All right, thank you for that introduction. As mentioned, my name is Kevin Betthauser. I'll get started with a little brief bio there. As you've heard a little bit about me, I will disclose I am a member of La Jolla Pharmaceutical Company Speakers Bureau. That should be not prudent to our discussion today. My objectives for all of you today are threefold. First, we hope to identify common contributors to and the importance of ICU-induced dysbiosis. We'll start talking a little bit about the microbiome. If you've been to any of the presentations over the course of the conference this weekend, you've probably seen many discussions about microbiome. It's a very hot, sexy topic and in all realms of medicine right now. So I'm not gonna dwell on it a ton, but I think it is an important concept for us to think a little bit about as it relates to this. We'll also review the role of anti-anaerobic antibiotics and aspiration pneumonia will really be our focus in the kind of meat and potatoes of today. And then I'd like to spend a little bit of time about a new paper that was recently put out in the European Respiratory Journal in October that I think drives home a lot of these new and kind of interesting perspectives on what the new role of anti-anaerobic antibiotics, particularly in aspiration pneumonia may be. So again, starting with kind of the GI microbiota here, the role and relevance, I probably don't need to tell this group a ton about, but it has an important role in protecting us against colonization by exogenous pathogens as healthy individuals. It has a role in modulating the immune response, also in mucosal barrier homeostasis. And as we learn more and more about the microbiome, it's becoming more clear to us that this has a role in the pathogenesis of some of our more commonly encountered ICU disease states, including ventilator-associated pneumonia and other types of organ failure. Similarly, it's being consistently shown to have correlations with ICU outcomes. So what are the contributors to ICU-induced dysbiosis? Many things will be very prudent to what we do as pharmacists, physicians, respiratory therapists, nurses, et cetera, but it's well described that antibiotics, which will of course be our focus for today, proton pump inhibitors, vasopressors, opioids, and total parenteral nutrition can play a role in the microbiota of our critically ill patients. Various invasive procedures, the pro-inflammatory response of patients' disease states can also be a significant contributor to these, and the consequences of these are multifold. Certainly, pathogen proliferation is perhaps the most important and relevant to what we'll talk about today, and I'll show you a figure on the next slide that will describe some of this in more detail. But particularly, organisms including extended-spectrum beta-lactamase, Enterobacterioles infections, and as well as vancomycin-resistant Enterococcus, which again are high-priority items for IDSA and SCCM that are becoming more prolific with this type of consequence. As mentioned, here's this figure. This is a nice study that was published in Nutrients in 2019 that I think gives you a nice visual of what happens in a healthy patient, or a healthy person, compared to when they get admitted to the ICU, and as we described, there's many reasons and contributors to all of that, but the short story here is, as you can see, in a normal, healthy individual, you got a nice, starting from the bottom here, intestinal epithelium, a solid mucus layer, and a fairly diverse group of various anaerobes and other microbiology that make up our GI tract that have a role in protecting us from that perspective. However, we've now known and have grown to describe the idea that when someone is critically ill, we have a pretty significant change to our GI microbiota. In particular, I've highlighted three in the middle there, particularly the firmicutes and bacteroidetes. These are phyla of bacteria that would be classified as anaerobes. So as you'll see, us, right now, being healthy individuals, have a lot of anaerobes in our GI tract. However, with all of these things that we often subject our ICU patients to, we see that go down quite significantly in critically ill patients. Similarly, you see proteobacteria. These are going to be some of your enterobacterioles and others follow the opposite pattern, where they actually are increased in the GI tract of critically ill patients. So this sets the stage for what could be a potentially bigger issue in patients who are admitted to the ICU. Of course, the idea of anaerobe preservation is certainly out there as well. And again, I don't want to dwell too much on this because it could be a talk in and of itself, and perhaps even was this weekend. But we know that in animal models, that depletion of anaerobes does increase susceptibility to bacterial pneumonia, lung injury, as well as mortality. And obviously, the preservation of anaerobes in the GI microbiome overarchingly with things such as selective decontamination is a very hot topic. These are just some numbers that were recently published in JAMA this year, looking at a large network meta-analysis, looking at, and ultimately showed an association with reduced ventilator-associated pneumonia and reduced mortality from a point estimate and credible intervals perspective when patients underwent selective digestive decontamination. Again, I don't want to talk about SDD too much, but it is a relevant topic to the microbiome and anaerobe preservation, and again, maybe adds to some of the context of where we're seeing the use of anti-anaerobic antibiotics. So again, I think we have a much better idea today than we even did five, 10, 15 years ago about the use of, or the role of anaerobes in our GI tract, and therefore maybe need to think a little bit differently about the use of anti-anaerobic antibiotics that has been the bane of many MICU pharmacists' existence for years on how to curb the use of metronidazoles and clindamycins in the setting of particularly aspiration pneumonia. So that's really where we'll kind of focus for the rest of the presentation today. There's a little bit of history slide here. Richard's not here to comment on the studies in the 70s and 80s, like he certainly could, and he was around for them, unlike myself. I asked if I could tell that joke earlier, so he's not, even though he's not here. So again, in the 1970s, we had studies that indicated that anaerobes were amongst the most predominant pathogens in aspiration pneumonia. Now, there's tons of studies that have happened since that that have not observed those same things, and probably the biggest difference in that is largely related to patient population. The patients in those 1970s and 80s studies were oftentimes much later in their ICU care. Many of them had chronic tracheostomies, they had known empyemas and other risk factors for likely anaerobic infections. Obviously, differences in sampling techniques and technology certainly have played a role in changing that as well, but it's probably fair to say the microbiome of a 1970s patient versus a 2023 patient is different for various environmental and other factors as well. And as mentioned, more recent studies have observed a very low frequency of anaerobes, and we'll put that into the context of some clinical evidence as well here, and an increased incidence or frequency of instead community-acquired and hospital-acquired and ventilator-associated organisms. These are gonna be your typical strep species, haemophilus, pseudomonas, and enterobacterioles are being much more commonly described, and perhaps where we should be targeting our efforts as it relates to empiric antibiotic use in our pneumonia patients. This is just a quick overview. Obviously, the IDSA guidelines came out a few years ago that specifically asked this question, is in the setting of aspiration pneumonia should additional anaerobic coverage be given? And their comment in this section is that they suggest not routinely adding anaerobic coverage and much of that comes from some of that prior data that I already mentioned to you. This is, again, a conditional recommendation, very low-quality evidence. I'm not gonna present any double-blind randomized placebo-controlled trials today, but this is still an area of interest and probably that needs to be moving in that direction. With the advent of the guidelines, we have, I think notably, and an applause to many of us in here and the groups that are working on this and have had this at the forefront of their minds, is that we have seen a reduction in the use of anti-anaerobic antibiotics over the course of several years. I have three observational studies shown for you here, the Keokia, or Keokia study, Marin-Coral et al, and Brumit et al, and those are in chronological order. They've been published over the course of the last six or seven years or so. So you can see in the first study there that about 90% of patients who were admitted with aspiration pneumonia received some sort of anti-anaerobic antibiotic, and then more recently, we're closer to that 60% kind of realm. So I think we have seen a significant improvement. Again, I don't wanna ferment on this too much because I think it is we're moving in the right direction, but as you can see, there's still a lot of room here for improvement. So how do we identify and kind of solidify the fact that we probably don't need to be giving anti-anaerobic antibiotics to every single patient that walks in here? This is that Marin-Coral et al study. This was a secondary analysis of the GLIMPSE study. The GLIMPSE study, as you'll recall, was a large international point prevalence study where they just simply had 200 plus hospitals, worldwide, and they asked several questions related to patients that were hospitalized with CAP at that particular time. In this secondary analysis, they compared patients who were admitted with aspiration community-acquired pneumonia, 193 of them of note, and then patients that had just standard community-acquired pneumonia. They broke that down into patients that had risk factors for aspiration versus did not have risk factors for aspiration. These included things like age, sedentary lifestyle if they were on parenteral, or enteral nutrition, et cetera, that they had deemed were likely risk factors for aspiration which could be debated, certainly, but that's how they stratified this. And then subsequently looking at just, again, outcome prevalence at that time. The most common microbiology that they had identified in those patients is consistent with some of the prior data that I mentioned, mostly gram-negatives and gram-positives. Only 2% of patients in this population had anaerobes at the time of the point prevalence study was done. When they compared the aspiration pneumonia groups to those patients with community-acquired pneumonia, again, you'll see a low incidence of anaerobes across the board there, 1.6 versus one versus actually none in the CAP risk factors negative group. And then gram-negatives being the most common that was seen specifically in the aspiration pneumonia group. Still, as we mentioned, we're in that 70% realm or so for patients who were on anti-anaerobic antibiotics at that time consistent with what I showed you on the last slide. So kind of those few big pieces kind of in context here, I think it's important to think about how do we solidify this and start putting these things in the context of clinical outcomes? And this is the paper that I mentioned that at the time of these slides was just in press at the time. It has been formally published now. I think it was in October of this year in the European Respiratory Journal. This is a very unique retrospective cohort study from the ID group at the University of Michigan. And I know we don't always get excited about retrospective observational cohort studies, but I think there's some unique pieces to this that intrigued me a little bit and I felt were important to share today. The primary goal here was to simply compare clinical outcomes and respiratory microbiology in patients who received and did not receive anti-anaerobic antibiotics. So kind of getting into the nitty gritty of that. And then subsequently, what I think makes this a little unique is they use their findings to then inform murine models and actually mimic what happened in that setting in order to better understand whether or not this plays out in this particular setting in a murine type of model. So I'll show you those results as we go through here. This was about a three year methods overview there. All mechanically ventilated patients that had been on the vent for at least 72 hours, all had received IV antibiotics. Again, there are two groups being described for you there. Primary outcome, VAP-free survival. And then again, they also had a microbiome analysis that several of their patients underwent as part of their routine care to help inform that murine modeling. So they did this via rectal swabs and it was only about 115 of their patients. But again, these were the microbiome analyses that informed those murine models. Here's a flow diagram. You'll note they screened all 26,000 admissions over the course of that timeframe. Ultimately ended up with approximately 3,000 patients who had been mechanically ventilated for 72 hours or more and had been treated with IV antibiotics. I think when we think about the generalizability here, I think we can think a lot of our patients probably meet these fairly simplistic entry criteria. Just that baseline here. I'm not presenting the entire table, but just some things to note. This was about a 55 to 60 year old patient population, largely males, non-Caucasians were the minority here. Apache 4 scores were reasonable, about 90 or so. Again, a fairly sick population being on the ventilator. And Charleston Comorbidity Index or comorbidity burden was not entirely small, but certainly consistent between the two groups. And there was no difference in these from a statistical perspective either. Antibiotics. So what antibiotics were these patients receiving to have their microbiome changed or wiped out, so to speak? You'll see that the majority of patients received combination therapy with vancomycin and then some sort of anti-pseudomonal beta-lactam, most notably in the anti-anaerobic group where they had about 2,000 patients. They received vancomycin and piperacillin-tazobactam as their primary outcome or as their primary regimen. You see a little bit of cefepime mixed in there too. And in the non-anti-anaerobic coverage group, the majority of these patients received, again, vancomycin and cefepime. So I think when you think about comparing these two groups and interpreting this study, I think it's important to remember what are we really comparing here? It seems that we're largely comparing vanc-pip-tazo versus vanc-cefi in the setting of kind of this anaerobic versus no anti-anaerobic. You'll see a little bit of a small degree of metronidazole and unison use as well. These are kind of their top line results here. These are the Kaplan-Meier curves for the first graph there being their primary outcome of VAP-free survival. You see the hazard ratios on your y-axis there and then over time on the x-axis. The purple arm is representing your anti-anaerobic antibiotics and the blue, the non-anti-anaerobic antibiotics. And you see a statistically significant finding there over time in terms of VAP-free survival seeming to favor those that were not receiving anti-anaerobic antibiotics. That finding was consistent in both infection-free survival probability as well as survival probability across the board here. So I think immediately intriguing and interesting here. Certainly again, a retrospective observational cohort, we can't make any major causal interpretations here, but a large sample and again, I think something to be thinking about in your patients. To kind of address some of the potential for selection bias and others, they did perform a Cox proportional hazards model to take into account some differences that may have existed at baseline that they were unable to account for. I showed you some of their baseline characters. They were largely the same, but I still think this strengthens the study. You'll see again across all three of those outcomes that the inclusion or the receipt of anaerobic coverage in the setting of aspiration pneumonia was associated with the higher hazards of VAP-free survival, infection-free survival, and overall survival despite controlling for several of these confounding factors. You'll note they also found that certain ICU settings may have been perhaps even protective. So those that maybe were the CT ICUs or even surgical ICU settings, maybe a little bit more in and out, probably less likely in an aspiration type of setting as well. So I think some interesting things as we move towards this precision medicine approach and does this apply to my type of patient, my ICU, and I think about what I've often heard as well, these studies don't apply to my patient population because they haven't been studied. I think this study does at least give you some observational evidence that your population has likely been studied in this setting now. These are some of their microbiology kind of looks here, kind of a busy graph, but the take home here is that again, those that received anti-anaerobic therapy had a higher association with frequency of enterobacteriaceae species here. That was even consistent in those that died or had a fatal infection compared to those that did not have anti-anaerobic therapy, and you see quite a striking difference there of 29 versus 3% from a mortality perspective, and those graphs are listed for you there, and you see the high proportion of patients who did have culture positives, largely kind of, again, centering on those VAP cases, and you'll note there are no positive cases for anaerobes. Again, some more microbiome analyses that they did. Again, they had this microbiome analysis in about 120 of their patients with rectal swabs to assess what these patients' microbiome looked like over time, consistent with what we've largely already known is that they had a reduced bacterial density. This is a 0.089 for their interaction. This was significant, and then again, they saw an increased abundance of enterobacteriaceae, very consistent with the graph that I showed you on the first slide, but I think puts this, again, into a clinical context with your patients that they were studying here. I mentioned they then used this to inform some urine models, pneumonia models, and what they found here was by wiping out the gut microbiome of mice with vancomycin and piperacillin-tazobactam compared to cefepime, which were the two agents they used in this study, consistent with what they saw in their results, that gut anaerobe depletion decreased the clearance of, in this particular case, Klebsiella pneumoniae, so I think another potential mechanism that's being described and considered in the setting of how does this contribute to ventilator-associated pneumonias or pneumonia pathogenesis is that perhaps with the wiping out of those anaerobes that you may actually be increasing or decreasing the ability to clear other potentially pathogenic bacteria. So in conclusions, I think the best practices right now surrounding anti-anaerobic antibiotics is really, we know that the GI microbiota is certainly dysbiosed in the setting of critical illness. There's significant biologic, physiologic, and pharmacologic implications to that. This is very new and something that's undergoing a ton of study, and I think we're gonna learn a lot more about it in the next several years. Certainly current data do not support the routine use of anti-anaerobic antibiotics, particularly in critically ill patients with pneumonia. I don't want to read too much into the mortality difference that's seen there. I think that's important to think about, certainly, but I think there's likely other things that are contributing to the mortality of our patients and whether or not they received metronidazole or received an anti-anaerobic antibiotic, but I think that's an important piece to think about. And then finally, I think right now we have to be reserving our anti-anaerobic antibiotics for those that have either confirmed or a very high clinical suspicion for a pathogenic anaerobic infection. I suspect that's gonna be some sort of concurrent intra-abdominal infection, maybe someone that has a known empyema, patients that have been on the ventilator for a longer period of time and may have a higher incidence of things like obstructive pneumonias, whatever it may be, and I think for now, at least empirically, it doesn't really seem that the evidence adds up to be utilizing empiric anti-anaerobic antibiotics in a setting of certainly aspiration pneumonia. I'll thank you for your time and we'll go to our next speaker. Thank you.

ICU-induced dysbiosis

anti-anaerobic antibiotics

aspiration pneumonia

microbiome

disease states

contributors to dysbiosis