Ready for some startling Steno statistics? In this big 1-parter, Callum & Jame go through Stenotrophomonas maltophilia, from start to finish.
Unlike Pseudomonas & Acinetobacter, Steno is much less commonly seen outside of ITU & the immunocompromised; but when it shows up you have to know what you’re doing. Luckily for you, there’s basically only 2 treatments! (In Europe: you’ll see what I mean).
2 crap puns in this one, so… get ready for that.
Questions, comments, suggestions to idiotspodcasting@gmail.com or on X/Threads @IDiots_pod
Prep notes for completed episodes can be found here (Not all episodes have prep notes).
If you are enjoying the podcast please leave a review on your preferred podcast app!
Feel like giving back? Donations of caffeine gratefully received!
https://www.buymeacoffee.com/idiotspod
Ready for some startling Steno statistics? In this big 1-parter, Callum & Jame go through Stenotrophomonas maltophilia, from start to finish.
Unlike Pseudomonas & Acinetobacter, Steno is much less commonly seen outside of ITU & the immunocompromised; but when it shows up you have to know what you’re doing. Luckily for you, there’s basically only 2 treatments! (In Europe: you’ll see what I mean).
2 crap puns in this one, so… get ready for that.
Questions, comments, suggestions to idiotspodcasting@gmail.com or on X/Threads @IDiots_pod
Prep notes for completed episodes can be found here (Not all episodes have prep notes).
If you are enjoying the podcast please leave a review on your preferred podcast app!
Feel like giving back? Donations of caffeine gratefully received!
https://www.buymeacoffee.com/idiotspod
Hi everyone, welcome to the Idiots podcast that's Infectious Disease Insight of two specialists. I'm James, that's Callum, and we're gonna dictate all learning that a listener requires regarding infectious disease. Soon may the editing come to this. Continue the taser son, one day, when the seerpiece done, will take our leave and go. Callum, do you know how many letter O's are in the introduction this week? I don't. Well, I'll tell you it's 10-0. It's 10-0. It's 10-0. I don't know why you used to be Callum, what? Oh, sorry listeners, I've broken Callum. If you could just give us a moment, it's so good.
Speaker 2:I was like well, what is happening in this intro? What is happening?
Speaker 1:I felt so wrong seeing it as well.
Speaker 2:I know After two years of he's forgotten.
Speaker 1:Oh no, I'll never forget. They're burning on the inside of my eyelids at this point.
Speaker 2:I'm actually having a drink right now. Mm-hmm. Yeah, I got it from my friend Phil. Yeah, so it's a maltophilia.
Speaker 1:Oh, yes, I understand. You understand you have to let me go. No, it was good. Thank you, callum, for that.
Speaker 2:Just a second fiddle to you, as usual in the pun game, james. So why did you even do that? What would we be talking about?
Speaker 1:Stenotrophomonas maltophilia, not maltophila maltophilia, as I have been corrected multiple times by multiple consultants.
Speaker 2:Your pronunciation is always the incorrect one.
Speaker 1:As.
Speaker 2:Twitter poll the highest form of evidence a Twitter poll has shown.
Speaker 1:Has recently shown. Yes, I suppose that's true.
Speaker 2:I don't really know, let's just say Twitter and pretend it's not changed.
Speaker 1:But this is the third of our knobbling the non-fermenters species that we're going to discuss Is knobbling a UK slang, do you think?
Speaker 1:I think it is. But I mean, if our abroad listeners are not used to us introducing ridiculous UK slang and not bothering to explain it by now, I don't know what they think they're doing listening to the idiots podcast. But yeah, knobbling is in to get the better of, if you were wondering. But yes, stenotrophomonas. So this is a species which, I must admit, I only learned about after I finished medical school. It was sort of at that point that it started showing up in UK intensive care units and proving difficult to kill, and I don't know if you remember when you first learned about it.
Speaker 2:It was a cold autumn day.
Speaker 1:I'm sorry you're entering story mode now.
Speaker 2:I'm trying to remember. No idea, literally no idea, probably quite late on.
Speaker 1:Yeah, but probably a cold day, because you were in Scotland. So well, that's true, chances are that it was going to be a cold day, yeah, so do you want to know a little bit about stenotrophomonas modifilia? I would love to.
Speaker 2:Like many things, it has had myriad of names of the genus genus oh my God, I'm starting everything now. Stenotrophomonas the type species is stenotrophomonas modifilia and that's really the key organism. It was initially found, I believe, in 1943 or so, one of the papers on Steno says, in pleurofluid, and it was made bacterium bucarae 1961, it was renamed pseudomonas modifilia, which sort of makes sense as a non-glucose fermenter the main thing that will come onto this later on. It differentiates, it means it's not pseudomonas and then eventually became the type species stenotrophomonas in 1993. Yeah, there's 14 other species.
Speaker 2:They all can cause opportunit infections, but they're basically environmental pathogens. Why is this important? Well, it is the most common carbapen and resistant gram Negative that causes a bacteremia. Overall it's the fourth most common non-fermenter in hospital isolates and I think it comes in after the other non-fermenters that we've already talked about. And yeah, a lot of the time it's cultured alongside other organisms. So this is something that pops up later down the line in your hospital admission. So you often find it alongside pseudomonas or intrabacteralis or staph aureus, staph aureus.
Speaker 1:Yeah, so very often, about two thirds of the time with with Steno, you're dealing with a polymicrobial infection, so choosing the right antibiotic is not as simple as putting them on cotrimoxazole and walking away from the patient. You usually have other things to consider when you're trying to treat it. So where do we find it, kalan?
Speaker 2:Well, it's all over. It's all around us. Just like love is all around us, stenotrophomonas is all around us. It's doubly so all around us. But it's not really a very violent organism, so you're probably exposed to this all the time it's in water, it can be in soil. So risk factors first, then the main thing is immunocompromised. So, as with many of these low virulence organisms, it's opportunistic. So once immune systems dampen down, so for example, hematological malignancy or patients that have chronic respiratory disease. So I guess there's two different ways in which your immune system is compromised. But in the malignancy side of things you can see this causing mainly like bloodstream infections of atremia or a hemorrhagic lower respiratory tract infection In people with chronic respiratory disease. It sort of colonizes the airways to see that in some people's COPD that's more advanced or maybe in like cystic fibrosis patients. And the problem there is that once you're colonized, like many of these opportunistic infections in patients with cystic fibrosis, is it associated with a progressive deterioration of respiratory function. So the main intervention there is to try and stop colonization.
Speaker 1:Yeah, but I mean, people aren't actually 100% sure. They're pretty sure but they're not 100% sure if the colonization with seno isn't just associated with the progressive deterioration. So you don't know that the bug is the cause, but having it there and about a third of CF patients are colonized with it, is that the patient group that we're going to deteriorate anyway. The microbiologist.
Speaker 2:Yeah, I guess there's a thing of chicken and egg isn't there? But in terms of you know, is it long? Is it only show up when the lung is sufficiently damaged and it's not actually the bacterium that's causing the issues, or is the bacterium there causing or exacerbating issues? The microbiology of sort of that group of lung diseases is incredibly complicated and well beyond either of us. It's a fall beyond either of us, I would say. And so I think maybe, if we're going to talk about that, we get someone in to talk.
Speaker 1:Yeah, more expert. So those are the patient factors. So like a lack of immune system or a compromise of lung tissue to the point where it can be colonized by biofilm producing organisms. What about the hospital environment? What about the risk factors there that would lead to seno?
Speaker 2:Yeah, so I think you know the main one is being in an intensive care environment and part of that will be just it's more present in the environment for partially to do point two, which I'll come on to, and the second point is carbapenem use. So it's some, you know we said earlier on it's a commonist carbapenem resistant organism and it's an environment. So one, if you give your patient carbapenem and they're colonized or exposed to senotrophilmonus, you're going to give it this sort of selective pressure for that organism to grow up.
Speaker 1:Yeah, or rather you're killing all those enemies.
Speaker 2:Well, yeah, so, but that is a selective pressure, isn't it so? And the other thing is, if you've in an ICU and you're giving people carbapenems, you know that whole environment. So we know that when people are given antibiotics, you can detect the antibiotics in their, in their sweat, in their stool. You know it's all over the environment. So if you're in an ICU and your ICU is using lots of carbapenem antibiotics, then there's, you know, a kind of area pressure. So even if you as a patient in intensive care unit aren't receiving carbapenems, maybe someone in the bed space before that was in that bed space before, or the other patients around you staff members are moving around, you know that's. That's a real good reason to try and overall limit your carbapenem use in the intensive care unit as a sort of area.
Speaker 1:Yeah, Because. Because I mean you can. You can try and clean a bed between patients, but you're never going to be able to sterilize it.
Speaker 2:No, you're just sort of suppressing. So yeah, and I guess the third thing is having lines or catheters prosetting material things. So that's the risk factors. What pathogenic mechanisms does it have?
Speaker 1:So there's, I don't we're not going to go into this in too much detail but the real big thing that it does is it's really good at forming biofilm. So it'll do that on abnormal lung tissue, you know, once it's got sufficient protection from, you know, alveolar macrophages and all that sort of intrinsic defenses, it's really good to do it on abiotic surfaces. So, like you know, things like intravenous catheters and ventilator tubing, things like that, and so that can lead to kind of deep colonization of these, of these things. That makes it particularly hard to clear and they're really good this is in one of the papers that I've quoted for the episode at forming multi species biofilms with pseudomonas, and so what they do is they influence this is a quote, by the way Steno substantially influences the architecture of pseudomonas structures, causing development of extended filaments. These changes arise due to diffusible signaling factor encoded by Steno. So they are telling pseudomonas what to do by producing signaling proteins and then just throwing them out into the biofilm environment. Isn't that cool.
Speaker 2:Is that an example of quorum sensing by the Mets? You know, I don't know.
Speaker 1:No, it's not quorum sensing, but it's just sort of the thing that it's doing is making the environment better. Biofilm better for it as well as probably for the pseudomonas.
Speaker 2:So, symbiotic?
Speaker 1:I hope so. I don't think that pseudomonas is negatively affected by it. But yeah, isn't that cool. And then they've got a bunch of other virulent factors. The big one that was quoted was they've got sort of inflammatory outer membrane vesicles, the, you know, secreted extracellular vesicles into the environment and that causes localized inflammation, mucus production. They can then hide in the mucus for biofilm or that kind of using these mechanisms.
Speaker 2:And we've talked about the site and risk factors. It's no surprise, I guess, that the clinical syndromes you see caused by stenotrophomonas is primarily hospital, hospital acquired pneumonia or ventilator associated pneumonia, and the mortality quoted for that is somewhere between 25 to 75%. So a quarter to three quarters are quite a big range, depending on where you're looking for data, but you know, not insignificant.
Speaker 1:Well, even if you take the median, that's half of people getting steno or ended up.
Speaker 2:You know I don't think we're saying that that's necessarily the pathogenicity of the organism and the certainly association with. If you're getting a stenotrophomonas hypervap, then you know you're probably a very unwell patient who's potentially in intensive care and the mortality rate baseline for that group of patients is going to be pretty significant anyway. So I don't know if we can put that down to it, but certainly you know, once you're in that bracket then that's a significant mortality. The other thing would be like IV line infections. So I think that's less so canally and more like long lines and so on.
Speaker 1:Yeah, central lines and whatnot Like if you got. If you had an affected PVC and it was steno, I'd be very surprised.
Speaker 2:But yeah, yeah.
Speaker 1:And the mortality from that's between 20 to 60%. So you know, call it 40. It's surprisingly high, but again, I suppose that's in all. That will mostly be in the hematological malignancy population where you're dealing with somebody who doesn't have a functional immune system. And of course, all the first line therapies, for you know nutrient fever they wouldn't cover steno. You know PIPTAS and carbapenems, like they wouldn't actually cover it.
Speaker 2:And then I guess UTI is quoted. I you know, I think that's maybe with a catheter never really seen that. I think I might see it in a catheter once or twice, I think it's.
Speaker 1:CAUTI's and, yeah, once I was. Once you get past HAPS, VAPS and IV line infections and bad dreamers, this is all small print.
Speaker 2:Yeah, quoted as I CNS, liver, bone, soft tissue, gastrointestinal I. You know, I think there's often, you know, you can find one case report or something and then it gets it into a textbook or a list.
Speaker 1:Yeah, so once it's in textbook, it's gospel, isn't it? Yeah, and you're like, does it?
Speaker 2:really cause that and you know, you remember a list of things. I think if you remember anything, it's respiratory tract and it's bloodstream. That's really it, yeah, and I guess I guess in terms of clinical syndromes, just to dig into that a little bit more in terms of experience. So I think I think this is something that you have to think about in the, in the patient who is on broad spectrum antimicrobials, or carbapenem in particular, and who who then develops infection or is unwell, because I often think about, like you know, what's the clinical syndrome, what are the likely organisms that I want to cover, and then what am I not covering?
Speaker 2:So with something like meropenem in intensive care. You're thinking I've got a really broad coverage, but I think Steno is one of those things at the top of the list. We're thinking like maybe they're deteriorating from ventilator point of view and they've got new fevers, or they've got increased, you know, pre-perial and sputum production secretions and so on. I think Steno is something that you're thinking there. So it's often. It's often in your mind, as do I need to think about this. We need to get samples to look for this.
Speaker 1:Yeah, it's an astheny to Batra, I think so we've. We've recently I can't remember what episode, maybe it was in the carbapenems episode we quoted the mnemonic or free stay, alert Elizabeth as our way of remembering the carbapenem resistant, and these were the stay was SDSD, Sten trophomonus, alert was astheny to Batra and Elizabeth was Elizabeth Kingia. Elizabeth Kingia is real small fry, though it's astheny to Batra and Sten trophomonus, which are the big carbapenem resistant sort of troublemakers.
Speaker 2:Yeah, Micro mode engaged. So yeah, this is an organism that we is in the glucose non fermenting or group, so I guess it doesn't ferment glucose. Ta-da, you're not going to leave that in, are you? Am I? I don't know.
Speaker 1:So yeah, so Cal, and tell us about the bug.
Speaker 2:So the bacteria. It produces energy aerobically, which kind of maybe explains why it's in a respiratory tract. Mainly it's a straight or slightly curved rod. It's non spore farming and it is motile. And it's a non lactose fermenter which is catalase positive, oxidase negative, which is a really important thing because most of the glucose non fermenters are oxidase positive. So differentiates it from the pseudomonads and pseudomonas et cetera. And it's also DNAase or DNAase positive, other rapid biochemical tests that can be used on the plate to look for this. It grows pretty well in standard blood agar. It doesn't need an enriched media. There's a selective agar for it, which is a media that's inoculative of colostin, because this is resistant to colostin and most other gram-negative organisms are sensitive to colostin. It's a very broad spectrum last resort antibiotic. The other thing that might grow on that agar is bercalderia copatia. That's one way to look for it in respiratory tract samples in particular. And another thing to note about is it's imapenine resistant intrinsically. So if you find an imapenine-resistant non-lattice fermenting organism then you might suspect stenotrophomonas.
Speaker 1:How does the colony grow.
Speaker 2:How does the colony grow? Well, it grows. It looks on the plate. It can look green or yellow. On a blood agar it might exhibit slight beta-homolysis, which is the sort of complete tamolysis, and apparently it has an ammonia smell. Don't smell plates. I've been listening to a lot of let's Talk Micro recently and I look at it. Every time you mention something he says it has a so-and-so smell. Don't smell the plate, so don't smell the plate.
Speaker 2:And then so basically, to find this, you're thinking you've got an organism that's growing. It should grow on blood agar. It should grow on macaunkey. It would be non-lattice fermenting. Macaunkeys is a sort of selective agar for gram negatives and the biochemical test you'll see this catalyst positive and oxidase negative. It might be independent resistance, you think stenotrophomonas. Most of the time you're going to add using the Malditov. Go back and listen to the Malditov episode and one thing to note that you've listed here which I wasn't aware of was that 16S. So that's the PCR, looking at the bacterial ribosomal subunit, is quite poor at differentiating stenotrophomonas.
Speaker 2:Acneeter bamaniai, calcoseticus complex and a chromobacter and also some pseudomonas species. And then there's other tests you can do, sort of like multi-locus sequence typing.
Speaker 1:Mlst for epidemiological work, or maybe whole genome sequencing is coming in there as well, I guess the Maldi is the main sort of machine that you would use these days. It'd be sort of interesting to see how you you know, if you don't have a Maldi there's plenty of labs in the UK that don't have a Maldi, and loads of labs overseas how you would finalise your. Would you use the Vitech too? Would you do something else? Would you just stop at an oxidised negative nonfermenter and sort of how would you tell between Acneeter Bacter and Steno, because they're both oxidised negative?
Speaker 2:I don't know, and I'd be interested to know if anybody was going to know, yeah, imagine a mix of the nonfermenter card on Vitech or APIs or the other.
Speaker 1:Maybe the API is probably better at doing it. Yeah, it was a 20.
Speaker 2:I can't remember which API it is, but an API is a sort of battery of loads of biochemical tests and then it gives you a number and you put it into a system and it gives you results, sort of like old fashioned, a Vitech, automated way of doing it. But we still usually help them kicking around in the lab as a sort of backup plan. Yes, yes, and I'm sure plenty of people still use them a lot.
Speaker 1:So oh, yeah, I mean, I told you, when our Maldi failed or the door to close the sample intake failed, we don't have a Vitech and so we had to rely, go back to rely on APIs and presumptive identification of grand positives. That's what we did.
Speaker 2:Yeah Well, revision. So yeah, that's. I think that's a micro mode covered.
Speaker 1:Yeah, well, except we need to talk about antimicrobial susceptibility testing, because it does not a straightforward callum, as you may thought.
Speaker 2:No, you just get the organism, you plate it out and then you put on your desk or your E test or you do your Vitech.
Speaker 1:It's simple, Callum callum callum you, sweet summer child. No, it's nothing like that easy, I'm afraid. So let's start with whether or not you've got anything to test against at all. So UCAST have issued breakpoints that you can test against, for are you ready for this extensive list?
Speaker 2:Yeah, list them off. It's going to be like when we listen to organism names and it's just like music to my ears when you speak. Jim, Do you have a pen and paper? No, I actually make notes digitally now.
Speaker 1:Okay. Well, that's very progressive of you. Are you ready? Yes, Okay, cotrim oxazole. Okay, that's it.
Speaker 2:No.
Speaker 1:No, no, kefederical the Trojan horse. They say that you can use the PKPD breakpoint, which I think is two. I've got it further down here and that's that's it. Yes, two, so that's the PKPD breakpoint. You have to do broth micro dilution for that and they've got a Cotrim breakpoint and they've decided to call it a day that, that that the US is an even worse situation, kind of.
Speaker 1:So, as you're aware, callum, there are multiple different breakpoint setting organizations, so there used to be just CLSI. Now I don't know what CLSI were doing wrong, but in 2009, the FDA decided they were going to be setting all the breakpoints. Thank you very much. And furthermore, that all susceptibility testing systems after 2009 had to use the FDA breakpoints. And that's great as long as the FDA actually produces breakpoints for the bug drugs for the bugs. But they have released only a keftazidine breakpoint for a stenotrophomonous. So that means any automated susceptibility testing system after 2009 can only test for keftazidine. So labs have to either use a system that was approved before 2009, because they can use the CLSI breakpoints, or perform off label testing on systems that were approved after 2009. And there's a further complication, which is, as we've said, two thirds of stenome infections are polymicrobial and a bunch of that is pseudomonas, and so there's concern that all the clinical evidence of keftazidine working against stenome could be kind of muddied a bit by the fact that they were being treating other gram negative infections with keftazidine at the time, and this I think is part of the reason why UCAS don't have a keftaz breakpoint.
Speaker 1:And there's another problem, callum, which is all of the susceptibility testing systems disagree with each other violently. So the reference standard that people use is broth microdilution and what people have done. There's a paper that I've gotten in the prep notes where somebody compared broth microdilution as the reference standard. And all of the other sort of automated susceptibility testing systems are the big ones, are the biomaries, vitec2, becton, dickinson's, phoenix and I can't remember who makes micro scan. Can you remember Callum? No, no.
Speaker 1:And then there's disk diffusion, standard disk diffusion, and then there's gradient diffusion tests like E test and MTS. I forget what MTS stands for, but it's like an E test. It's a strip and you put on, it's got a gradient concentration of the antibiotic of choice and there's a. There's a good table that I've sort of screen shot it and stuck in the in the notes and there's some stuff that it's, it's, it's a bit of a. It's a bit of a bit of a different thing than the notes and there's some stuff that it's it's. You know that's quite good for.
Speaker 1:So minocycling is accurate across most systems, except the Vitec, which doesn't test minocycling in in the car that you would use for stentrofemolus. All systems are kind of crap At agreeing with keftas, dim and broth microdilution. So the the agreement range is between 67% and 76%. So, you know, not very high at all. And the Vitet 2, which is a shame because that's what we use in Scotland is bad at testing for cauterium sensitivity, so it's got an agreement of 77% and the rest are between 93% and 98%. So if you have a cauterium R isolate and you're using a Vitet 2, you may want to retest that with an E-test or broth micro dilution, whatever you have to hand.
Speaker 2:I think we actually have a sense for a steno rather than Vitet. You can do, yeah, yeah so you can just do that instead.
Speaker 1:It's cheaper. So yeah, and this is. Then there are other things which have sort of PKPD breakpoints which may be kind of more useful. But this is sort of you know the you know, standard trophomonus and microbial susceptibility testing is a bit of a minefield, that's before you get to levels of intrinsic resistance in the organisms themselves. So take to sarcellan clavilanate, which is really difficult to access these days and there's none in Europe at all and I think they've pulled out of the US as well. They've kind of been dwarfed by PIPTAS. There are CLSI breakpoints. There's the SR breakpoints are 16 to 1 and 128. But it's not widely available and resistance ranges between 20 and 90%.
Speaker 2:So you know you can, it's difficult and it's not infrequent that you come across patients and I think we've been sort of touched on this and penifesal and allergy delay bling episode two where we talked a little bit about the sulfas score that was coming. It's not infrequent that people have reasons why you can't give Coatram, oxazole, trimeprim sulfanamethoxazole. Yeah, so UCAST 13 is the current version of the susceptibility results and it links out to some guidance document from 2012. So quite old now from UCAST about standard trophomonus multifilio. So they often have these documents that they've released when you know there are some areas of controversy or difficulty.
Speaker 2:And in that they're basically saying in patients where trimeprim sulfanamethoxazole is not suitable agent, you might be able to use ticker cell and clavionic, clavionic to minocyclin, ticker cyclin, colostin, chloramphenic or cithlosporins, but we don't really know if it works, so we're not going to give you breakpoints. So then it becomes really difficult. So then you go off and then you have to use TLSI breakpoints. The whole thing is just a bit difficult to know if you're giving people the right information. And also I think UCAST are saying you know one of the things this is you know, there's just not the data there to say what can we rely on? What is going to work what isn't going to work? Or maybe test it in vitro and you get it as sensitive. Does that really mean it's going to work?
Speaker 1:Yeah Well, this is the argument against keftaz, but, for what it's worth, about 27% of isolates are susceptible and the SR8.832, it's the only one the FDA approves of, but the IDSA doesn't recommend it because of this concern about it was actually treating other sort of co-colonizers that were contributing to infection, although if they got better. You know, yeah, I know, although if they got better. But like, if you've got, if you're trying to use something for Stan, it's not good enough to say, oh well, it's sometimes worse because it's treating something else. You want to know that it's actually targeting the bug.
Speaker 2:But I guess, like when we do tests and we grow an organism from respiratory tract samples being slightly different with blood, so maybe that's, maybe it's your point, but, like you know, is the stenotrophin one is the true culprit there, or are we just growing it? Yeah, I know that, is it just colonizing? But anyway, that's, that's an argument for it. There's so much uncertainty sometimes with results and no one's confused people.
Speaker 2:So we're just talking about stenotrophin. One is back on target. So, yeah, real headache, and I think this is, I guess, what the issue, I think, with UCAS approach is that you just can't, you kind of have to have other options and Well, I mean UCAS, have not a, not deaf to your concerns, kalman.
Speaker 1:So for that reason they've included a PKPD breakpoint for a Kephidere called the Trojan horse, and that's good because 97% of isolates are susceptible. But a, you have to do broth micro dilution, which will take time. But B, the biggest sort of trial in which they're, you know, mentioning Steno and and Kefeder call not not the biggest trial, but it was that it was the biggest Kefeder call trial at the time the credible CR. There were only five cases of central mnemonium of whom 80% died and they sort of noticed that this was like a quite a lot to. That was kind of out of keeping with the other studies that had been with with Kefeder call, to the point where they they, you know discussed it in the in the discussion and didn't really have a firm suggestion as to why that would be, except that it was it was out of keeping with with kind of other other studies. But that was enough for IDSA to shy away from recommending Kefeder call as a as a first line option.
Speaker 1:Not so the tetracycline, in particular minocycline, which is 99% susceptible, and about 93% of Kodromoxol resistant isolates are susceptible to minocycline. So that makes it a good second line option as an SR breakpoint of 416. And seems to have kind of lower MICs, you know, compared to other drugs and compared to Kodromoxol, which would imply that it would be pretty good for Steno, it's not good for urinary infections, it doesn't really get into the urinary tract that well, as opposed to, say, doxycycline. But yeah, and if you look at PKPD studies, this minocycline 200 milligrams BD has the highest probability of target attainment across its MIC distribution compared to the other drugs that we've discussed. What does that mean? It means so the if the target attainment is AUC over MIC and you you know you want to have, say, say, two thirds of your AC over your MIC, it will be able to. You will be able to hit that target.
Speaker 2:So say for beta lat times? Is that compared to?
Speaker 1:other tetracycline do you mean, yeah, compared to the other drugs? Oh, the drugs and all the other drugs, yeah, yeah. So say you have a beta lat times, say keftasin for example, your target attainment would be a percentage of time over the MIC. So say two thirds. Or say usually it's 50% for intrabacterial is and usually it's about two thirds for pseudomonas.
Speaker 1:So, say it was two thirds for steno. I don't know that it is, but you know. Just say then the PTA probability of target attainment is sort of like the final thing that you look for in your PKPD model. And then ticker cycling is also listed there. At a dosage of 50 milligrams BD ie the higher dose 82% of isolates are susceptible a wild type, but I don't have a break point to quote for you there. Then quinolones levofloxacin has a break point of SR break point of 2.8, about 80% of isolates are susceptible there, but only 50% of moxifloxacin isolates. So the IDCA recommends levohover moxif for this reason. And then there's the cotrimoxazole, the foliate antagonist, so CLSI has a SR break point of 2.4.
Speaker 2:The other thing to mention, I guess with the UCAST cotrimoxazole, or the sensitivity break point. So UCAST have it as sensitive as less than 0.001 and resistant as greater than four. So what does that mean? So basically, when UCAST have been doing this a lot recently, where they give the sensitive break point as an incredibly low number, you can't achieve. What they're trying to do is say it's susceptible at increased dosing and essentially they're saying for all senile infections you should use an increased dose of cotrimoxazole. So the dose of that would be this 1.44 grams twice daily. As a senitrophilmonist on this dosing and the standard dosing is 960 milligrams per day, twice daily- UCAST has a 0.0014 break points.
Speaker 1:They want you to use the higher dose, like you were saying there. So, callan, off camera, off mic. You were saying that you use the UCAST 1.44 grams twice daily dosage.
Speaker 2:Yeah, is that?
Speaker 1:right, yeah. So I think I've read elsewhere I think it's in the IDSA guidance actually that they recommend using a 10 milligrams per kilogram of the Tromethaprim component for a senit, which is why I put it here in the show. Yeah, that's right, Don't really care. I suppose it doesn't matter that much. I mean, if 1.44 grams BD, that would be sort of three grams roughly in totals, that would you know, that's still reasonably meaty dose.
Speaker 2:But yeah. So I guess other options that we don't really have break points for and you know, I think if you're back was up against the wall, you know, know their options. So chloramphenicol so I think that's just rarely used because there concerns about toxicity. Actually, I do have break points of 4 and 32.
Speaker 1:Revaquecycline so a ravacycline is the next options. There's no break points for that, but there's a really good paper that has done loads of kind of PKPD work and they've got figured out that an MIC 90 for a ravacycline would be two, which is very easy to attain in tissues. So that would be something to think about down the pipeline. And then, lastly, callum.
Speaker 2:Lastly, is Azutinam avibactam. So we've talked before a bit about Azutinam in our weird lactams episode.
Speaker 1:And we talked about it in the base. It's a bit of latimesis and everything yeah.
Speaker 2:And this is a sort of combination that we're hoping to get some point. So a moment to give this. Usually give keftazidim avibactam with Azutinam and similar to the effect that you see in metallobetalatimesis, that we see in other organisms and will come onto the resistance mechanisms of stenolytron. But essentially the reason this might work is Azutinam is stable against one of the beta-lactamases that it produces and avibactam protects the avibactam against the other one. So Azutinam stable against your L1 metallobetalatimesis, which is a sort of stenotrophomonas specific one, and avibactam protects against an L2 serine beta-lactamase. So together they are the perfect combo.
Speaker 1:So they would be if they were commercially available. So Astrea and Avavatam is in phase three trials as we speak, in 2023, but this combination would be, you know, center would be 98% susceptible in wild type against it. So it would be ideal, I feel. So that's a quick blast through the available options. So to you know, to very briefly summarize, there's Kefdazdim and Kefderakul as your big Latam options, minocycline and tigacycline and maybe a ravacycline from your tetracycline stable. There's the quinolones, but mostly just lethal floxacin, and then there's cotromoxazol and that's it. There has been some comparison of the of these regimens to see sort of if they can figure out which is best. And that's been kind of hamper scallion because there's no RCTs. These are all just observational studies, but they've, you know they've tried to do head to heads as best they can and you know they've compared cotromoxazol to quinolones and for monotherapy there was a odds ratio of good outcome of 1.46 in favor of quinolones, so suggesting that lethal floxacin was better. And again, for combination therapy, the odds ratio was 1.6, again in favor of quinolones. And then when you compare cotromoxazol to tetracycline derivatives mostly minocycline, other antibiotics or everything else, and quinolones versus tetracycline derivatives, there's no significant difference between those two. You know comparator groups. So maybe a signal that quinolones may be the better treatment, but not enough that anybody has actually recommended using quinolones in preference to cotromoxazol. So I mean, that's all the treatments that we've got available. You know what do the various you know societies say that you know the great and the good. So we've got these difficult to treat.
Speaker 1:Gram negative guidance that came out in 2022 from both SBID and IDSA, and the IDSA have just updated their guidance earlier on this year and with a plan to do it yearly. And if listeners want to get a, you know, really excellent discussion with the lead author for the IDSA guidance, we will. I linked the episode of February where she came on and talked to Sarah about the guidance in general. It's a two-parter and it's really worth a listen. But I will make the simple column.
Speaker 1:Sbid don't make any recommendations for stent and trophomonus at all. So the only thing that we've got to go on is the IDSA guidance. So what do they say? They say that for first line, you should use two of cotromoxazol, minocycline or tigacycline, levofloxacin or kefidiracol and to include cotromoxazol if it's sensitive. So you include that as a priority. So if it was sensitive to all four. You would use cotrim and you would use one of the other three categories a tetracycline of your choice, a levofloxacin or kefidiracol. For second line, they recommend this kefidazidimavabactam plus astrinam combination that we were talking about before. So if astrinamavabactam was available, they would recommend that.
Speaker 2:Yeah, but feeling that they wanted to use kefidazavi plus astrinam, which is interesting because it's like a theoretical thing and we've got no way of susceptibility testing organisms. So we had this discussion recently because I think it come somewhat outside of what people's comfort zone.
Speaker 2:Because we're used to saying like maybe we should use this antibiotic, take bug, do susceptibility testing it's sensitive or you know and then you recommend treatment. But when you've got guidance saying, use this, though there's no way you can test for it, just trust us, just use it. I don't know how many people are comfortable doing that.
Speaker 1:Well, more so than any other non-fermentor we've discussed. I feel that with Steno we have our backs to a wall. Yeah, you know, we've got two options with you know, for going by UCAST. We've got more with CLSI, but they're all. All these breakpoints are going to be historical, which is why UCAST doesn't have any. It's trying to be more scientific about it, but sometimes that means that there are no options. So what do you do then? Well then you kind of have to go with the historical breakpoints, right. Yeah, what do you do when you've got no option? Yeah, well, they're all drug classes that are kind of out of our comfort zone really. That's why the IDC I recommend Ecomalation Therapy.
Speaker 2:In fact, they say in the guidance we're doing this because the evidence is so crap that we don't trust any one agent to come in, which is interesting Because I guess we I don't know my, you know we just give coach remarks as all If it's sensitive and it's resistant and it's a bit of a headache, and we usually end up going with levofoxicinerminocycline. I've never seen a combination of heropicivan. I think it was a Baterenia. I would definitely think about that.
Speaker 1:Yeah, it also depends on the space into which you're coming, because if you're a Baterenia, also with like an E coli that you need to cover or an MDR-Calypsolla, you know it can get real murky real fast, can't it?
Speaker 2:Yeah, it's really difficult, right? It'd be interesting if there's some sort of stenotrophomonas expert that we could ask to come on, because it's quite well.
Speaker 1:I mean I can't get you an expert calendar, but what I can give you is a brilliant paper, which is by Coon's coin et al, called Stenosphere navigating the enigmatic world of emergency multi-drug resistant stenotrophomonas multifilia. That is a title for a paper. Stenosphere, yeah, and it's from Pharmacotherapy. It's in 2023. Pharmacologists at the coolest yeah, it was sort of promoted on ID, twitter, now IDX, by Gagba Basimganem, who's made a, who's really good at promoting papers.
Speaker 1:Loads of people subscribed to me just because he's like a journal article promotion machine. He's, you know, he's, he's, he's doing God's work and this one of these things came up and I was like that'll make a great podcast episode prep and so I just quietly saved it and it's. It's probably of all the papers that I've quoted, there's a bunch that I've I've included here at the Stenosphere articles one that I have used the most of into greatness and so and it's not even that very big, you know, it's like maybe 15 pages. So if you're like this is not worth doing, if you're like an F2, or even if you're a NST three and infection, but if you're like, you know, st four or five and you really need to get on top of particularly VAPS and HAPS and stentropomonas is coming up. You're revising.
Speaker 2:That's the paper to read.
Speaker 1:Yeah. Or revise some pure exam, yeah. So, speaking of revising for your exam, I don't want to talk about it, I know, but you need to know about all the resistance mechanisms for stentropomonas. But don't worry, callum, because I've got your back, okay.
Speaker 2:So I'm going to try and work my way through this. No, the problem with stentropomonas that we've talked about a lot is that it is intrinsically resistant to a lot of our usual antibiotics. And I'm sure everybody's crying out at home or in a car or wherever you are listening from but how is it resistant?
Speaker 2:Well, james got your back so intrinsically resistant, using most will to be to lat times. So it has chromosomes. So these are genes that are on the chromosome. It's not on a plasmid and it's inducible. So it means it's exposed to a drug and it turns on that gene and produces the enzyme. So it produces several beta-latomases. So an L1 metallo-beta-latomase, and that targets your penicillins, your kephalosporins, your carbapenems. It's a metallo-beta-latomase, it's in a sort of amber classification B, class B, I presume. And then L2, serine or serine beta-latomases, and that targets your kephalosporins and astrienam, although it's susceptible to claviglinate as avibactam. So those are the beta-latomase inhibitors. So you can see there so we've talked about this earlier on why avibactam with astrienam would work. Because your avibactam will inhibit the L2 serine beta-latomase, which is what is usually breaking down the astrienam, because astrienam won't be affected by your L1 metallo-beta-latomase. So the two together are the perfect combo.
Speaker 1:Yeah. It makes me wonder, though, why tymentin was purported to work at all, because, unless there are some stenoids, that don't have both of these, because the tymentin should be destroyed by the metallo-beta-latomase because, the clavilane won't protect against that.
Speaker 2:I guess, why does keft?
Speaker 1:has a deem work. Good question. But yeah, I mean I say that NBL breaks down pens, kefts and carbapenems. It doesn't break them all down the exact same amount. Yeah, it will have preference predilections for, and maybe keft has them as avoiding that, or maybe it doesn't work at all and that's why they were boiling it down and simplifying this quite a lot.
Speaker 2:So there's a lot of complexity about enzymes and their effects on drugs, and if the drug structure is different that might affect how the enzyme works, but I think that's a general approach. The other things that they can include so they can also have other beta-latomases like TEM2, so that's a beta-latomase and CTXM. So those are two of your ESBLs and SHV. So we talked about those. In the basics of beta-latomases, say we, james Todd, the basics of beta-latomase inhibitors. I was in the recording. I just sat there and said absolutely nothing the whole time, or was I not there, who knows? I have listened to it, though, and also can have carbapenemases, other ones.
Speaker 1:As in not one and one or two other ones as well. And so that's when I think about treating gram negatives. What are the drug classes that I rely on? Well, I rely on my two favorite drug classes, which are beta-latomase, which are best-latomase, but I can't use them here. But at least I've got aminoglycosides to fall back on, don't I Camon, nope. That's not bad so why is that Callum Well?
Speaker 2:we've talked before in Idiots Guide to Aminoglycosides about resistance mechanisms and you'll remember, of course you'll remember that the aminoglycoside modifying enzymes are the most common aminoglycoside resistance mechanism and basically Centrivolmonus has them on the chromosome so and 99% of them are resistant to aminoglycosides. So it's basically out of the window straight off.
Speaker 1:Yeah, and they also have some proteases as well. So even if they don't have aims, they've got proteases to break down the aminoglycosides too, and they're also chromosome-only encoded. So when you look at that Callum, you think this drug Bug couldn't be more designed to circumvent conventional neutropenic sepsis protocols. Do you know what I mean? Like it's resistant to almost all beta-lactam except this small thri as Trinam, and you have to combine it with Avabactam even to get that past the AL1 and L2 beta-lactamases, and then aminoglycosides are also out too. So you know, like that's in the UK, that's most of what you will give to a neutropenic sepsis patient first, off the bat.
Speaker 2:It's not great yeah.
Speaker 1:And so then let's talk about other sort of resistance mechanisms that we've got. So we've got acquired mechanisms that are common in Steno. So you've got for quinolones, you've got QNR genes. These are not unique to Steno, but they're genes which encode for a protein which will then bind the quinolone to prevent binding to topoisomerase 2 or topoisomerase 4, also known as DNA gyrase, to prevent those enzymes acting to unwinding and then unzip the DNA structure of the bacteria. So they've also got something called RNAs G which can be inactivated another resistance mechanism there. And then for cotrimoxazole there's class 1 integrons, which are the cell 1, cell 2, and DFRA genes, which are insensitive to cotrimoxazole, homologues of the cotrim target enzymes. So that's dihydrofolate synthetase and dihydrofolate reductase. So cell 1, 2 is a homologue of dihydrofolate synthetase and DFRA is dihydrofolate reductase.
Speaker 2:So that's target site modification as a resistance type.
Speaker 1:No, they're.
Speaker 1:So, bypass it. No, what these do? They act a bit like. They act like suicide inhibitors. They just swamp the cotrimoxazole and stop them from binding the cotrim actual target enzymes. So the cotrim wants to bind DHF synthetase, say. I think that would be the cell 1 and cell 2 that was doing that, but actually it will bind cell 1 or cell 2 gene products instead.
Speaker 1:But the biggest thing that Steno does is it has e-flux pumps and these work against a bunch of different drug classes all at the same time. So they've got ABC, mfs and R&D e-flux pumps and for an explanation of what they stand for, go back to our Pseudomonas episode or the Pseudomonas prem notes. And there's a little bit on e-flux pumps. Thanks, because I can't remember there as well. Yeah, no problem, the biggest one by far is R&D. So R&D was big in Pseudomonas and Acetobadri and it's big here too. So it will result in the e-flux of Betalatants, quinolones, aminoglycosides, tetracycline, cotrim and Polymixins. So that's a lot right. Mfs will only do Quinolones, aminoglycosides and Tetracycline and ABC will do those three plus Polymixins and most Steno have a bunch of different e-flux pumps that they can up regularly.
Speaker 2:Easy for this to become something you just can't read.
Speaker 1:It is really yeah, yeah, not least because you can't test, but also because it may well be intrinsically risen to a bunch of this stuff and again from the Kunz coin paper, the Steno sphere. They've got a really good table that again I've sort of pasted in here about all the different resistance mechanisms, split down by drug. That's worth a look at, most of which we've covered here. I've left some stuff out, particular details of which members of the R&D family cover which drug. I don't think that was really worth going into. But yeah, so I guess to sum up, you write this thing is hard to kill sometimes and we kind of limited. You know you've got a limited ability to detect what you can use and you've got a limited repertoire of what you can use and even at the end of all that you still might fail.
Speaker 2:God, I'm feeling pretty down about this.
Speaker 1:Yeah, sorry, there's no upbeat thing to end on. That's it. We made some of the stone there, Carl.
Speaker 2:That's our ending.
Speaker 1:Yeah, that's the ending.
Speaker 2:Maybe after the outro we can say something chirpy and positive. Thank you for listening to the Idiots podcast, the UK's premier infectious disease podcast. We are supported by the British Infection Association, but they do not have creative control over the episode content, so please don't blame them if we get something wrong.
Speaker 1:Questions, comments, suggestions. Why don't you send them into idiotspodcastingcom? Have a five star review in your pocket, calum, and I would love to have it. Please drop it in your podcast player of choice. We tweet at idiotsunderscorepodcom and if you want to donate to support the show, there's a link to do so in the description. But until next time, I'm James, I'm Calum.
Speaker 2:See you then, now that the episode's done.
Speaker 1:We hope you learned and had lots of fun. So go forth and treat people with some of what you now know I'm laughing at anything good to see.
Speaker 2:I'm feeling really depressed about that now.
Speaker 1:Yeah, sorry, sorry, I got you down everybody. I don't know that I can think of anything cheery to say.