Welcome everyone. I'm the moderator for today's session and I'll walk you through this here. This presentation, obviously we're not in Puerto Rico like a lot of you. I was rounding in the ICU this morning and so we're doing this virtually. And so the topic for this webinar will be pneumonia and sepsis in clinical care. And we're going to navigate a complex patient diagnostic workup and we'll see how complex that patient actually is. I'm fortunate enough that we have a great faculty today. I'm the moderator, Aaron Collett from Washington University in St. Louis. Deborah Goff is here, who's a professor of pharmacy practice at the Ohio State University College of Pharmacy. She's an infectious disease specialist at the Ohio State University Wexner Medical Center in Columbus, Ohio. And we're also really fortunate to have Dr. Seth Kodig, who's the chief of the pulmonary critical care medicine group at Kent Hospital in Warwick, Rhode Island. So again, we've got a very experienced panel that'll be facilitating things for us today. And really the disclosures are just shown here for you. You can read those on your own. And then really moving on here, we're going to get into the agenda. And the agenda really is what I've already introduced to you. We're going to talk a little bit about using molecular diagnostics, new technology for the evaluation of patients with infection in the ICU setting. And we're going to have a case presentation as well. So as you all know, pneumonia and sepsis are quite common problems for those of us who work in the ICU. They're also common outside of the ICU setting. When we think about sepsis in particular, I mean, it affects a large number of Americans in the US, more than a million people are typically going to be hospitalized annually. And the mortality varies obviously depending on the acuity within your own intensive care unit. But it can run anywhere from 20 to as high as 40 or 45%. And again, it really depends on the kinds of patients that you're dealing with. And it's an expensive condition. We all know that. And there are factors that may mitigate that expense to some extent. Pneumonia, on the other hand, is probably the most common infection that we treat in the intensive care unit setting. It accounts for almost 3% of all hospital stays. And it also contributes significantly to healthcare costs. And really, we saw that during the COVID pandemic, even though that was a viral process, but there were a lot of complicating bacterial infections as well. Let's go through the first question here. And it's really to set the stage for us. And I'll run you through this and you'll be able to make your selections. What are the potential benefits of molecular rapid diagnostic methods, as abbreviated, over conventional methods for diagnosing pneumonia and sepsis? And really, we'd like you to select all of the potential answers here that you think apply. And they include ordering fewer tests, a simplified workflow, particularly through the microbiology laboratory, no need for confirmatory testing, a higher diagnostic yield, enhanced clinical decision making, and improved outcomes. So go ahead and take a second here and pick the answers that you think are most appropriate. Okay, so again, we've got a lot of the answers selected here. The most common one is enhanced clinical decision making. And hopefully, as we go through the presentation and have some discussion, we can, you know, really reinforce that particular issue. Improved outcomes were also selected as a very common answer. We have some data to support that, particularly with some of the newer molecular diagnostic tests that was followed by fewer tests needed, a simplified workflow and a higher diagnostic yield. The one that really received the least number was no need for confirmatory testing. And that may have something to do with the fact that, you know, these new molecular diagnostics are relatively new, not every hospital uses them. And so for hospitals that are beginning to use them, oftentimes, they're using them in conjunction with more traditional methods, at least for the early adaptation of that technology. So let's just go through a brief patient journey here. And really, what we're talking about here is a case presentation. And I'll just walk you through this case briefly. This is the kind of patient that I think we all see in our intensive care units. It's a 66 year old woman, she has severe underlying COPD. She's admitted to the intensive care unit after being a passenger in a car having suffered a motor vehicle accident. She's got rib fractures, a lung contusion, and she's placed on a ventilator. It's important to note that at home, she's receiving oxygen therapy, it really gives us an idea of how severe her lung disease is. She's had recent corticosteroids for an exacerbation of her COPD, which required a hospitalization. During that time, she was also treated with systemic antibiotics, and those included cefepine and vancomycin. So during this current hospitalization, really for respiratory failure from the trauma that she sustained on day four mechanical ventilation, her condition seems to worsen. And it worsens in that she's developing hypotension. The physicians and nursing staff are all concerned that she's developing sepsis. She's on two vasopressors, norepinephrine and vasopressin, with a MAP of 53. And an x-ray that day reveals that she has new infiltrates in the right lower lobe and the right middle lobe. Now we also see that she's got worsening oxygenation, her FiO2 is 60% with a PO2 of 61. And she does have a COVID test that turns out to be negative. So the clinicians in the ICU start her on an antibiotic regimen empirically, and that's vancomycin and piperacil and tezobactam. So we have another question coming up. And we'll see what your answers are for this. And really what this question is trying to get at for this particular scenario, and it's somewhat of a generic scenario where someone's developing signs of an infection and possible sepsis. We're really trying to determine, you know, what tests that you all would like to order or apply in this case. And the options are perform a Brocavilla lavage with quantitative cultures or semi-quantitative cultures. Perform a molecular rapid diagnostic test. This would be the respiratory panel. Perform a molecular rapid diagnostic test, which would be the pneumonia panel. And the respiratory panels and pneumonia panels differ from one another. If you're not familiar with those, the respiratory panel tends to have more viruses. The pneumonia panel tends to have more bacteria along with the viruses, as well as elements of resistance measured by certain genes that are present. And then the fourth option or tracheal aspirate. So which of those, you know, if you had the ability to order them, would you select? Okay. Well, it looks like most individuals would go for the molecular rapid diagnostic, which would be a pneumonia panel. The more comprehensive panel, which would include bacteria, viruses, as well as resistance gene elements. Again, these are not mutually exclusive. I mean, that type of test can be applied on a BAL specimen or tracheal aspirate. We see that the next most common one was the respiratory panel. And that was followed by BAL and finally a simple tracheal aspirate. So with all of that as a background, you know, I think we'll go forward here and I'm going to turn the mic over to Dr. Goff, who will take us through some of these available panels. Thank you, Dr. Kulloff. So it was great to see that people were selecting these as choices. There are FDA cleared lower and upper respiratory panels. So for the pneumonia panels, there are two available. One is by BioFire, the Filmora pneumonia panel, and the Univero lower respiratory tract panel. And then there are several actually available for the upper respiratory panel. So what are the benefits of these molecular rapid diagnostic tests over conventional methods? So when we look at syndromic testing, it's the use of a single test that can simultaneously detect several pathogens, bacterial viruses, fungi, and resistance genes within hours. So the results are rapid. And what does that do for us as clinicians? It improves the diagnostic yield, which allows us to have enhanced clinical decision-making. So obviously knowing the organism rapidly rather than waiting for days really is an advantage because then we can have targeted therapy. So you may need to escalate or deescalate antibiotic therapy based on the rapid diagnostic result. So let's look at these, the two FDA cleared pneumonia panels, which would be most applicable in an ICU setting. You can see the Univero one detects 16 bacteria, a plethora of gram negatives and two gram positives, atypical bacteria, fungi, and 10 resistance markers. And it can be done on an endotracheal aspirate or BAL. And the turnaround time is about four and a half hours. The FilmArray panel similarly has multiple bacteria, gram negatives and gram positives, atypicals, viruses, including COVID, and seven resistance markers. And it can also be done on sputums in addition to BALs. And their turnaround time is only about 60 minutes. And what exactly do you get? On the FilmArray, you can see the virus is listed and COVID is amongst them. Many different bacteria are detected along with atypical bacteria and importantly, the resistance markers. So it doesn't tell you susceptibilities to different antibiotics. And this is really where a stewardship approach helping interpret the results. If you have resistance markers, it clearly implies only certain antibiotics can be prescribed. And that's where a stewardship team can help guide the interpretation of the test. The Univero panel also detects a plethora of bacteria, fungi, and also multiple resistance genes. So as clinicians, you can really see how this would help guide you to get your patient with sepsis or pneumonia rapidly to a patient with sepsis or pneumonia rapidly on appropriate antibiotic therapy. So I'm going to turn it over to Seth to talk about how to interpret the results. Great. Thank you, everybody. So obviously, you know, interpreting the results becomes something that we all have to do no matter what type of tests we are doing, whether it's an echocardiogram in the ICU, a chest x-ray, whatever. Cultures are no different. The way we interpret those results obviously has impact in what we're going to do next for our patients, both in a positive direction, meaning adding things, and sometimes in a negative direction, meaning we can pull things back from what we're doing. And I think here, some people, whenever we have results, we want to know are they qualitative or quantitative? And the first thing we're talking about here is that in the first group, the univero, it's more of a qualitative analysis. Is it there? Is it not there? Does it have resistance? Does it not have resistance? And the film array has a qualitative for your atypical bacteria and your resistance genes and viruses, but also some semi-quantitative data for some of the bacteria, 15 of the different bacteria. And you know, you can see here that whether it's detected or not, depending upon how you look at the results, you can see as we move to the right here, that is going to look like there are more and more copies of those bacteria. And this might be important for folks who have maybe underlying lung diseases like bronchiectasis, cystic fibrosis. This might be a way for us to determine which of the bacteria might be more important on that day. So this would be an example here of how these pneumonia panels would come back compared to the culture results. And here, we're just looking at one of them, which is the film array. And then we have culture here on the right. And so remember, the film array might give you a little bit more semi-quantitative data as opposed to just qualitative data. But here, you can imagine if a person has both Klebsiella and Pseudomonas. And here on the left, they actually have detected that there is a resistance gene that just might be allowing us to know that, for instance, this person would need one antibiotic over another antibiotic. So here, we would have a carbapenem resistant antibiotic or a carbapenem resistant bacteria. So you'd see Klebsiella and Pseudomonas here in our cultures, which obviously would take a few more days. It may look like this, 100,000 colony forming units of a Klebsiella, which is an ESBL, and 100,000 colony forming units for a Pseudomonas. That then allows us to see that it's carbapenem resistant. On the other hand, sometimes we may see below that Klebsiella, ESBL, many Pseudomonas. So again, these were going to give you qualitative and quantitative data depending upon which group you are using, which of the panels. And at the bottom, you can see it's very important for us to know upfront, we would like to be able to treat an MSSA bacteremia or lung disease or pneumonia, whatever the case may be, with a certain drug and maybe not vancomycin. So this allows us to learn very quickly whether our Staph aureus, based on whether or not the gene, so the MEK-A, is found. So you can see this is an example of how it would look. And so do rapid panels identify more organisms? Because one of the issues that we have is that when things become overly sensitive, the question is, what are we going to do with that data? And this plagues us all the time, right? We see things in our patients, on our patients, results for things on our patients. And we have to ask ourselves, is this a causative problem or is it just hanging out? Is it just coming along for the ride? And we can see here in the film array on the left, when we looked at whether or not we were using bronchoalveolar lavages and sputums in the normal way that we would detect things, culture, right? So on the right here, it says SOC, which would be the standard of care culture mechanism. You can see, I mean, that BAL gives you a fair number of positives, almost 50%. Sputum, I mean, we have a lot of bacteria and things in our upper respiratory area. So the sputum might be capturing a lot more. And there are a lot of co-detections. So there's more than one thing that we pick up in our regular way that we do things. If you look on the right, the pneumonia panels now identified at least one bacterial target in 63% more BAL specimens than standard of care culture. So meaning that these panels are extremely sensitive. And so if you were to see here, the pneumonia panel in this pie chart picked up 38 more than the standard of care culture out of all of the specimens that were there. And while you think that the sensitivity and the fact that you picked these up is better, I think this is where Dr. Goff and where we're going further that we need to have a way for us to be able to suggest that this is a bystander effect. Is it alive? Is it a dead bacteria? Did we pick up organisms that are there, but are not causing problems? And so we need to look at that very carefully. And that's obviously where the stewardship comes into play. And here, just to be equal, equal time between the Filmorae and the Univero lower respiratory tract panel. Again, what this is showing is that if you look at standard of care culturing on the right here versus the Univero on the left here, you can see that with the number of organisms detected as we move down from one, two, three, four, five, and six, that this is a much more sensitive way of picking up these types of bugs. And I think from now, then I will give this back to Dr. Goff and she will continue to look at the impact on antibiotic use. Actually, I'll be doing it. Sorry about that. Sorry about that. Yeah, I'm just going to build on what Seth was just talking about and really touch on a little bit about how these molecular methods might have an impact on antibiotic use in the intensive care unit setting. So there have been several sort of real life studies that have been done trying to determine what impact at the bedside these types of diagnostics would have. One is the study by Buchanan and colleagues where they looked at 259 patients who had a BAL where the molecular diagnostics were performed, really looking at what the opportunities would be in terms of altering therapy at an earlier point in time. And what all these studies really seem to focus on, and I'll go through this in the next two as well, the largest impact really seems to be on antimicrobial de-escalation, meaning that those of us who work in the intensive care unit, you know, for better or for worse, we want to try to treat any potential bug that might be causing a serious infection in our patient, particularly those that are immune suppressed or have a lot of comorbidities. And we often end up, particularly for those who are septic, who have septic shock, who have a severe pneumonia, particularly a nosocomial pneumonia, using broad spectrum antimicrobial therapy. So what we can see here from this particular study, almost half of these cases, one would have been able to appropriately de-escalate at an early point in time. Now there were also some situations where they could earlier escalate therapy, meaning that the initial antibiotic regimen was not covering the pathogens that were identified. And we know that in that circumstance, there are studies that have shown that mortality can increase, whether you're talking about a pneumonia or a bacteremic patient. And so, you know, the need to try to cover those pathogens is important. In this particular study, that was only 4.3%. And there may be some costs here as well. And you can see that there were some situations where inappropriate de-escalation or escalation might have occurred. The de-escalation in this particular study was a situation where they had four patients who had organisms that were not identified by the film array in this particular case, but they were all in very low quantities. So again, you know, what their clinical importance was, is still questionable. And then inappropriate escalation could occur in some cases as well, where again, you had low growth of certain pathogens that may have just been colonizers. So this sort of puts it in perspective, and it really goes back to what Dr. Koenig said about, you know, interpreting the data and potentially having some semi-quantitation to the values may be helpful in that regard. This other study that I'll go over by Pickens is a very similar type of a study. Again, they looked at the potential impact on antibiotic therapy, in this case by, you know, using the univero method in lower respiratory tract results and samples. And you can see here that again, the most common impact would be on antibiotic de-escalation. Now, this study actually showed that there would have been 10% of the patients who would have gotten escalation or expansion. That again, is important because it implies that bacteria were not being covered. And we know that in those circumstances, patients who are getting inappropriately treated may have a higher risk of mortality. You can also see that there were some situations where both could occur. And so overall, more than half the time, patients would have had some type of impactful event occur as a result of these tests at an earlier point in time. Another study, and this one was done by current colleagues, really sort of looked at it in a very focused way. The study, again, used the film array, and these were patients who had pneumonia on clinical presentation. And they really fell into two groups. Even though it was a small study, out of the 52 patients that were evaluated, they had a comparator group and an intervention group. The intervention group was the group that received the film array. The control group did not. There were 26 in the intervention group. There were 13 in the control group, if you will. And even though there were no differences in clinical cure, both groups had a similar clinical cure. If you look at the figure there, you can see, again, that de-escalation occurred far more often in the patients who had the film array performed. And those are the darker blue lines there. Escalation also occurred in a small number, one individual who got the film array. It was somewhat higher than what was seen in the control group. And discontinuation of antibiotics, again, was more common in the intervention group. Now, the other thing that this group was able to do is they estimated what the potential cost savings would have been in this particular study using this technology in terms of manipulating and affecting antimicrobial prescription. And their estimate was that there would have been about a $31,000 cost savings in this group of patients, primarily due to the de-escalation of antibiotic therapy. So, again, it implies that there may be some cost savings with this type of technology. Again, primarily from the antibiotic de-escalation. But if one can improve outcomes, that should lead to better costs as well in terms of cost savings. So, we're going to have a little bit of discussion here at this point amongst the panel, just to see if there's anything that we want to comment on. And I'll just open it up very briefly to the other two speakers before moving forward with a little more detail on our case presentation. So, Seth or Debbie, do you have anything that you'd like to say right now? You know, I'll just start. I thought the initial selection of antibiotics was rather interesting, since this patient was on chronic steroids and had prior exposure to cefepime. I don't think Piptazole would have been my gram negative of choice to put her on. It's sort of just similar therapy. So, we'll wait to see what she actually grows. But I found that to be sort of not a choice I would have made. Yeah, I would agree with you. The other problem, at least from my perspective, and our pharmacy group has actually done some work on this, at least in ICU patients, the combination of vancomycin and piperacillin-tazobactam is really the most nephrogenic, nephrotoxic. And again, it wouldn't be one that I would have selected. But in this particular case, that's what occurred. And in particular, if patients are left on that combination for more than 72 hours, the likelihood for nephrotoxicity significantly increases. So, I agree 100%. Seth, did you have a comment on that? I would have said the exact same thing that Dr. Goff said in regards to antibiotic choice. But since she asked that question, two points that I would be thinking about would be, number one, where is the MRSA nasal swab in all of this? And does that quickly give us an idea whether or not we need to continue and to, you know, vancomycin, at least if we're dealing with a lower respiratory tract infection at this point? I think that would, you know, be my first question to you. And then the second one would be, I think people, they would probably be asking hopefully that question. But also, if we follow guidelines, would we be just as good off? You know, would it be just as good to follow guidelines? And I have my own opinions about that. But I think that so far, that would be what I would be asking. Yeah, I would ask you, and I'll just say that in our ICUs, we routinely do nasal swabs for MRSA. It's something that, you know, we've looked at pretty thoroughly and we do it routinely. I don't know that it's a uniform practice, but we certainly do it. The question that has come up for us, since we also routinely now do the pneumonia panels in our patients, particularly those on mechanical ventilation, or who are obtaining a specimen via BAL, for example, you know, they're probably, we don't think that there's a need to do both. I mean, in that situation, if we're going to collect a specimen and do the pneumonia panel, we'll opt out of getting the nasal swab in that circumstance. And I don't know what your thoughts are on that. Well, I think that that's the reason I asked, is I think that people would need to be comfortable because it would be a shift of what, let's say, certain ICUs in certain hospitals are doing, and they would need to become comfortable with the idea that if we are going to be doing a lower respiratory tract specimen, I think, yeah, there's no need to do both. Currently, in my new hospital that I'm at, we're not yet doing the BioFire. So we are, or any of the specific testing panels. So we are relying, but we are using it appropriately. So if a person has pneumonia, and we have a negative MRSA, the likelihood of that being a culprit allows us to deescalate. And on the same note, at this current hospital that I'm at, you know, the question is, if we follow very carefully, you know, guidelines, would we be putting patients on the correct antibiotics? Well, let me move on. And I'll give a little bit of an update on the case that we had. And so just to review for everyone, this was a 66-year-old woman, severe COPD, motor vehicle accident, rib fractures. The next steps were a rapid diagnostic performed on a tracheal aspirate. She also had a BAL with a rapid molecular diagnostic. There were blood cultures that were ordered. We talked about the empiric antibiotic regimen. So roughly six hours after the specimens were obtained and sent to the microbiology lab, because they didn't do point of care, apparently in this setting, they were sending them to the micro lab, they got a result back that it was negative for MRSA. Also, the rapid molecular diagnostic results suggested that there would be pseudomonas present, and that it could be resisted to carbapenems based on the identification of one of the resistance elements that was identified on the panel. And blood cultures were also sent off that subsequently, meaning the next morning, almost 18 hours later, there was a gram negative that was growing, and it was subsequently identified to be pseudomonas. So the treatment plan actually changed in this case, based on the rapid diagnostic. Once they got that initial information suggesting that there could be the presence of a carbapenem-resistant pseudomonal isolate here, they made a switch to a different antibiotic. They stopped the anti-MRSA therapy, and in this particular case started cytasidine, maybe Bactin. So that's sort of the update for this particular case based on the molecular diagnostics that were obtained. Moving on, just to touch a little bit about sepsis and the importance of rapid diagnostics in sepsis. I think all of us know we all work in intensive care units, and there's been a lot of work done in this area, and our group has been doing work on this particular issue for more than 25 years. When you have patients with serious infections in the intensive care unit, the timing of antibiotic administration is certainly crucial. And we know that it's not a matter of just the number of hours that pass from initiating antibiotic therapy, but it has to be an appropriate antibiotic regimen, meaning one that has activity against the organism or organisms that are causing the infection. And the references here, including Kumar's study and others, really make that point, that timing is crucial, but appropriateness of therapy, having a regimen that targets the organisms is key. And in addition to that, you wanna be sure that the drugs are dosed in an adequate manner, so that you've got enough of the drug at the site of the infection to actually do the job. And that's where working as a clinical team with the pharmacists, the physicians, the nursing staff, really all comes into play in terms of getting this right from the beginning. So moving on here, and I'm gonna go through some of these briefly here, and this is actually taken from a review article from one of our attendings here, Christina Vasquez-Guillemot, who's an ID critical care person. This was just a review paper on rapid diagnostics, and all I'm doing here is showing you some of the PCR approaches, both the uni-PCR as well as the multiplex PCR, that can be applied to blood. And there are a number of them here, and you can see the potential pathogens and resistance elements that can be identified. Some of these are going to be specific for gram positives, such as the gene expert. Others will be broader, including the gram negatives, and that would include the biofire, the varigene, and then we have some that will also include fungi or yeast. And the turnaround times are shown here as well. So depending on what the need is within a particular unit, one can actually apply one of these tests in the micro lab in order to get rapid results from blood specimens as well. So we're now talking about blood and not pulmonary specimens. It's also important to keep in mind that every microbiology department will be different based on the resources they have, the type of workflow that they need to establish. Our group actually has significant multi-TOF mass spec technology and capability just because of the sheer numbers of blood culture specimens that have to be run through. And again, if you're dealing with larger specimen yields and workflows, technologies like that may be helpful. Peptide nucleic acid, FISH may be also useful as well, and there are several that are available that are shown here, one of which includes a rapid microscopy-based system, and that's the Accelerate Pheno test. And then we've got others here as well, including NMR, which uses whole blood to actually try to rapidly detect the presence of bacteria and or yeast. So from the blood side of things, there are a number of different platforms that are available, and it really is crucial that when one's considering the use of these technologies, that the microbiologists be involved in this, really to try to determine what the best approach is going to be, both from a workflow standpoint and in terms of getting the best information for you. Going forward here, again, we can see that the FDA cleared multiplex rapid diagnostics, and we've got three of them shown here, a film array, varigene, and gene mark. They're going to vary in terms of the targets. And you can see that gene mark is going to have the largest number of potential targets. And again, they're also going to vary somewhat in terms of their ability to identify resistance genes. So if this is something that's important to you, again, you're going to have to try to select the diagnostic platform that is best going to fit with your needs. And finally, the turnaround times are all under four hours. So from that standpoint, they really don't differ very much. I did mention the T2 bacterial in Canada blood panels. Again, this would use whole blood. You can see the bacteria in the Canada species that are identified here. So in a situation where you might need to have a rapid identification of Canada, something like that, along with certain bacteria, this platform might be helpful to you, potentially in a DMT area or dealing with immune suppressed individuals. It doesn't mean that other platforms can't be used as well. Some might be targeted to specific groups of patients. So again, this would be something that would have to be worked out with the microbiology group and really getting down to the FilmArray panel here. You saw what the pneumonia panel was that FilmArray had. This is essentially similar to that in that we've got gram-positive, gram-negative bacteria. We've got a number in yeast here and we've got a smaller number, but we do have antibiotic resistance genes that can be identified, including KPC and some of the gram-positives, including MEK-A and DAN-A and DAN-B. ViraGene, again, similar, probably a more extensive resistance gene platform here. So again, if you're going to be more focused on this, depending on the numbers of patients that you see that potentially might have these resistance genes present, that might influence the selection of the panel that you might use. And then moving on here to the GenMark-Eplex, again, probably the most extensive panel here in terms of the sheer number of pathogens that one could potentially identify. We're also a significant number of resistance genes that can be identified both for gram-positives and for gram-negatives as well. Finally, I'm going to say a couple of words about biomarkers. I'm not going to really focus on this too much. For the most part, I think biomarkers have some utility in the ICU setting. If we think about them from a diagnostic standpoint, that's probably where they have the least utility. I mean, there've been studies done, for example, showing that one can use PCT, for example, but its utility in diagnosing a nosocomial pneumonia is quite poor. So from a diagnostic standpoint, they probably don't have a key role to play. From a prognostic standpoint, I think most clinicians probably don't use them in that setting routinely, but there are some data suggesting that they could potentially predict the onset of certain complications, particularly if you don't have resolution of that biomarker. And from a therapeutic standpoint, this may be the area where they have their greatest utility, but even this is limited from the standpoint of trying to identify whether or not patients need pro or prolonged courses of antibacterial coverage. And although I'm not going to focus on this in detail, the data for procalcitonin, which has probably been studied most aggressively over the last several decades, still I think has limited utility in most intensive care units for differentiating, particularly with nosocomial infections, the presence of bacteria versus viral infection. Probably has a greater role for patients coming in from the community and probably has a greater role in the outpatient setting as well. But again, each hospital may wish to determine, you know, the utility of their biomarkers for use in their individual populations. And then, you know, looking at sepsis management, again, there've been a number of studies trying to focus on biomarkers and sepsis, and my comments are really similar. You know, some of the panels that are going to be moving forward in the future will even offer the availability of having some of these biomarkers available like PCT and CRP. But again, in terms of dictating therapy, I think we have, you know, less strength in terms of the data supporting that we can, you know, mitigate our antibiotic use based on these biomarkers. And this is where the microbiology probably plays a greater role. All of us are very familiar with lactate, and oftentimes we use it from a prognostic standpoint in terms of determining the patient's response in septic shock, for example. And so that's something that I think we're all very familiar with. So I'm going to turn it over now for some clinical considerations from the rapid molecular diagnostic testing standpoint to Dr. Kone. Great, thank you. So, yes, what are we going to do with these rapid molecular diagnostic testing that we get back at the bedside? And I think ultimately, that's what we're going to need to decide. And so on the left, you know, what are the benefits for using these molecular rapid tests? I do think if you have a lower respiratory tract process and that's your syndrome of hypoxemic, hypercapnic combination, respiratory failure, infiltrates, you know, maybe you'll get more results from one test instead of having to do a tracheal aspirate and a lavage. The other thing is getting these done quickly. We all know that the benefit of any tests diminish very quickly, especially after you start antibiotic therapy. The syndromic approach of getting what you need early on, it's rapid. I think that for me, the idea of following standard guidelines, doing a nasal swab and all of these things are great, but even when you do the standard approach, you're still at the mercy of that bacteria or virus or whatever it is being detected in a normal way. And so you will get an improved diagnostic yield and you can have enhanced clinical decision-making. And I say it that way, because remember that what results you get, then how you use those results ultimately is what is going to be either beneficial or harmful for the patient. And so when you wanna have some things to keep in mind when using the new tests, obviously you're gonna wanna use a test at your institution that will be able to find and predict the sensitivities of the organisms that are important to you and where you are working. And that these results, some of them are gonna be qualitative, some of them might be semi-quantitative. And again, that has value depending upon which type of patients you're seeing. So if you're seeing many de novo community acquired pneumonia patients with maybe only mild past medical histories, that might be different than if you're dealing with patients who have, as Dr. Koloff said, who are bone marrow recipients, who are on chemotherapies, who have underlying structural lung disease, that might play a role into the types of things that you would choose, the way you would choose the panels. And this was shown in a previous slide. This just makes it look by eye appeal a little bit better. And we all know that every hour that you have an inappropriate antibiotic on board, the chances of survival and morbidity and mortality, it goes up. And so we wanna be real careful about choosing the appropriate antibiotics upfront for our patients. And interestingly, and this was interesting to me even to look at carefully, is that sometimes we're very like, all right, well, in New York, we got these bugs that you need like gorillacillin or something like that to take care of because they're all like this. We'll just give the patient meropenem and all these different antibiotics. But in fact, the risk of antibiotic resistance, each day that a person is subjected to certain antibiotics, you really develop resistance. And maybe it's not important today for that individual, but maybe it will be important tomorrow or for a different individual when these resistance patterns pick up. So with that, I think hopefully now correctly, I will hand over this to Dr. Goff. Thank you. So let's talk about the role of antibiotic stewardship in this. Can a test really make a difference in outcome? And I say the answer is absolutely yes. Time is of essence, especially in the management of patients with sepsis. So this timeline just shows you with the different rapid tests available, we can go from minutes and hours versus what we traditionally have been used to, waiting days for cultures to come back with susceptibility testing. They are game changing. When we implemented our very first one almost 10 years ago at Ohio State, it really was a game changing test in the management of patients with bacteremia. So my personal experience with these show, yes, it absolutely can make a difference. But what about the literature in support instead of my opinion? Well, this is a great meta-analysis done by Tristan Timbrook and colleagues that looked at mortality outcomes of the rapid molecular diagnostic test versus conventional testing. And you can see almost every study favors outcomes in mortality benefit. And this is a slide that I recommend every hospital, ICU attendings, struggling with getting in a rapid diagnostic test because they are expensive and that's always a barrier. And this cost lies in the microbiology lab. And so we need to work with our microbiology labs to help get support to bring these tests in. And the idea of, well, let's just stay with what we've had to me is just archaic. When you have so much data now to support the impact these have on patient outcomes and impact of mortality, specifically as this slide shows. This is a slide every CEO needs to look at, but remember a rapid test is only a value to impact mortality outcomes if it's acted upon rapidly. So just putting the result in Epic faster isn't gonna change the game. And so that's where a stewardship team can really contribute meaningfully. And that is what I've observed in our own institution. So diagnostic stewardship obviously is in the hands of the microbiology lab, getting the right test for the right patient at the right time. So when we look at, for instance, the T2 test, that's not a test you can just implement at your hospital without any direction because it is direct from blood. You can't send every blood culture draw to the lab to be done with that test. It's not cost effective, nor is it necessary. So you have to have some stewardship guidance to figure out whose blood you're going to run through that test. And then the stewardship team really helps in terms of the interpretation of the test. Yes, Dr. Conant went through the pneumonia panels reporting the results in copies per ML. What does that mean? I mean, that's not intuitive. It's not something we've ever seen before. So you need someone to really provide guidance. What does copies per ML mean and how do you interpret that to make change in antibiotic therapy? So it is a collaborative effort to get this right. And I love this paper that Rich Wondering, a ICU physician at Northwestern put together. And I think it really just summarizes stewardship in the critical care setting. It is a team effort of, as in this paper, the authors were US ICU physicians and European physicians, CDC physicians, nurses, and ICU pharmacists. I'm very proud. My colleague, Tony Gerlach, was the surgical ICU pharmacist author and a very integral advocate of SCCM. And they showed that stewardship has to be the core competency of critical care practitioners. And so why do critical care physicians prescribe antibiotics in excess? It's fear-based. It's not a knowledge deficit. And no one wants to miss something that results in the death of a patient. And so I absolutely understand that. But now that we have rapid tests that can guide that, so we're not prescribing based on fear, it's based on facts. And their own literature shows 30 to 60% of antibiotics prescribed in an ICU are actually either unnecessary, inappropriate, or suboptimal. So when you think of how can a rapid diagnostic test impact patient care, it's all three of these. It can prevent unnecessary antibiotics for days on end or inappropriate or suboptimal. So I think we've gone through a lot of the data to show support for this. And this is a new study. I just am so excited to share. Can the order of infusing the antibiotics make a difference? This is a stewardship 101. Every hospital needs to put this into place tomorrow. Titled the early beta-lactam catches the germ. How clever is that? So these researchers asked, what do we know? Prompt initiation of appropriate antibiotic therapy impacts the survival of patients with bloodstream infections. So they evaluated, does the sequence of ordering the antibiotics and infusing them make a difference? So if you give your vanco first versus your beta-lactam, does it make a difference in mortality? What a simple question to ask. And the answer is it absolutely made a difference. So for patients with suspected bloodstream infections, administer the beta-lactam antibiotic before your vancomycin. And it protected not only against seven day but 48 hour mortality. This is a process improvement. Any hospital with limited resources can put into play today. Educate the ICU nurses when they go to get the antibiotics from wherever they're delivered by the pharmacy department. You know, no one instructs them, does it make a difference which bag they grab first? The vanco, the peptazo, the cefepime, whatever. It absolutely does. So this is a new study. I hope everyone implements this tomorrow. It's very simple and we now know it makes a difference. So making the case for stewardship, it is team-based care. I think COVID taught us we can't possibly manage these complex patients by ourselves. It is a team-based approach. Microbiology, intensivists, ID specialists, physicians and pharmacists, and our infection control practitioners and nurses at the bedside. It takes a village to manage patients in the ICU and we do it together. So Maren, I'll turn it back to you for our closing remarks. Yeah, I think since we're running out of time, it might be nice to go through some of the questions. And I'll just go ahead and pick a few of these questions here. The first one is how certain are we that the presence of resistance genes on panels discussed translates to actual antibiotic resistance, meaning antibiotic disk zone growth inhibition? What studies have addressed this? Deb, do you want to try to take that on? Sure. You know, when the panels were FDA approved, they really had to go through rigorous comparisons to our standard culture-based waiting for resistance to be identified. And in my personal experience with them, there's a very good synergy between them. So I think it has been very well studied and the results support their use. Good. And then sort of a follow-up question to that is, is the rapid test panel, does it remain sensitive after antibiotics are started? And so, go ahead. Go on, finish asking. I was just going to say, you know, from a pulmonary standpoint, we know that if you do a BAL more than 24 hours after starting new antibiotics, the sensitivity falls off. The sensitivity for these techniques will remain because they're not actually relying on growing bacteria. So you're essentially identifying DNA snippets, you know, in these specimens. And so their sensitivity will remain in that setting. So from that standpoint, they may be somewhat helpful if for whatever reason, the patient started on antibiotics and then the test is performed. And I think that's a huge advantage because you look at the patient that you presented the case, you know, they already had prior antibiotic exposure. And we know in the ICU, if you're a referral hospital, half of our patients come from small outlying areas where the patient develops sepsis. They come on two and three antibiotics when we first see them. So when we're doing a rapid diagnostic test, that's a big advantage versus waiting for traditional cultures where then your yield actually drops off significantly because of prior antibiotic exposure. And I think what people might want to reflect on is that does picking up DNA without a live culture actually mean that you still need to have antibiotics? And I think that that's where the sensitivity and specificity for these organisms really probably relies, as all of us have said, on a team approach, because for instance, we all know that our cystic fibrosis patients or our bronchiectasis patients have multiple bugs that might be harboring in there. Maybe they've been on suppressive antibiotics. And so just finding them brings up that question. And I think that's why that was an important question by whoever asked it is that, does dead DNA equal a need for antibiotics? It's the same idea of when we first had the COVID, right? You're just getting a COVID positive tested. That mean that you were still infectious or did you just have dead stuff in your nose? Yeah, the next question here, wouldn't you feel that PCT plays a role in antimicrobial stewardship and de-escalation of antimicrobials, especially in the ICU using PCT to de-escalate antimicrobial therapy to reduce patient exposure to those drugs? I'll just throw out a comment. I'm interested to hear what Debbie, you, and Seth have to say about this. In our ICU, more than 15 years ago, Scott Besick, who's still here, published a paper where we had formal rounds in the ICU, where we had clinical pharmacists addressing antibiotics on a daily basis and found that once that was implemented systematically, that the average duration of antibiotic therapy fell off by more than two and a half days. If you look at the two large European studies that were done in ICU patients using PCT, where they gave physicians reminders, there were two RCTs. Essentially, they showed essentially the same timeframe reduction in duration of therapy. They really didn't focus on de-escalation. In those European studies, there wasn't a formal protocol in the control groups, meaning there wasn't a clinical pharmacist who was overseeing things for the group. They were essentially sending a reminder to patients or to the physician saying, hey, your PCT is low. Do you need to continue antibiotics? It had nothing to do with de-escalation. We don't routinely use PCT in our ICU because they're closed units. We have a multifaceted approach with clinical pharmacists. I'm interested to hear what you all think on that particular problem. Yeah, I think I would agree. We've gotten away from using PCT for two reasons, and both of which were touched on in this presentation, that a lot of people fear getting rid of antibiotics more than their knowledge base. And so once we really enhance the idea with our clinical pharmacist team, that we all know that the duration of antibiotic therapies can be reduced. And who knows where it'll end up eventually? Who the heck knows? But so I think if we follow very carefully the guidelines that suggest decreasing the number of days along with clinical pharmacy and the culture results that we already have, regardless of whether we're using some of these new film arrays, we really have gotten away from using procalcitonin. Debbie, how about you? Yeah, I'll just add, we don't routinely use it, but I will cite a study by Tom Feil, who's an ID physician and works on stewardship with his ICU physicians. And so they're at Akron General in Ohio. And with his clinical pharmacist, they did do a study using PCT and found really the ability to stop antibiotic therapy in the ICU. So I think there are examples of places that have successfully used it to guide therapy, but it's not used as a single isolated test. It's with CRP, clinical signs, and a very experienced ID physician to guide them and continue to follow the patient. So I think, you know, if you have that structure, it could be of value. Okay. There's another question here, which is, will these types of markers or tests be helpful for patients who have a history of multiple MDRO infections in the past? So would you be able to use these panels in that setting? Yes, absolutely. And I think that's part of the biggest advantage is you do get these resistant genes. And so, you know, prior antibiotics or prior resistance isn't gonna preclude the value of the test when you're seeing the patient for the third time or however many times the patient gets reinfected. So, you know, they are valuable in that perspective. There's a question here. If we suspect pneumonia or sepsis, but do not have it confirmed, when do you start the antibiotic and what do you usually start with? Anybody wanna take an initial stab at that? Well, I think in the remaining 30 seconds, I think that's what we got. I would say, again, that's really gonna depend on the population of patient that's come into the hospital and what your antibiotic nomograms, you know, look like in your hospital. I think, you know, people need to remember community acquired pneumonia is community acquired pneumonia and people should feel comfortable using evidence-based medicine for that. And folks who are coming in with underlying lung disease, it's a different challenge. Well, we're running out of time and I don't think we can go over, unfortunately. And there are still many questions here that haven't been addressed and I feel bad about that. But I don't know what else to do about it. So with it, all I can do is thank our speakers for participating in the discussion today. Again, if this were in person at SCCM, we'd have the capability of standing outside the room and maybe carrying on the discussion here. But I just wanna thank everyone for participating and taking some time today. Thank you. Thank you. Thank you very much.

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