104. IDSA Difficult To Treat Gram negatives Guidance 2024 with Breakpoints podcast

IT'S A BREAKPOINTS BREAKOUT!

Jame and Callum are joined by the drugnamic duo of Julie-Ann Justo & Erin McCreary from the Breakpoints podcast to delve into the IDSA DTR Gram negative Guidance.

Show notes for this episode are here.

Breakpoints podcast can be found here: https://breakpoints-sidp.org/

Lyrics: 

Tryin’ to use some drugs to kill these bugs

Erin and Julie are PK PD thugs 

Gonna make these two ID:IOTS look like mugs

It’s gonna be a Breakpoints Breakout

Sorry the song sounds so tinny, Podcast host is doing something strange to it. Link to original MP3 here. 

Transcript

Jame: 0:00

Callum, our guest tonight should need no introduction, but podcasting etiquette demands that I introduce them anyway. This drugnamic duo has been running the excellent Breakpoints podcast for the past few years and doing much better downloads than we have, by the way, on behalf of the Society of Infectious Disease Pharmacists in America. One is the pride of Pittsburgh Pharmacy. The other did the denizen of drugs in Dartmouth. America Dartmouth, not real Dartmouth. With a presentation style both kinetic and dynamic, their podcast is a racemic mixture of essential antibiotic pharmacology and crap Taylor Swift puns. All I can say is that Justo and McCray must be their trade names, as these two are anything but generic. Having mastered the art of podcasting on breakpoints, they're here to take over idiots and show us how it's done properly. That's right Callum, it's a breakpoints breakout. Tryna do some drugs to kill these bugs, Erin and Julie are PKP thugs, Gonna make these two idiots look like mugs. There's gonna be a Brave Boys Breakout. Gonna be a Brave Boys Breakout. There's gonna be a Brave Boys Breakout. Gonna be a Brave Boys Breakout. Erin Julie. Welcome to the show.

Julie-Ann: 1:31

No comment.

Jame: 1:32

Well, starting with an insult, that's how

Erin: 1:34

Okay, first of all, the Taylor Swift puns are exceptional, so I resent that.

Jame: 1:39

guys, thank you so much for coming on, the show.

Erin: 1:43

Thank you for having us.

Julie-Ann: 1:44

Yeah. I'm super excited. We've been talking about doing something like this for a while. So thank you.

Jame: 1:48

Well, do you, I have recently guested on an episode of, Brave Points, Calum was invited, but, would you like to talk a little bit about the show to any loyal listeners who have not subscribed just yet?

Erin: 2:00

So break points is the podcast hosted by the society of infectious diseases pharmacist, which is a growing organization. We accept pharmacists and non pharmacists you can join. If you're not a pharmacist, be an associate member, be our friend. it, is run by an absolute village of amazing volunteers. So we have a committee of about. 40 people that run that podcast. Julie And I both have the privilege of hosting it right now. but we try to just put out, you know, really relevant ID content and try to stay funny and try to

Jame: 2:26

Save lives one drug at a

Erin: 2:27

save lives one drug at a time. Yeah. I'm sorry. I'm

Julie-Ann: 2:29

Yeah. I think,

Erin: 2:30

me why I couldn't even get my video to work, to record this podcast. I shouldn't be allowed to do podcasts anymore. So

Julie-Ann: 2:35

girl. You're doing great. I think the only thing I would add, we, the original idea for the podcast was back in 2017. just to echo what Erin said, we are so. Proud of our community of infectious disease pharmacists and important allies. And we knew we could crank out really cool content, but. Everything was turning into a continuing education seminar, and we were getting pretty tired of that. So we wanted something to keep going with that, but then to come up with something new. and that's where the idea of the podcast, came up. I was probably in the minority when I originally was like, I love podcasts! I listen to them all the time! I'm an audiophile! And everybody was like, a pod what? But, thankfully, we've really benefited from The growth of podcasts as a medium over the last eight years or so. and I mean, hats off to Erin. She really made it sing when we selected her as the original host. But I really think the thing that we try to do in terms of our mission, aside from safe and effective antimicrobials for now and the future is let's talk about the stuff that We can't talk about within the confines of continuing education. What are the water cooler conversations that all of us are already having within infectious disease, microbiology and pharmacy? Let's push the envelope and try to hypothesize what we think is coming next. and I think that's been a little bit of the secret sauce to try to maintain a discussion of the evidence and then a discussion of, what are the through lines that we're seeing from the science all the way through to the bedside? So

Jame: 4:00

So are you purposely getting to the cutting edge of whatever the topic is for that episode?

Julie-Ann: 4:05

we try.

Jame: 4:05

You're not, like doing the meat and potatoes bit on that. You're trying to save what the latest research and evidence basis.

Erin: 4:13

When we started it, we said that we wanted it to feel like you were at a conference and the sessions ended and then you went to the bar with your friends and you sat around the table and you were all hanging out and catching up and you were having that excited dialogue about what you just heard. And that's the vibe we wanted to bring to the conversation. And so that's what we've strove to do. Admittedly, I was in the school of I've podcast before when they approached me about starting this podcast, but learned a lot. And it's been one of the. One of the greatest joys of my life in doing this and actually I'm funny. I'm looking up at a cork board in, my office I have a post it note from Ryan Shields. It says we'll do podcasts and he signed it because I Amongst our first episodes we had we had no idea what we were doing And so we had a podcast recording studio pit pre pandemic when we could go places in person and I was like ryan, please please come sit with me and talk about what we learned at id week and those were amongst our first episodes that we recorded, which ended up being a series of, I think, eight episodes, that we launched it from there.

Julie-Ann: 5:11

They knocked it out of the park. I mean, it really was two friends who were talking about the stuff that they thought was cool with an ID. So that's really the litmus test of the stuff that we talk about. If we are not interested in, and if we don't have questions about the topic, we'll still do reviews and stuff like that, but we got to find at least one thing that's new and exciting. So try to bring it from the learner level all the way up to the cutting edge for the expert. So it's a tall order. Not sure we always hit the mark, but we do try.

Callum: 5:40

Always useful to hear about how other people are navigating infection podcasts. What are we here to talk about today?

Julie-Ann: 5:47

Heard you guys had some questions for us about gram negatives.

Callum: 5:50

are questions, questions that need to be answered.

Jame: 5:54

So, I do have some questions, particularly about the IDSA difficult to treat gram negative, guidance. So we've done episodes on Difficult to Treat Gram Negatives. You guys have certainly covered it, quite a lot in the past, but you also are involved with the IDSA's development of the Difficult to Treat Gram Negative, guidance, which covers ESBL, AMP C, and carbapenemies, producing interbacterales. Difficult to treat Pseudomonas, Acinetobacter, and Stenotrophomonas. And these were first produced in 2022 and have been revised, yearly. So maybe you could chat for a couple of minutes about what your involvement is with the development of this, guidance.

Julie-Ann: 6:34

Yeah, So I can start there. I'll say that I've had the honor of being on the guidance panel for about a year. So I joined in 2024. and it was, I think the biggest distinction is to understand the difference between a guidance versus a guideline. Many people are very familiar with, the clinical practice guidelines that, the IDSA has put out for, many years. they purposely decided to make this a guidance just because it was felt that the evidence base was changing at a relatively rapid pace. in addition, novel antimicrobials were coming to the market and they wanted to be able to comment on, recommendations and utilization of those novel agents as they came out, instead of the average turnaround time. of a guideline at that time, which might be five or 10 years. I think IDSA is doing a lot of good things to improve the turnaround time for revising their true clinical practice guidelines. and so that's another topic for another day. But it was felt that having a more nimble Document with the intention of being updated. Every year is a guidance, would be something that was useful for the community. in addition, an important distinction is that we don't have a methodologist on the panel as we, as IDSA would have for one of the official guidelines. and so there is a difference there and the underlying methodology.

Jame: 7:54

would they be doing?

Julie-Ann: 7:56

so they'll have their own, Librarians and, really statisticians, um that are going through and conducting meta analyses if necessary to collate the data that might be necessary for a clinical practice guideline recommendation. And then the strict information about, how you would grade, the evidence as well is important. so there is a lot more detailed methodology that goes into a clinical practice guideline, that is. It's a little bit more free and nimble and a little bit more of a hippie vibe for lack of a comparison. That's my, characterization, not ideas. but we're trying to be fast, and relevant, with the up to date information. and so this was something new, that we tried particularly for this disease space. and it seems to be very, successful to date. But There are some potential downsides for that if there are things that need more detailed. Meta analysis, then that's not necessarily going to be something that. The 6 of us would have provided on the guidance panel. but last thing I'll say is, I feel like I'm a guest member on this because a ton of the work was done by the original six, members of the guidance panel, not least of which is led by Praneet Atama. huge shout out to those, original six, because it's much easier to update an existing document than it would be to start it from scratch

Erin: 9:13

I love this. It's an important document to have for sure. it's a conversation we've all loved having for years and now it exists to help people have this guidance. I would say the original panel was kind enough to involve a series of pharmacists in the first iteration. So we served as unofficial peer reviewers largely and that's where my role came in So I was fortunate enough to see early versions of this Sam Aiken was the first pharmacist on the guidance and represented us really well. Okay. He's brilliant. He knows a lot about the grim negative space. Yeah, Sam's fantastic. And so him and Pranita and Amy and Robert, friends of pharmacy and just of wanting to do the right thing for patients had looped a handful of us in to say, okay, we want this dosing table. What should that look like? What are the recommendations for these complex infections that are beyond package inserts? what should we position here? What are the implications if you're treating patients in under serviced areas and under resourced areas? What if you don't have these drugs? What if you can't get genetic testing? And that was a huge thing. We discussed at length of if you don't have resources to get genotype and phenotype, how are you going to provide guidance and what are we going to do in that setting? And what are we going to use as a surrogate marker? And is that even accurate? And so that was really wonderful to be a part of that. I feel honored that they had looped us into that. And I will say though, you have, six people or so in, in these conversations, in addition to the six guidance office authors and trying to come to consensus. And I would say there was much disagreement. And so I think that's something I've learned along the way, something that's just very. compelling to me and humbling and that I think we need to keep in mind is that you can get the 15 world leading experts on a topic in a room and have a 50 50 consensus and this is our best guess as experts and here's the data. We might not even all agree with this, and I think there's something to be said about that, and I know it's very hard to live in a space of gray, but I think these topics are very gray, And, you want this black and white, well the guidance says this, and I'm doing this, And that's it, and just often with these complex scrim negative cases, it's not that simple, and I know that's such a mediocre answer sometimes, is it depends on the patient, it depends, or I know the guidance says this, but actually I'd recommend this, And that's just something to keep in mind that even amongst these experts, and we have these discussions that there could be very reasonable disagreement. And that's okay. That's what makes us all better. And that's what drives research questions and further areas of study.

Julie-Ann: 11:31

And the one additional comment that I'll say to that is, if you are using the guidance document, particularly to take care of a patient that's in front of you, don't just read the recommendation. Don't just read the summary. Please go through and read the rationale because I think it, I do also use the guidance document myself in clinical practice. And usually the answer is in the rationale. It's not as simple as the top line summary of Oh, this is the preferred agent. We're going to use this. We spend a lot of time. On the language there.

Jame: 11:59

Yeah, there's a lot of detail in the justification

Callum: 12:02

And there was just what you're saying there about it being guidance and trying to get rapid fire. There was a talk at ECMID a couple of years ago, and they had done a review of guidance and the evidence base, and the takeaway from it essentially was that they found that for evidence to get into guidelines, it took average about five years and for guidelines to change clinical practice, it was taking about five years. And it's one of those debates I always have in my head is I've got this Yeah. Really well written, really well searched, great methodology guideline from 2018. But I know that there's been a lot of data out since then and it can be quite hard almost to say like, well, you know, my colleague says guideline X says this, so you must do that. Whereas you know that isn't up to date. And what's so great about this guidance is that it is up to date. And so I. Personally would rather I think there is something to be said for that balance between, completely rigorous, completely accurate guidance, but has to be balanced against as particularly in such a fast moving field and being so up to date. So I can understand why I approach it like that.

Julie-Ann: 13:11

Yeah, we would argue our patients can't wait five or 10 years for the practice to change. They need the drugs yesterday.

Jame: 13:18

And, it is fast moving, not least we were talking before we went on Mike about the European guidelines, the ESMED guidance that came out in 2022 and how. in, in being renewed annually. The IDSA guidance is rendered at. Obsolete and to the point where in, at a recent talk at FIS, one of the experts who was talking about difficult to treat gram negative guidance said that she just doesn't follow the recommendations in SBID anymore. She looks to IDSA because the. Document is more up to date and contains more of the cutting edge research that has produced in the past couple of years, a complete sea change in how we would treat stenotrophomonas, carbapenem resistant acinetobacter baumannii, all that sort of stuff. there's stuff, that we are talking about today. That's just not mentioned in ESMID 2022.

Julie-Ann: 14:12

That's really, that's really fascinating. I don't think we realized that. I think I can tell you that the guidance panel definitely thinks about the implications of what we're writing. Outside the United States. I think we're clear to state in the introduction that this is written with the United States and its epidemiology, and healthcare system in mind. I think, to Erin's point, there's a lot of folks that, think about the logistics of what we might write down as a preferred therapy. that doesn't necessarily get completely spelled out. but I think it actually encourages, it encourages, Me and Erin and others, we've had conversations about a more global approach to antimicrobial resistance. I know, for example, is doing a lot of work, and trying to think about international, bugs of interest and strategies that could even be more than what's outlined in the guidance. So, I think it's important to state that the guidance is focused on the United States, and it's epidemiology. and it's healthcare systems. So I think that's an important caveat, but it's helpful to hear that the work that we do to try to stay timely is useful.

Erin: 15:11

think though, there's, I think there's a lot of value though, in, in increasing these global collaborations. And I would hesitate to be like, Oh, this organization's guidance is trash. Cause I picked up this organization because it's more relevant. I think rather it's okay. How do we all get together? And do we need three different organizations to produce guidance on the same thing? Or can we all globally work together to be more nimble together? And again, I'll just reiterate that. With fast moving nimbleness comes a humility. So you have to be willing to publish something that a year later you publish something completely opposite because you say, Hey, in 2024, we made our best guess with the available evidence that this was the right thing to do. And then an RCT came out and it proved there's no difference whatsoever. So why are you adding two drugs or why are you doing this? And now in 2025, we're going to recommend something totally different. And that's really challenging. And so I'd say that. this, I think is the way we need to head for sure. But I understand why for clinicians, there's a little bit of pause here in that we speak like it's. the be all end all source of truth because it is at the time, but with science, we're just constantly learning and getting better, but it's hard to say, I recommended this a year ago, and now I'm recommending something different because I just know more today than I knew yesterday, but that's challenging to move through. And then I would say, too, we do need to keep in mind these guidance documents and in terms of access, and I'll harp on that forever, but we can talk about countries that don't have access to certain novel agents for sure, as a whole. But I would say even in the United States, you have a lot of hospitals that don't stock or carry these drugs simply because they rarely, if ever, see it. and so they're not going to keep a 10, 000 box of antibiotic on their shelf, right? However, then that multi drug resistant, carbapenem resistant acinetobacter pops up from a transferred patient, or we're increasingly seeing metallobeta lactamases in the community, or these scary things and these hospitals see something for the first time and they go, I just had this happen at a UPMC hospital that's, About two hours outside of Pittsburgh in a relatively rural part of Pennsylvania. And they had this come up on the Friday before a holiday weekend, and there's a snowstorm, and they can't get drugs shipped in. And they go, okay, I know I have to give this patient sulbactamderlobactam per the guidance, and per what we say is the best choice for that patient, but we have none. The closest hospital is two and a half hours away and it snowed three inches and the snow's coming down and I don't feel safe putting anyone in a car. There's no couriers because no one's driving and I can't get this drop ship till Tuesday because it's a holiday weekend. So what should I give my patient for the next 96 hours even though I live in the United States, I have access to this drug and I'm in a health system that absolutely knows the guidance, right? And so I do think there's something to be said about providing guidance in those settings too, which is perhaps where. Those global guidance documents come into place more helpfully, or as Julie said, as we continue to push ourselves of this is the optimal care for the patient, and if you can't do that, what should you do next to first do no harm and then try to get here. So I think that's something we try to keep in mind too.

Callum: 18:01

Yeah, there's a recent paper that came out that examined exactly that question about where the antibiotics are available, which we went through in episode 88, where all the new antibiotics, which was really eyeopening to me when, told me all about it. So, really, useful to have that approach of what do we do. So talking about the guidelines, james, what do we do for, and maybe let's start with ESBL.

Jame: 18:27

So, the IDSA, guidance does something that I, I really like. which divides the recommendations into lower uti. I. Upper UTI or complicated UTI and non UTI as in systemic, infection and makes no differentiation between bacteremic and non bacteremic, infection, which I, unlike the spen guidance, which I prefer as a strategy. So for lower UTI, they make a recommendation to use Nitro tune or roaz. and if you need to, you can, use things like carbapenem, kefapim, piptaz. If started in the patient, improving, you can continue that. and then other things like quinlones, oral fosamicin only for E. coli, or a stat dose of aminoglycoside, but these are the second line options. For upper UTI, they're recommending cotrimoxazole or equinolone with second line options of a carbapenem or an aminoglycoside, but for carbapenem, trying oral switch as soon as possible. And then for non UTI, their recommendations are a carbapenem, with the exception of ertapenem for intensive care patients or people in a low albumin state, for reasons that we could discuss a few. and then, Other recommendations would be for a use of quinolone or a cotrimoxazole for oral switch if sensitive or susceptible. and they finish by, recommending not oral switching to Interfer, Andone Phosphomycin Icla or, doxycycline or cylin. So, let's ask a few questions about that then, shall we?

Callum: 20:03

so. I find it, it's really interesting and a lot of that reflects what I would be doing and what I've read in the guidance before. One question that we had was, so for lower urinary tract specifically, historically have certainly used doxycycline as an option when we're kind of stuck, um, accepting that it's not a normal agent for urinary tract infections, which we can go into. so I guess, why does doxycycline not appear here?

Jame: 20:33

Well, it does here appear though. It just says don't oral switch for like non uTI infections. But yeah, I have used it a little bit for eSBL, UTIs, particularly E. coli.

Erin: 20:46

so doxycycline right is the best drug. Like I feel like if you come on an ID podcast and you say negative things about doxycycline, you get banned from all future conversations, perhaps life. So we love doxycycline just to be clear. And I think we've all used it for urinary tract infections as you described them. So I heard you say, Cal, I'm like, I got nothing else and I have to give them something and I want to send them an oral. So I give them doxy. I actually think that's exactly what the guidance is saying in a saying, don't use it. It's saying don't use it, but like squint and maybe sometimes you have to, but it's not the best UTI drug. And so are you going to give doxy for a lower UTI for cystitis? It's a risk benefit decision and like probably not, it should be your, I really got nothing left. And so why is that? There's a few things to break down here. so first when you look at. An in vitro susceptibility report. So you get that culture report back that says this E. coli is susceptible to doxycycline. As we know, with every antibiotic, that means nothing without context, right? so, we need to talk about what infection we're treating, what's going on with my patient, site, source, how much drug can I get there, am I going to be able to kill it? Just because something kills something in a petri dish doesn't mean it's going to work in humans. And I jokingly was like, yes, doxycycline is in vitro active against ESBL E. coli, but so is bleach. but probably too soon for that joke in America. Anyway, so Julie will love this. Keep that in the pod. Julie will love this. the PK PD lovers enter the chat, right? Like all pharmacokinetics and pharmacodynamics come into play, but we'll come back to that one. But I think most importantly, we have not one, but four, four RCTs showing that tetracyclines have failed against standard care for UTI. And so I, and I think honestly, people may not be aware of that because those RCTs come in the pearls of drug development, which is why it's very cool to watch drugs come to the space and even drugs that. fail teach us a lot. And so that is what we really try to follow as ID pharmacists. So I'm sorry, we don't fail in ID. We're non inferior or we're not non inferior. Yes. Correct. Yeah. Put that? on a

Jame: 22:50

like that, yeah. Are you talking about the OMADA cyclin and the ARAVA cyclin trials? Because I would argue that their urinary excretion is much less than DOCSI's. So DOCSI the urinary excretion is variable, but it's sort of around 30 to 40 percent.

Julie-Ann: 23:05

So it is better,

Jame: 23:06

as opposed to what, 10 percent or something like that with ARAVA? I, I, I'm, frankly, when I, read that I was kind of shocked, because we talked about ARAVA and OMADA recently.

Julie-Ann: 23:15

I rather it's like 4%. It's

Jame: 23:17

I was shocked that that was trialled for a UTI. That seems like an obviously stupid move on the drug company's behalf, but i, I mean, who knows why they do what they

Erin: 23:25

Well, what's the urinary excretion of ceftriaxone?

Jame: 23:29

is it about, what, 10%? Something like that?

Erin: 23:32

It's not high. So I think that So I think that there's I think that there's a lot to unpack here. So, but yes, that's exactly what I'm talking about. And so I think, interestingly, Arava cyclin was studied in the IGNITE 2 and the iGNITE 3 trials, and in IGNITE 2, it was studied as an iV to PO step down, and it was for complicated UTI against levofloxacin. They had 908 patients in that study at 10 percent non inferiority margin, and it was not non inferior to a very rigorous FDA responder outcome that's a composite of clinical cure and micro response that we're seeing in UTI trials. So we're seeing low success rate in UTI trials because of the strict composite set by the FDA. but this is why oral oravacycline doesn't exist, which is Interesting, right? Like oravacycline is only available IV and people smash drug companies and like, why wouldn't they develop an oral? They tried and the study, they studied an oral therapy and failed and therefore the oral wasn't improved.

Jame: 24:25

And it's funny because it's only about, it's something like 25 percent bioavailable, but Amada's 13 percent bioavailable!

Erin: 24:32

right. Also a headache.

Jame: 24:33

and you just give three times as much, so why didn't they just give four times as much of the Arava, but maybe, I mean, the GI side of it's

Julie-Ann: 24:39

usually it's tolerability. Yeah, there's usually a

Erin: 24:41

Yeah, that would like absolutely destroy your stomach. But yeah, so no oral or rhabdocycline for that reason. But your point is well taken on the urinary penetration for sure. but that's a failure. Ignite 3 was a failure and non inferior. And then oravacycline had two trials. So one for cystitis against nitroferantoin and one for pylo against Cipro, all not non inferior.

Julie-Ann: 25:00

I don't want it if I'm sick with a UTI. Thank you.

Jame: 25:04

I mean, next frame tone is actually pretty hard to beat. it's never been beaten as far as I know in a head to head. I'm using it

Erin: 25:09

No, that's the demise of phosphomycin, right? And against nitro trial, nitrofrantoin is fantastic. they just have those trials, but the point is taken, those are not doxycycline. So alas is doxy different. And when you really dig into like, do I have data to support using doxycycline for UTI? That's where it's just fascinating how little data there is in that space. And So the guidance does a good job to Julie's point of, read the explanation. so the guidance does a good job of talking through some of, these main trials in the interest of time will be very brief. But there's McCurdy and colleagues 1969 and chemotherapy. This was a clinical trial of doxy for u. T. I. S. 26 males, seven females. So I love infectious diseases, right? All our data comes from 33 patients. Yes. Kill them. There was one infant in that. So fascinating. There was 12 children,

Julie-Ann: 25:55

Yeah, there was peds in the

Erin: 25:56

adults, 33 people. So five months to 80 years. Can you imagine doing such a study in today's day and age? Anywho. So one infant, 12 children, 20 adults. Doxy was here's, here's a good one. So Doxy was given only to the people who had not previously received a sulfonamide. or other antibiotic, which were very minimal at that point in time. And then they basically gone. So they gave 200 milligrams a day. So a hundred BID is what we do now for two days, but then they gave a hundred for five days. So they gave 50 BID for five. So the dose was different. And then they basically said nine patients had really bad response. Four patients did meh. And then 20 patients had an excellent or fair, which I wonder what that means. What is fair, excellent, who knows? My gosh, it's chaotic when you read it. And then when you go through it, six of these patients had a pseudomonas species. So that'd probably be out the door, but then 14 club, 12 E. coli also interesting from a Euro pathogen epidemiology standpoint, this doesn't really track with what we'd expect, which is usually 70 to 80 percent E. coli. But anyway, that's a case series of using Doxy for UTI and patients that had basically failed other antibiotics. There's a 1975 publication in JID. it talks about two patients that had chronic UTI that got tetracycline for a year and a half. And then it also mentions a pilot clinical trial where eight of 12 patients with UTI were given a tetracycline, even if the tetracycline was resistant. So you can see like the robust quality of data we're talking about here as we walk through these. And then there were some other sparse clinical data, particularly when you look at resistant gram negative. So there's a 2012 case series by Alexander and colleagues that was three patients with. Carbapetamase producing club pneumo that had success with the tetracycline, and we could go on about these kind of 1 to 10 patient series, but all that to circle back and say, if you have no other good option for your patient, it's in vitro active, and you really want to try to keep them on oral and avoid I. V. Sure, give doxycycline for cystitis a try and see how it goes and maybe your patient will do fine. Your patient may also do fine with cystitis if they drink a lot of water, right? Who knows? but all in all, it's not our go to drug. Just looking at the available data that we have point to tetracyclines maybe aren't it for UTIs. Um, Julie, anything to add there?

Julie-Ann: 28:19

I agree with everything you said. and thank you for outlining your rationale so well. I think overall, if you look at the guidance panels coming down on the side of, there are other agents in the class that have fallen flat on their face, to treat what should be the easiest thing, in terms of urinary tract infection. and then the data for clinical outcomes for doxy in particular, which we agree with you, pharmacology wise, It's the most likely to have a good outcome because it does have better urinary penetration, at about 30 to 60 percent compared to the other tetracyclines. But when we went back and looked at the outcomes data, they are very scant. and so when you, when. This was, you know, our opinion as a guidance panel. But when you look at the totality of the data, transition to oral doxy is not something that we would do or recommend on a regular basis. That being said, I personally have done it. I have transitioned patients with ESVLE, to oral doxycycline and tried it. I think that comes down to, who's the patient in front of you. What are their goals of care? What is it going to mean to give them IV therapy or a PICC line or to try an aminoglycide or to try other things? so I think, it was well summarized as well on breakpoints. So we just had our hundredth episode this past summer of 2024, and we wanted to highlight tetracyclines. And at first people were like, tetracyclines, why is that like your quintessential topic? And it was because they, as a group, we all feel that there's too little attention paid to tetracyclines and just looking at the scant data that she just summarized for clinical outcomes. And then really the paucity of data for PKPD for a wide variety of organisms, not least of which ESBLE, like we're talking about here. they came around in a time. And science has progressed since then, but unfortunately, DOCSI really, in my opinion, hasn't been optimized. So I don't feel comfortable saying, Oh yeah, on a routine basis, if you put somebody on DOCSI, a hundred PO twice a day, you're going to have the effectiveness and safety outcomes that you would expect of the comparators that we're talking about in the guidance document.

Jame: 30:19

Why don't we just drop down to the ESBLR beta latinum options. So, there are a couple of other, options which aren't mentioned, and I, sort of think I know the reason, but, there's a couple of beta lactam options, which are useful in ESBL, producing organisms. I'm thinking particularly of T macillin and PIV macillinam, which you've only recently got access to in the U. S. Are there, any plans to include them in future updates? And is their non availability in the U. S. the reason that they weren't included as options in the guidance?

Julie-Ann: 30:52

Why, Jane, we are discussing those. I'm so glad that you brought those up. That's actually something that, Erin and myself and the rest of the ID pharmacists are, Really reading into and going back and learning about these agents again. So, yes, there have already been lively discussions about, in particular, PIV, Miscellanum, as the newest agent for us within the United States, having just been FDA approved in April of, 2024. so it's not yet, purchasable on the U. S. market. So we're still waiting for drug development. to finish and make it to the market, but in preparation of that, the guidance panel is discussing, the data that led to the FDA approval, but I don't want to take air and sunshine because I know she's got a lot to talk about this particular drug.

Erin: 31:33

So yeah, we're, you're eagerly awaiting a commercial partner in the United States. So the story is not available despite being approved almost a year ago, which is a bummer because I think.

Jame: 31:41

Oh, can you still not get it?

Erin: 31:42

No.

Julie-Ann: 31:42

cannot get it yet. Nope.

Erin: 31:44

not but you know, once the FDA approves the drug, then the company has to bring it to market. And often, especially smaller companies, they need to find a commercial partner. And I think they've been trying to find someone to market this drug. And I, it's a need, we need oral ESBL options. And so it? because we've talked about, doxycycline, we just talked about fluoroquinolones are fraught with issues, nitrofrantoin, not everyone can take it. So, This is a need. I think this is maybe one of the greatest needs is an oral ESBL drug to keep people in the community and out of the hospital. So we'll see, but we don't have it yet. but I think there's a lot going on in the outpatient UTI space for ESBL. So you have tebupenem, you have jepetitis, and you have pibmacillin, you have sulopenem, others, Some of those are being studied only for CUTI. Some of those are being studied for UUTI. There's some nuance there with their regulatory pathways and approvals, but in general, we're looking for oral options for ESBLs. And that's great. And honestly, I think the first one that's available is going to take this market. They all have pros and cons, they all have ups and downs. They have different dosing schemes, different considerations for different patients, but. If we have one available, I think this is going to be used and I think it's a need. And so people need to understand the caveats with each of these drugs, respect the stewardship principles. And I think something really important is to respect again, the PK PD, because people are going to try to use these off label. They're going to try to use them a step down for bacteremia. They're going to use them for pilo. They're going to use them for IAI. They're going to use, I am, yeah, sure. Yes, absolutely. We're going to try. to get keep patients on oral and come up with creative dosing regimens that are safe and effective People really need to spend the time and the data understand the PK PD here and see what they can and cannot do. I think the European experience with this drug is very intriguing. That whole lack of resistance development thing seems like a little too good to be true. But I'd love to explore that as it hopefully gets real world use across the United States. The dosing's all over the map, right? When you look at the studies for this drug, it's interesting, but the FDA approved dose is 185 three times a day for three to seven days. There's limited data that suggests you could double that dose and have it be safe. but who knows? But, Yeah.

Jame: 33:49

Here, in the uK, we're using a 400mg load, and then 200mg three times a day, for three or seven days,

Erin: 33:56

that's the same dose. yeah, Sorry. Yeah, it's the active component.

Jame: 33:59

Oh, right. Okay. Fine. But yeah, the Scandinavians Have a lot more experience of using this particularly for pylonephritis, which I've not really done. I've not really heard of it being done in the UK, but they have published papers on real world usage, not trials, but retrospective studies comparing it to other agents. Like I think third generation Kevlar sporens and no. apparent difference in reasonably hard outcomes. So it will be interesting to see if it comes onto the u. S. market if you have, a differing

Erin: 34:31

It's a space I'm super interested in, and I will say shameless plugs. So SIDP and Esquimalt are hosting a PK PD conference in June of this year. Everyone should come. And we're going to have a whole session on this drug, actually. The PK PD. Yeah. Thomas Tangen from Sweden's going to give it. So he, they have a wealth of experience. He's an expert in this space. So yeah, so definitely try to come. It's going to be great. Registration's open June 2nd and 3rd 2025 not to like totally plug all of our stuff here, we are also offering up to 14 scholarships. So 2, 000 for international folks, 1, 000 for domestic to support travel because we try to pour everything we make at SIDP back into research and, travel support. So.

Julie-Ann: 35:10

In addition to PIV Macillinum, uh, the guidance panel is also evaluating the Oral Penum Antibiotic, Celopenum Etzadroxyl, which is being combined with Probenicid, which was approved, October 25th of 2024 for uncomplicated urinary tract infections in adult women with limited or no alternative oral antibiotic therapy options. So That was a mouthful just to get through the indication, but you can see what qualifications that included. The FDA put around that particular label for that newest agent. So to Erin's point, we really need, ESBLE agents to treat UTIs, particularly that are oral. this could potentially fit the bill as well, but the one caveat, about this particular agent that's important to understand is that it's development has been a bit fraught. So it was, originally developed in the mid 1980s, and culminated in an NDA being submitted in 2020. But, the FDA stated that there was a lack of supportive efficacy data for the indications of complicated urinary tract infections. and complicated intra abdominal infections. and this included trials that were starting with celopenam IV, then being switched to the oral form, which is that celopenam etzadroxyl plus probenecid. That's the oral component. and specifically the study, the FDA also found some issues with the uncomplicated urinary tract infection phase three trial, of that oral celopenum, exodroxyl and probenicin combination. So all this to say, there's a lot of data that the guidance panel and others are currently sifting through for this, new oral penum. Specifically for study 301 on uncomplicated UTIs, there was a signal that the celopenum ethodroxyl probenicid was inferior to the comparator in that trial, which was ciprofloxacin. Specifically in the subgroup of patients that that had Ciprofloxacin susceptible isolates, So the overall response at test of cure with the coelopenem oral was only about 67 percent compared to about 79 percent in the Cipro, susceptible arm that was treated with Cipro. So, then the oral seal upon him was superior to superfloxacin in the super resistant population. So the FDA kind of looked at that and went, okay, I think we, we need to redo this study and UTI and pick a different comparator, which they did. So the company to their credit went back and did a second phase three UTI study, which is study three 10. That is ultimately what's helping to support, the FDA approval for UTI.

Jame: 37:31

And what's the comparator there?

Julie-Ann: 37:33

right. So that. Second phase three trial for UUTI was comparing the same investigational agent Stilopenem etzadroxyl probenicid to oral amoxicillin clavulani. Overall, it found that this new drug was not inferior to oral amoxiclav with, rates of clinical outcomes, 61 percent versus, about 56%. And the oral C. lupenum was superior to amoxicillin clavulonate in the amoxiclav susceptible subgroups. So kind of the opposite of what they found with the first phase three UUTI, trial within ciprofloxacin. So that gave the FDA a little bit more comfort, that oral C. lupenum could really stack up when compared to another active oral agent. Numbers in the amoxiclav resistance subgroup were really small in that trial, so it was too small to draw definitive conclusions. But of course, all of us are going to parse that apart and, see what we think about that outcome. overall, both of these studies only had about 10 to 13% of pathogens that qualified as ESBL producing enterobacterialis, which I think is an important caveat to understand. so more data, regardless of where this new oral pendant falls, in practice, more data will be needed in that population of ESBLE UUTI over time. Okay. So it's. I'll wrap this up just to say that it's another oral agent potentially, coming down the pike for E. S. B. L. E. U. T. I. But it particularly has pretty significant restrictions around indications. And you probably will see. Similar language to that in the guidance document if and when we talk about it. And this is not an agent that I would personally feel very comfortable with trying to go off label, which is different from the conversation that we had about PIV miscellaneum that does have a lot of, efficacy and safety data, particularly internationally,

Erin: 39:28

which is so funny. Talk about urinary concentrations. It's a urinary drug that they marketed with prevenison

Julie-Ann: 39:33

all right, so another day you can have us back on and we'll talk about probenicid.

Callum: 39:37

we would love

Julie-Ann: 39:37

we will not be talking about temosilin because we don't have access to it in the US.

Callum: 39:42

Okay.

Jame: 39:42

Let's finish the ESBL section by talking about question 1. 4. Which is the question about is there a role for PIPTAS in the treatment of infections caused by ESBLE? And this question has obviously been pretty heavily influenced by the Merino study, which was a study comparing carbapenems with PIPTAS for the treatment of ESBL infections. And it was hoped by the authors who said it themselves on a recent podcast episode, communicable, I think, where they were talking about this, they were hoping that PIPTAS would prove non inferior. To Meropenem, that's piptaz four times a day versus Meropenem, three grams a day. And they did not prove that. So there was, 30 day mortality was 12.3% of the Piptaz group versus 3.7% of the Meropenem group. Statistically significant, that was 30 day mortality and so was not non-inferior. And this was reported pretty heavily at the time. And clearly it's influenced the use of PIPTAS in ESBL infections. I'm going to make an argument to you guys and then you guys can tear it apart. and I'll be interested to hear your opinion about it. the 30 day mortality in those with PIPTAS sensitive isolates was 11 percent versus 4 percent of the Merpinum, group, which was not significantly different. But if you go and look at the, actual primary outcome mortality data that was in supplemental, table six, of the Merino trial. 30 people died in the group overall, 23 in PIPTAS and 7 in Meropenem, which is a big numerical difference. But all of them, the cause of death is listed as malignancy, other comorbidities, new infection, or a combination of all of those. It doesn't appear that any of them died of the initial infection. So, I put it to you that this may just be a mistake and that these deaths were numerically higher in the PIPTAS group but that has nothing to do with actual death related infection.

Erin: 41:54

the Merino trial will forever hold a special place in my heart because I accidentally tweeted the results before they presented them because, yeah, it's like, I, like, David and Patrick have since forgiven me, but that, so Ekman released the late Breaker Abstracts in the app that year, and I was just on my phone on Twitter and I saw it and I was like, no way. And I tweeted it and they, that was a mistake. they, weren't supposed to have done that. And so I like tweeted that before the late breaker session. And then when they got up to present it, they're like, some chick already tweeted this and that was me. So, and it was like. Oh man, but no, now we're all very good friends. I love them dearly. They're fantastic. But, anywho, so if you talk to David Patterson, who is just a gem of a human, used to be at Pitt, and Patrick, who presented these data and the rest of the team, to your point of they, none of them died of this, the index infection. So this is trash. I guess they're. Two things. One, that's every study when you look at 30, 90 day mortality. And then two, they said perhaps these patients were so frail that their sepsis episode tipped them over the edge. And if you get superior antibiotic therapy, you're more likely to live. And that's the story they've told when they present these time. And again, I don't know if I agree or disagree with that. I think it's just food for thought. That's the author's kind of justification for that to the point of. They died more if PIP taser was resistant. I'd actually challenge that because if for two things one it was they when they were randomized, they thought it was susceptible. It was only then when these isolates were then sent to reference lab and went through additional testing that you then see these errors. And this is real life. Like this is the ins and outs of antibiotic susceptibility testing. I mean, PIP Tezo in particular, if you have a Vitek system doing your AST that's fraught with errors, it has a really tough time with that antibiotic so that what clinicians got results and treated patients in real time, which is always what's going to happen. And so taking those Oh, but actually it was resistant on the backend. Well, that's the case every single day. Right? So we can't really, that's tough to make that call. And then last but not least, if you look at. They actually did an analysis of an association between M. I. C. beta lactamase genes and mortality with these PIP TASO patients. This was published 2020, Henderson and colleagues. And a couple things from that, I love this paper and I'm so glad They did it. This is what everyone said, They're like, Oh, the MIC, if it's less than one, it's fine. First of all, no AST system reports BipTASL less than one. So you will never know that. Okay. And two, the best you're getting is less than or equal to two. And two, when you look at figure three of that paper, it's actually a very distinct U curve. So patients with MICs of four and eight didn't die for some reason. Patients with MICs greater than eight died and patients with MICs of one and two died. At pretty much the same rate. And so that's a really important nuance. I think because when you dice it to less than or equal to a and greater than yes, there's this big difference. But when you look at the rates by M. I. C. It's actually a very distinct you. And so there's more to the story. M. I. And then last, but certainly not least, Maggie Minogue. Pharmacotherapy 2021, a must read paper. In my opinion, it's the role of tasobactam based combinations for the management of ESBL infections. It's an SIDP insights paper, and it really gets into tasobactam exposures and it gets into enzyme type. And so what we learned in Merino is that OXA1 happens to be a very important enzyme that we don't routinely test for in the lab, but it actually may significantly impact utility of tasobactam. And then the second thing is like with. With PIP Tazo, if you're giving 4. 5q6, you're giving 2 grams of Tazo a day. When we look at Ceftolazane Tazobactam, if you're giving 3q8, you're giving 3 grams a day. And that extra, because Ceftolazane Tazobactam actually looks to be a heck of an ESVL drug, perhaps. And it, that extra gram of Tazobactam probably matters, and we probably could give a ton more beta lactamase inhibitor, which might solve some of these problems. And so, now I pass it over to my dear friend Julie, who's going to talk more about beta lactamase inhibitor PKPD,

Julie-Ann: 45:40

I don't think I could say much more than that was already very artfully summarized by Erin here. I think marina will continue to be a seminal trial that folks will do journal clubs on probably for 20 years and parse, the potential imbalances and randomization and the potential attributable mortality. As, Jamie, you so astutely pointed out, the best stuff is always in the supplement, right? but reality of it stands. I personally, like, I'll just tell you straight up. If I am sick with an E. S. B. L. E. serious infection that's landed me in the hospital. even if it says it's susceptible, do me a solid and give me a carbapenem because that's what I would want for me and for my loved ones. And I stand by that. I've practiced that way for 15 years. I, again, we don't, yeah. Practice on anecdotes, but, I think when you have a randomized controlled trial that has such a significant, difference in the primary outcome of, mortality is something that we're really interested in, and then it does corroborate what you've seen in clinical practice. You can see a through line there. Further still, when you look at the PK PD story, The through line further makes sense because piperacillin tazobactam probably has just enough tazobactam to do a little something in the test tube, but it's plausible that in a not small portion of the human population, you infuse tazobactam, especially if you're giving it as an intermittent infusion, that tazo has a wickedly like small half life and it just goes, those curves just go whoop, boop, whoop, boop. they just go up and they go down they go up and they go down as I say, piperacillin, he's got no pants for the second half of the dosing interval, particularly if you're in a situation where you're doing intermittent infusion, which some centers will still do.

Erin: 47:18

Well, Marino was intermittent. That's

Julie-Ann: 47:19

and it's important too, when you start talking about, some folks argue very, fervently over whether or not they think piperacil and tezobactam will work. and they do bring up their anecdotal experience. and there's two people talking on either side that are using different infusion strategies, which for tezobactam is critical, right? And

Jame: 47:38

in the ICU is not PIPTAS on the ward.

Julie-Ann: 47:41

Yeah. So just to summarize, I think for those that are interested, I would take a look at that at that publication by Maggie Minogue And colleagues from pharmacotherapy in 2021. It was a question that SADP had and so they, they turfed it to really talented members to go look into the question and I think they did an amazing job of writing out the story so much so that of course break points wanted to do a whole episode on it. So we do have an episode. on beta lactamase inhibitor, PKPD. We won't go into all the details right now because we don't have time, but we talked to the original members that did a lot of that publication that we're actually trying to develop ceftolazate and tezobactam to bring to market. So it's a fascinating story. We talked to Paul Ambrose, we talked to Mike Dudley, really trying to understand how much BLI do you need and for what proportion of time in order to provide a durable effect of both effectiveness and safety. So at the end of the day, I'll just. summarize it to say the guidance panels rationale section on this particular controversy will continue to evolve. We're not just responding to the Marino publication and the post hoc analyses, et cetera, that were talked about, but we're also responding to the real questions that we get from clinicians. Hey, my patient has an ESVLE, pylonephritis, bacteremia, and they got started on piperacillin tazobactam because we didn't know that was our best guess at the time. Now they're doing better. What do we do? and so in that rationale section that was updated with the 2024 version, we try to outline this is how we would approach it. But realistically speaking, if there's anything that's going in the dangerous direction for that particular patient, if you have a retained source of infection, if they're immune compromised. any, they're not responding clinically by 48 to 72 hours the way that you would expect. We would make the recommendation to switch to a carbapenem as a definitive agent. And we would still, we still hold to that even though I think honestly the guidance panel gets a lot of flack for that.

Erin: 49:33

I'll just chime in and support and a mentor told me this once and it's resonated deeply. And this is a good steward. if you're not using carbapenems for ESBL bacteremia, what are you saving them for?

Jame: 49:44

CRE, are you? Yeah,

Erin: 49:45

Well, yeah, we'll get here later, but they're trash for pseudomonas, like porin mutations develop very quickly in any. If you see really sick patients in an ICU, I bet you Mirapenem is your worst anti pseudomonal agent. Okay. If you? use it. And then maybe for AMC, which we're going to talk about next, and then you can't use it for CRE. So like, what are you saving them for use them for ESVL bacteremia. That is their role in therapy.

Julie-Ann: 50:06

but I do acknowledge, I'm always happy to have this conversation with folks because at the end of the day, I feel like it comes from a good place of people trying to be stewards and trying to maintain carbapenem sparing options. And so again, I'm happy to have this conversation, but at the end of the day for us, the guidance panel, we're still going to recommend if it's a serious infection and you know it's an ESVLE, you need to switch to the definitive agent that's stable.

Jame: 50:30

Well, let's talk about AMPC now. So we've got, recommendations in IDSA for AMPC and, I'll briefly, summarize these. So for unknown or low risk AMPC organisms, then you can treat as per your susceptibility. results that you get. So if it says it's Keftraxone S, then you can use that. For moderate to high risk organisms, or it's now just moderate risk organisms, isn't it? So that's your Enterobacter cloacae, Citrobacter freundii, Klebsiella aerogenes. There's a recommendation to use agents such as, Imipenem, Ertopenem, Meropenem, or Kefapine. or your non beta lactam options, and there is a range here, in a table, which we'll leave in the prep notes, but in the interest of time we won't, talk about in particular. So, a couple of questions here, Callum?

Callum: 51:18

So yeah, one thing that we've talked about before in the pod and is really useful is heck yes. So half the, did you just say this? You didn't say it this way. Half the LVI enter, enter batcher, uh, Chloe K complex, such a batch of fruity and a erogenous and something that always surprises people when I tell'em this is the inclusion of Hania alvi and yesinia intera because they're not really things that we're often thinking about from C expression. So, I guess why are they in that, mnemonic and do we need to worry about them that much?

Erin: 51:50

Well, I think I can tell you the insider scoop here is Yersinia was. Sam Aiken was legitimately just trying to make this a fun acronym and God bless him. we love him. But he was like, Oh, if we had Yersinia, we can say yes on the end. And Yersinia definitely has some inducible AMC. So we're like, let's go for it. But I mean, good. Sometimes things aren't evidence based, right? So, but that's, it is, that that's where it's an amazing acronym. I updated our entire system app using it. It's great.

Jame: 52:16

Mean, it's more evidence based than Escapum, which has loads of stuff that's just not, isn't even a thing anymore.

Erin: 52:21

mixed around positives and negatives and like, why was that? No one knew if the P was like pseudo or proteus Or, yeah. yes, I was. That was chaotic. And then it was like, is it space? Is it spice? Is it, I don't even know. So it's great. It's cleaner, but truly the Yersinia was, we thought, heck was. Polarizing and heck yes, sounds really excitable. So that's why Yersinia was added. But there is data behind This the landmark paper in this space was Coleman and colleagues in JAC 2018. This was the first paper, to look at species specific mutation rates for amp C de repression. and in that paper, they found and confirmed that Enterobacter cloacae, formerly Enterobacter r. i. p. and Citrobacter frondii and Hafnia have higher rates of ampcd repression and expression than providentia and serratia, which then are significantly more than morganella. So morganella was like the weak sauce at The end. And so hafnia in this paper Is categorized with enterobacter. So from at least that laboratory standpoint, it earned that spot in the heck. There are way less clinical data because like when's the last time you treated a hafnia infection? I mean, it's not something that people see every day. And So, it's not something that has a lot of clinical data but that is where that came from and I'm happy to share with you guys if you want to post we've actually gone through and tried to improve our Antibiotic cascading and reporting as I think, most pharmacists have tried to lead this So we now bucket our organisms as the inducible ampsies, which are the heck. Yes bugs non inducible AMPSIs, which we put Morganella, Providentia, and Serratia in that bucket, and then the non inducible AMPSI that are a somewhat different category, which is pinnarii, because those have some unique enzymes on their own that change how you look at ceftriaxone and ceftazidime for these bugs, and So we've bucketed our, ours in those three categories, and We suppress certain antibiotics accordingly, Yeah.

Jame: 54:20

Okay. and quick question. The IDSA guidance sort of mentions the potency of amp C induction as a feature of some of these drugs. So as an example, imipenem is a potent amp C inducer, whereas kefapim is a weak amp C erypenem are unknown sort of potential. Do you pay any attention to that when you're selecting the best drug for your patient?

Julie-Ann: 54:45

Realistically, that induction potential is really not the first thing that we're going to think about. again, just thinking the United States and our practice, imipenem is mostly going to be relegated to indications for treatment of non tuberculous mycobacteria or nocardia. and our carbapenem of choice on most hospital formularies in the U. S. is going to be. Maripenem, at least as an anti pseudomonal carbapenem. and so I think that's. Part of, the discussion on why you don't see more discussion about Imipenem and its induction role is because in terms of U. S. market share, it's relatively minimal.

Jame: 55:20

Okay, yeah, no, it's not very commonly used over here either, I think, Cal, would you agree? We do have access to it, it's just that we, the number of use cases where you wouldn't want to use Meropenem are very scanty.

Callum: 55:32

Yeah, I've got this table in front of me that you've written there in, basically, the first column is the organism and the grouping. The second one is

Erin: 55:42

the second column is the drugs we suppress. So for our inducible amp ce, we're gonna suppress ampicillin, cefazolin, cefuroxime amp, amox, cla, sulbactam, atrium, cef tad, And ceftriaxone. So we, do suppress those agents. We report pIP Tazo for now, but I think that's an area of debate to the point of, do you worry about molecules that induce AMP C. Tazobactam can induce AMP C. So is it a strong enough inhibitor with that induction potential to keep up with the enzyme? Who knows the observational data is a mess. I would want cefepime If it were my mom, but we didn't feel there was enough to go on suppressing Peptozo for start until these bugs. But I know some sites that do, we do suppress them even for UTI, even for urine sources, because a couple of things, a lot of times those urine sources are going to be surrogate for invasive infections like PILO or even bacteremia. And then patients who tend to have these bugs tend to be a little more complex than your run of the mill outpatient E. coli cystitis. So we do suppress them. but I guess if there was a way to tease out, if your system was smart enough to say this is an outpatient culture, then, and it's urine cystitis only, then perhaps you could maybe get away with a MoxClav. But I think that's a whole nother conversation.

Jame: 56:57

Yeah,

Julie-Ann: 56:57

Yeah, and just clarifying question. 2. 5, the guidance document does go through the role of piperacillin tazobactam for the treatment of these enterobacterialis at moderate risk for, clinically significant AMSI production. And so again, that summary, the suggested approach is piperacillin tazobactam is not suggested for treatment of invasive infections caused by enterobacterialis at moderate risk of clinically significant, inducible AMSI production. So that's, the enterobacter cloacae and the like that we were talking about, but they do talk about again. The greatest stuff is in the rationale, I think, because that's where, that's clinical practice is that nuance. And it does talk about PIPTASO may be reasonable, and we give some examples of situations where if you're treating mild infections, such as an uncomplicated cystitis, and so on, you can look into it. But I think Face up, we're not going to recommend it as a guidance panel for, these moderate, uh, production AMSI organisms on the

Jame: 57:48

Yeah. Yeah, fine,

Callum: 57:50

So, so just to wrap up there with the amp c stuff. So in the notes, we've got this table that, Super helpful.

Julie-Ann: 57:57

It's, funny that you say that because the guidance panel keeps trying to redo an AMSI table. It's been floating around for a couple of years and we tried again for 2024. So this is giving me ammunition to go back and try again for 2025.

Callum: 58:09

what we need. We need something like this because it's a headache and looking at this, for example, you're saying that in inducible high risk amp C organisms, you suppress astreonam. I don't think we do that in my lab. I'm pretty sure we just release astreonam

Julie-Ann: 58:22

The problem is that the data are still evolving, particularly for the, bacteria that have fewer, volume of infections and incidents of infections like hafnia, right? So I will tell you, we went, I went back and looked at the hafnia that was at Dartmouth and I was trying to see if I can glean any evidence from that. I didn't, cause otherwise you would have seen us publish on it. And I know Pranita has done that, Robert's done that as well. So folks are going to continue to try to collate data, particularly, by species to see if we can get some. Meaningful clarity here. and there's also, there's still data that are coming out even after, we closed, the 2024 guidance that was published. we cut our literature search at the end of December of 2023. and then, right at the beginning of 2024, there was more data from Mayard and colleagues that came out. So we're probably going to be talking about that in the next version of the guidance as well, because there's some signals of there with mortality, particularly with Morganella and serration folks wanted to it. Wanted to know what the guidance panel feels about those data. so this can, this conversation will continue, in part because they're tricky, right? And you're talking about at any given moment in time, what is the AMP C production level at that moment? And what's it going to be in the future? And a lot of that has to do with who is the host? What is the, starting inoculum over time? Can you kill? the bugs fast enough in that particular individual for that particular syndrome or syndromes in order to get to, homeostasis again, before you have something that turns around and emerges resistant. And that is a very difficult

Erin: 59:48

yeah. The other, there's a practicality piece to this too. So we do report PIPTASO, which the guidance says don't use it for invasive infections, but we've also found too, I mean, we have a lot of polymicrobial situations. And so say you have like Enterobacter and E. faecalis osteo. Are you really going to give that patient cefepime and dapto or cefepime And vanco for six weeks? Or can you just give them continuous peptazo at home and monitor them and hope for the best? And so, sometimes there is just like a practicality to this too.

Jame: 1:00:16

I mean, it's worth a shot at least if, like you can give it a go and if it fails, then you can back up to Geff and Bindat

Erin: 1:00:22

right. And then also what's the exposure you needed on week two, right? If they got a week of cefepime up front, right. and they go home on peptazo

Julie-Ann: 1:00:30

yep.

Erin: 1:00:31

dead bugs don't mutate. So like you know what? It's there's so much we could talk about this all day.

Julie-Ann: 1:00:39

Well, the whole component of time is something that's understudied. So we'll just leave it at that. Right. but we have these discussions on the guidance panel as well. So it's a little bit of a balance of, the focus of the guidance is The front end of therapy when you know the organism that you're dealing with. So it is definitive therapy, but it's at the front end, which I think is important to caveat, which is different from what you might be transitioning someone to,

Callum: 1:01:01

you get the lab data back.

Jame: 1:01:02

totally. Totally.

Callum: 1:01:03

So we've gone into a lot of detail there about, ESBL and AMPC. So now we really come to the crux of the matter, the carbapenem resistant enterbacterioles. And so maybe Jamie, you could summarize what the guidance says, and then we can ask some really complex, difficult questions.

Jame: 1:01:21

Well, in the interest of time, maybe I'll focus on the use of the new beta lactam and beta lactamase inhibitors in particular for CRE, because I think that's where the most sort of interesting discussion might be

Erin: 1:01:33

them.

Jame: 1:01:33

to be

Erin: 1:01:34

Next question.

Jame: 1:01:35

So, we've got, yeah, so we've got, just as a reminder for the loyal listeners, we've got Meropenem Vaporbatum, Keftazidime Avobatum, Impenem Silostatum Withrelobatum, Kefiderico the Trojan Horse, Aztrinam plus Keftazidime Avobatum, Aztrinam with other new beta lactamase, beta lactamase inhibitors, and then your non beta lactam options, Tiggi and Arava, Polymyxins and Carbapenems with an other agent, those last two you specifically recommend against using for any CPEs. Thank God you included that in the guidance. I'm pointing to that regularly, as are you Callum, when we're trying to dissuade colleagues from using Coliston, with everything with a pulse and for confirmed CPE, you are splitting your recommendations by mutation. And so for KPCs, your recommendations in sort of order of preference would be Merovab, Keftazavi, and Imirel. And then for Oxford 48, it would be Keftazavi or Kefderacol. And then for your metallobatal atomases, it's Aztreonam plus Keftazavi or Kefderacol. And from reading that out, it should be obvious that this guidance has come out before ASTRAE and AMAVABATAM got its license and testing susceptibility got released by UCAS. And I think CLSI had a testing protocol first as well. But all of that has happened sort of since this guidance was released. Hands down, this is my favourite bit of the guidance because I think it makes, when you go into the details about this, I think it just makes so much sense about it. So, but maybe we should just talk about what why the preference for different agents. Why not just recommend Keftaz Avi for everything, for example.

Julie-Ann: 1:03:20

Well, that is a very real question, especially for the readers of this document that are trying To make formulary decisions is there one BLBLI, that we can bring on, that's going to fit the, bill for the majority. And I think, right now, particularly in the United States, SEF TASAVI is a workhorse in a lot of cases. but I think the overall theme and message of this section of the, guidance is you really need to understand not only the, organism that you're dealing with to the species level, but you also need to understand the underlying mechanism of resistance. It is no longer. enough to just state, overall, this is an anti psychomotor agent. It'll cover this will cover CRE, it'll cover this. You really need to start getting specific, which is why, the guidance panel works at reorganizing, those questions in a flow that makes sense, every year. And we. advocate for clinical microbiology labs to make the use case that they actually need to have these novel technologies. that, would bring in and identify the underlying mechanism of resistance. So I think that's really important. Yeah, and I feel like we go through the document and walk through when we're going to use certain ones. So for, Oxford, it's really important to understand, like, stuff has heavy. That's the one that if you just look in vitro and Look at the underlying mechanisms. That's the one that's going to make the most sense. conversely, if you look at some of these others, you can have some issues with potentially, if you're looking at KPC, you can have issues in the data. There's small numbers guys. So you really have to read the rationale. But when we're summarizing the evidence base that currently exists, we are seeing some signals of pretty consistent emergence of resistance rates of 20, 30 percent with Ceptazidine, maybe Bactam. There's a pharmacologic underpinning that it's plausible that Bactam might have a lower rate of emergence of resistance. And so these are subtle differences that we walk through within the rationale document. It's not to say that You can't use ceftazidime avibactam, it's included in there as an option. But if you read through the rationale, which again is going to be my drum beat for the entire podcast, you'll understand for us when we're faced with, a KPC klebsiella pneumoniae, it'll be pretty clear that we have a slight edge to, maravibor for that type of patient first.

Jame: 1:05:28

And this is because of Vabor Bactam's being a bit better at inhibition of KBC than the other beta lactamase inhibitor second generation agents that we've got here. Is that right?

Julie-Ann: 1:05:39

Yeah, it's based on being, one of the boronic acid BLIs.

Erin: 1:05:42

Vapor Bactam. Yeah, Vapor Bactam was developed specifically to bind to KPC And you're giving six grams of Vapor Bactam a day. So to our point earlier about high doses of BLIs, I mean, what a beautiful drug Mira Vapor was to perfectly matched Mirapenem and Vapor Bactam exposures and you're giving such high concentrations. That's why we don't see resistance develop. I, will say one thing, cause I think it's a really cool point. I don't know if. A lot of people have seen this that the, so any rail is positioned as a KPC drug, which is probably the one thing I probably disagree but yeah, I think any rail is tough because first of all, like you have other KPC drugs and second. There are some case reports now coming out of Italy in particular, or places that may not have had access to, MiroVapor, that have used it for sure. There's clinical data now we didn't have a couple of years ago, but I also think there's really compelling data. one series was published in IJAA in October of 2023. And then there was a followup series in AAC in 2024 that pretty compellingly shows that MIREL exposures with KPC breed KPC mutants. And so that resistance is developing to MIREL and treatment. At a faster rate than maybe some of the other drugs. And so I think that's something to keep an eye on for sure.

Julie-Ann: 1:06:52

usually the agent that has the least clinical data is something that's going to be lower in the list when you're looking at just, seeing a string of preferred options. And if you read through the rationale, it'll talk about at the time that we published, we had very little. Data on any row for this particular organism. So that's part of why this is a guidance, and we try to look at these data every year. So I agree with Erin, like some of these data, particularly the ones that have come out most recently, we're all looking at that going, huh,

Callum: 1:07:19

can I ask them the question, that I imagine if anybody's listened to episodes 27, 28 of this podcast, where Jamie and I went for the 2022 guidance, it's probably wondering about now, which is also, I'm wondering is what would, in terms of, CPEs, what's the main changes in the guidance, from 2024. guidance to 2022 because obviously there's a change in how you lay out the guidance and in the rationale, but it seems broadly similar. Would that be fair to say?

Julie-Ann: 1:07:50

I think that would be fair to say, I do recall when we were talking about it, one of the most alarming things was some of the more recent epidemiologic data that we're looking at within the United States. We saw a significant increase, particularly around 2019, data that NDM was increasing, along with other metallo beta lactamases, but that is still the most common metallo beta lactamase that predominates. So I think prior to, version four, there was a general consensus that, metallo beta lactamases were still relatively infrequent within the United States, but we got some newer epi data, with that round of literature review that really heightened all of our. Concern at the rate of change, the rate of increase in metallo beta lactamases, particularly NDMs within the United States. So I think most of it was just going through that entire series section and cleaning it up and making sure it was airtight in terms of if this is the underlying mechanism of resistance, being laser focused on what we would recommend based on the data that were available to date.

Jame: 1:08:49

I think as a reader, I think the big difference from a couple of years ago is that I seem to recall, And maybe I'm misremembering that Kefiderikol was being put up there as like a bulletproof. unkillable, no resistance possible, drug that was being, you know, recommended for metallobatelatomies, certainly in the ESME guidance, And the impression that I got subjectively is that? everybody thought we've licked it, we've invented the antibiotic that can't have resistance mechanisms against it, And then what happens, NDM 5 comes along and just starts. murdering Kef Derakul as if it was just like any other Kef Lesporan. And I know that's been deprioritized a little. Like it's not first line for any of these. It's not first line for MBL or OXA or KPC. It's second line behind other more resistance, resistant choices, if you know what I mean. Do you know what I mean?

Julie-Ann: 1:09:51

yeah, I think you're picking up on that. It's funny. I like to say that's a federal call has no pants. Um, he he's just walking around without a beta lactamase inhibitor, which always seems a little bit unusual to me, to be fair, those that developed the drug, which is. A remarkable compound. I think we can all agree in, in the lab, it looks wicked amazing. and it was, and is still incredibly exciting as the backbone beta lactam, for these resistant gram negatives. but I'm not altogether sure that. Sider for component is sufficient to overcome the bevy of mechanisms of resistance that these gram negatives can throw at it. Particularly when we start talking about pseudomonas and stenotrophomonas and Acinetobacter and so on. So, I think I, this is my personal bias I've. Always been hopeful that they would, pair sophitricol with a beta lactamase inhibitor, which is going to take care of some mechanisms of resistance, but not all. And so, shinogi is actually, in fact, working with QPEX to partner sophitricol with, ziruborbactam, which is a wickedly, broad spectrum beta lactamase inhibitor as well. So, hopefully, we'll get to see, Some data in a couple of years time, where we're federal call has some pants. But I think it's being specifically investigated to help maintain that robustness and counteract some of those, Ndms that we're seeing come out.

Erin: 1:11:19

I think an important point here too, though, is like at one, absolutely. Yes. Can't wait to see suffiteracol paired with a BLI. And that BLI is beautiful. but two bugs are just smarter than us. And it keeps us moving and honest. Like we have never really thought about target mutations as a main mechanism of resistance in enterobacterialis, right? and especially not for gram negatives, it's all been enzymatic resistance. And then all of a sudden, what's the main mechanism of resistance to Astrina, maybe Bactam pbp3 mutations. And it's like, since when does, since when do gram negatives do that And so that's just not, we design, look at everything developed for gram negative resistance outside of sophiteracol or non beta lactams. it's been Novel BLIs, it's been enzymes. And now all of a sudden the bugs are mutating different ways.

Julie-Ann: 1:12:02

Well, and it comes to a broader, theme that we're probably going to see more and more of, which is maximal PPP, saturation, particularly for these deepest, darkest organisms. So if you do have PP3, PPP3 mutations, does the addition of the ceftazidine that we're putting with ceftazidine, maybe back to menastriatum really matter? I think that's an open question. I don't know the answer to that. I haven't seen definitive data. I mean, the closest thing that comes is like the Lodez and colleagues, hollow fiber model from 2020 that was looking at, Oh, maybe you're getting, some regrowth with a stream. I'd be back time alone, but then when you throw in some of the seftazidim in the models at that last time point, you're still getting bacterial kill. That is a very subtle, in vitro finding. We really need clinical outcomes data to, to compare. But the hypothesis of having, two beta lactams that are really going for PVP3, does that really matter? there's a very active discussion about, what is the maximum beta lactam therapy, the optimal therapy that we can give combined with what is the optimal BLI therapy that we can give.

Callum: 1:13:06

And I'm sure just since we conquer these beetle atomases, something else will come along to ruin the party.

Julie-Ann: 1:13:13

I haven't even mentioned efflux bumps

Jame: 1:13:15

Yeah.

Erin: 1:13:15

Oh, I was going to saY, you know, it's a cool drug, but didn't go after enzymatic resistance. And instead went after PPP binding enhancement and efflux pump avoidance stuff, tolazane, if we want to transition into stuff, told Tezo and pseudo.

Callum: 1:13:27

The issue of this topic is that there's so much nuance and stuff to talk about. And as we've said again and again, go read the guidelines, read them in detail, read them again and read the rationales. But maybe now we can move on to everyone's least favorite bacteria, Pseudomonas aeruginosa, at least my least favorite because it's so damn annoying to treat. and so I guess, James, you maybe want to just very briefly outline the general approach and then we can pick up some more detailed questions.

Jame: 1:13:55

fine. So, let's talk about the general approach to treatment. If you have the option to use a non carbapenem beta lactam, use a non carbapenem beta lactam over a carbapenem. And we've been hinting to that throughout the episode and we can give a short justification in a moment. If carbapenem resistant, give extended fusion. Beta-lactam if it's susceptible to, Paz or ke beam and avoid combination therapy. And for, treatment recommendations for carbapenem resistant pseudomonas. aerosa. For either lower UTI. Upper UTI or systemic infection, you can use Keftolazine, Tazobatam, Keftazidamabobatam, Impinam, Silostatin, Relabatam, and you can use Kefidercol, although for systemic infection that would be second line. And then for upper UTI and lower UTI, you can use Topramicin or Amikacin. And if you absolutely must for a lower UTI, you could use colistin, but it's not recommended for any other, disease state, and fosamicin is absolutely not recommended.

Callum: 1:14:56

So one question, you mentioned not to use a carbapenem for, for Pseudomonas unless you had really no other option because the readiness of it to undergo porin loss, I guess in our heads we often think carbapenem. is an effective therapy in gram negatives in general. So when people are worried about patients, they put them onto meropenem and then we get pseudomonas back and sensitive to meropenem. And even if it's sensitive to PIP TAS, they're still sitting there being like, I'd rather use meropenem because the patient's really unwell. So I guess, so even if they're on a carbapenem, if you then get sensitivity back and you could use like Keftazidime or PIP TAS. The data is suggesting that we should be switching those patients away from a carbapenem. That's really interesting.

Erin: 1:15:43

Pseudomonas is a fascinating bug because it's one of the main ones that really drives home the point of your local epidemiology matters. So the pseudo in your hospital is very different than the pseudo in my hospital, or maybe they're similar, but you have to explore that. So this is one bug where antibiogram really drives your empiric decision making. And then also pseudo is something where patient history of, I mean, this is always important, but if a patient has had a history of pseudo and then what they received. for that pseudo is very important in your subsequent treatment decision because exposing Pseudomonas to any drug is going to breed resistance. Like it's just an organism that becomes resistant. And so with Mirapenem, so you can talk a little bit about the novel drugs and then Julie, please keep me honest, but Mirapenem, the main mechanism of resistance is loss of OPRD, which is porin loss. And so. That elevates the MIC, and then that's usually coupled with upregulated efflux pumps, which is going to increase that mIC further or just cause frank resistance. You could also have carbapenemases in Pseudomonas. That's less common, especially in certain parts of the world, but that's another thing that could cause carbapenem resistance. but that's what's driving it. It's not so much, the Pseudomonas AmpC, which are different than the ampC and Nact, so these are P Amp Cs. but pseudomona, AmpC Miropenem is generally stable to that. We don't really think about enzymatic resistance that much with carbapenems and pseudo, at least with Miropenem. So if meropenem it's porin loss and it's efflux, porin loss comes at a huge fitness cost to the bug. They need to get nutrients, they need to survive. And so mutating that so that the drug can't get in is hard for the bug. And so when you expose pseudomonas to meropenem, you're going to see that porin loss and that elevated mIC after one. not to treatment courses like resistance will develop. It's just a matter of when. And so you can use mirror if it's susceptible. Sure. Use it. That's great. Just know that you're maybe going to get one to two courses out of it. And if you keep exposing that pseudo to mirror, it's going to become resistant pretty quickly.

Julie-Ann: 1:17:34

and max doses at extended infusions, please. Thank you.

Erin: 1:17:38

Yes, that'll help for a little bit, but then, you take that mirror, put them away. You let that pseudo sit and leave. It will be miripenem susceptible in a month. It will revert back to wild type because again, that mutation comes at a fitness cost to the bug. And so it's not that it's a bad drug per se, it's that honestly, with any anti pseudomonal, you get a couple courses and then it's going to become resistant. We see you know, a 20 to 40 percent resistance rate, even amongst novel agents. And so that's just something to keep in mind, but it's a good point when you talk about your novel agents and which aren't so novel anymore. They've been out, Ceftoltazol has been out for like 11 years, we're so old. But when you talk about these agents, we generally say mirapenem vabrabactam is not your go to anti pseudomonal for that reason. So mirapenem, we just talked about the resistance mechanisms. You add a beta lactamase inhibitor, oh, It doesn't do anything, right? It's not going to fix the main problems. And so that BLI isn't helping you favor. Bactam is also a relatively weak amp C inhibitor compared to other beta lactamase inhibitors. And so it's just not adding much. So your parent drug is good enough to your BLI. Maybe we'll get you a dilution or two. It's also the break point for Mirapenem is set at 1q8 the break point for Mirapenem Penum Vapor Bactium is 2q8 of Mirapenum over a 3 hour infusion. So you might get a dilution or two, but it's really, it's just not your best, right? And so, that's why we don't generally position it as an anti pseudomonal, but you may ask, why is Imipenum Rilobactium different? Because that's actually a heck of an anti pseudomonal. And that, it's so cool, these drugs come to market and we learn things we didn't realize before. We talked about, we don't really use Imipenum in practice, but we learned from the advent of Imirel that Imipenum induces and as we talked about, and it's hydrolyzed by amp C and so rela Bactam helps that. And so that the beta lactamase inhibitor here is very helpful because the enzymatic resistance is a bigger player. Imipenem is not effluxed really, but rela Bactam is. So you can see imirel resistance from efflux from the, from exporting rela Bactam. and then porin loss is also a player here, but that amp C component is actually quite meaningful for imipenem. And so the addition. of relabactam helps. But Julie, do you want to talk about ceftoltazo? Because that's the coolest one.

Julie-Ann: 1:19:46

So I'm actually, I think the most interesting thing, so if tolizane happens to be one of the most potent beta lactams we have, against, pseudomonas, but I think some of the most interesting things that have come out lately are comparative effectiveness data, which is actually the cactus trial, which Erin was a part of. So Erin, if it's okay, I actually want you to talk a little bit about what the cactus trial found, which is something that's. that we hope to, that we will include in version five, of the guidance panel that's coming out soon,

Jame: 1:20:14

hmm.

Erin: 1:20:16

Oh, thank you. Sure. I'd say my greatest contribution to the cactus trial is I recorded the video on how to enter data into the red cap. And so I'm like, pretty sure everyone hates me because I did that demo. Anywho. so this I want to give all the flowers and credit in the world to Ryan Shields and Jason Pogue, who are the thought leaders behind this study. They said, Hey, let's get a bunch of like minded people together all across the world, the United States and collect these data and answer these really important questions that are hard to do in a clinical trial. And so what they looked at was looking at Seftoltezo versus Seftaz Avey for patients with drug resistant pseudo and, The punchline here is the adjusted odds ratio of success after treatment with ceftaltazo compared to ceftaz av was 2. 07, which was statistically significant for clinical cure. And then in patients with pneumonia, clinical success was observed in 63 percent of the CT treated patients and 51 percent of the ceftaz av treated patients, which was also significant. But mortality was similar and since developed about 23 percent of the time to both drugs, which is crazy. But this is a very robust study published in Lancet ID this year to show that perhaps ceftoltazo has a clinical benefit over ceftazab for pseudo and why, I think ceftolazine is a really cool drug. We could talk about it a lot, but it's more potent for penicillin binding proteins and pseudo. It isn't hydrolyzed by pseudomonas amp C as readily as other drugs. and it isn't effluxed as much. And so honestly, the tasel back tames along for the ride. It's frankly irrelevant to pseudomonas here. It doesn't do anything. but the ceftalazine pieces is quite neat.

Jame: 1:21:47

Yeah, lovely, lovely.

Callum: 1:21:49

Can we get that in the UK?

Jame: 1:21:51

I'm not sure that we do have a license for it actually. I think the trouble is that we've been so spoiled by having Kefiderikol and Keftazavi on the subscription model that it's really difficult to get access to other things. So locally we've used meroVab, for some stuff. and but you would increasingly have to justify it. Like, why can't you just use KeftazAbi because That's free for the trust or cheap. and So I don't know if we've got Keftal, Zain, Tezabat, I'm readily accessible locally.

Julie-Ann: 1:22:21

I think is part of the discussion, right? it goes back to something earlier that we were discussing. can you get away with just one or two of these, novel BLDLIs on your formulary? And I think, again, a lot of people do in fact, go with Cef Tazavi to begin with maybe with some combination of Estreanum if you need It, here, there, the other. And people were talking about, at least early on, there was some discussions about, we're just going to have sophiterocol because it takes care of everything. We're going to wipe everything else off the formulary. I think that has come, that discussion has come and gone now. maybe that might be a different story if sophiterocol ultimately gets paired with a BLI down the road. But, I think the important thing to understand is, that's part of why, the precedent network, with Jason Pogue, and Ryan Shields, it was really an important study to look at real world. What was the clinical outcome difference? was there any clinical outcome difference between, toll TAS And Cazavi? and I think there's enough there to support that you really should consider toll TAS as a definitive agent for Pseudomonas, for dTR Pseudomonas infections.

Jame: 1:23:16

would you use it up front as in you would use it preferentially to the other two that we've discussed?

Julie-Ann: 1:23:22

I personally would, in my. clinical practice. I practiced for 10 years in South Carolina and DTR Pseudomonas was by far our biggest MDRO. it was the huge headache that we had. and so we, we had a lot of success in using it up front. And I think that comes to a broader conversation of if you really are suspecting DTR Pseudomonas, empirically even, how and when you bring Told has, and I know Erin's got some really awesome patient stories of where she's advocated to bring it sooner versus waiting for, four days in to find out that you're dealing with the gnarliest pseudomonas that the unit has seen in a while. If you have, it goes back to her earlier point where you can see. the prior pseudomonas isolates and map out, you have culture, and then you have a course of peptazo. Then you have culture. Then you have a course of meropenem. Then you have culture, and you can see the resistance just accrue with every single beta lactam. So we really do sequence, and a lot of these patients, they're chronically ventilated or they have LVADs or they have chronic osteomyelitis. They have, on honestly retained sources. so goals of care becomes a really important discussion. But if the intent is to treat a serious infection, this is my personal opinion, not necessarily the, that of the guidance, but, I do preferentially use, cephthaloxanthazobactin and I advocate for it to keep it on the formulary specifically for pseudomonas.

Erin: 1:24:35

I do, I'll just chime in. I, we do as well. Ceftalazine is our number one drug resistant pseudo drug. In addition to everything Julie said, it's just. For us being fortunate to have all of these drugs, it's very targeted. It's a pseudomonal drug and maybe an ESBL drug. If you have a polymicrobial pseudo ESBL, or if you have a patient on Valproic acid and you have to avoid a carbapenem, right? But otherwise it's that's it. That's its role in therapy. So we should use it. Whereas Ceftazivi, maybe I need it for that oxa 48. Maybe I want to use it for that metallo in combination with a strain. And maybe I want to use it for a different pseudo. And so we try to save these drugs for their true role. And that's where that. is important. And I I would say, if you're listening to this though, and you're like, what you just said, I only have access to, Ceftazavi. You're not taking care of your patients. And I want to underscore that you're doing a good job with what you have It, these are, that's a very reasonable option. I think it. if you have a patient with a new KPC who's never seen ceftazavie ever, sure, give them ceftazavie, of course, but what we're talking about is perhaps If you had a patient with, a urosepsis KPC producing infection and they got seven days of ceftazavie and went home and they come back two weeks later and they have a urinary source bacteremia again and you know it's a GNR, maybe give them mirovaber that time because good chance it's that same bug and good chance it's resistant now and so And in that case, we'd empirically switch and same with pseudo. If I had a patient with drug resistant pseudo, they got two courses of ceftoltazo on their back again, and that respiratory culture is going GNR again for a persistent half back. And maybe now I give them MIREL upfront because they've already been exposed to ceftoltazo twice, and I'm going to expect to start to see some AMC mutants and some other things going on. So that's another thing to consider.

Jame: 1:26:15

Yeah, all the more reason, I suppose, to have multiple different options and to

Julie-Ann: 1:26:19

Well, that goes to a bigger situation, which is the. The business model, is it better just to have a license to use these antibiotics versus having to purchase them and have them on the shelf and then wait for them to expire if you're a rural center or a center that doesn't use these as, as often. So it goes back to usually realistically speaking, what I'm seeing done is, and we talk about this in the guidance document is it's really important to understand what are your problem gram negative organisms within your center. And then to understand what the antibiogram is, particularly across these more novel agents to those problem children, because realistically speaking, whatever your top two main pain points are, for example, if it is DTR Pseudomonas, you could make a case for having a Toltaz on the shelf. whenever a patient comes in, you've got it, it's ready to go. And so that's why all these conversations, it's, we have to go through everything of all the different resistance mechanisms, because ultimately what I'm seeing in, and so what we're seeing in the real world, particularly in resource limited settings, is that folks can't have every single one of these on. So they might just have the top two that'll solve the majority of those gram negative resistance problems. And then they have other mechanisms to get the merovibor that they might need for the rare KPC that can show up if that's their epidemiology.

Jame: 1:27:34

This has just been absolutely fascinating. I've loved listening to this. All of it. I don't know what to say. Thank you so much for coming on and talking to us about all of this stuff. This has been utterly fascinating. It's a shame that we didn't manage to talk about crab and Stenotrophomonas. If only there were an episode of Breakpoints where we could be talking about stenotrophomonas.

Julie-Ann: 1:28:00

there.

Erin: 1:28:02

giving

Julie-Ann: 1:28:03

Well, you might just get your wish.

Erin: 1:28:06

If people aren't sick of listening to Julie and I yet, which I hope you're not, Julie, myself and Dr. Amy Mathers, we'll be talking about a very deep dive into Steno and then in the February break points episode.

Callum: 1:28:17

Something else that we didn't get a chance to talk about, which I guess can be another plug is aminoglycosides, which, as, Jamie and I flying the Scottish stall tire, as the, the premier gentamicin, and aminoglycoside fan, country, I guess in the world potentially, I would recommend going, have a listen to the break points, talks, break points, I mean, a glycoside episodes, which really goes into some of the details, I guess not quite the same topic as this. And there's some nuance in the guidelines about when and where to use them, glycosides for, pseudomonas in particular, but, resistant gram negatives anyway,

Julie-Ann: 1:28:50

Well, just for you, because I'm also a fan of aminoglycosides. I will say that my MAGA is making aminoglycosides great again. And so me and a few other folks within SIDP, we are working on hopefully some upcoming publications within 2025, where we would also have some more information on modern. Dosing optimization strategies that can hopefully make aminoglycosides a little bit safer. they are used most predominantly, internationally, but there is still a place for them within the guidance document. If you so read mostly within uTIs right now, but we'll see.

Erin: 1:29:23

they're amazing. You amazing UTI drugs, but

Julie-Ann: 1:29:26

It is a great UTI drug.

Erin: 1:29:28

are

Callum: 1:29:28

it's. There are first line, backbone gram negative cover for all coming infections.

Julie-Ann: 1:29:35

The short story is time is of the essence. You got to pay attention to duration. Keep it under a week.

Callum: 1:29:40

yeah, we need to publish as a nation

Julie-Ann: 1:29:42

You do. Oh my gosh. That would make us

Erin: 1:29:44

the short story is your amicus and is not a hundred percent susceptible. so I think it's the break points of.

Julie-Ann: 1:29:49

Yeah, Also go, go tobramycin, which we don't have time to go through all this, but we should,

Erin: 1:29:54

that was really like actually rude to drop the aminoglycoside carrot at the very end when we're already really far over for like too far.

Callum: 1:30:02

had to at least mention

Erin: 1:30:03

talk

Julie-Ann: 1:30:03

I was so excited for that section.

Erin: 1:30:05

literally, I'm like, I could talk about aminoglycosides for another hour. So we'll just come back. We'll come back and talk about aminoglycosides.

Jame: 1:30:11

we,

Callum: 1:30:12

Well, maybe you should, maybe you should

Erin: 1:30:13

I'm going to call Julie on my drive home to talk about aminoglycosides.

Julie-Ann: 1:30:17

You know, this is my favorite topic. I'm like, I'm going to let Erin talk about Pseudomonas, Amerivapor, and all this stuff. And then I'm going to get to talk about aminoglycosides.

Erin: 1:30:24

She was so kind to let me wax poetic about

Jame: 1:30:27

Erin,

Erin: 1:30:27

but

Jame: 1:30:31

Julie, thank you very much for coming on the show.

Erin: 1:30:33

thank you for having us. It

Julie-Ann: 1:30:34

for having us. It's been a pleasure.

Erin: 1:30:36

a true pleasure. Thank you. guys.

1:30:39

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. Questions, comments, suggestions, why don't you send them in to idiotspodcasting at gmail. com. Have a five star review in your pocket? Kalman, I would love to have it. Please drop it in your podcast player of choice. We tweet. 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 Jayme. I'm Callum. See you then. Now that the episode's done, we hope you learned and had lots of fun. So go forth and treat people with some of what you now know.