in the Indian sub continent, Southeast Asia and North Australia. That's where almost all the cases happen.

Callum: 6:54

Yeah,

Jame: 6:55

Are we the only host?

Callum: 6:57

no, there's two hosts you and me.

Jame: 7:00

Oh yeah, yeah. Yeah.

Callum: 7:03

Uh, so no, we're not, humans aren't the only hosts for, so it can also infect. mammals, so pigs, cats, dogs, goat, sheep, horses, and others. Quite a wide range,

Jame: 7:19

I, but all mammals, I, I, I guess that's what we're seeing.

Callum: 7:22

Yeah. Is that all mammals? That's all the mammals.

Jame: 7:26

Uh, and instance, like of an issue is this?

Callum: 7:30

yeah. So again, as we don't have complete data, it's an estimate, but a hundred, and there's an estimate of 165. cases per year with approximately eight to 9,000 deaths, which is a very high effort.

Jame: 7:47

Yeah, but I mean it, it's happening in places where access to healthcare is tricky, and the antibiotics that we'd use to treat this in some places, they're just not available. So I'm not surprised that there's a 50% death rate So where would you find pseudo AI in the environment? Cal.

Callum: 8:02

As James alluded to, there it grows, it's free living and grows in the soil and it's in, what people turn the rhizosphere, which is basically the area around plant roots in plant life which is where a lot of microorganisms live.'cause there's sort of nutrients that are going on there. So, and there's grasses, rice, aerial portion of grasses and also in feces of grazing livestock and native animals. So it's quite widespread in that environment. So you can imagine an agricultural. Agricultural society that would be, a major risk. It can also be found in surface water and sometimes in storms it can be end up being aerosolized. So that's another risk. You know, we'll come on to when it's most reported, but that, that would give you a hint. What are the risk factors, Jim?

Jame: 8:51

So the number one risk factor is diabetes.'cause it makes the host more favorable colonization and subsequently infection with pseudomona eye. But anything that can cause immunosuppression with a notable exception of HIV, it's not a significant risk factor at all. Um, so that sort of implies that CD four T cells are not the most important thing for pseudomona eye host resistance, but liver disease, renal disease, alcohol, excess thalassemia. Uh, which is common in Southeast Asians cancers non HIV immunosuppression, especially steroids and cystic fibrosis, to the point where most cystic fibrosis societies will advise CF patients not to travel to melo endemic areas, uh, For risk of getting this. And if they do, they need to take measures to try and avoid contact with them. But yeah if a CF patient gets amelio, particularly in the lung, it's big trouble.

Callum: 9:47

Hmm.

Jame: 9:48

in about 16 to 36%. Of cases, and those numbers are from Australia and Thailand, respectively. There's no risk banter. But aside from everything that we've talked about before, there are a couple of risk groups. So in Southeast Asia, it's farm workers, people that are tending the soil. And in Australia it's the indigenous Australian population. And that's the population that I was having contact with. They were coming into the hospital with. With acute and disseminated myosis. And that's again, because of regular contact with the land. Particularly in kids. A lot of them are wandering around barefoot and that's causing contamination or predisposing to colonization. That way. The way that it gets into you is you either inhale it, it can go in percutaneously, or you can ingest it. Either contaminated soil or water or stuff that has been contaminated with with those things. There are actually a couple of reports of animal transmission. And these are really rare, but there, there are case reports where there've been outbreaks in sort of zoos and farms and that's through contact with the animals themselves and and or their feces. And therefore usually inhaling a high inoculum. And in fact, I've not put this down in the Preuss Cal, but one of the, one of the worst ways to get a really aggressive fulminant meite pneumonia. Is to almost drown in Southeast Asia. And then you get like a quite a high inoculum into your into your lungs. Yeah. Nasty. Do you wanna take through us through pathogenic or will you

Callum: 11:24

Yeah. Yeah. So the organism it has an intracellular lifecycle and so like many organisms that. That do this, it allows it to evade the immune response'cause it's hiding within your own cells. And it can replicate in both phagocytic cells, so your sort of neutrophils and other things and non phagocytic cells. And then it goes between cells. So it has something called an infected sinia,

Jame: 11:52

yeah. And I, I think just for curiosity really, and we can talk about virulence factors that they've that they've got. So one of them is BIMA Bico Daily Intracellular Motility Factor A, which promotes the host cells actin polymerization, and that leads to, uh, sort of cell to cell spread. So they're changing the way that the the cells are structured. They've also got some type three secretion systems which deliver bacterial molecules into the whole cytoplasm to improve their chance of survival. Type six secretion systems. I have quite forgotten what these do, but apparently they help promote intracellular survival. And then the other factors are things like capsular, polysaccharide, LPS, flagella, the same stuff that would be considered variance factors in other gram-negative organisms. And then there's something lastly called Al d DL Lethal Factor one, which sounds very cool, but I didn't look up what it did

Callum: 12:47

Presumably it kills you.

Jame: 12:50

presumably.

Callum: 12:51

I was just looking up one, what Initia is.'cause I actually didn't know what that meant. Uh, to my

Jame: 12:56

Oh, a, a multi multinucleate cell, uh, cal. See your respiratory syn virus that promotes accumulation of several cells into one massive cell, and they still retain the nuclei. That's what a syn is.

Callum: 13:09

Yeah. Well that's embarrassing.

Jame: 13:11

Alright, Carl, take us through the clinical syndromes here.

Callum: 13:14

So the usual incubation for, for this so the time between being exposed and becoming ill is is the mean. The average is nine days and usually ranges up to 21 days. However, it is an organism that can, that can actually persist for a very long time. And so there, there's reports of it coming on as quickly as two days, but there's also reports of it becoming clinically apparent until several years later. I think this is classically described in prisoners of war. Because they had more investigation essentially, but prisoners of war coming back from World War ii that had been stationed in Southeast Asia or kept prisoners of war and they,

Jame: 13:56

And actually the longest I think documentation was something like 26 years or something like that in a Vietnam vet uh, as well. that, that's the other big war that happened in that area that resulted in, in delayed onset of

Callum: 14:08

Yeah, a lot of medical research gets done or has been done historically. So the latency, so I guess we don't know what the prevalence of people having latent Meli is.

Jame: 14:21

So if you look at antibody studies in kids the. In, in Southeast Asia. So in Thai children, about 50% of them were sero positive, the ones living in rural, Areas. So that implies tons of latent infection. So we we are probably, it's probably a tip of the iceberg situation. We're seeing the clinical cases, but actually there's loads of people that are infected but not getting any symptoms or just fighting off the infection and then developing antibodies.

Callum: 14:49

Yeah, so they think about 3% of people convert active infection if they're laly infected. And then localized disease. So there's, I guess we can split this up into localized OID disease, acute OID disease, and then disseminated infection. And finally chronic infection. So if we stick with localized first. So essentially the major report, maybe Jane, you can comment on this, have you, I dunno if you've seen it or not, but in Australian children they can present with a skin lesion. Which is specific to me.

Jame: 15:24

Yeah, and I've linked to, to derm net. It looks like gouty tophi, but on the arms and the legs, you know, it looks to me at least, but people can open that up and sort of see, see examples of it and. You know, it's interesting the disease kinda hits differently in Southeast Asia compared to North Australia because in Southeast Asian kids it's parotid lesions that they get mumps like lesions. Whereas in, in Aussie kids it's usually skin and soft tissue infections, um, which can be chronically presenting.

Callum: 15:57

If you're getting exposed in a different way, then different presentation

Jame: 16:00

Well, it can do, but they also they talk about this, oh God, at this point, Callum, I should, uh, go 20 minutes in. I'm a fool for not doing this upfront. Almost all of this episode is based on an excellent nature review microbiology article by. Titans in the field of LIO Osis research, including Susanna Donkey, who is local to Oxford, but does lots of research in Thailand. And Bart Curry, who is an infectious disease professor and consultant in Darwin, who I had the pleasure of briefly working under. When I was working out there, but he's a sort of world expert on Amelio, so is everybody that's wrote in this article. As far as I can tell, I googled all their names and they were all, they all seem to be very high up and they did a nature review, microbiology. It came out in September, October of this year. I've included a DOI in the web link. It's got. Everything that you need to know about melo, including loads of stuff that I'm not saying and that we haven't put in the prep notes because I didn't want to just replicate it fully. And then, there's a little bit of information from the UK, SMI, um, really it's I. A comprehensive article that tells you the absolute state of state of the art on Lio lordosis. So if loyal listeners ever encounter a case of oid, I would strongly encourage them to get their hands on that review article.'cause that tells you everything you want to know. And then email some of the authors,'cause I'm sure they'd be able to help. But yeah. So anyway, returning to the returning to the,

Callum: 17:35

we've yes, we've got localized, so Australian children's skin lesions, southeast Asian children parotid lesion lesions. Then we move into acute meteoroid. The presentation, so 50% of people with acute meteoroid are presenting for lower respiratory tract infection. So they presumably have inhaled it in that case, and 50% of people present and are found to have a bloodstream infection.

Jame: 17:58

They can call present just non-specifically shocked. And, and so in that case, if they were from the right area, you would start empirical cover for, uh, MOSIS, at that point, at the time it was me, penem. It has changed now as we'll come on to shortly. But yeah.

Callum: 18:16

And so yeah, you've got this, quite, either respiratory or non-specific presentation as Jane alluded to. So a fifth of people have septic shock. Whether that's on presentation or later on down the line, but that's a very high rate. I don't think many other bacterial diseases cause that rate of shock. And if you don't treat this, 90% of people die. And I think that was alluded to in the epidemiology we mentioned earlier on, where, you can see that, almost half the people globally that are getting this disease are not surviving it. It can be complicated. So you've got your acute and this can then be complicated by disseminated infection. And this was described in some detail on the autopsies in their initial description where they were looking at lungs and they described when they looked at the lung that there was a strange cheese, like consistency, which wasn't in keeping a fu genic or in I guess bacterial pneumonia or tuberculosis. So the organs basically can disseminate from the blood and go into several organs. So it's usually the liver or the lung or the spleen. Or the prostate. And it forms abscesses in those areas unless common location. Less common locations can be bone joints, other viscera, lymph node skin or brain, which is interesting because most, saying it's unusually lymph nodes, you're bypassing that immune defense, which kinda speaks to its intercellular nature, doesn't it? That it's, things that are usually spreading in the bloodstream stream. You're gonna find them in the lymph nodes first, and you're gonna get a generalized lymphadenopathy. So the fact that it's not commonly there. It just speaks how good it is and it's probably getting stuck in places like liver, lung, spleen, because there's loads of capillary beds, and that's just where a lot of your blood cells end up.

Jame: 20:01

Yeah. Yeah. In particular, actually it's a common known cause of Gen two urinary disease, so the whole urinary tract can be affected. It To particularly favor the prostate. And so a lot of the time, Antibiotics have a bit of difficulty getting in there. I don't really know why it favors the prostate. But it certainly does, certainly in the North Australia form and yeah, and if, look at this list that we've just mentioned for disseminated action is basically everywhere, right? It's

Callum: 20:28

Yeah.

Jame: 20:29

everywhere, but it's, very commonly liver long ple in prostate and. It's, that's, means that you need to get the right kind of antibiotics to treat abscesses and infections in those areas after drainage if possible.

Callum: 20:43

And then your final group is the chronic cases. So that's after you've had acute, and then it can, it can become disseminated, but it could also become chronic. So about 10% of cases can develop chronic disease, and that is defined as if you've got symptoms lasting greater than two months people call it like a TA TB like respiratory infection or the other option is a non-healing skin infection. So, you know, I think it's a mimic. And in places where you don't have diagnostics available, you can see how easily, if you have a chronic respiratory tract infection. making you know that would be a very easy to mix it up with TB if you didn't have any other way of doing it. And we also know that, the diagnostics for tb that are available, like smears and stuff are not a hundred percent sensitive. Difficult but the overall mortality about 10 to 40% and that's with treatment. So 90% untreated, but 10 to 40% with, with treatment. So it's a really severe illness.

Jame: 21:43

Yeah. Yeah. True. Micro mode,

Callum: 21:46

micro engaged,

Jame: 21:48

okay. So culture remains the mainstay of diagnostics for familial doses and what can you culture, but you can do blood sputum urine if you suspect gen urinary disease, and you can either, get a skin swab if you've got something too swab where you can get a pus sample if you've got a skin abscess. Importantly you need to tell the lab if you're suspecting this, because at least in the UK this is a hazard group. Three organisms. This needs to be taken into the CAT three Lab for processing. And what will you find once you process it? Well, it's a gram-negative bacilli. Obviously, it's quite motile. It is oxides positive, nitrate positive, and indu negative. It grows actually quite well for a CRO dairy. It will grow on standard blood or chocolate agar. Um, there are no specific commercial agars available for growing this, but there are a couple of others that you can try and it will grow at 35 to 37, but it'll take a couple of days and it can be easily outcompeted by other bugs. So for that reason, people do try and use a selective agar and there are a couple to mention, one is called ashdown agar and ashdown agar contains gentamycin and crystal violet as selective agents. Um, and this is. Sort of used in an endemic areas. And there's a sort of a website that's trying to get all the me lordosis researchers together, me lordosis called info. And it's run by some of the Thai doctors and some of the Australians. And it's a central resource and it's got a link to a YouTube video for how to prepare Ashdown agar for those interested. That's a little something for the, lets stop micro fan boys. And then the other agar you can use is BCSA, Bural, dairy Capacious, selective Agar, because that's got crystal, Viola, and Gentamicin as well as polyx and B as well as vancomycin, neither of which will effects Burd pseudomona particularly. Um, so you can try and grow it on that as well. If you want a Bural ds, select Vigar and again. A couple, three or four days in, in a air at 35 to 37 degrees is what's recommended. Uh, the colonies can take, a couple of days to appear and initially they'll be small and creamy with a kind of a metallic sheen to them. And later on they will become rough and corrugated. And interestingly, on Ashdown media, they're purple, which is why the Ashtown media's preferred. It's easy to identify them on colonial coloring. In terms of the microscopy they would appear as densely packed chains. And they'll exhibit some bipolar staining as well to secure the diagnosis, you can use maloff and as the databases for maldi become more and more accurate, um, they used to be misidentified as der Thailand dense. Uh, but that is becoming less and less of an issue. And of course, if you're suspecting Meli and B Thailand dense as turns up in your Maori results, you will probably think this is probably still Meli.

Callum: 24:48

What is B Thailand instance? Is that a cacia complex or just a different?

Jame: 24:54

No, it is a behold area that we've not discussed and we're not going to.

Callum: 24:57

Okay, great.

Jame: 24:58

There is a sort of characteristic antibiotic sensitivity pattern that you can use. So for disc diffusion testing, if it was resistant to poly mixings and amag glycosides, but sensitive to cosla, then that would be a presumptively diagnosed in endemic areas as a pseudo, um, it is not recommended to use the Vitech or the API. 20 E, uh, because that will co usually mistake pseudomona for rad complex.

Callum: 25:29

Hmm.

Jame: 25:31

Uh, and then lastly the sort of commercial test that you might have would be antibodies. Now this is more useful I think for us if we are. If you even have access to it in people that don't live in endemic areas and then you come back and they're sick and then you test them and they've got antibodies, then that would be interesting. In endemic areas, lots of people will have antibodies and so that makes it much less useful as a test. In, in the UK at least a lot of the time, these would be sent to a reference lab for confirmation. So they'd go down to Collindale, uh, in London and there they could use MLST. PCR and 16 SRNA as well.

Callum: 26:10

The treatment. It is all. Sorry. So yeah. So what, what can you test? So you cast Oh, I can't believe we, we, how far are we into the episode now? Like 30 minutes or something? The, and we've taken it this long to, to talk about you cast 14. Maybe we'll have to do a separate episode that's been requested on what the changes the break

Jame: 26:31

See what it has. Yeah.

Callum: 26:32

Yeah, so that means we have to do it now.'cause anything you ask for, we have to do. That's how this works. And.

Jame: 26:38

But you know, how interesting is it that, that we've got UCAS break points for pseudo, and that was because of a herculean effort from the OSIS info researchers uh, presenting data on, what works and Data for what Callum.

Callum: 26:54

Well, the things that you can test are you can test against ccl, Kazadi, imipenem, and Meropenem, doxycycline, chloramphenicol. And Cotrimoxazole and all of these have apart from the carbapenems, but all of the ones apart from Imipenem and Meropenem, they have the the ucas the way that they do it now, where they want you to use the increased dosing. So they put the susceptible break point as less than 0.001, which is not a, it's not an achievable target. And so you'll never get a sensitive to Comox. pseudo, you'll only ever get a I for increased inpo, increased exposure, sensitive, susceptible, increased exposure, or you've got an R,

Jame: 27:45

Yeah. Yeah.

Callum: 27:45

which I think definitely

Jame: 27:47

True.

Callum: 27:47

something to, you have to communicate that clearly to your clinician if you're doing the report because people say, oh, well it's, I took mcl, but it's S to Meropenum. Why would I not use Meropenum? Which is just. No, not good, but there's work to be done on communicating that. So that's the antibiotics you have available. The other thing that was lookeded at was roc, so the MIC 90 was 0.125, but there was no clinical data to say if this was effective. So I guess you could consider that if you we're stuck, you can maybe use that as an agent, but we just don't know if it works or not.

Jame: 28:26

Hmm.

Callum: 28:26

So what do you, that's what you can test against. What the what does that Nature Paper recommend that we do with the antibiotics? How do we treat people? What? What did you do when you were

Jame: 28:36

Yeah. Well. What, what I did in Australia, in when I was in Australia has now changed because there was a paper comparing use of ketta deemed to conventional therapy that found that ketta was better at the job. Uh, so there, there's two stages to treatment. One is an induction phase and the other the maintenance phase. The induction phase is usually for one to two weeks, although it can vary according to where the. The bug is, and, and consult that Nature Reviews paper for, for details. But usually it's about 10 to 14 days and you will use either keft or carbapenem, preferably keft, taine and plus or minus cotrimoxazole. And you will add that in if you've got CNS skin, bone, and joint or prostate involvement.'cause Cori oxil penetrates these things quite nicely. And then there's a further maintenance phase of about three to six months. Where you just use KO triazole, but you use quite a high, uh, dose which I'll come on to shortly. If you've only got localized infection, you can just use KO triazole. And That's particularly useful in when it's diagnosed in places far away from a hospital and the patient doesn't want to come in for, two weeks of four times a day ctdi, or three times a day, Meropenem, they'll if they say no, you can say, okay, I can just use. Try at least to just use cotran. And then in terms of dosing regimens the cine is 50 milligrams per kilo, a maximum of two grams, six hourly, and meropenem would be one gram eight hourly or two grams if it was for CNS infection.

Callum: 30:12

that cine dose is higher than normally.'cause normally you would use up to two grams every eight hours.

Jame: 30:20

eight hours, yeah, you're right, it is higher. Um, and then for Cotrimoxazole, it's six milligrams per kilogram of the trimethoprim component, maximum 320 milligrams of trimethoprim every 12 hours.

Callum: 30:33

Can I sidebar? Why do we, so we talk about antibiotics and cotrimoxazole is a very commonly used antibiotic and there's other antibiotics. I know it's a combination, so it's slightly different, but why do so often the dosing comes as the of trimeth. Is it because there's variability in trimeth to suox ratios, or is it always the same? In which case, can we just say a oxil dose please?

Jame: 31:01

So if there was variation between the, uh, the Ethin and the su methol, there isn't anymore. It's always in a five to one ratio. So when I say six milligrams per kilogram of ethin, blah, blah, blah, I could also just say 36 milligrams per kilogram of oxone, and you would get exactly the same dosage. It's infuriating Callum, but every time that people are recommending a dose of cotran. Which is more than 960 milligrams twice a day. So if they're using it for PCP or for this or that or the other, they always freeze it this way. A milligram per kilogram of the trimethoprim component.

Callum: 31:40

If you know the answer to why we do that, write in and tell us why. The other thing that gets

Jame: 31:45

please do write in'cause I do not know.

Callum: 31:47

The penicillin dosing in million units. I hate that it's outdated. It's just going bin. I mean, that's.

Jame: 31:55

Yeah, true. I agree. I agree. Uh, if you were going to use scl I honestly Kam, I don't really know why we do it, and I never, I don't remember. Ever using this in Darwin? So when we were treating a pneumonia in the dry season, we would use either comox or ceftriaxone. And in the wet season, because of the risk of boid, we would use Meropenem as our upfront, um, pneumonia treatment. Yeah. To the point where I remember this the medic, there were some medical students from Adelaide and they were doing their kind of final block up in Darwin, and then they went back south for their finals. And in the finals there was a question which was like what would you give for this person? They've got a pneumonia. And they all put Meropenum. And then the uni phoned up Darwin, Royal Darwin Hospital and was like. Why are, why is everybody putting meropenum for treating a pneumonia and bar curry had to get on the horn and say, actually it's because that's what we use here because of the OID risk that happened whilst I was working there in 2012 to 2013. So yeah. The sla, yes. Technically what I, what I've done here is the, um, keft and Cotran, those doses are all from the. The the review paper and everything else here is from the uca higher doses, but I've never used Comox lab this way, so you'd have to use 2.2 grams of Comox eight hour, so that would be two grams of Amox and 0.2 of clavel acid, which we don't have in the uk. You would have to give 1.2 grams of SCL and then a separate gram of amoxicillin to get this

Callum: 33:30

Whenever I prescribe the high dose oral, the 6 2 5 Comox with 500 milligrams of amoxicillin,

Jame: 33:37

Yeah, the boo

Callum: 33:37

would always get a phone call from someone being like, if you've made a mistake, and they're like, no, this is what we want to do. Uh, just'cause

Jame: 33:44

No, you made a mistake buddy.

Callum: 33:46

Yeah, I, yes, you might have a different formulation available in your country.

Jame: 33:52

Of course. Yeah. And then there, there is a dose for Chloramphenicol, which is two grams, six early, and then for doxycycline, they're uh. The, the dosages document of, of UCA says dosage varies by indication. And so I went to the UCA break points table and looked for pseudo, and then looked for doxycycline, and then it says something in consulted dosages document for details. So, so well done for that Circular logic there. uca. So I don't know. I'm not even sure how you would use doxycycline really in this context. Luckily, Callum resistance is not common. With pseudo Mali eye, it doesn't, it, it is usually sensitive to all the first line things. Yeah, no. So it is usually sensitive to all the first, the frontline things. And thank God it is the, there are some risk factors for resistance and that would be a high bacterial burden. An abscess that you haven't drained osteomyelitis, obviously. And if you've got it in a bronchiectatic patient. so the, the resistance mechanisms are here in a in a graphic, which I have, I've pinched unceremoniously from the Nature Reviews article.'cause I just thought it said absolutely everything that needed to be said. And it's the resistance mechanisms that you can get. So if there are some beta ess that will confer resistance to. Cosla, Keft, Tadi and if produced in high enough values. Imipenem Keft Tadi obviously is an anti-pseudomonal drug. And so it, it does that by working on PPP P three, which is pseudomonas favorite ppp. You can pseudo and then lose that to confer resistance. Um, there are. Methyl transferases, which can confer resistance to doxycycline if you end up using that. And then lastly, there's our favorite resistance mechanism, Callum confusingly named EFL pumps, which will confer resistance to a variety of different antibiotics.

Callum: 35:52

gonna go through the names. If you, the names of all the pumps you can go to the prep notes. Look.

Jame: 35:59

Exactly. But yes it's luckily it doesn't seem to be a significant issue with with Malio if you hit it hard enough and if you drain all abscesses, so if you, uh, if you treat this with intent to kill, let's see.

Callum: 36:16

So when you say treat all drain all abscesses, is that? If there's multiple pulmonary abscesses you would be trying to get, I guess anytime there's an abscess or pus under pressure, as ID doctors will be pushing for those to be drained, but

Jame: 36:32

I mean, KA all depends on finding a radiologist or a interventionist that was going to be willing to do it for you. And that will probably be more possible in OID endemic area, like North Australia or or Thailand than it will be, if you get a patient that comes back here. But I think. You Particularly as the treatment for pseudo is already so long and involves, pretty dangerous drugs, pretty dangerous doses, frankly for long periods of time, that getting as much puss out as possible is the best thing for the patient, particularly given the high mortality rates, 90% untreated, maybe. A quarter untreated, so that's a lot, right? To be going with that staph emia levels of on treatment mortality. So it should be treated with similar seriousness. And just like that we come to the end of the episode.

Callum: 37:25

That was, I think. I remember sitting in shock here because that's, it was a very straightforward, you know, run through it and there was no massive tangents. It's done.

Jame: 37:41

Yeah. Well that's good, right?

Callum: 37:42

I don't know. I don't know what we're waiting for. It just feels like, and we're done. What's what we learned? Should we summarize or something?

Jame: 37:50

Uh, yeah. Okay, fine. So, something at Myosis is a, likely underdiagnosed and when it presents as a symptomatic infection, quite an aggressive gram-negative illness that affects Southeast Asia and North Australia particularly. But there are known outbreaks in endemic areas popping up all over the world. Notably sub in Sub-Saharan Africa south America and Southern United States. Early diagnosis is essential, but that is hampers by the reduced likelihood of recognizing it outside of it. Endemic areas and the lack of availability of standardized culture media. Uh, when you do suspect it expert advice is recommended and osis info, it would be a good place to go to, to try and get that. And once you make the diagnosis there is a standardized treatment with antibiotics, which luckily the pathogen remains susceptible to year after year to avail yourself of.

Callum: 38:51

Lovely summary. That's not right. A lovely summary. Thanks Tim.

Jame: 38:57

Bye.