In this session, we're going to be talking, this is about antimicrobials in critical care. We are going to focus heavily on pneumonia, figuring this is a pulmonary critical care meeting, and in terms of the sine qua non of sepsis and critical illness, that pneumonia is going to be a good area for us to talk about. We're going to talk a little bit about new antibiotics, about current guidelines, and then do some case-based discussion. We 100% encourage you guys, ask questions, interact, we'll talk. This is breakfast. I was actually feeling kind of weird that you guys are all eating, and I'm standing up here looming over you. All right, so this is going to be about, I'm going to talk for a bit about novel antibiotics. My name is Ryan Mabes. I'm a professor at Wake Forest. I'm an ID physician and a critical care physician and practice in the ICUs there. Just for disclosures, usually I say none of these are relevant to my talk. One of them is somewhat relevant. I served on an advisory panel for Shinogi, which makes Cephidericol. I will talk about Cephidericol, but I'm pretty sure after you hear what I say about Cephidericol, you're not going to think that I have some overwhelming industry bias. All right, so, you know, I think we all, you know, the ICU is an antibiotic-rich environment, and what that means is we are constantly exerting evolutionary pressure on bacteria and fungi, increasingly, to develop new resistance mechanisms. Now, we have actually made some pretty impressive improvements in the antibiotic pipeline since 2012. There are a couple laws passed in the U.S., the GAIN Act, which is part of an overall FDA overhaul act, and the 21st Century Cures Act of 2016. These led to an accelerated approval pipeline for antimicrobials. One of the downsides is they accepted a lot of kind of surrogate endpoints, which limits a lot of the applicability of the approval trials to the intensive care unit, though. There's also this thing called a Qualified Infectious Disease Product Designation, which helps move things through approval fairly quick. And the end result of that is if you look between 2022 compared to, say, 2011, the drugs, a lot of new drugs have been approved recently, and that has mean the Phase III pipeline has dropped. You see, the number of drugs in Phase II and Phase I is still actually pretty robust. There is a decent pipeline coming along of new antimicrobial products. So this is, generally speaking, good news. If you compare this to what we're facing in kind of U.S. hospitals in terms of MDRO rates, of multidrug-resistant organism rates, it's been pretty stable since 2012. It's actually been pretty stable. It is still unacceptably high, but it is reasonably stable. One of the newer things we see more of, however, is community-onset MDRO infections. Now, sometimes these patients wonder how community-onset is it if they had been, you know, say, for example, relatively recently exposed to broad-spectrum antibiotics or relatively recently stayed at a long-term care facility of some manner. But by and large, seeing things like ESBLs from a community-acquired pilo, for example, has become somewhat more of an issue. COVID did not make this better. There were a lot of things we forgot during the pandemic. One of them was certain routine infection-control prevention measures. As the acute phase of the pandemic has dwindled down, it'll be interesting to see how that pans out as infection-control measures are getting a little more, shall we say, rigorously enforced. So you see books like this every now and then living in the post-antibiotic era. You know, not quite yet. You know, someday maybe, but not today. Since 2010, these are, this is a, at least on antibacterial drugs, are mostly the new agents that have been approved. Now, I'm going to focus in this really on the beta-lactams because those are the ones that have the greatest applicability to the intensive care unit. I will allude to some of the others in red just kind of briefly. Plazomycin is a novel aminoglycoside that didn't get a lot of play, I think, just because in part that there's a generation of physicians who were trained thinking that aminoglycosides are poison. They're not. But it is a pretty potent agent. I think most of us have probably used fidaxomycin at this point for treating severe C. difficile. Lepamulin is an interesting drug approved for pneumonia. Not a lot of ICU experience with it, but it is an interesting antibacterial with a novel mechanism of action. And then arabicycline and imatocycline are two novel tetracycline derivatives that have some utility in, for example, certain multidrug-resistant organisms. Don't have a lot of activity in pseudomonas, but have some activity in things like VRE, acinetobacter, ESBLs, and the like. They do not get a lot of play in the ICU mainly because of their similarity to tigacycline, which has data supporting increased mortality in the treatment of critically ill patients. But there is probably a niche for them in the unit. I think the likelihood of an intensivist initiating one of those drugs without ID input is relatively slender. But nonetheless. So let's talk first about ceftaroline. This is kind of the oldest one on this list. This has been available in the U.S. for a number of years now. This is a cephalosporin, but it's unique or somewhat unique among beta-lactams in that it has activity against MRSA. And when you think about the spectrum of it, you can kind of think of it as like vanc plus ceftriaxone in one drug. Approved in 2010 for community-acquired pneumonia and complicated skin and soft tissue infection. There's relatively limited data in VAP and bacteremia. The package insert dose is Q12. Dosing at Q8 is probably the way to go, at least in the ICU. And this has to do with a number of pharmacokinetic concepts in critical illness, including altered volumes of distribution, augmented renal clearance in certain patients with sepsis. Bolus and infusion might be okay as well, but that's all relatively investigational. I'd say in the times I use it in the unit, I tend to dose at Q8. And for bacteremia, that is sort of the received wisdom, but there isn't a ton of prospective data. When you look at the data for bacteremia, it looks roughly comparable to daptomycin. This was an observational study published last year of 187 patients who got dapto versus 83 who got ceftaroline. And the failure rates were a little bit low with ceftaroline in terms of composite failure, but 30-day mortality was roughly pretty comparable, so not a ton of difference. Dapto is a decent drug. Ceftaroline is a decent drug. There's not really a great niche for it now. I'll say most of us, when we use it, we use it as a salvage agent for non-resolving staph bacteremia. But it may turn out to be a great, like, flu season monotherapy drug, right, when you're worried about MRSA pneumonia and the like. Now, there have been a ton of what we'll call beta-lactam, beta-lactamase inhibitor combination agents coming out in the last several years. And I think, like, I'm an ID doctor, and I sometimes wrestle with, what's the difference between these agents? When do I use them, and what are they for? And so we'll kind of talk about the data and give you a framework to think about when one might use one of these agents versus another. So ceftolazate and tezobactam, ceftazatebactam, mirovabrabactam, and imipenem. Imipenem, silostat, and relabactam are the ones. Now, when we think about kind of what they're for, and if you have to create sort of a mental map, ceftolazate and tezobactam, which is marketed under the name Zerbaxa, is for carbapenem-resistant pseudomonas, right? That's what that's for. Ceftazavibactam is for carbapenem-resistant entrobacterialis, particularly Klebsiella, but some others as well, right? That's what they're for. Now, sometimes Avicaz or ceftazavibactam will treat pseudomonas. Sometimes ceftolazate and tezobactam will treat carbapenem-resistant entrobacterialis. But in general, this is a worthwhile framework, right? And it's sometimes interesting to check one if the other one doesn't work. Miropenem, vabrabactam, and imipenem-relabactam are really for carbapenem-resistant Klebsiella, right? That is mainly what they're for. And this is sort of an interesting thing, right? The cephalosporins in this case are broader-spectrum agents in general, particularly ceftazavibactam, compared with the carbapenems, which is just an unusual place to be. And we'll talk about what the niche for those drugs is. So looking at ceftazavibactam, avibactam is active against carbapenemases. Two big groups, KPCs, which are the most common carbapenemases in North American hospitals, and ESBLs. But it's not active against other, some less common ones. Metallobetalactamases are a good example. Those are common in many parts of the Indian subcontinent, Southeast Asia, and the like. There's also a lot of non-enzymatic resistance mechanisms, particularly in pseudomonas. These are like efflux pumps, downregulation of porins in the outer membrane. Those, all the betalactamase inhibitors in the world aren't going to do anything for. So the big trial that is sort of of critical care relevance is called the REPROVE trial. This is a double-blind, phase 3, non-inferiority trial of ceftazavibactam versus mirapenem for VAP. Pretty big study, 726 patients and a modified intention to treat. Cure rates were 68.7 with ceftazavibactam, 73% with Mira, right? So non-significant difference, it met non-inferiority. But you also see not radically better, right? Not radically better. And this is one of the things I think it's kind of worth for us to take, I don't know, comfort in, I guess, is that every now and then it comes up the idea that should we be using these very broad-spectrum, last-line agents as empiric therapy, right? Knowing we have this rising tide of drug resistance, knowing that delays in active therapy, particularly in septic shock, increase mortality. So should we just put everyone on AVCAS when they hit the door, right? And the short answer is no. In all of these trials, the broader-spectrum agents, and you're compared to mirapenem, right? I mean, it's like how broad do you want it? They are not dramatically better for empiric therapy. So we are not achieving a meaningful public health goal by starting on the broader agents. There are other trials of this drug. Similar results in complicated intra-abdominal infection. These were conducted particularly in areas with high rates of carbapenem resistance. Like there's a very large trial performed in India where carbapenem resistance is a particularly marked challenge. And ceftazabactam was not superior, it was not inferior, but it was not superior to empiric miro. So clinicians practicing in those areas can take a little bit of comfort that not everyone needs to be put on this. But when you got it, you got it, right? Now, ceftazabactam is an anti-pseudomonopedicillin, or sorry, cephalosporin, combined with beta-lactamase. This inhibits sort of like, it's tezabactam, right? It's in PIP-TEZO, right? That inhibits what we'll call regular beta-lactamases. Also inhibits ESBLs and AMP-C. That's what like entrobacter and clevirogenes and citrobacter and serration make. So this was the ASPECT-NP trial. This is double-blinded phase 3 non-inferiority. Again, ceftazabactam versus miropenem for intubated patients with HAP-VAP, right? Again, 54% versus 53% cure rates, identical mortality rates. So again, largely interchangeable. This is not a reliable agent for carbapenem-resistant entrobacterialis, so like CLEB or E. coli. But it is a pretty good pseudomonas drug. And I will say that I periodically use this in my practice, right? Mirovabactam and imipenem and relabactam, I'm going to lump on one side, but I'll just upfront tell you, I have never prescribed these drugs. I'm a transplant ID doctor who works in intensive care units. I have never prescribed these drugs. But I do think they have a niche, right? They do have a niche. So these beta-lactamase inhibitors are pretty similar. They're similarly active against ESBLs, AMP-Cs, and KPCs. They don't have any activity against OXA48, which is another common kind of carbapenemase. Avibactam does cover that. This does not. There's pretty limited data in critical illness. There is a thing called the TANGO trial that was, there's also an HIV trial called the TANGO trial, so I find this irritating, but that's a separate story. Mirovabactam versus Piptazo for complicated UTI, and then the Restore-Immi trial. Again, imipenem, relabactam versus Piptazo for HapVap. And they are, again, play out about the same. But there's still a niche for these agents. So relabactam and vabrabactam, this is a little chart that just shows what gets inhibited by what in terms of different beta-lactamase inhibitors and different types of beta-lactamases. So relabactam and vabrabactam are actually a bit narrower spectrum than avibactam, like I said. But it is interesting because there are the occasional Ceftazavibactam-resistant isolates that Miro or Immi with their combination drugs do treat. So there is a niche. There is a niche for these agents. The main advantage for these guys, just in my perspective, is that there are times when you kind of specifically want a carbapenem, like mixed infections, like a mixed intra-abdominal infection in someone with a KPC or an ESBL in the mix, but you don't want to have to give like, you know, Ceftazavibactam plus Vanc plus Flagyl plus, plus, plus. So there is definitely a niche. There is, again, this sort of reassuring finding that these drugs are not superior to rupine-empiric agents in critical illness. So we can reserve these for highly drug-resistant infections without harming other patients by withholding what would be potentially life-saving care. Right? That make sense? Cool. Cephidericol, again, disclosure, previous disclosure. I did some consulting for Shianogi, who makes this drug. So this is Acidrophorcephalosporin. It's kind of this novel mechanism of action. So bacteria have iron transport mechanisms, right? Like, I had a resident who went into hematology, and every time he was in the unit, he would try to correct everyone's iron deficiency anemia with IV iron. I believe Dr. Goodfellow knows whom I'm referring to. And I had to tell him, so, like, why does ferritin go up in acute illness, right? It goes up to try to suck iron away from bacteria, because iron is bacteria food. So, like, please stop doing that. So Acidrophorcephalosporin hijacks bacterial iron transport systems so they can bypass resistance mechanisms, right? So it's kind of a neat thing. Broad coverage against otherwise—this is very much a drug of last resort, other than, say, like, colistin, okay? It's very broadly sensitive against multiple resistant gram-negative isolates, you know, MBLs, carbapenem-resistant pseudomonas, carbapenem-resistant acinetobacter. So, you know, it's a very broad-spectrum gram-negative drug. But this was an APEX-NP trial, compared cephidericol to Miro for gram-negative nosocomial pneumonia. Same, right? The outcomes are the same. There is no particularly demonstrable benefit to this drug. No, have I used it? Absolutely. I have a guy with AML and otherwise untreatable pseudomonas who I have on this, right? So it is definitely a drug that has a niche, it has a role for highly drug-resistant gram-negatives, but is not a panacea. It is nice to have—I think it's probably a little bit better than colistin, quite frankly, but that is also not an overwhelmingly high bar to give it. Being a better drug than intravenous detergent is not, strictly speaking, a great accomplishment, right? All right, so in terms of novel agents, like what—so this just got approved, and this is very much a niche drug, right? This is not a drug that anyone will ever prescribe empirically, but it's kind of neat. So sulbactam and drilobactam. So they don't ever use, like, Unison for—I mean, it's a trade name, but it's like a 40-year-old trade name, so I don't think anyone's going to mind. So you don't ever use Unison for acinetobacter, right? So you have to use massive doses of Unison. It's like 9 grams IVQ-8 to treat acinetobacter. And the reason for that is that the active drug in Unison against acinetobacter is not ampicillin. It's sulbactam. The beta-lactamase inhibitor is the active drug. So when you use it for acinetobacter—and this comes up in my burn unit a lot— you have to give, like, marginally subtoxic doses of it to treat. So someone finally figured, why don't we just, like, market sulbactam as a drug? And they combined it with drilobactam, which is another beta-lactamase inhibitor. So it's two beta-lactamase inhibitors is basically what you're giving them. It doesn't do anything for anything that isn't acinetobacter, right? It treats just acinetobacter. But it seems like a pretty good drug. And actually, the interesting thing about this trial for it, the ATT&CK trial, is actually the sicker patients on the vent were actually more likely to be randomly allocated to the sulbactam arm. And there was a non-inferiority and maybe sort of an early trend towards superiority. So it's certainly no worse than colistin. It's probably less toxic. And these were the curves. You see, I always kind of hate it when people say that there was a, this is all-cause mortality, so higher is worse, lower is better. The blue line is sulbactam, the red line is colistin. This is what they mean by trend towards superiority. Like, yeah, that does look like those curves do separate pretty well. And if it was a larger trial, that might be more clear. And this was published relatively recently in Lancet Infectious Diseases. This is a drug that is not available in the U.S. It is available in Europe and the U.K., not yet available in the U.S., but it might be soon, because this just came out in the New England Journal. That's usually kind of an opening shot from a drug company that they're going to try to get something FDA-approved in the States. So this is also, like cefcaroline, a cephalosporin that binds penicillin-binding protein 2A. That is the molecule that makes MRSA MRSA. So this drug treats MRSA, enterococcus faecalis, and pseudomonas, although weirdly not ESBLs. And if you think of it in terms of spectrum, it's kind of like vanclocefepine in one drug. So, interesting, and also sort of novel in the sense that there is a teaching that enterococci, an accurate teaching, by the way, that enterococci are intrinsically resistant to cephalosporins. This is an interesting exception to that rule, right? So the eradicate trial, this was a double-blind RCT of ceftabiprol versus dapto for complicated staph bacteremia. So they actually did the staph bacteremia study that we've never gotten for ceftaroline. 387 patients. The downside, so these were enrolled in Eastern Europe, including in Ukraine. Some of this was presumably going on during the conflict in Ukraine. Relatively little endocarditis. It's not really clear from reading the study how many of them were truly septic. But for what it's worth, it was non-inferior to dapto. So that is at least knowing that this is a potentially promising agent for staphylococcal bacteremia will be nice to know if and when that gets approved in the U.S. These were the outcomes of that. Roughly 70% efficacy in both groups. All right, so that is a whirlwind tour of new antibiotics. You guys got any questions before we move on? We're doing okay on time. All right, so in general, armamenthermia is a resistant pathogen. It's growing. We still obviously have challenges. There's no silver bullet. There are very limited trials for non-beta-lactam agents so plazomycin, imidacycline, and aravacycline are kind of the three that I would be the most curious about. We are not yet at the point where there's an empiric role for these drugs. I was at a meeting a few years ago and there was some talk from some of our surgical colleagues about maybe we should be using empiric AVCAS, ceftazidime, for intraabdominal infections. And I got up and I said, I love you guys, but the thought of surgeons starting people on empiric AVCAS makes my heart drop into my sigmoid. I was very proud of that line. Sir? What are some of the common things to watch for in ICU side effects? Yeah, I mean, it's pretty standard issue beta-lactam stuff, right? So the dose-limiting toxicities of beta-lactams are actually generally neurologic. And so we see this if you look at large series of people with acute kidney injury who we don't do. So in septic shock, the first dose of any antibiotic is a full dose, right? You have to fill up the tank and get to steady state. So when someone has a creatinine of 5 and they show up in shock and you're going to give them cefepime and Vank, the first dose of cefepime is a full dose, right? But then failure to modulate that over time, or the occasional people who are on double beta-lactam therapy, what we see are seizures. It's encephalopathy and seizures. A personal bugaboo is that neurologists, if you get consulted, they get like a delirium consult, and if someone moved a bottle of cefepime through the room, they blame it on cefepime. This has become recently popular. But there is some truth to that. But it is actually a class effect. It is a class effect that generally what you're going to be looking for from ICU toxicity is going to be neurologic, and that is dose-related. And then you have the standard issue side effects. So cephalosporins, cytopenias are common. It usually takes about two weeks for that to really start. But leukopenia, when we give people, like, say, ceftriaxone for outpatient pronal antibiotics for endocarditis, for example, around week three we start to see the white count dropping. With the penicillin combination agents, LFT abnormalities become relatively common about the same point. And then you have the omnipresent concerns of allergy and C. diff. But I will say allergy, I think we've all had this beaten to our heads now, that true beta-lactam allergy is considerably less common than is reported. And I would be, shall we say, reluctant to withhold a potential life-saving agent because they said their mom said they had a rash when they had penicillin when they were two. But, yeah, neurologic ones, I think, are probably the most under-recognized ones. We don't really think about that. Everyone was like imipenem and seizures, right? But that's actually every beta-lactam. My ID fellowship program director is, when he was a fellow, there was sort of this apocryphal story back at the old Bethesda Naval Hospital that there was a guy who said that the most common cause of cellulitis were staph and strep. You treat staph with nafsulin, you treat strep with penicillin, so he'd give everyone a combination, nafsulin and penicillin, and then he couldn't figure out why all of his cellulitis patients were having seizures. Apocryphal story never validated many years ago. Right. Sir. Very good talk. Thank you so much. Thank you. So you mentioned there's no reason for us to introduce any of these medications, using antibiotics as an empiric therapy. Right. Shown in the slides. As everyone here, they work on their local antibiotics and try to determine what to do based on their local antibiotics. In your experience, what percentage of resistance that we see in the local antibiotics should trigger us to think, okay, you know what, we need to start switching our antibiotics? I would actually say I don't say that I never use these drugs empirically. Sometimes I do. But that's rather a question of looking at the individual antibiogram of that patient. Old cultures can be predictive of future cultures. And one thing I do when I'm doing a consult or when I'm admitting someone to the unit, I try to pull up any old culture data I can in Epic or what have you and see what this person has. I'm thinking of one gentleman who gets admitted to my ICU with some frequency, continuity of critical care. He's a primary care intensivist. I know that this guy has grown KPCs out of his blood many times. This guy shows up in the emergency department. He's getting AV-Cas. So in terms of what's a threshold, that's going to depend a little bit on the local math. Five to ten percent resistance rates in ICU patients would be a typical time to start reconsidering what your empiric therapy is. But it's actually very individual. Like at Wake Forest, for example, cefepime is more likely to be active against pseudomonas at my hospital than miripenem is. So we use very little empiric carbapenems unless we know that someone has had a thing in the past. But 5-10% would be typical, but that's going to be very much an institutional decision and driven by other considerations as well. It's a great question. Thank you, sir. All right. Thank you. All right. Good morning, everybody. Thank you, Dr. Maves. He has just reinforced for me why my local I.D. doc is my best friend in the ICU. I appreciate you all coming this morning. It is bright and early, so thank you for coming out. My name is Namita J. Prakash. I am an emergency medicine and medical intensivist based out of Henry Ford Hospital in Detroit. I also serve as the associate medical director for quality and safety for the emergency department and the lead for the system sepsis program, so overseeing the five acute care hospitals. I am a researcher. I currently am doing a study that's more biomarkers in heart failure with Abbott, so not as much of a conflict for this particular talk. I'm going to be talking about really severe pneumonia. We're going to go through the current guidelines today and describe approaches for the diagnostics and the therapeutics when it comes to severe pneumonia in the ICU. Community-acquired pneumonia is a very common illness. As an emergency physician, as a medical intensivist, it is one of the most common diagnoses. As a quality lead for the system sepsis program, number one diagnosis for sepsis admissions in my health system is community-acquired pneumonia. One to 25 cases per 1,000 inhabitants per year is the incidence for community-acquired pneumonia. 40% of these will require hospitalization and 5% go on to require ICU level of care. Severe community-acquired pneumonia, or CAP, is still one of the most common precipitants of ARDS. And interestingly, 3% of those who are hospitalized with pneumococcal CAP will get ARDS. So when we talk about categorizing or describing or defining severe pneumonia, we commonly apply some severity index scores. So the pneumonia severity index score, sometimes referred to as the PORT score, was first described in 1997. It uses demographic parameters such as age, sex, whether a patient has been a resident of a nursing home, comorbidities, physical examination findings, and complementary laboratory and imaging tests. The score categorizes patients into classes 1 through 5. And these classes are really defining the 30-day mortality risk. And so as you progress from classes 1 through 5, the mortality risk increases from 0.1% all the way up to 27%. And it's often used as a benchmark of recommendations and how patients can be treated in the outpatient setting versus the inpatient setting. Another scoring system to help define severity is CURB-65. I'm going to be honest with you. One of the biggest advantages of CURB-65 is as an emergency physician at the bedside, when I'm seeing a patient, I can very much remember the variables of CURB-65 of neon-sick confusion, urea greater than 7, respiratory rate greater than or equal to 30, hypotension or age greater than or equal to 65 much, much better than I can all the variables of PSI. So there is a real-world pragmatic advantage for CURB-65. But similarly to PSI, CURB-65 categorizes patients based off of the 30-day mortality rates. And so the scores are 0 to 5. The higher the score, the higher the severity. And again, CURB-65 breaks it down into recommendations for outpatient versus inpatient care. And CURB-65 also distinguishes between short versus longer inpatient cares. The real indicators here is the higher the score, that's more likely the patient who has the risk of being admitted to the ICU. So that's the type of patient that us as intensivists are going to be more focused on. In 2007, the IDSA ATS guidelines recommended a different approach of categorizing and defining severe community-acquired pneumonia. So for major criteria, so patients with septic shock because of pneumonia requiring vasopressors and those who are requiring mechanical ventilation, they're going to go to the ICU. Pretty straightforward. Severe cap. However, there are also three or more of the minor criteria met. These patients have a validated increased risk of needing admission to the ICU. So if you've got three or more, you can define that as severe community-acquired pneumonia. But frankly, the bottom line is severe community-acquired pneumonia is community-acquired pneumonia that's going to require the ICU. That's a much more simpler and easier way to categorize and think about these patients. So I'm going to pivot and talk about what do the guidelines say. The most recent clinical practice guideline published from IDSA and ATS and the diagnosis and treatment of adults with community-acquired pneumonia is from 2019. In the 2019 guidelines, there is a recommendation of using PSI over curb 65 for describing the severity and categorizing cap. The strong recommendation for admission to ICU, straightforward. Patients requiring basal presses if they're mechanically ventilated. What if they don't meet the above criteria? The 2019 guidelines continue to endorse the application of the minor, three or more minor criteria from the 2007 guidelines. And why? It's because they remain sensitive for predicting the need for ICU admission during the hospitalization. So you have severe community-acquired pneumonia. A patient's been categorized. They're admitted to the hospital potentially needing ICU or they're in the ICU. So what are the important diagnostic tests? Well, if it's influenza season, make sure you get your influenza PCR. Blood and respiratory cultures are recommended, Legionella urinary antigen, and if available, the respiratory cultures and nucleic acid assays. A strep urinary antigen is recommended by the 2019 guidelines. And if initiating any anti-MRSA therapy or if the patient has risk factors for MRSA, grab a MRSA PCR. OK, so we have the QR code in the bottom if you haven't had a chance yet. But I would love to hear from you. When you're admitting a patient to the ICU with severe community-acquired pneumonia, what's the antibiotic regime that you prescribe? All right, very interesting. So beta-lactam and macrolide, beta-lactam, fluoroquinolone are the top choices. So let's move on and see what the guidelines say. So the 2019 guidelines do recommend a beta-lactam with macrolide or a beta-lactam with fluoroquinolone. Now, the recommendation does include stratifying the patient based off of risk for MRSA infection or risk for pseudomonal infection. And so if those do exist, the coverage of anti-MRSA and anti-pseudomonal. Any questions on what the 2019 guidelines are saying? Any reflections on the interesting practice the group, the bank, and staff have made? I know a lot of my colleagues do that in the emergency department, so it's not uncommon. Yes? Good question. You know, the risk, yes. So in, can you hear me okay? So in pure community-acquired pneumonia, right, like not recently in the hospital, no underlying structural lung disease, which is sort of the, and not significant immunocompromised, like diabetes is, of course, poorly controlled diabetes is a form of immunocompromised, but assuming that it's not, you know, someone with leukemia or what have you, it is extremely rare to find MRSA or staphylococcal pneumonia in general in the absence of concomitant influenza or human metadenoma virus infection, to the point where the guy who writes the clinical virology textbook said in public that I don't think it exists, right? Now that may be an exaggeration, but nonetheless, so the incidence is going to vary by season, right? So in respiratory virus season, it's going to go up because of post-influenza pneumonia. For ICU-level sick, it kind of comes down to how lucky do you feel, right? Because I think relatively, it is relatively rare that we admit someone to the ICU in septic shock on the ventilator who does not have some immunocompromising condition or prior healthcare exposure. And, you know, my perspective on this is I respect what the guidelines say. I don't actually like the quinolone idea, but that's separate. I don't think that adds much to a macrolide, but blah, blah, blah. But in someone who's on the vent and on vasopressors, those are the people who syndromically could have staphylococcal pneumonia, right? Staph aureus pneumonia is not a subtle entity. And so as an ID doctor, I honestly don't care what anyone does in the first 48 hours of antibiotics. I am just profoundly disinterested, right? You do what you got to do. Get cultures, get specimens, get the MRSA-PCR so that we can dig ourselves out of the hole, right? But what you do first, you feel like giving Vank, brother, give him Vank, right? And we'll deal with it later. As long as you get cultures, as long as you get the PCR, as long as you give us a tool to dig ourselves out of the hole. Thank you for making that statement. You said the first 48 hours of waiting patients. Yeah. In terms of creative sepsis. Yeah. As long as there's a flag of B.S. collected. Yeah. Exactly. Follow-up question. Stations that get admitted for community-acquired pneumonia have a lot of risk factors, like drug use. Yep. Vaping. Yeah. Recreational. Activities. I mean, is there any increased risk of STAT or risk factors? With injection drug use specifically, yes. Absolutely. That is a well-known and well-described risk factor. And someone with a history of injection drug use, absolutely. With vaping and things like that, you start moving to more non-infectious things, right? E. vali and D. synophilic pneumonias and the like. If marijuana, it's actually aspergillosis. It's not STAT. Yeah. I just wanted to add something to what you said, Ryan. The regimen of Vaxosin or Vaxazepine, although it might be adequate, we have to remember that we're missing the atypicals, which also can cause severe infection in the ICU. Yeah. Yeah. Thank you. Great points. One of the, I didn't say one of them, but a criticism of the 2019 guidelines is that they were very specific in recommending the beta-lactam, microli, beta-lactam, fluoroquinolone, and didn't emphasize as much some of the local epidemiological factors and the local microbiological data, and certainly how do you define the validated risk factors. And so I think those are great conversation points for things to take into account. And it oftentimes, I know the ones that stick out in my mind are the unexpected MRSA bacteremic patients or the unexpected MRSA pneumonia patients. Everything screams community-acquired pneumonia, and guess what? Not getting better, and the cultures are growing MRSA. I've been there. So moving on, the guidelines, in terms of procalcitonin, they're specific and don't use procalcitonin to guide initiation of therapy. Now, what they do acknowledge here is that there is data that supports that. There is a distinguishing feature of procalcitonin between viral infections and bacterial infections. However, that threshold is not so clear. And so that's where the recommendation remains. Don't use it to initiate therapy, but has great value in de-escalation. Duration of antibiotics, no less than a total of five days, but for suspected MRSA and pseudomonas, continue for seven days. The biggest change in the 2019 guidelines was the abolishment of the term of healthcare-associated pneumonia. So that is an obsolete term. The wording on the guidelines was actually that it should be abandoned as a category. It's very strong where it's in my mind. And there's some emphasis here that the reason for abandoning that is that there is local epidemiological, there are validated risk factors to determine that need. So the broad term of categorizing, if you've been in the healthcare setting, is not as refined. And there's emphasis on de-escalation if cultures are negative. So as Dr. Mance said, first 48 hours, you might be going broad, but de-escalation here is key. So I'm going to pivot now and talk about the 2023 European guidelines. So these were published earlier this year and is a combined guideline from the European Respiratory Society, the Society of Intensive Care Medicine, Clinical Microbiology, and the Latin American Thoracic Society. So the European guidelines define severe community-acquired pneumonia that's requiring ICU admission. So in that, there is acknowledgment that ICU admission is a very heterogeneous population, especially when you don't have shock or need mechanical ventilation. So the caveat that they describe is these recommendations should be cautiously provided, accounting for that heterogeneity in the non-shock, non-mechanically ventilated patients. The guidelines did not consider immunosuppressed patients, so those on steroids, chemotherapy, undergoing transplant, hematological malignancies, HIV, et cetera. In terms of diagnostics, the 2023 European guidelines accounted for the emergence of new technologies, so rapid microbiological techniques from the respiratory tract, so multiplex PCR testing specifically. Do you need that on all your patients? The suggestion is not necessarily. However, say that you are considering a non-standard antimicrobial regime. That's perhaps the time to get a multiplex PCR if it's available in your unit. Procalcitonin, again, a suggestion to use procalcitonin for reducing the duration of antibiotic treatment, but not necessarily for initiation. Empirical therapy. So the 2023 guidelines favor Dr. Mavis' approach of add macrolides but not the fluoroquinolones to your beta-lactam regime. This is a conditional recommendation with low quality of evidence, so just a suggestion. Influenza. So if there's confirmed influenza by PCR, most definitely add oseltamivir. If you're in influenza season, there is a strong suspicion but perhaps not necessarily confirmed, we do also recommend adding oseltamivir at that point. He says suggest using prediction scores to assess for drug-resistant pathogens and so to determine the most appropriate broad-spectrum antimicrobial, integrating those risk factors and the local epidemiology and most importantly, the previous culture results, so previous colonization. You already heard the old cultures can be predictive, so using that data as you're deciding what your empirical therapy is going to be for that first 24 to 48-hour period. Risk-based therapy regime over standard antibiotics for aspiration. The 2023 guidelines recommend you don't need to necessarily specifically cover for anaerobics coverage here, so suggesting standard CAP therapy even with aspiration risk. Now venturing into the therapeutic space, the 2023 guidelines did start looking at hyponasal cannula, non-invasive ventilation, so they both are recommended versus standard oxygen therapy for that severe community-acquired pneumonia patient population. So a patient who doesn't need intubation immediately, consider hyponasal cannula, but there's that subgroup that perhaps are remaining hypoxic on the hyponasal cannula, maybe not quite meeting those intubation criteria just yet, that next step up may be to consider non-invasive ventilation. Steroids and severe CAP. We're going to touch on this a little bit more in the cases, but neither one of the guidelines have strung suggestions for steroids. So the 2019 ATS IDSA guidelines, they suggest not routinely using steroids in adult severe CAP. The 2023 European guidelines suggest the use of steroids if you've got shocks, so more on the septic shock management guidelines. Both of these guidelines, however, were published before the publication of the hydrocortisone in severe community-acquired pneumonia trial. So this trial was a phase 3, multi-centered, double-blinded RCT. It focused on adults admitted to ICUs with severe community-acquired pneumonia, tested intravenous hydrocortisone, 200 milligrams either for 4 or 8 days, depending on the clinical improvement at the 4-day mark, followed by a taper. The primary outcome was death at 28 days. So it ran from October 2015 to March 2020. It was stopped at the second interim analysis, and so in total had 800 patients. There was an improvement in the treatment. There was a positive treatment effect for the primary outcome with the steroid group compared to the placebo. And also you can see in the graph at the top corner here, that that's actually looking at the percentage of patients that were discharged from the ICU, so favored the hydrocortisone group there. So the authors concluded that they did indeed find an early treatment benefit with hydrocortisone, where the 28-day mortality was reduced among patients who were admitted to the ICU with severe CAP. So key takeaways here. Severe community-acquired pneumonia is defined by admission to the ICU, or if you don't have that obvious needs, vasopressors, mechanical ventilation. Look at that 2007 minor criteria, and if there are three or more present, define that as severe CAP. Alternatives include the PSI and CURB-65 scores. Obtain your cultures, respiratory and blood, multiplex PCR if you're thinking about non-standard antibiotics. Stratify risk for MRSA and pseudomonas. Treat with oseltamivir for confirmed influenza, or if you're in influenza season and there's a high suspicion. Procalcitonin, not good for initiation of therapy, but has value in your de-escalation. High-flow nasal cannula and non-invasive ventilation have a role in your hypoxemic patients. You may not need immediate intubation. And steroids, well, that landscape is evolving and more to come. Any questions? Yes. I mean, are there any updates regarding COVID testing and treatment? Regarding which testing, sorry? I mean, COVID testing. Neither one of the guidelines focused on COVID-19. They were both, I guess the European ones were during that period, but neither one of them specified focus on COVID-19. Yeah, I mean, I think we've all kind of learned that at least new onset COVID pneumonia, the incidence of bacterial superinfection is quite low. I know that, you know, I would be lying if I said I never put them on antibacterial drugs when I intubate them. And I think that's probably, I think all of us have emotionally done that. I try to de-escalate rapidly when I don't have the intestinal fortitude to withhold them. That's not true of every virus. With influenza, for example, bacterial co-infection in the ICU is extremely common. And the guidelines do reflect that, that cap coverage of some flavor is appropriate, including usually some degree of anti-staphylococcal coverage. And metadenovirus is the same. Actually, RSV is the same too, of course, with the increased attention to RSV lately. About 10% of hospitalized patients with RSV pneumonia will have concomitant bacterial superinfection. Another 10% will have another viral pneumonia on top of it as well. So, yeah. Yes. That's a great question. I know in my own institution, we use it as on the initial admission and then at 48 hours and looking for that 80% reduction. So, that was from the original, the MOSES trial. So, that is one approach to take. I don't know if you guys have any other thoughts on propalsetone. Yeah. It's mostly on pneumonia, and it's only helpful if it's elevated and you can use it to de-escalate, but more to shorten the duration of antibiotics. Because, I mean, typically we treat for seven days, but if you check that day four or five and the patient is clinically doing well, that should be reassuring enough to stop the antibiotics at that point. But, unfortunately, if it's low at the beginning and still a bacterial pneumonia, I mean, it's of no help. Yeah. The 2023 guidelines do emphasize that if you see clinical improvement in your patient, there really isn't value in following the propalsetone at that point. So, because of the cost factor and the resource utilization. But when it's done, it should be done in a protocolized manner, like standardized every whatever 48 hours would be typical, right? There's a paper coming out in critical care medicine relatively soon looking at, I think critical care, looking at basically are we doing it wrong, right? The idea is that most procalcitonins ordered in U.S. hospitals are single measurements, and a single procal is like a single troponin, right? It's a number of no value. It's the trends that matter. There are a couple other questions here in the chat. One is duration of antibiotics for pseudomonas or MRSA for underlying chronic lung disease, seven versus 14 days. I'm actually going to cover that on my case, so. Oh, so Dr. Coase will address that in his case next. All right, so we will cover that. But there is some controversy, certainly. And then, don't floor quinolones in the hospital. Increase C. difficile infection. At least that's what the ID doctors told me. The ID doctors are correct. It does. And I think that's one of the reasons to maybe shy away from it. Sort of pound for pound, very few things provoke as much C. diff as quinolones do. Interestingly, tetracyclines might be protective against C. diff. There is a lot of observational data suggesting that doxycycline-containing regimens actually reduce the incidence of C. difficile. The problem is, you know, if you look at the pneumonia guidelines, doxy is offered as an alternative to azithro. But there's actually no trial for that. Like, there is no actual study. There's an observational study out of Australia, and that's it. And in a bit of reckless self-aggrandizement, I'll say that I wrote an article for a European ID journal saying that we need to actually do that trial. Because it would be interesting to see if that would be a way to address atypicals, like Dr. Coase pointed out, without increasing the risk of C. diff. But that's, like, hyper-hyper-theoretical. I can't hear the question. For initiation. So, they're not so much as saying it's not recommended, more so as there's not enough data. So, it's an acknowledgment that there is a signal that there's a difference between viral and bacterial threshold. But the threshold is what is not so clear. And so, it would be interesting to see in the next guideline updates where that goes. But right now, it's not as much that they're not recommending it. They're just saying we don't really know. And in general, for sepsis, the sensitivity is not high enough. So, the problem is that if we rely on procalcitonin to decide whether to initiate antibiotics or not, we would be withholding antibiotics for patients that have sepsis. And as you know, in sepsis, our margin of error by withholding antibiotics means the downside is mortality. So, that's why we should not rely on procalcitonin. It's more of a clinical judgment. There was a trial, not trial, an observational study run by, I think it was Wes Ely who did it, published in 2017 called the EPIC study. And they looked at procalcitonin patients with microbiologically confirmed bacterial, viral, pneumonia, co-infections, and the like. And it turns out that the negative predictive value of a very low procalcitonin, they cut off like 0.1, which is extremely low, in ICU patients is still, like the negative predictive value is like 80%. That's not nothing, but that means there's a 20% chance that person could still have bacterial pneumonia presenting with that syndrome. I don't feel that lucky, right? And I think that's the basis for that guideline recommendation. In more stable patients, it might be acceptable. Okay. I think we can move on to our cases. Good morning. Welcome to our session. My name is Angel Koza. I am a pulmonary and critical care. I work at the Cleveland Clinic. I have no disclosures. And we will use some cases to solidify some of the concepts that we have been discussing. So here we're going to talk about a patient with COPD. So it's a 75-year-old patient with history of very bad COPD with an FEV1 of 25% on oxygen at home, who presents with shortness of breath and increased sputum. It seems like my slides are not advancing there. Thanks. What do you see there? COPD, FEV1 of 25%, shortness of breath, and sputum production. Those are the vitals. As you can see, febrile, more oxygen, a little bit more tachypneic, but blood pressure is still adequate, a little tachycardic, increased work of breathing. And basically, this is the X-ray, you can see. And this is the initial lab work. I'll give you a minute to take a look at that. But as you can see on the left panel, there is an increased white blood cell count with bandemia. The lab work shows maybe elevated bicarbonate, which probably goes with the chronic respiratory acidosis. And then the ABG shows that there is hypoxemia. And the likelihood is 3.8. So in the ER, kind of going the same, I don't know how vancomycin ended up with that. I actually like it better that way. That is to reinforce that vancomycin should not be the regimen of choice on every patient, which seems to be a common practice. So I apologize for that. And you may see that it's a familiar practice that patients are all sent to the hospital who get vancomycin, irrespective of what the source of infection is. And I think this should give us pause as far as if it's pneumonia. We need to think about exactly what we are missing by using this regimen. So blood and stool cultures are sent. There is no signs of hyperperfusion. The capillary field is adequate. Urine output is adequate as well. And then the patient, because of the work of breathing, the patient is transferred to the ICU for BiPAP. So now if we are going to treat for pseudomonas, we talked a little bit earlier about the risk factors, right? So which one of these is the most predictive or strongly associated with a recurrence of pneumonia or a risk of pseudomonas pneumonia? Excellent. So most of you, although I think I gave it away when I said recurrence, but that's okay. Yes, it is correct. Although all of those are intrinsic risk factors for pseudomonas. So those are the risk factors that we need to look. But there is different strengths of the association. So this is a study that actually looks at the risk factors for pseudomonas in communic heart pneumonia. Here on the left, here you see all the patients that were hospitalized with communic heart pneumonia. And then on the middle panel is the ones that require non-invasive support or no vasopressors. And on the far right is invasive or respiratory support. And what you can see is that the presence of a previous pseudomonas infection, which is a history of lung disease, in combination were the ones that had the most, the highest prevalence of pseudomonas infection. And then here in green is patients who have history of pseudomonas infection in the past, but no history of lung disease. And by lung disease, what we mean is a decreased FV1 or bronchiectasis or cystic lung disease. And then if they don't have either of them, the risk of pseudomonas is very, very low. You can see in communic heart pneumonia is around 2%, kind of negating the need to use Spank-Sosin on every patient. Because, as you can see, the risk of pseudomonas short of those indications or short of those risk factors is very low. And when these were put into an odds ratio, as you can see the prior pseudomonas is the one that conveys the highest risk. The odds ratio is around almost 20. And then indwelling catheter is also associated. History of inhaled corticosteroids also, but not as strongly. Having a tracheostomy or having severe COPD are also associated. So going back to the question, patients who have history of severe COPD could have, but that is not as common as having a history of previous pseudomonas infection. So going back to our case, and now the patient is in the ICU with you. And, of course, now we look at all the previous cultures. And we learn this, that about a year ago this patient had a pseudomonas that was fairly friendly. Cefepime, meropenin, piptezo, gentamicin, tobramycin, susceptible. Then February 2023, a few months ago, that pseudomonas was not as friendly anymore. It had intermediate to cefepime and then intermediate to some other agents. So, I mean, of course, it's very early. We don't have antibiotics, any data for cultures yet. And then we have the nasal swab for MRSA, but it's negative. So what do we do now? Do we do vancomycin and meropenin? Do we just do meropenin? Do we do AV-Cas or do we do vancomycin? Good. Any comments, Dr. Maves? No, I agree. Good. It's a good choice. Yeah. So, definitely with the MRSA swab, we no longer need vancomycin. And the data for that comes from it. There's different studies. I just chose one of them. And this is a study that looked at patients with all types of pneumonia, but also CAP and HCAP when it was a thing, or VAP. And as you can see, the negative predictive value is in the mid to high 90s. So with a negative MRSA swab, we can have a high degree of confidence that that infection is not caused by MRSA and that we could safely stop the MRSA agent, in this case vancomycin. So two days later, patient is hemodynamically stable, still febrile, no longer requiring BiPAP, but still having fevers. So not totally out of the woods yet. Oxygen requirements have improved. And now your cultures come back. So this is a pseudomonas now that is present in this admission and compared to the previous one. So the question is now, based on those cultures, what would you do? Excellent. They were paying attention when you were. Yeah, so most of you. So colistin is not wrong. However, it is probably too big of a side effect profile. And if we have, maybe in the past when the other drugs were not available, it would have been probably the only option. We discussed earlier AVCAS is a drug that we use for carbapenet-resistant enterobacteria and also could be used for carbapenet-resistant pseudomonas. And now to the question that we had in the audience a little bit earlier, how long would you treat in this case? So we have a patient who has had pseudomonas three times now. Will we treat for seven or eight days or will we treat for 14 days? Hmm. Divided. Excellent. So I think this is an area that still is a lot of controversy, but kind of going over the data that informs. I would personally treat for 14 days, and I'll explain why. But the data is still very, very controversial. When we look at the data for treatment of ventilator-assisted pneumonia, the study that kind of changed our practice from treating pneumonias from 15 to 8 days was a French study in the early 2000s that showed that there was basically no difference. However, if you read the fine print, when we're talking about gram-negative oxidase-positive rods, aka pseudomonas, there is a higher risk of recurrence if we treat shorter courses. So the two guidelines, both the IDSA, ATS, and the European guidelines, in the latest rendition they recommended that we should treat for seven or eight days using meta-analysis data from several trials. However, in this case, I would argue that this patient has had already pseudomonas recurrence several times, although it's not necessarily a recurrence, but it's a pre-infection months later. And I would personally treat 14 days, but there's definitely some argument that you can say to treat for eight days if you want to be stewards of antibiotics and not treat for very long. However, there's also the risk of recurrence, and I will be curious to hear Dr. May's thoughts on this. You know, it's interesting you say that because I think after the publication of the 2019 guidelines, my own institution moved very much towards an eight-day regime. Does it feel like we're seeing a lot more recurrence? It kind of does feel that way. But I think for antimicrobial stewardship perspective, a lot of places, I feel, have moved to that eight-day regime. I mean, for this guy, this actually might be a place where ProCal has a pretty real role, right? If he's improving and normalization of procalcitonin. I mean, because the downside of this guy is that you're putting in a PICC line. You know, if he's getting better and he's going to leave the unit, he's getting a PICC line and OPAT and the outpatient parental antibiotic therapy, and that is, or he's going to a SNF or he's going to stay in the hospital for 14 days, right? There's real costs and risks to him, not just costs to insurers or what have you, or to Medicare or Medicaid, but, like, there are risks to him. It's about a 10% complication rate with PICCs for OPAT, meaning combined incidence of DVT or secondary bacteremias, right? So the risks are real, and if we can avoid OPAT in this situation, this might be a time where we use a biomarker-based strategy to try to discontinue. What I actually wonder about this guy is does he need to be on, like, inhaled amikacin or something going forward to reduce his future risk, and would that perhaps be a better strategy for him? But I agree, the seven versus 14 days is a gray area, and I would not fault a colleague who said, I'm treating this guy for 14 days, like, I hear you. Yeah, I get it. Yeah, it's a gray area. As you can see, there's different approaches, and I think they both have arguments to say that they are correct. So it's kind of taking procalcitonin would be a great option here, unfortunately. I don't think I included that in the case. And also it's because a lot of times it's not something that we do in a protocolized way, so it might be day one and then day seven. So it's something that needs to be more strategically done on a consistent basis. Want me to go to the next case, or do you want to do one of your cases? We should probably keep going. I mean, do you want one of us to do ours? We might push to 7 o'clock, but at 7 we probably need to cut you guys loose so you can make it to the next sessions. Is that all right? Any objections? Do you want to do another infection or do you want to do the steroid one? It's up to you. Why don't we move over to the next one? Okay. I'm happy to do it. Yeah, I can do my next one. Why don't I do that? Okay. All right. Okay, so this case is a 56-year-old kidney transplant recipient with cough, dyspnea, and fever. Me again? Okay, so 57-year-old man presenting the emergency department, 10 days of minimally productive cough accompanied by fever and night sweats and worsening dyspnea. He works as an accountant in Charlotte, North Carolina. He is a lifelong nonsmoker. His history of HIV infection diagnosed in 1998. His last CD4 count was 583. He has a viral load of zero. In clinic last month, long history of excellent adherence to antiretroviral therapy. He's on a regimen of dolutegravir and lamivudine. This is marketed as Dovado. This is a very good regimen. He has a history of ESRD due to FSGS. He had a deceased donor kidney transplant in April of 2020. He is CMV donor negative, recipient negative. Creatinine is 1.3 at baseline. He's on a fairly standard immunosuppressive regimen of tacrolimus, mycophenolic acid, and prednisone at 5 milligrams a day. He takes dapsone and acyclovir for prophylaxis. Our kidney program kind of keeps you on PCP prophylaxis forever. No episodes of acute rejection. No recent hospitalizations. His only surgery is a kidney transplant and appendectomy in childhood. He's married. He lives with a spouse in a single-family home. No children in the home. They have one pet dog. They traveled to Spain and France on vacation six months ago. Seven days ago, he was spent seven days in Arizona. A month ago, he camped in Saguaro National Park with some friends. So when you see him, he's febrile, 38.2, normotensive, but tachycardic at 127, tachypneic at 32, hypoxemic at 87% on ambient air. He's alert, but he's in visible distress. He's got bilateral vesicular breath sounds. He's tacky without murmurs. Belly's soft. No lymphadenopathy and no rash. White count is 80% neutrophils. Creatinine is 1.4, which is his approximate baseline. Blood and sputum cultures are sent. He has a respiratory viral panel and MRSA PCRs. Those are negative for mesonaries and nasopharynx. He's placed on heated high-flow nasal cannula, 90% FiO2, 50 liters per minute, and admitted to the ICU. This is his chest X-ray. This is his chest CT. Relatively bilateral multilobar consolidations, but particularly dense in the left lower. All right, so this is a dirty question. We're taught not to write negative answer questions, but, you know, what are we going to do? What does he not have on this list? The answer is PCP. He doesn't have PCP. Okay, so the reason is this. Dapsone is very active. For his HIV, he doesn't have PCP, right? If you have viral load of zero, you don't have pneumocystis. I don't care if your CD4 count is two. If you have HIV and you have an undetectable viral load on antiretroviral therapy, you don't have pneumocystis. But he's also still on Dapsone as well. He's far out from his transplant. PCP, the odds of this are essentially nil, right? But everything else is on the list, right? Like, he could have everything else, including, so he's CMV donor-negative, recipient-native. He could have de novo primary CMV infection. All right, so I will be more patient this time. It's my itchy trigger finger. What would be a reasonable empiric regimen for this guy? So I have linazolidazithro and leviquin, unison and doxy, vanc, ceftaz, and flagyl, cefepime, azithro, and ambazome, and ceftriaxone and fluconazole. Let's go back to this so you can see it. Oh, there we go. All right. I agree. But, we'll go into a little detail on this. I agree, cefepime, azithro, and ambazome, right? Now, let's see. Okay. What's, am I clicking through? There we go, okay. This is why I think that, right? This is kind of, this is a no perfect answer kind of question. This is what I argued. So, linazolid, maybe, but he's MRSA negative, so he doesn't need it, and there is overlapping toxicity and spectrum of activity with azithromycin and leviquin. There's basically, outside of like some NTM infections, there's no reason to ever give a macrolide and a quinolone at the same time, right? You're just going to give this guy torsades. Which I think probably a lot of us have seen happen, right? Amstel, baccium, and doxy, that's actually not a bad CAP regimen. Like, that's actually a pretty good community-acquired pneumonia regimen. So, I think it would be unconventional, but, I mean, if he was just straight-up community-acquired pneumonia, and he didn't have a kidney transplant, that would actually not be a bad regimen, right? And if he wasn't, perhaps that's sick. Banxiftazin flagell, metronidazole has no role. We've discussed this. There's a handful of sittings in pulmonary medicine where anaerobic coverage is important, but it's like lung abscess, certain complicated perineumotic fusions, and empyemas. He doesn't have that. And he's MRSA-negative. So, cefepimeazithro and liposomal AMFO, I'd argue he has respiratory failure from a fairly high probability of an endemic mycosis, and that's empiric ambyosome. I will tell you that when I do things like this, my transplant nephrologists absolutely soil themselves with rage, right? But, I mean, got to do what you got to do, right? And then ceftriaxone and fluconazole, you know, maybe if you suspected Coxian and he were less sick, that's, again, there's probably some rationale to that. So, none of these are perfect. I think there's room for dispute, but it's an interesting kind of thought exercise. All right, so there are guidelines on, or a consensus statement, anyways, from CHESS, from 2020, on the treatment of communicable pneumonia in immunocompromised adults. And this, you'll notice the year of its publication, and probably appreciate why it didn't get a ton of traction. It came out in, like, peak COVID, but it's a really good paper. And, you know, they talk about what are the, what qualifies a person as immunocompromised, right? Because all immunocompromised is not the same. And so, in the case of our patient, solid organ transplant, and he's on, there's a cyclosporin there, or tacrolimus is the same thing. So, he, you know, he meets criteria, meets the definition by a couple of criteria, but his HIV is fine, and he's only on five of prednisone. So, appreciating what makes him immunocompromised. When you look at the duration of the sorts of things, of opportunistic infections that happen with patients with different phases, the time of their solid organ transplantation, he's greater than six months out. He's a few years out. So, he is at some risk for things like, you know, nycardia and rhotococcus and so forth, but the risk declines over time. He's far enough out that he is not as immunocompromised as day one post-transplant, but he still is at some increased risk. That risk of infection diminishes pretty dramatically after most solid organ transplants. So, once you're six months out, you start to see fewer opportunistic infections. This is liver transplants. This is old PCP data, but still pretty good. This is a drawing I made for my colleagues once on how to treat infections in transplant recipients. You can use it or not. At the bottom, call Bhavata or me. Bhavata is the other ID-trained intensivist at my institution. And then, just a comment about severe disease due to endemic fungi. Classic sepsis syndromes due to cocci and histo are rare, but they do occur. The diagnosis is usually delayed due to infrequency and syndromic similarity to bacterial sepsis. There's about a 75% mortality with these things. Survival is roughly correlated with the use of Amphotericin B, although imperfectly. This was a series I published with colleagues in San Diego where I used to work recently. And it's very hard to read. I'm just going to say that the only unifying feature in the patients who survived was receipt of Amphotericin. A lot of people who got Ampho also died, but everyone who didn't get Ampho died. So, for what it's worth. That's it. Thanks, guys.

antimicrobials

critical care

pneumonia

new antibiotics

current guidelines

case-based discussions

bacterial resistance

fungal resistance

risk factors

opportunistic infections

immunocompromised state