In Part 2 of our episodes on Acinetobacter we talk abouit resistance, and then do a deep dive into the evidence base for the management of CRAB: Carbapenem-Resistant Acinetobacter Baumanii-calcoaceticus complex.
Do have a look at the prep notes for this episode if you want more information on Acinetobacter.
Links to podcasts mentioned in this episode
ID:IOTS Episode 41: Bugs Without Borders
Febrile episodes 76 & 77: Piece de (Gram-negative) Resistance
Episode 76
Episode 77
For links to the papers we used, see the prep notes!
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
In Part 2 of our episodes on Acinetobacter we talk abouit resistance, and then do a deep dive into the evidence base for the management of CRAB: Carbapenem-Resistant Acinetobacter Baumanii-calcoaceticus complex.
Do have a look at the prep notes for this episode if you want more information on Acinetobacter.
Links to podcasts mentioned in this episode
ID:IOTS Episode 41: Bugs Without Borders
Febrile episodes 76 & 77: Piece de (Gram-negative) Resistance
Episode 76
Episode 77
For links to the papers we used, see the prep notes!
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 going to tell you everything you need to know about infectious disease. Soon may the editing come to discontinue. The taser sun, one day, when the seer piece done, will take our leave and go. So last week we talked about Acneetabatter in general and we talked about treatment. We're now going to talk about resistance in Acneetabatter, which is a big topic.
Speaker 1:I've got some great references for this, which I put at the end of the prep notes, but the highlights are that this is absurdly resistant. So about two thirds of isolates could be considered MDR. I'm not sure by what definition the paper I pulled that from was using, but suffice it to say it's difficult to treat, particularly if you're going by UCAST breakpoints, so they don't give you a lot of options. It's very naturally resistant. It's great at living in biofilm. So, a bit like Pseudomonas, it likes colonising damaged lung or immunologically impaired lung and then it forms a biofilm and then it's really difficult to shift. So, callum, what kind of being a lat-time resistance and do you know about?
Speaker 2:Well, I've listened to the basics. Of being the lat-tomase inhibitors In Acneetabatter, we know very commonly that they harbor oxa-carbopenemase. Why is it called oxa? Because it breaks an oxacillin. The oxacarbopenemase is our ambler class D, so go through to ambler ambling through Bt-lat-tomases and Acneetabatter particularly harbours oxa-2440 and also oxa-23. They can harbor any ambler class, such as class A, which should be your TAM1, or they can also harbor C, which is like amp-C, or D, which is the oxas, and they can also acquire metallobetalatomases, which is class B.
Speaker 1:Yeah, it's less common, though, and they tend to favour D the oxacillinases. But yeah, they can really acquire anything.
Speaker 2:Also a bit like Pseudomonas. They can undergo porin loss, which just is a pain. And then solbactam. So we talked last week about solbactam being a potential treatment option for more resistant Acneetabactors. But it can develop resistance by mutating. Penicillin binding protein free or 1A1B.
Speaker 1:Yeah, so those are the prime targets of solbactam. So it's got a particular fin here for PbP3 and PbP1A and 1B in Acneetabacter and so a bit like MSSA can become MRSA by swapping out PbP2 for 2A, then solc in Acneetabacter mutate PbPs in order to create target modification resistance.
Speaker 2:If you want a visual representation of this, jame has put together in the prep notes on a notion, a little table which gives you the resistance mechanism and what it confers resistance to.
Speaker 1:I've summarized other clinically relevant mechanisms in a table and they're divided into four sections. One's porin loss, which really only affects the belatams Enzyme modifications, that would be belatimes for belatams, mono-oxygenases for tetracycline. And they've got other enzymes which can affect amnoligalicicides, quinolones and sulfonamides. So sulfonamethox is all the component of Coatrim. And then there's target modification, so if you can modify topoisomerase, and that will lead to quinolone resistance, ribosomal protection for tetracycline and ribosol-RNA methylation, which is a good way of getting rid of amnoligalicicides. And then the other mechanism is eflux pumps and we talked about eflux pumps in a bit more detail in the pseudomonas episode, so I will not include their definitions here. But you've got mate-MATE pumps which do the quinolones, smr which do amnoligalicicides, mfs, which do amnoligalicicides and tetracycline, but by far and away the broadest in terms of what they throw out of the SLR-RND eflux pumps, which throw out everything Beta-lactam, amnoligalicicide, tetracycline, quinolones, sulfonamides and polymixins. So the overproduction of RND eflux pumps can lead to global resistance very difficult to treat.
Speaker 2:We should go back and we should do an episode which is just like all resistance mechanisms, summarized Like how do antibiotic resistance happen?
Speaker 1:Yeah, it could do Mechanisms? Yeah, good idea. And then below that I've taken a table from Kidiakidis et al and that's one of the references down at the bottom which has a really good summary of all of these resistance mechanisms as well, and that paper is really worth a read. So now we come to the vexed question of crab. Do you like crab Callum?
Speaker 2:Yeah, I think the white meat is better than the brown meat. What do you think?
Speaker 1:Do you like the little crab sticks that you can get in the supermarkets? Callum.
Speaker 2:No, they're awful, I hate them. They are awful. Yeah, I tried them once. They were bad.
Speaker 1:It's not food, but they're not as bad as carbapen and resistant Acinetobacter bamania calcoaceticus complex, which is the fourth leading cause of antimicrobial resistant death worldwide, has a 28 day mortality of more than 45% and accounts for 60% of all Acinetobacter bamania calcoaceticus complex cases. So that's bad right. If most of your isolates are crab and its mortality is almost half of all the patients that you culture it in, it's worth giving special consideration to how you're going to treat this, because you know, if I last week we talked about our things that we had, you know, reliable breakpoints for, and then we mentioned that really there were only three things that were really relying on for lung infection in particular, and that was the quinolones, cotromoxazole and a carbapenem Well, the carbapenems off the table. Then you've only got those other two to rely on, and if the organism is MDR, which two thirds of them are going to be, probably one or both of those are also going to be off the table, and then you're on to the real small fry stuff.
Speaker 1:So I think it's worth doing a deep dive on this. So for the rest of this episode, we're just going to talk about the evidence base for crab in reasonable detail. This is pretty high level. So if you're somehow an F1, I have to stick to this. This, you know, is probably way more detail than you need to know. If you're an early years trainee, this may also be more detailed than you need to know, but I think that, particularly for senior year's trainees, consultants and interested parties, this is really worth getting your head around, because this is one of the cases where I think infection doctors can really really make a difference.
Speaker 2:Really, really, not that much experience in this field. It's not something that we've had much of a problem with, I think, because of stewardship. Infection control practices in Scotland are, you know, apparently good yeah.
Speaker 1:I think that we're a bit blessed in the UK in general, in Scotland in particular, you know, like, for all I love my from my home nation, it's not particularly populous, do you know what I mean? And so I think that you're protected a little bit from antimicrobial resistance, purely from the fact that there's not a lot of people in, you know, in Scotland and neither are there in native or south. But I haven't counted this a couple of times, and it is, you know, important to know what to do about it, particularly if it's in the, you know, in the lung, because you need to. You know, in terms of the PK and PD of antimicrobial, you need to target both the lung parenchyma, which some of these drugs are good at doing, but also the epithelial lining fluid. You need to be able to penetrate the basement membrane and go into the epithelial fluid, and that's not what, that's not something that all the drugs are good at. So amniotic laksides are particularly good at.
Speaker 1:Colostin is crap at it. And so for this reason and this is partially because of a lack of lots of evidence culmination therapy is usually advised for for crab infections, because people don't trust drugs in isolation, the ones that we're going to be talking about. So for this I really have to give credit to one paper in particular, which is Shields et al. Shields et al navigating available treatment options for carbapendone resistant, asthenetobacter bamania and capoceticus complex infections. It came out in CID in May 2023.
Speaker 1:It's a really good breakdown and I've pasted in one of the figures which is a timeline of all the crab trials that have gone on over the last few years, and then I sort of pulled out relevant sort of statistics. You know for them, because people have been wondering you know lots of things about it primarily what the benefit of adding stuff to colostin is, because colostin is really the baseline therapy that people have been using for the past. You know few decades and whatnot, because you know, once carbapendones are out of the game, you really want something that's kind of going to sterilize the sterilize the infection. So we've first, we've got do not do.
Speaker 2:James say are there last, last time that colostin's not great getting into lung.
Speaker 1:It isn't great getting into the lung and people know that, but nonetheless it has remained the standard of care.
Speaker 2:And do you think that's going to change that, that we've got some newer drugs? Oh, maybe you'll come on to this, but I guess I'll call but yeah, maybe and maybe.
Speaker 1:Yeah, we'll talk about it. Pal Okay, jumping ahead. So in 2013, we've got two trials comparing colostin to colostin plus rifampicin. They're Durante, mangoni and Edemir et al. Most of them have 28 or 30 day mortality as their primary outcome. Edemir has inhospital mortality as their primary outcome. Both of them are non significant, with p values of 0.95 and 0.66 respectively. All of this is in a big table which, on the on the right, most calm, has the reference, in case you want to go and look at it yourself.
Speaker 2:Adding revampicin to colostin didn't make any difference.
Speaker 1:No, and not really. And the next thing that we tried was the addition of phosphamycin. So we've not mentioned it really in the treatments and there's no breakpoint for it. But phosphamycin does have some activity in vitro against a bunch of gram negatives, including non fermenters, like like pseudomonasin and like acnetobacter. So, and particularly I think this isn't true in the US but it is true in Europe you can give IV phosphamycin. You have to give it as was. The dose calms at 8 grams three times a day. I look it up it's a lot of drug but you can do it and you. We sometimes use it as a hail melee for Difficult to treat gram negative infection. So they tried adding it to Colston. See what happens. And nothing happened. You know, 54 versus 44% p value, 0.51 for 28 day mortality.
Speaker 2:So that's a CD jet to fat Et al so this I gets 12 to 24 grams and two to three divided doses. Yes, I'm, 24 grams would be eight grams, three times.
Speaker 1:I think that's the standard dose. Yeah, so you know that's a lot of drug Coming on board For no benefits, particularly in this setting. Same next we have a positive trial. So in twenty-een more science et al in the Iranian Journal for Macalgy research I compared Colston with leave of fluxes in to ampicillin. Cell back time plus leave of fluxes in. Mortality rates were 82 and 42 percent respectively and A p value of not point. Not for importantly, this was only in 23 patients. Those these are really small Trials with with not very big numbers.
Speaker 1:So they got half the mortality rate they did, and that's a signal that we've seen sort of elsewhere. The next trial is a clearly et al in 2018, 20 day mortality, colston plus Meru Versus I'm so bad and plus Meru. And, as a reminder, this is Carbopenam resistant. As need to back to my money, I and you might be thinking yourself why are we adding a carbapenam to a colston? You were thinking that, no doubt to Callum. Well, yeah, it's meant to be resistant.
Speaker 1:Well, the theory was that, in vitro at least, you can detect synergy in Carbopenam resistant isolates when you add colston. So the the thought was that colston Meru might have a synergistic kill. That meant that, even though it was Carbopenam resistant, adding Merupenam or impenam, silo satin would still have Benefit, and so this was the first sort of test of that and comparing colston Meru with ampicillin sulbatam and Meru. So the you know, even though they're two different agents. Here, the the question is that I think clearly is trying to answer is is there a Synergistic effect with colston that you can detect? That you don't find when you give ampicillin sulbatam with Merupenam? Reminder, the sulbatam is the active antimicrobial there and you can't.
Speaker 2:42 versions, 33 percent p-value of naught, point nine, nine, as Nonsignificant as it gets Callum although it's kind of makes you challenge the most science paper in 2018, because their comparator arm cost and Leo Foxen has such a high mortality rate of 82 percent compared to pretty much every other child and they seem to have as much. So I Don't know. I just seems a bit. I've not read the paper, so maybe you can.
Speaker 1:Well low numbers, callum, so I'm not sure that we should comment on it. Okay, okay, it's only important because it's the only significant one. So Then we have the first of two trials which are very specifically testing whether a carbapenam added to colestin is Significant, is going to result in improved Outcomes. It's the Ada trial. Paul, a town came out in Lansing. Infectious disease, colestin versus Colestin plus Meru. Wow, 20 day mortality rates, 40 to you versus 45 percent p value 0.78 Nonsignificant now is 406 patients.
Speaker 2:That's the biggest trial them.
Speaker 1:Lot of that is by far the biggest trial that has ever been done in in crab Infections, so really definitive, I think. Yeah, only one trial, and so there's another one, that's all but replicating it Later on, the overcome trial in 2022. It's, it is the general club on, actually, and that I we're going to discuss, but I'm going chronologically so. And next we've got Macros et al Colston versus Colston plus Ampicillin saw back, then non significant p value 0.52, only 40 patients though. So, and then poor, a darr et al Colston with nebulized colestin versus Ampicillin saw back time plus nebulized colestin, nonsignificant p value 0.27, only 28 patients. But the Ampicillin saw back time group, the mortality was 17 percent versus 38 percent. So an underpowered study with a sort of interesting signal, and In all of the trials that I've mentioned so far in which Ampicillin saw back time was one of the comparators, that arm always has the lower mortality, so people were thinking about that.
Speaker 1:The next trial that comes is the credible CR trials. This is one of the Kefederikol trials, the Trojan horse, and in it it had some patients that got that had carbapen and resistant acetylobacter and their endpoint was end study mortality and here usual care, which wasn't defined but almost always involved Conliston, when you go into the supplementary data versus Kefederikol, usual care beat the pants of Kefederikol with a mortality of 18% versus 49%, and this was statistically significant with the p-value of 0.04 in 56 patients. What Very strange, and the authors actually comment on this in the discussion. This is completely at odds with other publications of Kefederikol in MDR infections and at odds with the in vitro data as well. They weren't really sure what to make of this.
Speaker 2:Also, 80% is a very low mortality compared to a lot of the other arms.
Speaker 1:Well, it is yeah and so they sort of mentioned that too that this is also at odds. This could very well be just an aberration.
Speaker 2:Yeah, it's a very small number of patients. There's just vitro.
Speaker 1:Although one of the bigger trials in terms of numbers for Crab. And then I'm just going to skip over attack and get to the over. No, hang on, I'm just going to change the orientation. That's what I'm going to do, fine, and then we've got the overcome trial in 2022. Ke et al.
Speaker 1:This is Colston plus placebo. So this is a match placebo versus Colston plus meropenem. It came out in Negem evidence, one of the new New England Journal. It's an open source Negem journal. Numbers of 328, the second biggest trial for Crab, next to Ada. And again, no significant difference 46 versus 42% p value of 0.21. So there's, I think, overcome, together with Ada, put to bed the idea that adding a carbapenem to Colston does anything for your Crab infections.
Speaker 1:So what are the take home messages from this? First, the calma would say that the numbers in these trials are tiny. Almost all of them are fewer than 100 patients and some of them are published in real kind of small fry kind of regional journals, you know the Indian Journal of Critical Care Medicine, the Iranian Journal of Pharmacological Research, and which is not to say that they're not working out, because at least these people actually had a look at this pretty important infection. And then we've got some other research like that's a bit bigger in terms of numbers, like the aid of trial which came out in Lanta ID, and the overcome trial which came out in the Edge of Memorandans. The second is that subactam containing regimens tend to do better than non-subactam regimens, and that's a trend almost always non-significant. That's seen across multiple trials which lead us to think that or led people to think that subactam was probably quite a good potential target to therapy for crab. And the third is that if you add meropenem or roofampicin or phosphomycin to colostin, then it doesn't seem to do anything. You don't get any additional kill.
Speaker 1:But people did come back to this and think, well, maybe subactam is the thing for us to use and maybe we should try and marry it up with something else to protect it from belatimizes. And so that led to this last trial that we're going to talk about, which just came out a late last year, which is called the ATAC trial. It's Altaaric et al. It came out in Lanset Infectious Disease. Again, it was actually published as a pre-print in 2022, but it was finally published in May 2023. So this is fairly hot off the presses, but it's been doing the rounds and there's a tweetorial or a tweet summary, I don't know. I live tweeted this, so it was presented at the World Pharmacology Congress 2023 in Glasgow. I was lucky enough to be able to go there for a few days, and so one of the lead authors, called Matt Ronsheim, was talking about sobatimdurlabatim for Crab, and why did they set up this trial?
Speaker 1:Well, crab has actually been listed by the CDC as one of the six most troubling organisms to worry about in the future, so that you can not sleep at night, loyal listeners. The other five are VRE, cpe, mrsa, esbl and difficult to treat pseudomonas, all of which certainly cause me to have some restless nights. Crab itself has a 50% mortality. There is not much consensus on what the ideal treatment is, which you'll see in a sec when we talk about the SBID and IDSA DTR guidance, and that led to the development of Solbactam with Duralobactam. So Duralobactam is a beta-latimase inhibitor with activity against amylur A, c and D, but not class B, so the metallobatal atomases. But in particular, they're really good at inhibiting class D, and that's good, because Acetobacter has mostly class D.
Speaker 1:So the drug companies started working on this product. They eventually got licenses Zacaduro, that's the trade name, but we'll call it Solbactam-Duralobactam. Thank you very much. And so firstly they put out a sort of Neutropenic mouse thigh model which is a sort of in vitro or in vivo model, kind of showing kind of improved two log kills. So that would be a 100 fold reduction with Solbactam-Duralobactam compared to Colliston as the reference standard.
Speaker 1:And then they did a sort of enhanced phase one, two, and then they did a phase three well-designed trial that had a hard outcome of 28-day mortality. And they did it everywhere. They did it in 16 countries, 59 separate sites. They did it in Southeast Asia, they did it in the EU, they did it in South America and they did it in the USA and Mexico. So they had lots and lots of different places, which kind of is good for generalizability. And they were looking at Colliston plus imapenem versus Solbactam-Duralobactam plus imapenem. So they still had this carbapenem backbone that they were working to. But I think, for the reasons I've said previously, the ADA and overcome trial kind of make me fairly confident that there's no treatment benefit that could be attributed to imapenem here.
Speaker 2:So why do you think they put imapenem in?
Speaker 1:Because overcome hadn't been published at the time that they were running this trial.
Speaker 2:And.
Speaker 1:ADA had only just. In fact I think maybe ADA came out after their study protocol and being published. But don't quote me on that, cal. That makes sense. That came up in the questions but I didn't write it down. But questions that people were asking this guy afterwards were why did you include a carbapenem? Because it kind of seems obvious now.
Speaker 2:Everything looks obvious under the retrospective scope.
Speaker 1:Well, exactly, and ADA was only published five years ago and these kind of trials they take ages to cook up and so the trial protocol gets locked in early. So I'm not surprised that they included it. I don't think that it really makes that much of a difference. But then what was the primary endpoint? The primary endpoint was 28-tier mortality and it was 32% in the Coleston imapenem arm versus 19% in the Selvathum-Durlevathum arm. They didn't posit a p-value but they had confidence interval treatment difference of 13. Minus 13.2%, with the confidence interval of negative 30 to 3.5, which met their non-inferiority criteria. This was a non-inferiority trial. This wasn't a superiority trial. So even though this is crossing zero, that's good in this case, if you see what I mean. So yeah, and then they've included some other this is in the tweak that we're going to include a link to in the show notes that I put out there Kind of looking at various secondary endpoints in both the ITT and the MIT-modified ITT population, 14-day ass-knee debacter specific mortality and 20-day all-cause mortality.
Speaker 1:And again, there's no significant difference there between the two. In terms of clinical cure rates, they were higher in the Selvathum-Durlevathum arm, with 62% versus 40% in the Coleston arm, and in terms of safety signals there was. You know it was reasonably well tolerated. There was lower nephrotoxicity than Coleston, which I'm sure will surprise nobody, and the adverse reactions that you saw were kind of abnormalities of the LFTs, so not liver failure but kind of. You know, ast and ANT are going up, diarrhea, anemia and a low potassium, and this is kind of similar to other Bailatum-Bailatum Anebuter, a combination of tazasin, your comorciglobs, napsil and subatum obviously.
Speaker 2:So do you think the attack trial, you know, do you think it would be? We just used Durlevathum and Sulvathum on its own, and we don't add a carapenum.
Speaker 1:I don't think that based on all that other trial data, that the use of a carapenum for crab is justified. I mean, I have my problems with synergy in general. I think it's an in vitro phenomenon with very little, if any, in vivo evidence, and it's another thing that we're going to have to do deep diving later on.
Speaker 2:And do you think someone needs to try a colustrum plus Sulvathum, durlevathum? You know, because all the trials have been in Coliston and you know the combination is being with a car repair.
Speaker 1:That would be interesting. So I think Coliston versus Coliston plus Solbatham-derlebatham versus Solbatham-derlebatham would be a really interesting study to run. I'm not sure if the drug company would be all that interested in doing it, but you know, maybe. I think at the moment they've got some pretty good evidence that Solbatham-derlebatham is superior to the current standard of care. Yeah, for Crab, which is Coliston and all the other kind of evidence is that the previous thing that was likely to be better than than Coliston was Ampicillin Solbatham, and so the Solbatham is the important bit there. So if you protect that with a really broad spectrum second generation banal atomase inhibitor, ideally you should get improved Acne to batter kill and that's what they seem to have found there, you know.
Speaker 2:So that's really in depth. Look for the evidence base. I'm not sure I'm going to remember that, but I'm going to come back to that table and the prep notes and use it if I have cases to manage.
Speaker 1:Well, I mean, luckily Callum Esmid and IDSA have your back, because you don't need to remember all that.
Speaker 2:Yes, we mentioned that we went through the guidelines, the IDSA and ECMID guidance about difficult to treat gram negatives.
Speaker 1:And well, we did, although, you know, importantly, we left out the non-forbenters, yeah, and we were going to talk about them during the relative episodes. So those episodes murdering MDR, that's now.
Speaker 2:Hey, that's now.
Speaker 1:Which we'll have to update, actually because the IDSA brought out their revised 2023 guidance. There is a recent Feb episode on that, by the way, for those that are interested. But yeah, the Esmid and IDSA also include recommendations for Crab which we'll talk about here.
Speaker 2:Yeah, so I guess they split it up into, or we can split it up into, like a HAP-VAP situation and then severe high risk infection. Yeah Well, let's talk about the HAP-VAP first.
Speaker 1:So what do Esmid advise?
Speaker 2:Well, they're saying monotherapy and they say if it's sobactome sensitive and there's some issues about how you test sensitivity to sobactome If it's sobactome sensitive, you use sobactome monotherapy, and if it's sobactome resistant you take a high dose. So would that be 100 twice daily?
Speaker 1:I think so. It's whatever dose went head to head with imipenem for IEI and came out non-inferior or polymixin so-called. Yeah, I mean, it's an interesting recommendation, callum, because if you have a look at my table in which I try and sort of list the breakpoints, you will see that for TIGA cycling there is no formal breakpoint. But you can't list the MIC 90 of 2 to 8 and say just try and get above that or below that.
Speaker 2:So why do that and not just give a breakpoint?
Speaker 1:Well, esmid, don't tell UCAS what to do, though, so we're talking about recommendations from different organizations that aren't joined up. Yeah, they're related quite closely. But if you're in the UK it's difficult to get a hold of sobactome and there are no breakpoints for TIGA cycling, so you're sort of driven inexorably towards using a polymixin, to using polystyne, and polymixin was not available, wasn't it?
Speaker 2:Quote sensitive against no breakpoint and I think I'd probably rather use TIGA cycling, as much less toxicity and in other areas where you trial it it's sort of a better agent than polymixin. I mean know that polymixin doesn't tend to get into long tissue that well, so I mean, you're out of luck, callum, because that's the only game in town.
Speaker 1:So that's Esmid's recommendation. I guess they don't have a specific recommendation for that. They just talk about severe or high risk infection, and both of the organizations recommend a combination of two agents.
Speaker 2:And for so just sort of hat that Esmid are saying monotherapy, IDSA are saying always use combination therapy. They're not giving any recommendation to give monotherapy. So I wonder if my Esmid are saying monotherapy and hat that.
Speaker 1:I don't really know. I'm not really sure that I'm comfortable giving monotherapy. You know, usually when we recommend giving combination therapy is because the evidence base is crap and you want, you know, double cover. You know, just in case something fails and where we've looked at it in detail, like there was a trend for giving double therapy for staff or use ages ago and then there was a few studies that said this is probably not doing anything except creating toxicity and we stopped. And so to the pseudomonas double cover. There's more and more evidence that that it's not adding anything.
Speaker 2:Yeah, I think there's multiple reasons to give multiple agents.
Speaker 1:Yeah, but well, I think one of the reasons is that you don't have evidence, and I think that's the case.
Speaker 2:Yeah, you're just not sure one of them are working. Or maybe there's three reasons. One is not enough evidence, you're not sure which one's going to work, if any. Another reason is supposed synergy, and I think that is generally going out the window and situations yeah. And then the third one is, you know, empirical cover before you get sensitivity. So I quite often do that pseudomonas If you're there, if they're quite unwell, I don't know Like often. You know who knows it'll be resistant to bitters or gent or meri-penet.
Speaker 1:Yeah, and I think, particularly with the non-fermenters double covering up front and then rolling back, I think that's perfectly justifiable and I'm not sure with that, Steve, about time. Whatever, roll back.
Speaker 2:Yeah, so. So, ekman, they're saying for severe high risk combination two of solbactum, polymixin, zaculostin, high dust tick, acycline, menoglycosides or extended infusion meri-penem at six grams per day if the MIC is less than eight, so sort of resistant at lower level.
Speaker 1:Yeah. So this is I mean this is kind of coming back to Vin, explain this in excellent plain English in the Micromail collab episode that we had Bugs Without Borders. But essentially if you've got you can have sort of low level resistance meri-penem. So the S breakpoint for meri-penem is two and the R breakpoint is eight, except in meningitis when it is two, but we're not really talking about meningitis here. So for the, if the organism is meri-penem, I can you still use carbapenem. Espen say yes, as long as you give two grams three times a day, which each dose being infused over three hours, the extended infusion protocol. So if you think if you're giving it three times a day for three hours, that's nine hours out of 24 on meri-penem, really you can only do that through a central line in intensive care. So that's your patient population that you're talking about there.
Speaker 2:So it's different. It's not saying you must use one of the, it's just a combination of any of the two.
Speaker 1:Any two.
Speaker 2:Yeah, I just say. In contrast, say you sold back to him at 69 grams per day, regardless of sensitivity.
Speaker 1:Yeah, and that's because there's I didn't really get into this in detail, but there's issues with testing for subatom sensitivity, and so even if it's subatom R, you can't really trust that recommendation. And so for that reason they say give it, but give something else too.
Speaker 2:So it's interesting. So ecomet are saying it's not necessarily sold, sold back to backbone. It's just two drugs. Idsa are saying sold back to backbone for every patient. Have that part of anything else plus one of polymixin or high dose Ticocyclin or Minocyclin and Cathedral call, which they say is the last resort, trojan heart.
Speaker 1:So they're, they're worried by the credible CR trial results and so, although it's got in vitro, you know sensitivity, and about 97% of isolates are sensitive in vitro they they're a bit worried about that and so they say, fair enough, let's, let's not use that unless we absolutely have to. And I mean at least they're making a recommendation like the expert or not recommending catheteric all at all.
Speaker 2:Yeah, and I think I think often guidelines, you know there's what's ideal and you're often saying like this is what's ideal but there's not enough evidence. You know it's kind of unhelpful sometimes to just be like we're not going to make a recommendation about this because this is a group of experts, have sat down and really in debt, read for the literature, and if you're, you know, busy a weekend and you're trying to help someone, you know I think it's at least saying like okay, well, you know it's not ideal, but maybe you can try this. Who knows if it's going to work. But, like you know, at least give people a little bit of help to when you get into the real back against the wall situations or crabs where you're really not going to need options.
Speaker 1:Well, I mean, I think it's really easy to get into that situation as well, particularly with this organism. But yeah, and then in terms of what's the organized societies don't recommend? Both of them don't recommend Raphapsin or Phosphamycin or extended infusion carbapenems, except with asbestos. They say that if the MIC is less than eight you can try it, as we said before. And asbestos don't recommend. They recommend against Kefederikov, whereas IDSA say you can use it as a last resort. So they give you the option still, but they say not unless you have to. And then the only other thing to say is that the ESPID don't make any recommendation about nebulized antibiotics. So there was that trial on nebulized colostin and the IDSA specifically say we don't advise using nebulized antibiotics. So not very convincing, I don't think it's very convincing, but it's. The nebulized antibiotics work for the end of this situation. So now they're organization are particularly keen on using that.
Speaker 2:Wow. Well, I feel like there's something I really knew very little about and I'm not sure I'm going to memorize all that, but certainly have a better understanding. I think some key take hold must from me. There was that acneetobacter is a really troublesome organism to treat. It can easily pick up resistance mechanisms. It's likely to have class D Amblur. So Oxa, there's been quite a lot of trials done looking to try and figure out what's better than colostin and possibly solbactin or lobatom is the future. But I think probably need a bit more evidence before we're saying that empirically. And the ECBID and IDSA guidance are useful, but they're only as useful as the evidence base which they're based on. So we're really still in a situation where we do have many options and combination therapy is probably here to stay.
Speaker 1:Yeah Well, I'm not sure that it's here to stay. In the long term, I think that we will get better at sort of doing these.
Speaker 1:You're just staying for now. Fine, it's here to stay temporarily. It's the Airbnb. Fine, it's the Airbnb of antimicrobial recommendations. Yeah, the thing about this evidence base is that, although it's spent a lot of time going over it, we've been able to summarize it basically within half an hour. It's not big, it's not deep. If you tried to do this with any cardiovascular area you want to look at, you would be stuck for days on the nuances of this.
Speaker 1:Yeah, and you'd fall asleep for sure. But then the take-home messages I think are, as you said, that carbapenems and some other agents basically don't add very much and that if you had a preference than using a sol-bactam containing regimen would be ideal. I'd be surprised if sol-bactam-dural-bactam didn't get a license in the next little while. In fact, I think Calam is a pretty good candidate for-.
Speaker 2:All of the subscription models but the.
Speaker 1:Netflix model yeah, for subscribing yeah, so just like Kefeder, called the Trojan horse, and just like Kefeder, I have a bactam which you can combine with Astri and I am to form a pretty good antimicrobial combination. I think sol-bactam-dural-bactam on subscription would be an ideal way to deal with these kind of crab infections, because everything else is available. Yeah, do you know? Polymixants, tigger cyclin, mincycline yeah, kefederical, yeah. Amyglacides yeah, extended infusion marrow you can pick your choose and you can form a concoction out of all that, borrowing from both S-MID and IDSA guidance, so you can go between the two to create a regimen that's optimizing your patient's chance of cure.
Speaker 2:Great Well, thanks very much, james for going through that in such detail, presenting it. And oh, he's a cyber leaf.
Speaker 1:Good, it's the mammoth work.
Speaker 2:It's so well-present and the tables are amazing, really visual representation. So if you haven't looked at the show notes already, then have a look. I think you'll find it useful and I'm going to certainly be coming back to it whenever someone phones me about a snita batter. So thanks, no problem.
Speaker 1:It's sort of built to be a reference for the loyal listeners, but yeah, so hopefully somebody will find it useful To us. A labor of love, Callum, as is all your work. Thank you. Save the date. The BIA are having a dilemmas day on the 24th of January 2024. In Newcastle, this is going to be on the theme of transplant infections. More details to come.
Speaker 2: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, callum, 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 on, james and Callum. See you then.