Dr. Muszynski is going to speak about infectious diseases and antimicrobials. OK. So if Scott Weiss says that everything is all about sepsis, then clearly everything really is all about infectious diseases, right? So here we go. All of infectious diseases and antimicrobial agents in 20 minutes after lunch. OK. Objectives are here. You have them. I won't go in detail. I still have no relevant disclosures. So why is it important to think about our antibiotic strategies and how we approach antibiotics in the ICU? Well, so it turns out that, as you guys probably already realize, antibiotics are among the most common drugs we prescribe. And so it makes sense we ought to approach that thoughtfully. And in fact, depending on how you define antibiotic appropriateness, it's possible that up to 60% of antibiotics that are prescribed may not, in fact, be appropriate. And so, hmm, begs some thought, right? So what is our general approach to antibiotic selection in the ICU? And this is going to really provide the framework for the rest of the talk. So one, it's based on, of course, where's the infection and what are the organisms that are likely to be causing that infection based on your body site? What is the ability of the given antibiotic to actually get to that site of infection, right? Because if it's just circulating your bloodstream but your infection's in your brain, then that's not going to help if the antibiotic can't get in your brain. What is acceptability to the organism, to the antibiotic of the organism? And that's going to have to do with what's in your community, what's in your hospital, and what your patients individually are at risk for. So I think, again, coming back to sepsis because, yeah, OK, a lot of critical care is about sepsis. When we think about empiric antibiotics for sepsis, it's helpful to think about what are the common etiologies for sepsis. And so this is from a point prevalence study in Europe that really broke down the epidemiology of the sites of infection that precipitate sepsis. Bloodstream infections were most common. In this study, meningitis and encephalitis was next, followed by others, as you see. Looking globally, so this was the Worldwide Sprout Study from 2015, again, here found a predominance of respiratory infections as the inciting factor for sepsis, followed by bloodstream infections. And this kind of annoying dark blue there that is other unknown and otherwise known as culture negative sepsis, right, the bane of our existence, it's real. It's there. Some of the difference here, of course, is epidemiologic in terms of how many centers and where the centers were. But some of it also is the definition. Harkening back to yesterday, where I'm sure you heard of sepsis as a syndrome that has multiple different definitions. But I think this is a helpful touchpoint for thinking about our empiric antibiotic selection and choice by thinking about what are the common sites of infection for the patients in your ICU, and what are the common organisms infecting those sites. Speaking of common organisms, if we break down, again, this is community-acquired sepsis, right? So your community-acquired and your nosocomial are going to be a little bit different. But for community-acquired sepsis, a bit of an equal split between gram-negative and gram-positive organisms. A fair proportion of viral organisms, and I would say virus only versus virus plus bacteria sometimes can be a little bit hard to define. Among your bacterial organisms, Staph aureus is going to be a common gram-positive organism, at least at the time of this study. And what's important to note here is the epidemiology of these infections do change over time. And so staying abreast of what's commonly reported in your area is important, right? So right now, if you were to repeat this, it's entirely possible you might see group A strep popping up a little bit higher than Staph aureus in that epidemiology. Pseudomonas species are going to be there, probably a little bit less commonly in community-acquired sepsis, but not zero. And then, of course, fungal infections are also, when you get into a critically ill patient population, your epidemiology is a little bit different than when you are thinking about a general ID population. That's another key take-home point. When we're thinking about the epidemiology of infection, our ICU patients are a little bit different. They're going to have a different epidemiology and may require a different approach to empiric antibiotic, or antimicrobial therapy, I should say. So patient-specific things that are going to play a role. Age, obviously. We all know the classic table that I think is in another slide here of different organisms that patients are at risk for in the pediatric age range based on age. Immunization status, geographic region, of course, as well as the presence of chronic medical conditions, frequent contact with the health care system, and hearkening back to whatever an hour ago, immune compromise. All right, so this is that classic table. I'm not going to go through in detail, but you should know it because this is an easy thing to test on, and it's a good thing to know in life. So your patients, based on their age and or immunization status, will be at risk for different types of organisms to cause serious bacterial infection, including meningitis and or bloodstream infection. So you have this table. Take a look at it. Put it to memory. So what about multiply drug-resistant organisms? Obviously, a really important topic within our field for two reasons. One, we need to try to be careful to not make the problem worse. But we also know from multiple studies that the faster we can get the right antibiotic for the patient into their body, the better they will do. And so there's this push-pull between, I want to be really broad because I want to make sure I cover everything, versus, well, actually, I don't want to be really broad because now I'm potentially contributing to antimicrobial resistance. So how do we approach this? Well, one way to approach this is I say, know thy antibiogram. How many people have seen their hospital's antibiogram or look at it regularly? At least a few. Good. Excellent. This is where we have really wonderful pharmacists who will put this together and will send it out periodically. But what's important to know is that each geographic region and even individual hospitals within a geographic region will have different antibiograms. And so if I know that 60% of Pseudomonas isolates in my hospital are resistant to cefepime, then maybe for a critically ill child with life-threatening infection that I'm suspicious of Pseudomonas, I wouldn't use cefepime as my first choice for that child, regardless of what literature from other places might say. So being patient-specific and location-specific can be useful. Now, why might I think that someone is at risk for Pseudomonas or another type of enteric cram negative or a multiply drug-resistant organism? Well, I might think about risk factors for health care associated organisms. So your community-acquired organisms are going to be much less likely to be drug-resistant. Your health care-associated organisms are going to be much more likely to be drug-resistant. And so this is from a study that was published a few years ago that looked at a whole host of different risk factors and, through multivariable regression analysis, identified a set number of risk factors that had a fair predictive ability to predict health care associated organisms. So organisms that would likely need different antibiotics than your typical community-acquired organisms. So that's anybody with potential health care associated organisms. Immune compromise, oh, hey, this table came up again. So you can look at it again. Something, again, easy to test on and an easy thing to kind of remember as you're thinking about, what is my patient potentially at risk for in real life? OK, so that's patient-specific selection of antibiotic based on what organisms. All right, what are all of these antibiotics? OK, so I thought that was going to fix the problem, and it didn't. There's a whole host of different classes of antibiotics. Each of those antibiotics have different mechanism of action and different spectra of activity. It's important to know a little bit about each of these. Again, just like the drugs on the last talk, I could stand here for 20 minutes and go through each one of these drugs, actually take more than 20 minutes. And in our post-lunch lull, I would bore you to death. So I'm not going to do that, but it's not because it's not important. It's because me talking at you is probably not the most effective way for you to learn that. So the full version of the slides goes into much more detail about each of these antibiotics classes and the antibiotics within those classes. So I encourage you to take some time with that. Other thoughts about when we think about, OK, now I've picked the right antibiotic. Great, my job is done. Except there's more to think about, right? Because now we have what the pharmacists are thinking about with us, because pharmacists are some of the smartest people I know, and I love them very much. They're my favorite people in the ICU. Everybody here, notwithstanding. So we need to think about the pharmacodynamics of that antibiotic. And the pharmacodynamics mean, what are the properties that help make that drug efficacious? It's different from pharmacokinetics, right? So pharmacokinetics are what's going to dictate my blood concentrations or my concentration of a drug in a particular space, what's going to dictate the clearance of that drug. The pharmacodynamics is, how is this drug working? And what do I have to think about in terms of this antibiotic actually killing the microorganism, which is what we want, right? And so the two main things to think about from this slide really are that some antibiotics are going to be concentration dependent. And for those, what you're monitoring to have effective killing is your peak serum concentration. So they are concentration dependent, versus other antibiotics that are time dependent. And so really, it's the length of time that the organism is exposed to the concentration of that antibiotic that's above the MIC, or the minimum inhibitory concentration, right? So two slightly different pharmacodynamics. It's useful to have some idea of which broad classes of antibiotics fit into which category, because that's going to change how you might monitor that antibiotic. It may change how you dose that antibiotic in the setting of differences in pharmacokinetics driven by differences in organ function in our patients. OK. So now we've selected the right antibiotic. We've thought a little bit about how we're going to dose that antibiotic based on the information here. What happens when our friendly ID group, and actually my ID group carries candy with them when they do this now, and it's the antibiotic stewardship team. And they're like, here, want some candy? I'm like, oh, I'll take your candy, but you can't take my vancomycin away. OK. So antibiotic stewardship. So I said in the beginning of this that we have a really challenging goal ahead of us, right? Because as an intensivist, I have my patient in front of me who has a life-threatening infection. I want to give them all of the antibiotics, like every thing that I have in my arsenal, I want to give to that patient. But I also know that I'm a good citizen of the world. And the next patient coming after that patient, I don't want to have a multiply drug-resistant organism that now I don't have any antibiotics for. And so antimicrobial stewardship is important. And it is an important, again, I'm going to hearken back to that term multidisciplinary from the last lecture. It's a really important place for that bidirectional multidisciplinary conversation. And in fact, there are some studies to support this model of multidisciplinary collaborative antimicrobial stewardship programs. And while there isn't strong efficacy data for one specific program over another, there are a number of different studies out there looking at basically, if you have a protocol at all, particularly one that is centered on good multidisciplinary collaboration and communication, you can improve outcomes in terms of actually improving your hospital's antibiogram, and in decreasing the amount of multiply drug-resistant organisms, and decreasing exposure to things that might be nephrotoxic, like mancomycin, if Raj is even still here. And so the idea here is there may not be one particular protocol that's been shown to be efficacious, but doing anything probably is. And so these are just some of the examples of the success stories that are in the literature that I talked about. The different references are there, if you're interested. And like I said, there are single center studies. There are multi-center collaboratives that are working in this space. And like I said, the really exciting efficacy here is you can actually see a shift in resistance patterns. And here, this is an example of one of the multi-site antimicrobial stewardship programs in pediatrics. I encourage you to take a look at this one, because it's a really great example of a multi-center implementation science approach, and also can get some really good ideas about different ways to approach antimicrobial stewardship. And they've openly shared some of their forms, and the policies, and some of the documentation that they used. So it can be a really helpful resource. OK, so enough of me just jabbering on. Again, in our post-lunch slump, it might be fun to do a few cases. And so we're going to go with this case number one of a seven-month-old who is unimmunized, has a three-day history of fever, emesis, and increased sleepiness and irritability. And then the vital signs and the physical exam that you see before you. So I want you to think for a moment. Let you read that for a minute. And as you're reading that, think about two things. What's the most likely site of infection? And what's the most likely organism or organisms? Who's got a site of infection? Yeah. Sometimes it is that easy. Yeah, OK. What are the most common organisms in this patient, do you think? Yep, so you've got a strep pneumo. H flu. Yeah, probably a little bit of noceremeningitis, yep. Of course, in an unimmunized infant, I'm going to pop strep pneumo and H flu pretty high on that differential. All right, what antibiotics are you going to start? Yeah, so ceftriaxone, potentially amicomycin, depending on your antibiogram and the rate of strep pneumo resistance, absolutely. And so we come back again to this table that I said we're not going to go through in detail, but know it, right? And so our patient sort of fits into this three to six months with no immunization. And why is it going backwards? I don't know, sorry. And so you guys are exactly right. Strep pneumo, H flu, and noceremeningitis. Right on. OK. And in terms of empiric therapy, you have your ceftriaxone or ceftaxime and vancomycin. Exactly right. OK. Now for something a little bit different. We have a 14-year-old now. Still has two days of fever, still has vomiting. But this person has now diarrhea, body aches, progressively worsening headache, confusion, and rash. Two weeks ago, this individual fell off a skateboard and got a cut to his right knee. Laceration was closed up at Urgent Care, some Seristrips, and now presents to your emergency department, awaiting PICU admission with the following signs and symptoms. OK. All right. So what do we think he has? I heard staff. I heard something, something. Toxic shock syndrome. Yep, yep. Yeah, so we have sepsis. We have toxic shock syndrome. Wow, say that three times fast. Exactly. So what are we going to empirically start for this individual while we're waiting for all of our studies? What antibiotic can you use? Yep. Yep. So we're going to cover particularly what types of organisms? Gram positives. Right. So you're going to throw all the gram positives at him, right? So you're probably going to try maybe vancomycin at first, right? This is probably life-threatening and you don't know whether or not this is MRSA, plus another antibiotic to give you a little bit of a broader spectrum, right? Because vancomycin alone is only going to get you gram positives. It's not going to get you anaerobic. It's not going to get you gram negatives. And so probably you're going to do something like a ceftriaxone or ceftoxime with your vancomycin. Yep. What else might you do for this patient with toxic shock? Clenomycin. Clenomycin. Why? What does that do? Toxic shock. Yeah. So what is toxic shock? What causes it? Toxic shock. Yeah. So it's due to the toxins. I love things where the mechanism is in the name, right? So toxic shock syndrome, it's not just the bacteria itself, but it's the toxins that are created by the bacteria, right? And so you combine your antibiotics that are going to be killing the bacteria with something that works by a slightly different mechanism. So the reason why you might add something like clenomycin is that its mechanism of action is to decrease protein production. And so that is going to decrease toxin production. What else might you do for this patient with toxic shock syndrome? Source control. Oh, I love the person who just said source control. You're my favorite. So yes, source control. I'm going to be calling Ortho to take a look at that joint. Absolutely, because without adequate source control, you can give all the antibiotics in the world, and it may not make a lick of difference, right? So source control is important. It was highlighted within the most recent surviving sepsis guidelines for pediatric patients is the importance of early and effective source control. And I'm sure it got covered yesterday. So yes, source control. What else might you do for this individual? That's not an antibiotic. I suppose I can throw that out. Yeah. Would anybody give IVIG? Yeah. Yeah. So why? What does IVIG do in this scenario? Yeah, I think you got it. Just blocks the antibiotic. Yeah. You're going to block the toxin. Yep. So toxic shock syndrome and or there is actually some evidence for efficacy in gram-positive sepsis as well. You're blocking toxin. You're trying to decrease the production of toxin. You're trying to kill the bacteria itself, and that includes adequate source control because your antibiotics aren't necessarily going to penetrate if that now is a septic arthritis from where that laceration was. Okay, great. So you guys got this. So you got toxic shock syndrome can be caused by either staph or strep. It's toxin mediated. And what those toxins do is they actually trick the T cells into activating. So usually T cells are only going to activate based on very specific signals. But what the toxins do is they cause those cells to aggregate and say, oh, I'm just going to turn on willy-nilly. And you get that's what causes that cytokine storm, that's what causes the signs and symptoms of essentially very similar to sepsis. There was a question in the back. Never mind. Oh, you're good? Okay. Good. So diagnostic criteria are here. I'm not going to read those out to you right now because you have the slides. You can do that. But it's important to have some understanding of what those are. There's some difference in theory between staphylococcal toxic shock syndrome and streptococcal toxic shock syndrome. The degree to which these differences actually manifest in real life, a little bit questionable. But it's what's out there. It's worthwhile at least knowing about this. Okay. So your risk factors, particularly if you have colonization with a toxin-producing gram-positive organism, be it staph or strep, obviously you're going to be at higher risk. Having the absence of a protective antitoxin antibody. So there's a lot of work on the research side trying to understand why are certain people more susceptible to getting toxic shock syndrome when they're exposed to the same bacteria that you or I might be and maybe we don't. And so it probably has to do somewhat with the bacteria but also somewhat with the host and the host's ability to mount an effective immune response that isn't an exaggerated immune response. And then depending on whether you have a certain primary source of infection, how long that's been infected, and whether you've had source control. So certainly a lot of times you'll see, the reason you'll see in a question stem oftentimes that there's some sort of skin laceration or it might even be a small cut somewhere is that's, in real life, oftentimes how this starts. And so really important for these patients to do a good head-to-toe physical exam because what might have been something that they might not even mention in the history, it might be a minor injury that nobody thought anything of, could actually be the root cause of the problem. And if you don't evaluate that and take care of that, wow, I think I've said source control five times now, that might be meaningful, then you're going to be behind the game. So also really thinking about whether there's a foreign body somewhere, because again, source control would mean you have to get rid of that foreign body. So antibiotics, there it is again. Number seven, I think, source control. Hemodynamic support, organ support, just like we would with any other patient with severe infection or sepsis. IVIG, as we mentioned already, provides neutralizing antibodies that are going to counter the effects of the toxin. So we're going to try to kill the bacteria, keep the toxins from forming, block the toxins, and get our source control. And I've lost track of, I have five minutes, I think? Case three. Where am I over? Five minutes? Okay. Ooh, okay, this is the last case. 14-year-old, high fever, body aches, shaking chills, cough. Now on ECMO. And everybody in the house has URI symptoms. They all got vaccines except nobody got a flu vaccine. And community rates of influenza are high, right? So for this person, what bacterial organism are you suspicious of? Ah, I think I just showed the answer. What bacterial organism are you suspicious of and what antibiotic are you going to start? Staph. That's right. And the point of this is when you look at mortality from influenza in children, much of that mortality is actually driven by bacterial co-infection. And the most common bacterial co-infection, particularly for fatal cases, is Staph aureus. Either MRSA or MSSA. And so the point of that is if you have high suspicion of influenza plus a bacterial process, that's a place to empirically give good Staph aureus coverage, including MRSA coverage, if it makes sense for your area. Okay. So the other piece here is in your slides, kind of a provocative study that suggested that double covering MRSA in the setting of influenza might have some efficacy. Take that with a boulder of salt that you take all observational data with, but food for thought and probably hypotheses for future studies. So I will end there. Summary is life-threatening infection is a common cause for ICU admission. A thoughtful approach to antibiotic therapy is imperative, rapid administration of antibiotics while also avoiding unnecessary antibiotics if you can, and then thinking about what's driving your antibiotic selection.

infectious diseases

antibiotic strategies

sepsis epidemiology

antimicrobial stewardship

multi-drug-resistant organisms

ICU