95. FIS 2024 part 1: AMR & Bacteria

HO HO HO, MERRY FISMAS!!!

On the First Pod of FISmas these ID:IOTS have to you… a terrifying update on the Antibiotic Apocalypse!

Jame and Callum attended the Federation of Infection Societies 2024 annual meeting in  Liverpool; here they share their reflections on the sessions  they attended on: Bacteria and Antimicrobial resistance.

Episodes on viruses, fungi etc. coming soon!

Notes for this episode here

Transcript

Jame: 0:18

Callum, how are you doing?

Callum: 0:21

I'm doing good. I actually am feeling very positive. we've just got back from a big national conference and something that really struck me was, Jayme, that we've been doing this podcast for a little over three years now. And I have to say, at times I thought it might fizzle out,

Jame: 0:39

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

Callum: 0:43

well, today we have a debrief on the excellent Fizz Conference 2024 Federation of Infection Societies, this year's hosted by the Healthcare Infection Society, Fizz is a collaboration between the Healthcare Infection Society, the British Infection Association and the Microbiology Society.

Jame: 1:05

and other related societies too. Yes, that's right. But those are the big three. yeah, so the, this is a bit of a fixture in the UK infection, Training calendar. It happens every year in November, and it sort of rotates between a bunch of different places. Think of it as ID week, but not as big, or EskMed, but nowhere near as big. but it's pretty well attended. We had about 700 people this year, I think they said.

Callum: 1:31

Yeah, it was hosted in Liverpool, and there's a really great, atmosphere, lots of collaboration, lots of exciting science and research being shared, and lots of great opportunities to catch up with colleagues, both near and far. And what we thought we'd do today is just give you our highlights, Of the conference some things that we took away and hopefully be taking back into clinical practice for those of you that weren't lucky enough to be there or maybe were there and didn't manage to catch some of the parallel sessions

Jame: 1:59

the thing, sometimes there's too much to go to.

Callum: 2:01

Yeah, exactly. I found that this year and I guess a big thanks to all of those uh colleagues who were manning the fort at home and allowing people to go and learn.

Jame: 2:13

So, without further ado, let's get into it. So we're going to divide this into sections, Puscast style. So we're going to start with an AMR section, and then do bacterial, viral, fungal, and other. So we start with the AMR 2024 to 2029 action plan, which was given on the Wednesday, by Dr. Mueller Pebede, from the UK HSA. And then they were talking about the so the UK's got a five year plan to try and reduce antimicrobial resistance. But what was really interesting was the stats that they had on how big a problem EMR is. So they're referring back to that sort of Lancet paper that we've mentioned before. But yeah, about 1. 14 million deaths in 2021. By 2050 an estimated 30 million. 39 million dead when it comes to bloodstream infections. A fifth are now a classified as resistant. And the, then, refer to the S power, report,, the English surveillance program for antimicrobial utilization and resistance. So this comes out every couple of years. And the latest version has just been pulled out, talking about where the prescribing happens in the UK and about 80 percent of it is in primary care, actually. So on. a fifth is in secondary. But we are increasing the number of antibiotics that we prescribe, particularly in ED and other specialty services, which I think means surgical specialties and things like that. An overall increase of 2. 4%, so they were a bit worried about that. And then, They talked about the five human health targets, so one is to prevent increase in a specific set of drug resistant infections, presumably that's MRSA, ESPLE, Coli, Apses, et cetera, et cetera. Prevent an increase in gram negative bloodstream infections compared to the 2019 baseline. Because of course, if you compare it to 2020 and 2021, the numbers would be all funny. Increase knowledge of AMR by 10%. How you do that, I don't really know. Ensure 70 percent of antibiotic uses access, WHO access category, and reduce total use of antibiotics in humans by 5%, again, relative to the 2019, benchmark. And that's all I have to say on that. And then the other thing in the, AMR section was there was a presentation sponsored by Pfizer on AstraZeneca Avobactam. And so, Cal, you'll be, aware that we're having a bigger and bigger problem in the UK with NDM metallobatylactamase. So of the three big metallobatylactamases, NDM is now the dominant, CPE, And they are associated with more intensive care stay, more length of stay in hospital, more mortality overall, etc, etc. And there seems to be this trend where serine beta lactamases, and your KPCs, are co locating with metallobeta lactamases over time. So you're getting organisms with, two or more copies, and that's very worrying indeed. And, most of our, beta lactamase inhibitors weren't really able, were paired up with stuff that wasn't really able to challenge, metallobeta lactamases. But as Trenam is stable and elsewhere in the conference they mentioned that Kefadecol, they were getting increasing issues with resistance, particularly with NDM 5. to, Kev Derkel, and that was mentioned in the BSAC, Autumn Conference or Spring Conference as well I forget which. So, yeah, the, as, the idea is that we combine Aztrinam with Avobactam, and we've sort of been doing that by giving KevdazAvi with Aztreonam, and the Aztreonam is, protected from hydrolysis by ESBLs, which it is not resistant to, by the Avobactam, and it takes care of the metallobatelactomies. And that's good, and if you have a look at the sort of spectrum map, I've put a copy of it somewhere in here, you'll see that it is active against Most of the interbacterial is producing NDM with a couple of exceptions. One of them is Pseudomonas aeruginosa, and that's because they've got other resistance mechanisms like efflux pumps and, and things like that. And, Because of that, metallobatelactomies producing pseudomonas, only about 10 percent of them will actually be susceptible to astreinam avi. And the other one is, uh, astenitobacter biomaniae chalcoceticus complex. And that's because astreinam doesn't have any activity against astenitobacter. And even if it did, afabactam doesn't work on the intrinsic oxycylanases. that ABC, has, which are OXA 23 and OXA 51, for those that are interested in it. but it seems to work for intrabacteriales, and it seems to work for stenochophomonas. And to the point where UCAST has, issued breakpoints, for it, for intrabacteriales, not for steno, not just yet. For steno, you have to use the PKPD. breakpoints. And in vitro, the susceptibility, to astreonam, if you combine it with avobactam, goes from about 75 percent to 99. 9 percent for intrabacterialis, if you give that combination. So you're gaining quite a lot of extra coverage., And it's been licensed now with indications of, complicated UTI, hospital acquired pneumonia, or complicated intraabdominal infection when other agents are not suitable.

Callum: 7:36

Yeah, it was a good overview talk. and, in the notes, we've got some more, information about the dosing, which we won't go over here, but, yeah, it's a little bit complicated, the dosing. So you just be aware it needs a loading dose and then the maintenance doses, going over quite a long time. So it's quite a commitment, treating a patient with this antimicrobial in order to get adequate drug levels. But, obviously in this situation you're usually pretty desperate, aren't you?

Jame: 8:01

Yeah,

Callum: 8:03

there was also some discussion about the aspect of having two different drugs and making sure that they get the right compartments. And I think we should come back and talk about that in our sort of PD episodes in the

Jame: 8:12

yeah, we'll probably, yeah, we'll come back and cover that because that bit was quite interesting, actually, so the, combining Avobacterium with Astrianab is not the same as combining it with Keftazidime, and you need to get different concentrations in order to, get target attainment,

Callum: 8:28

it's always going on about the need for a new sort of beta latinase, inhibitors and, The sort of dosing and how you get, make sure that both aspects of the drug get to the target site is, tricky. they did share some data from some of the clinical trials that were involved in getting the license to rejuvenate and revisit. which I won't go into in detail, but, essentially they were able to show non inferiority in comparison to the standard of care. which, I think is hardly surprising given that we already knew that it was working when we're using the Kedi, avibactam of Astrium combo. so yeah, so that's that's astrium avibactam So staying in bacterial world. So you mentioned briefly there acetobacter or Carbopenum resistant asking me to, uh, asking me to Bacter bone mani or crab. So, you went to an update about that. I, there was a session as well about a pan resistant crab and a panel discussion about how they manage that. So I'll maybe dwell on that, but do you want to take us through the sort of crab update first? For the loyal listeners, you'll know that we've recently done an episode in our non ferment, ennobling the non fermenter series on Acinetobacter and crabs specifically. And so you can go back for a comprehensive overview. What did you learn at Fizz that was additive to that?

Jame: 9:41

not a huge amount more, because we based, episode on the sort of latest data and not a huge amount has happened in the next, the next few months, but it was really good to go over all again. In particular, the, there's a picture in the prep notes about the beta latamases in which class, Ambler class are in which organism. And I, really liked that because they've also got which beta latamases are common in pseudomonas And, yeah, they again restated. It was actually the same person. It was, by Louise Sweeney. But yeah, going over the IDSA guidance, which she now says that they use exclusively, they're not using the ESCMID guidance at all, it's just too out of date. And this field is moving too quickly for guidance in 2022 still being relevant today. But yeah, so the traditional guidance is to use ampicillin sulbatam with one of, uh, non betel atam options, so levofloxacin, minocycline, coltrim, aminoglycoside, colostin, or kefidercol, depending on what you've got susceptibilities to and what you think is going to penetrate the target site. And then they talked about, ampicillin sulbatam, and Durlabactam, Sulbactam, being difficult to access in the UK, but that they might come in the future. And then they had a little bit about what they're doing in Manchester, which is where she's based. And particularly for, they've got their, first line guidance for their CPEs and difficult to treat pseudomonas, but they also have for CRAB, they've got first line Ampsylbactam with a second line Kefradericol, and they use it in combination with one of those, that list that I've just stated, and that's taken directly from the IDSA guidance. So that was interesting to look at. Interesting to see how they've applied the IDSA guidelines in a UK context. They must have some sort of supply of ampicillin salt back time that they can get a hold of though.

Callum: 11:37

Yeah, so maybe that's a good point for me to come in. there was a session, from. The conference chair, James Price and colleagues about a case that they managed, where they'd identified a Acinetobacter baumannii, which on testing at the reference laboratory turned out to be pan resistant, so it had sort of cathedral core resistance as Trinamabibacter resistance. And, it was quite an all encompassing discussion about the challenges of, managing that I thought it was really a very open and honest discussion about the issues that we're encountering in the search of circumstance. It was an ICU setting. There was issues, issues with major issues with the design of the unit. And they talked a lot about how they use it's an opportunity to make a lot of improvements to their unit, improve the infection control and the surfaces there and work with the clinical team and managing the anxiety around these organisms and clinical team was a big focus. So it was going beyond the sort of pharmacology. Pharmacology and talking really about the sort of behaviors and the team and that communication challenge and the infection control in a really comprehensive things. I took away a couple of points there about, they quoted, Martin Kiernan, who's obviously big in infection control world and hosts the, IPC matters. Podcast, who says, never waste a good crisis. So I think they've really embodied that, where they, use that opportunity to try and improve things and prevent the issues in the future. But yeah, really scary, to be thinking that we're in the era of no treatment options for some of these organisms.

Jame: 13:05

yeah, because we, came up in that, that, that world, didn't we? Where the only thing we had was colistin and then we got Broth microdilution testing for that, and then we got access to Kefta's AVI, and that sort of concern went away a little bit. I felt it retreating a little, and now we're right back where we were a few years ago, but just with more agents to test against. Tell me about the credits trial, Callum.

Callum: 13:32

Yeah, so I've popped this in here. there was a session by NITCAR, which is The National Infection Teams Collaborative for Audit and Research. And, there was lots of great stuff, presented there, including stuff about sort of gentamicin data, and two of the things that I want to talk about. So one was, CREDITS, and that stands for Carbapenem Resistant Enterobacterioles Descriptive Infection Trainee Study. So essentially what they're proposing to do is do a retrospective multicenter audit throughout the UK to ask sites to collect non duplicates consecutive CRE sample data, over the last year. And they're going to look at what, carbapenemase testing was done and the carbapenem-resistant intra rallies. And then what antimicrobial susceptibility data that we have. And the real why of it is that we. Are I guess a lot of sites are seeing patients presenting and you identify that they have a carbapenem is producing organism on getting the data back from your reference lab can take some time

Jame: 14:36

Yeah.

Callum: 14:37

on. So trying to get some real world data on what. What A. S. T. Data are we getting back and then publishing that by carbon pandemics and a lot of other data as well, though quite a limited amount of data collection happening. If you go into our show notes, there's an email address or, Ioannis, who's, I think, leading the audit, you can email him to find out how to get involved. And I'm sure there'll be some on the Nick car website.

Jame: 14:59

Yeah, he's a real up and comer actually. He's just published, something about the resistance profiles of CPEs in a large center in England. And again, showing this, uh, increasing resistance to Keal the Trojan horse, in the uk. so very scary, but at least we know about it and can deal with it.

Callum: 15:17

I've put the link for that paper, into the, show notes, so you can look at it if you're interested

Jame: 15:22

Yeah, he's on Twitter as at Greek Dock, and I don't know what he is on Blue Sky, but, hopefully it's the same because I hate it when people change their names when they move from, Twitter to Blue Sky. Callum, can I ask you something? What did they say about djent?

Callum: 15:37

CodeGent was a study where they looked, across the UK at people's practice, and they were, reviewing how people are using gentamicin and auditing the sort of compliance of, of people locally to the, their guidelines and how they were dosing it. they presented some, lots of data. the main thing that I took from it was that, most sites over 50 percent were using a normal graph to monitor gentamicin levels and of those, most of them using Hartford, but others using urban Craig, Barnes, Jewish or others. And 47 percent of sites were actually using pre dose therapy to drug monitoring to guide therapy.

Jame: 16:11

Oh, yeah.

Callum: 16:12

And then, just over half were using electronic prescribing, just under half were using a gentamicin dosing calculator. And, most sites were still using five milligrams per kilogram. There was a EUCAST position paper and they've moved to a dosing recommendation of seven milligrams per kilogram for gentamicin. And obviously there's a controversy about breakpoints. So it's interesting to see that most centers are still using that sort of lower dosing., So I guess it was just some real world data on what are centers actually doing. and, I guess there's going to be a lot of work coming forward about, how do we line what we're doing with what the, what you cast are recommending and break points that they're releasing

Jame: 16:52

Okay. Right, tell me about the duration trial then, Callum.

Callum: 16:57

duration trials. So I believe you know about something about this already, Jim, but I'll let you come into that. Yeah, so. This is presented by Martin Lle, University of Haltesville Sussex. And I've, in the show notes, I've put a link to the trial protocol and also some information on the, Oxford Research, Centre, about the trial. Now, very cleverly, they've managed to put UTI into the trial, duration. And essentially this is a study asking the question, how long do we really need to treat uncomplicated UTI in women? And it's based off a sort of trial protocol. relating to duration of antimicrobial therapy and they, there's some clever statistics going on, which essentially means that they need a reduced sample size. So he started off by talking about the issues with a shorter is better the approach, a big shout out to Brad Spellberg there. And he put his table up and then pick some holes in it, which I thought was quite interesting. And Jane might be covering his ears at the heresy. But. I think we made some good points. So I guess just to run through a quick example, he was talking about a study for acute otitis media in children at five versus 10 days. And actually in that, it found that the clinical cure rate was better in patients received 10 days rather than five. So it's exception to our rule. But his point was really, if we dichotomize our durations like that, do we know with seven days? Have been better than 10 would have been adequate cure levels or maybe actually extending to 15 days might have had better cure dates than 10 days. And his main point was the need to individualize treatment plans. So when we say we only study five versus 10, we don't know the optimal duration. If you say that 10 days, is the standard of care in that study, two thirds of patients actually recovered by five days. So if you give everybody 10 days, then two thirds of your patients are getting You know, double the antibody exposure that they needed. And so it has a lot of questions and I guess the study is trying to unpick that. So they're randomizing people to six different durations for six, eight, ten, twelve or fourteen days. and looking at microbiological and clinical outcomes. So yeah, really exciting to see, what comes of that. They've also got some sub studies looking at qualitative data, behaviors, and also looking at people's fecal microbiota. So, yeah, I think you're, you've been slightly involved in this trial, Jayme, and I think, everybody that's treating infections, if this trial design can work, it seems to me a really appealing way of trying to better answer what our durations of therapy should be for a range of conditions.

Jame: 19:31

yeah. Agree.. Okay, and then to finish off our bacterial section, let's talk about C. difficile.

Callum: 19:40

This was presented by Stephen Hughes, presenting from Imperial College in London. And, essentially they'd done a retrospective cohort study of 21, 000 patients in whom 54 people had a healthcare associated C. difficile infection. So they presented some data on, their C. diff case, and they found that overall their cases had dropped since 2007, but they'd seen a grumbling increase over the last five years, 13 percent increase. And their 30 day mortality for hospital onset was about 22%, which is lower than it had been, and communities is about 10 to 15%. And they positive some theories about what, was driving this sort of higher violence. Historically we know that the c difficile outbreaks that we saw in the sort of 2000 that were around 2008 were primarily driven by the o two seven Ribo type. which had intrinsic resistance to things like ciprofloxacin, now, current ribotypes in the last five years have been sort of stable prevalence. so, some ribotypes might be associated with higher virulence. they also talked about, whether more antibiotics are being used, frail elderly population, maybe perhaps a lapse in our contact precautions and infection control and particularly hand washing in hospital. with more focus on COVID and mask use,

Jame: 20:59

and in particular C. diff spores don't get, inactivated by alcohol hand gel, which has been a focus of, respiratory, precautions, in hospitals.

Callum: 21:08

Yeah. and I think, all the epidemiology was interesting. The main thing I was interested in from the study was their discussion about what impact the risk of C. difficile. So we all know, antibiotics equals, C. difficile risk. and, I'm sure many have been taught about, 4C antibiotics. You know, the Keflasporins, Clindamycin, Clomoxaclav, and Ciprofloxacin. and there's lots of studies that I've read that try to risk stratify different antibiotics, and we talk about high C diff risk, and we talk about spectrum activity, and we talk about whether it actually has activity against C diff or not. Now, essentially, they were trying to say, what is the link? Really? Can we demonstrate a link between antibiotics that are being used and, the risk and their data really was showing that their main antibiotics links locally were comoxaclavin, peptazine, encephalosporins, clindamycin and fluoquinolones. But that was really related to how much they were using, and, they were basically saying they didn't really see any link between antibiotic class or specific antibiotic and CDF risk, and suggested that actually what they felt was more likely to be impactful was longer durations. of therapy, other microbiome disturbance, so things like concurrent PPI use, and they were showing that durations over seven days had adjusted, hazard ratio, increasing exponentially.

Jame: 22:37

Yeah, I thought this data was quite interesting, and I know that since the O27 ribotype has become less prevalent in the U. S., also some retrospective studies have not really been finding as high a C. diff risk as we had thought we were going to find, and so I'm willing to entertain the idea that Quinlones are not super high risk for us. Seed of a seal. Now there's other reasons not to use them and there's other reasons to preserve their use, but I thought this was an interesting talk, but I don't necessarily agree. With their conclusion, because I don't think a, single center retrospective study can invalidate every other systematic review and meta analysis of C. diff risk associated with broader spectrum antibiotics. but, I'm willing to entertain the idea that, the risk with the four C's is not, equivalent between all four of them. I mean, we know that in the community, clindamycin use is associated with quite a, quite a marked increase in C. diff onset compared to hospital, hospital use, where it's very similar to the other, the other three of the four C's. They also mentioned a little bit about PPI use, Cam, didn't they? The overall risk is about twice, compared to if you're not on it. And so current use is about two times the risk. Use within the previous zero to six months is 1. 5 times and six to 12 months is 1. 24. times with that, with the confidence interval, 1. 00 to 1. 50. So almost statistically insignificant. So I thought that was really interesting that the PPI uses actually last a little while after you discontinue it, you're an ongoing risk of, developing C. diff, but nowhere near the risk of using high risk antibiotics, which is something like between four to seven times an increase of whatever your baseline is. Which of course will be going up as you're older. But I have a picture Cal, of a point that they were making. which is that, exposure to number of days of antibiotics, but also the, total number of different kinds of antibiotics or what they think are the main drivers of C. diff risk. So if you have to go on lots of different ones, and if you have to go on lots of different ones for a longer period of time, Then that's the one, the thing that's most likely to, result in you getting C diff. But I suppose because this is retrospective, you can already see the confounders of that. If you need to be on antibiotics for a long term, if you need to be on lots of different ones, you're likely to be sicker, and more likely to be more hospitalized, more exposed to C diff spores, et cetera, et cetera, et cetera. But I, I thought this was a really good presentation and nonetheless, even if I don't agree with all of it.

Callum: 25:26

Yeah, I think I'd probably maybe a more, the whole like this antibiotic bad for C. diff, this antibiotic good for C. diff. Argument. I think, you know, we had that discussion with Tash about the microbiome impact and sometimes it doesn't really align with what you think is broader or not broad spectrum. So I think that was maybe too broad brush approach. and actually we're maybe starting to see a bit more nuance in the data. I still think that the standpoint of, trying to avoid use of broad spectrum antimicrobials is important.

Jame: 26:01

I mean that's good on its own. Yeah, totally.

Callum: 26:03

But, you can look at things like keflosporins, like that's probably too broad a brush, like kefazoline is comparatively much narrower spectrum compared to something like kefapine. So, simplifying things like that too much ends up with areas of inaccuracy. And so I don't know if I'm, I don't really teach 4C anymore and I think I just keep it more general and say, broader spectrum. Higher C. diff risk, narrower spectrum, less C. diff risk. With some exceptions potentially.

Jame: 26:33

Yeah, fair enough, fair enough.

Callum: 26:35

And then the show notes. So one other thing that I thought that was quite useful was they gave a little bit of an overview of C. difficile treatment. And so they divided that up and there's a table that I've put. copied and put in the show notes. So thanks for presenting that Stephen and essentially it's summarizes what the nice guidelines say compared to the IDSA guidance 2021 and the ECMID guidance and they're quite, concordant main exception being that in the UK we're going for vancomycin still first line, which I would be aware of as a sort of cost effectiveness strategy. and it's got some antibiotics for sort of life threatening C. diff, including sort of the option for tigacycline, including the ECMID guidance. but one thing that was new to me was this extended pulse for Daxamycin regimen, which is now in the BNF. As one option. So under Fodaxomycin, it's got some dosing recommendation for extended pulsed dosing, which is something that you could consider for your patients where there's, recurrence with specialist advice, obviously. But just, it was just interesting to see that because obviously we were used to using vancomycin in our pulsed, setting and some days it felt like you, you had to do that, even though Fodaxomycin is a better drug. with lower risk of relapse, so good to have that option for that as well,

Jame: 27:47

Yeah. And that brings us to the end of our bacterial and AMR section. Tune in next time for our viral, fungal and other sections.