All right, good morning. My name is Maren Colliff. I'm from Washington University in St. Louis, and I'm chairing the program this morning. Thanks for showing up so bright and early. It's my pleasure to have Deborah Goff with me from The Ohio State University and Amanda Harrington, who's from Loyola in Chicago. And we're just going to have a brief presentation this morning on diagnostic approaches for patients who are infected in the ICU, primarily centering around pneumonia and sepsis. I'm going to go ahead, and I've already made our introductions here. You've already had the introductory video. So we'll go ahead and start. And as you know, you can ask questions through the iPads that you have, and feel free to do that. And we'll try to answer those as we go through and have some discussion, and please feel free to partake in that discussion. So I don't need to tell this audience, I mean, you're intensivists. I've spent the last 35 years working in the ICU. Sepsis is an important problem. It affects many patients in this country. It's the most expensive condition that's treated in U.S. hospitals. The numbers are around 24 billion in 2013. So obviously, the numbers are higher at the present time. For those of us who work in the ICU, we recognize that there's a time dependency when we're dealing with these patients, times of the essence when it comes to making decisions. And most of us have bundles at the institutions where we work for managing these patients. One of the key aspects of treating patients with infection is understanding what the organisms are and obviously how to treat these organisms. And unfortunately, a lot of our institutions still utilize older methods, methods that Pasteur developed many years ago. And so there can be delays in identification as well as in having information on how to treat these organisms. And I think the most important issue for those of us working in the ICU setting or in the emergency department setting is we just want to know, okay, what do I use to most effectively treat this serious infection that I'm dealing with? And we'd like to have some sort of a rapid diagnostic. For those of you who are, you know, Star Wars fans, I mean, obviously Bones is able to identify these bugs very quickly and come up with a treatment approach. We're not quite there. And hopefully we'll be there in the future, but we're moving along and we're going to review what we have available to us. And the essence for all of this is that, you know, we need to get the right antimicrobial therapy to the patient for the organism. And so that's the key thing. I think too often we think about just giving any antibiotic, but the reality is we really need to get the right drug and we'll talk about a few studies to highlight that point. So just to present a case very quickly, a pretty straightforward case, I think. This is a 69-year-old man. He's got a history of diverticulosis. He's had a recent hemicolectomy. Unfortunately, he ended up in a long-term acute care center, and we all know what that means. He's had multiple urinary tract infections there, all of which were treated with antibiotics. He's had nosocomial pneumonia, including a CRE gram-negative bacteria. And now he's admitted to your ICU with septic shock, and he has a CT scan there showing a retroperitoneal abscess. So this is the first polling question, just to get a feel for how you might think about treating this person empirically. And you can go ahead and answer, and then we'll review the answers. So one, meropenem vancomycin, two, septazidine lenazolid, three, piptezo vanco, place an RP drain, obtain a rapid microbiologic test, and you can have more than one answer. Okay so a lot of diversity here. I think quite a few said that we would start meropenem vancomycin. The lead vote getter was number four, placing an RP drain, and obviously source control is a critical issue here. And then number five, obtain a rapid microbiologic test. So really about half the population, half the group, would get a rapid microbiologic. I'm assuming maybe the other half don't have access to a rapid microbiologic diagnostic at their institution, and we'll find out more about that. So getting antibiotics on board in a timely manner is really a key issue when you think about the surviving sepsis campaign guidelines. There are really three main pillars for that program. One is source control, the other is resuscitation, and the third is broad-spectrum antibiotics. But broad-spectrum antibiotics really requires a little more definition. These are data from the group in Utah that were published in CHESS recently, like a lot of other studies, making the point that when you have patients who enter the hospital with sepsis, that there's a relationship between the timing of antibiotic administration and outcome. So what these types of studies assume is that, you know, we're talking about appropriate antibiotics, antibiotics that are active against the organism. But that may not always be the case, depending on susceptibility patterns within institutions and how antibiotics are restricted. We do have now a one-hour bundle, and this is a very controversial bundle, and I'm sure there'll be other discussions at the meeting about this. I'm not going to go through it in detail here. I've highlighted really the one area there, which says, obtain blood cultures prior to administering antibiotics, and right below it, broad-spectrum antibiotics. So you know, it's controversial because, you know, not everyone needs broad-spectrum antibiotics. You have to pick the right antibiotic against the organism. There have been a number of editorials and responses to this one-hour bundle, including one that we wrote. And I think that it's important just to recognize that's a much more complex issue when one says, okay, administer broad-spectrum antibiotics. So you have to really understand the timing of that. There's also the dosing issues that are involved. If they're underdosed, if the patient has augmented renal clearance, obviously that becomes problematic. And not everyone has sepsis when they're initially diagnosed with sepsis. A lot of our hospitals have this urgency to make that diagnosis for a number of different reasons in order not to get penalized for potentially missing a septic patient. So one just has to be aware of these controversies, and obviously when you're designing strategies for treating patients in the emergency department, in the ICU, it's really a matter of really focusing on what's the best option and best approach for those patients. And so I work at Barnes-Jewish Hospital in St. Louis, about a 1,400-bed hospital. It's different than St. Mary's Hospital, which is right across the street, which is about a 250-bed community hospital, spending all the time in the ICU. The ICUs and the hospital in general, when you're talking about these large urban medical centers, are nothing more than collecting bins for resistance genes. I mean, we have probably eight LTACs that send patients to us now, nursing homes. There are 14 other hospitals in our system. So we're nothing more than collecting these genes that come into the intensive care unit. And many decades ago, ICUs used to be thought of as a place where emergence of resistance would occur regularly. I think now we know that that doesn't really happen that often, but we just seem to get patients coming in who are bringing these organisms and these resistance genes with them. This is actually data from a study that we did a number of years ago now, and it's quite dated, if you will, but it's still the largest prospective study where we looked at 2,000 patients in our medical and surgical intensive care units at Barnes-Jewish, and essentially just asked a simple question. Who's infected and did they get treated with an antibiotic that's active against the organism when that first IV therapy was administered? And it turned out that we had roughly about 30% of the patients had an infection, but a quarter of them got treated with an antibiotic that was not active against the bug. And this goes back 20 years ago when ceftriaxone, ceftazidime was sort of the main agents that we were thinking about using at that time. And so if you didn't get the right antibiotic on board, those patients had a much higher risk of mortality, all-cause mortality and ID-related mortality. And there have been many, many other studies published since that time really reiterating that point, regardless of the infection of the organism, that if you don't get the right antibiotic that's active against the organism, whether it's Canada, whether it's MRSA, whether it's a gram-negative resistant organism, then the outcomes are worse. And those delays are obviously carried forward. Now we now have a randomized controlled trial that confirms those points, and this is a Merino study. The Merino study was published in JAMA a little over a year ago. And just to summarize very quickly, because it is an important trial, what the authors here did was they asked a very simple question. Is piperacillin-tazobactam optimally dose equally effective to meropenem for the treatment of E. coli and or Klebsiella bacteremia when those organisms are resistant to ceftriaxone, meaning they're ESBL producers? Now in many parts of the world, people would be happy dealing with just a simple ESBL because there are many more forms of resistance out there. But this was the question that was asked, and the trial was really designed as a non-inferiority study, and unfortunately, they could not show non-inferiority. The mortality was actually higher in the group that received piperacillin-tazobactam. So if you will, this is a randomized, multicenter, prospective trial demonstrating that yes, all the observational studies that we've done in the past to suggest that appropriate early therapy is important are actually correct. So that's the key issue here. It's not just getting an antibiotic on board, but making sure it's the right one. Obviously, we don't want to be overly broad if we don't have to because there are stewardship implications related to that as well. So as a result, we have rapid microbiologic diagnostic tests that have become available to us. Many of our hospitals have them. It's a very confusing issue, and we'll try to shed some clarity on this topic. This is from a review paper that Christina Vasquez-Gilamant at our institution recently published, and it just sort of highlights some of the available PCR and multiplex PCR commercial technologies that are out there for us. PCR-based methods, as you know, typically are going to be single tests for a single organism or single resistance gene. The multiplex systems will have a battery of them that they can run simultaneously, and so there are a number of these that are out there that your laboratories may be able to use, and I'm not going to go through them in detail. But the important point is that compared to traditional microbiologic methods where you might have to wait 48 hours or more to get your susceptibility data and potentially even your ID data, here you can get that information back typically in less than six hours, and in many cases even less time than that. And we also have other technologies here, MALDI-TOF, which our institution uses, MALDI-TOF really being more of a method for identification using high volumes where the lab can process many specimens. There also are add-ons to MALDI-TOF that can give you a rapid susceptibility, and we also have PNA-FISH, which again can be linked into certain rapid microbiologic microscopy methods like the Accelerate Pheno system to give you a rapid ID and a rapid susceptibility, although there are costs involved with that as well. So sort of outlining what's out there very quickly, the next polling question is really to assess your confidence in these rapid microbiologic tests. And if you can, let's go ahead and answer this. Okay, well, not surprising. So about half, actually more than half are not or are slightly confident. It's kind of crazy if you think about it. I mean, here we are, you know, we're the frontline clinicians dealing with these patients along with the emergency medicine doctors when they come into either the emergency department or the ICU, yet we're not confident in technologies that can really help us in terms of better understanding, you know, what the organisms are, and more importantly, how to treat them. And this is really a global issue, particularly as resistance is rising. And here in the U.S., as most of you, I think, are well aware of, we're somewhat spared some of the resistance problems that are being seen in Europe, Asia Pacific, South and Central America, which are much more severe than they are here, let alone talk about the coronavirus. The other thing is that, you know, we now have panels that are syndromic, meaning that there are microbiologic rapid diagnostics that are tailored for a specific syndrome, whether it's bacteremia, pneumonia, urinary tract infections, central nervous system infections. And so these panels are commercially available for the microbiology laboratories. Again, these are just several of the FDA cleared panels that can be used for blood cultures and bacteremia, if you will, or patients who have sepsis. And I'm just going to go through them very quickly here. They're available to you. But the point is that they vary from one another in terms of the number of organisms that one can assess for, gram negatives, gram positives, yeast. And there are some differences in terms of the abilities of these tests to identify specific resistance genes. And it's important to keep in mind that these molecular methods don't give you a true susceptibility like you see in a Petri dish when you're, or if you're doing an E-test in the micro lab, they're just telling you that this organism has a resistance gene. It's got a CRE, or it's got a metallobatylactamase. And therefore, that infers that there are certain antibiotics that you cannot use in that setting because they won't be effective. We also have T2. T2 is a more specific panel, if you will, dealing for bacterial as well as fungal pathogens. Again, giving you rapid results within three to five hours here. It's FDA and it's actually cleared for bacterial and fungal infections in the bloodstream. And I'm just going to go through these panels very quickly, just to illustrate the breadth of the pathogens and the resistance genes that they can identify. This is the film array blood panel. You can see that it can identify a number of gram positive bacteria that are listed there, the more common ones that we deal with. The resistance genes are shown there, MEK-A, VAN-A-B, ENBLA, KPC. And then we've got the gram negatives here, as well as yeast. So it's a fairly broad panel dealing with most of the pathogens that we're likely to see in most of our intensive care units. This is the varigene blood study, if you will. It's very similar. And you can see here, again, the gram negative organisms that are shown here, along with resistance genes that are detected. A little broader here in terms of the types of genes that one can identify. And then similarly, we have the gram positives and the resistance genes that are there as well. So again, one maybe being a little broader than the other in terms of the resistance mechanisms that can be identified. And then we've got the GeneMark-Eplex, if you will, somewhat broader, even more. We've got the gram positives, the gram negatives that are shown here, as well as the yeast. And these can be ordered separately, or you can order the panels together, meaning you can just order the gram positive, the gram negative, or the yeast. So already, we can see how complicated this is. I mean, we don't have just one system out there. There are multiple systems that are even more than the ones that we're showing you. And so it's really important to work with the microbiologists within your institution in terms of better understanding these tests in order to really optimize which one is going to have the greatest bang, if you will, for the dollar at your institution. There are studies out there, quite a few of them, that have used these types of technologies often in conjunction with the stewardship program. This is one from Banerjee and colleagues at the Mayo Clinic. And it really was a randomized trial where they had three groups, a control group, if you will, a group where the patients or the clinicians could order the test, and then a third one where the rapid diagnostic was combined with a stewardship approach. And the important thing to keep in mind here is that, yes, the rapid diagnostics are useful, but it's when they're combined with a stewardship program, meaning that the results are acted on, that one really sees the most effect on antibiotic utilization, particularly from the standpoint of earlier de-escalation. And early de-escalation of broad-spectrum antibiotics when they're not required is really important. And there are other studies that have demonstrated that one can reduce the emergence of resistance with active de-escalation and that mortality and outcomes may actually be improved. And we don't normally think of antibiotics as being harmful, but the reality is there are many circumstances where they can be. And our own group has actually published on this even recently, looking at the combination of piperacil and tasobancomycin combinations resulting in nephrotoxicity. And this is a meta-analysis that was in CID really echoing that point, really saying that, okay, if you look at all the tests and studies that have been done to date, when we look at the rapid microbiologic studies evaluated for patients with suspected bloodstream infections, one can see that overall there seems to be an improvement in outcome, in survival, but only when they're combined with stewardship, meaning that, again, the results are acted on. And that's where we can see a reduction in mortality. So not only do we have individual studies, but we have a meta-analysis now demonstrating their efficacy. And in fact, when you look at what organisms seem to be most impacted by this, they're all of them. They're the yeast, the gram-positives, but it's really the gram-negative bacteria where you see the greatest influence on outcome. And that probably has to do with a couple of things. One is that if they're not treated, and very often we're missing our gram-negatives when they're resistant, that can have a large bearing on outcome. But more importantly, if we're treating these patients who have a gram-negative infection with antibiotics that they don't necessarily need to be exposed to, that can promote more emergence of resistance over time. So let's get back to another polling question here. Does your institution use rapid molecular multiplex panel tests for sepsis? Okay, so more than half said no. About 27% are not sure. Only 18% said yes. So in the U.S., the country that's most technologically advanced, if you will, in the world, less than a quarter of our institutions are using these diagnostic approaches. And I guess there are several issues for that. Debra and Amanda will highlight those, but cost obviously is one, and that's something that one has to sort of keep in mind. Okay, so moving forward very quickly here, we're going to talk a little bit about some of the advances in rapid microbiologic tests as it relates to pneumonia. If you will, this first part of the discussion was more focused on sepsis. When we talk about pneumonia, again, it's a very common condition for all of us, probably the most important nosocomial infection that we deal with as outlined by the CDC, and it accounts for a significant number of hospital stays. So I'm going to show you a case. This is a case of a patient I took care of in the ICU. It's a gentleman who has COPD. FEV1 is diminished. He had a right upper lobe resection three years earlier and has been in and out of hospitals, nursing homes, LTACs with multiple infections and multiple pathogens, including multidrug-resistant pseudomonas. So this patient now comes back to the hospital. He's admitted four days earlier with respiratory failure. He's empirically treated initially by the team with vancomycin, piperacil and tezobactam. But since admission, his white blood cell count has increased from 15 to 24. He has increasingly purulent secretions. His FiO2 has gone up, and his PF ratio has decreased. And that's his chest X-ray there. So the question is, what do you do at this point? He was initially treated with vancomycin, piperacil and tezobactam. The options are you can empirically at this point just switch him to meropenem lenazolid. You can do a BAL with quantitative cultures, if you have that available to you. You can perform a rapid diagnostic respiratory panel. Or you can perform a rapid diagnostic pneumonia panel. Or you can do all of them. Okay, so we're pretty evenly split here. So about half would switch antibiotics at this point to meropenem lenazolid alone. About half would do a BAL with quantitative cultures. A little over a third would do a rapid respiratory panel. And half would do the pneumonia panel. And so the fact that there's some discrepancy here between the respiratory panel and the pneumonia panel is important. And we'll spend a moment or two talking about that. So the respiratory panels are the ones that we typically use when we're worried about upper respiratory tract pathogens. We've been using these for quite a few years in our own institution, primarily to identify atypical bacteria as well as viruses. They're a little different than the pneumonia panels, which are really targeting a broader breadth of pathogens, including gram negatives. So there are some differences when you look at the manufacturers and what they're able to provide to us. And they're just labeled in this arbitrary manner. So the FDA cleared panels are shown here for both respiratory and pneumonia. And there are only two that are out there for pneumonia. And they're targeting, if you will, more nosocomial pneumonia. And we'll actually go through what they represent in terms of the pathogens and the resistance genes that they can identify. So the next polling question, how confident are you in your knowledge of rapid molecular diagnostic tests for pneumonia specifically? Okay. And again, really similar breakdown to what we saw earlier. So probably worthwhile reviewing some of this. We'll move forward here. Okay. Okay. There we go. And so this is the BioFire film array. It's their pneumonia panel. It's different than their respiratory panel. It's a broader panel in terms of the viruses are very similar. And obviously, you can see coronavirus number two there, somewhat different than the coronaviruses sort of causing havoc worldwide. We've got the bacterial pathogens that are there. It's not just the community-acquired pathogens like Strep pneumoniae. We can see Acinetobacter at the top of the list. So it encompasses the nosocomial pathogens. We've got the atypical bacteria, which are also in their respiratory panel, but this is the pneumonia panel. And then we've got a broader group of resistance elements there, primarily because we're going to be dealing with more organisms that are likely to harbor antibiotic resistance. And you can see we've got KPC, NDM, and we've got a number of ESBLs there as well. This is the Curitis Urnovaro panel. And it's described here. It's also a very broad panel. We can see the bacteria that can be isolated here as well, including nosocomial pathogens. It includes pneumocystis, which isn't on the BioFire. So if you're thinking that you're seeing a lot of pneumocystis, that may be a consideration here for one over the other. We can see that we've got the KPC and other resistance elements in the middle there in terms of resistance genes. And then we've got the bacteria on the right side there as well. And the point is that these bacteria for both the respiratory and the pneumonia panels are going to be similar in terms of the elements that can be identified. So let's move into another case here. This is another person that I took care of in the ICU. This goes back to the same gentleman that I presented earlier. This gentleman was started on linazolid and meropenem. Remember, he had the upper lobe resection, had been failing his other antibiotics. He had a rapid diagnostic performed on a BAL specimen that was sent off. And it was from the right middle lobe. And it was positive for KPC. So in less than eight hours, we knew that he had a KPC there. And it had implications from an antibiotic standpoint. He was switched to linazolid and ceptacidi, maybe Bactam, because of the presence of the KPC. Forty-four hours later, after the BAL was performed, the microbiology laboratory confirmed for us that he had a KPC producing Klebsiella pneumoniae. So almost a day and a half later, we had the confirmation from the microlab. So it really highlights the rapidity with which we can get this type of information in a case like this. This is another case. This also happens to be a man with COPD who had an infarct, a right MCA infarct, previously. Comes in six days later, develops a hospital-acquired pneumonia. Ends up getting ventilated. So now he has a ventilated HAP, which we know has a different implication than a non-ventilated HAP from its standpoint of outcome and resistance. His initial therapy here is linazolid, piperacil and tazobactam. He's intubated. Post-intubation, he started on meropenem, linazolid, and given one dosage enomycin. So he started on empiric antibiotics. He's getting worse. Now the antibiotics are switched empirically. So the question is going to be, what do we do at this point? Continue meropenem, linazolid for 10 days. Perform a BAL. Perform a rapid diagnostic using a pneumonia panel. So what would you want to do? And as you can see, these are fairly complex cases because of the comorbidities, the prior antibiotic exposures that these patients receive. And so most people now would say, yeah, let's do a rapid diagnostic test, okay? So what was the outcome here? In this particular case, and you can see about half, again, about half the people in the audience are doing BALs, which is about right. So let's go on and see what the outcome is here. So a pneumonia panel was sent in this particular case from a BAL specimen, and they were negative for resistance markers, negative for Staph aureus, MRSA, acinetobacter, and pseudomonas. So that's important. We know we're not dealing with MRSA. We know we're not dealing with a non-fermenter in this case. We know we're not dealing with the most resistant pathogens. The results were positive for E. coli, and so the patient was switched. They were de-escalated at an earlier point in time. Forty-one hours later, the BAL results from the micro lab confirmed the presence of a susceptible E. coli. So this case is different than the prior one. In the prior one, the clinicians were at risk for treating with an inappropriate antibiotic regimen and worsening outcome. In this particular case now, we can see that the initial therapy may have been overly broad, and there was an opportunity for de-escalation in this case. This is just from a study that our clinical pharmacists did at Barnes-Jewish Hospital. It's a single-center study. It's a small study, but it illustrates a point that there are many implications from these testing methods for stewardship practices. I happened to look at patients who were being treated for community-acquired pneumonia who had a rapid microbiologic assay performed primarily to rule out atypical pathogens. And in this particular case, if the atypical pathogens like mycoplasma legionella were ruled out, de-escalation would occur from the standpoint of eliminating the macrolide antibiotic. And in fact, that was achieved. So in the group of patients that had the microbiologic assay performed, and there was no evidence of an atypical organism, and the macrolide was de-escalated at an early point in time, one can see here that the outcomes were no different. In fact, they were better. The mortality rates were lower. So de-escalation can be done. This is a simple example. There are many other examples of that. And so now we're going to switch over to the next polling question, which, does your institution use rapid molecular multiplex panels for pneumonia? And I suspect that the results are going to be very similar to what we saw for blood. OK. And here we go. So we see here that the answer is no, and about two-thirds. OK. Good. Well, I'm going to switch off here. And before we tackle some of the questions and the next speaker is Amanda Harrington from Loyola, who's the head of microbiology there, and really will take us through some of the clinical considerations for rapid molecular diagnostic testing. Thanks, Dr. Colliff. So as these new tests come onto the market, I think it's important to kind of talk about how we're going to use them. It's not just something that you can start up and expect to just run with without having a little bit of understanding about how the tests work. So what are the benefits? And then what are some of those key features of these tests that we need to keep in mind when we're getting the results? And so we wanted to start with our first polling question. These tests have a lot of good opportunities. And so we wanted to see what the audience thought about some of these. So you can select all of these. So what do you think are the benefits of these new tests for pneumonia and sepsis? Yeah, so it looks like the results are spread pretty much throughout these options. No need for confirmatory testing. And I would agree with you. I still think there's a lot of value in culture and susceptibility testing. So I would agree that these tests go hand in hand. But hopefully, we could get a rapid, more simplified workflow by using some of these tests. And the key, of course, is to improve outcomes. So that's great. So overall, these new methods of the syndromic approach give us a more directed and rapid workflow. Your patient has a clinical syndrome. We can send one sample to the laboratory. And in a pretty quick period of time, we can get an answer for a pretty broad spectrum of organisms, which is great. So that really does improve diagnostic yield. We know there are organisms that were traditionally missing in culture or really we have trouble capturing in our traditional diagnostics. And then we can get that information back into the provider's hands very quickly to help improve clinical decision making. So one thing I think we need to talk about when we talk about diagnostics is, what are we really getting when we're getting that test in our medical record? And so just to go back to the fast and the furious, I think we need to kind of pump the brakes a little bit, take a peek under the hood, and look and see just a couple of the differences between these new tests. So the pneumonia panels are really the new kids on the block. They've really just been out a little bit in the market. So that's great for those institutions that actually already have these on board. Some of the considerations that you need to think about when you're reading the results are things like this, conditional reporting for antimicrobial resistance genes. And what's really great is that these resistance markers are only going to be reported for the organisms where they apply. So that's helping guide how to use these results. And so you can see them listed here. Our ESBLs could be reported for any of these organisms here, as well as our carbapenemases. So depending on the type of carbapenemase, it will only be reported for the organism most likely to carry that gene. And there are two tests, as Dr. Kalliff mentioned, two tests available. And they're not exactly equivalent. So the Curatus univero panel does have a little bit different menu in that you get pneumocystis. So that's a great advantage, especially if that's a significant organism in your hospital population. The Filmorae panel does include the viruses. And it does include a couple of different organisms, like group A and group B strep. Both tests will take either BALs or endotracheal aspirates. And the pneumonia panel for BioFire includes sputum. The univero panel also will include sputum. But you won't get pneumocystis with that. And the BioFire panel runs a little bit faster, about 70 minutes, as opposed to four and a half hours. The univero panel will give you a yes or no answer for your organisms. You'll get detected or not detected. And that can be really helpful. The BioFire Filmorae will give you a semi-quantitative answer. So I'll go into that just a little bit more. So this is going to give you a semi-quantitative amount for the bacteria that are detected. But it's nucleic acid. So that's an important consideration. We're used to talking about detection of organisms in terms of the number of bacteria. With our traditional culture, that becomes CFU per mil, so colony forming units per mil. But for our PCR assays, that's a little bit different. And so it's not a one-to-one correlation. And that number you're going to get out of the instrument tends to run a little bit higher than what we see in culture. So for those of you who are used to making your decisions based on a cutoff, something that you'll see as a number, that's an important consideration when these results start becoming available. And so as we've looked at the comparisons between PCR and culture, there is a really nice correlation between the PCR answer and the CFUs per mil. But it tends to be a range. So I've had that listed here in this table just for reference. So here's just a couple examples of how some of the results might come out from the PCR assay and then how they'll compare with culture. So you can see here on the left that results from the BioFire film array will come out in 10 to the 7th copies or 10 to the 6th copies of organisms. And here we've recovered or identified Klebsiella and Pseudomonas aeruginosa. And the test has also picked up a CTXM gene, which is an ESBL marker. It can't tell you which organism this is attached to. But it tells you that it was detected. And then we can see how that correlates in culture. So we found a significant greater than 100,000 CFUs per mil for each of our organisms. And the laboratory was actually able to confirm that that was the Klebsiella oxytoca that was carrying the ESBL. Now not all of our laboratories do a quantitative BAL. So you may see these as reported as many and moderate, those sort of more semi-quantitative reports as well. And that would correlate just as well. So here's another example where we saw 10 to the 6th copies of Staph aureus. And it was actually able to tell us that the MEK-A was not detected. So that translates to methicillin-susceptible Staph aureus. And that is, in fact, what we found in culture. So I'm going to hand this off to Debbie Goff. Good morning. So I'm going to talk about our stewardship program and how we combine this with a rapid diagnostic test. So what does your stewardship program look like in the ICU? Hopefully the answer is it's multidisciplinary. So I always say stewardship really just steers the ship, but we need all hands on deck. We're never going to tell our ICU physicians what they can and can't do. They're going to be part of the decision making. And what I really like is in our program, what is right in the medical ICU might not be right in our surgical ICU. So those clinicians are involved in guiding how we set up guidelines and what antibiotics or rapid diagnostic tests will be used. And again, it's multidisciplinary. All right, so there's diagnostic stewardship and then antimicrobial stewardship. So the diagnostic stewardship is really getting the right test. You know, they've gone through all these tests that are available. I'm so disappointed to hear how few hospitals have these. And I think that becomes really the role of stewardship to work one-on-one with the microbiology lab to try to cost justify these. If I asked, it's not a polling question, but I'm sure why doesn't 100% of you have a rapid diagnostic test to help guide you? I'm sure it's probably the cost is the rate limiting factor. And so how do you get past that? And that's really where a stewardship program can help advocate. You know, we have our ICU physicians identifying the need. You know, Maren's gone through all the studies or many of the studies that have shown time to effective therapy translates to improved outcome. Amanda's gone through the different tests available, but yet most hospitals don't have them. So who's going to advocate for these? And that's really what I feel is the role of stewardship and is the signature of our program. So it's the right test on the right patient at the right time. So once you have the organism identified, then you move to the role of antimicrobial stewardship is the right interpretation. I think that's what is so interesting. And we'll go through a couple of the studies. You know, you can't just have micro implement a new test and send out an email and hope everybody reads that there's a new test available. A, most won't even understand the way the results are printed. And I'll show you our example of our first rapid diagnostic test to just drive that point home. And so you really need a team based approach. How are you going to implement them? And I think as you, you know, looked at what is your confidence in understanding these, it was quite low because it is somewhat complicated. Most of us aren't microbiologists. So we need our microbiologists to explain some of the results, you know, copies instead of colony forming units. That's not going to be intuitive to everybody. So we have to work hand in hand. And that's how diagnostic stewardship and antimicrobial stewardship works together. So Maren went through this. This is just Mayo's experience with bloodstream infections. And I think if you just look at the little triangles, you see rapid diagnostic tests, the red squares, you get the result faster. But if you don't know how to interpret and change therapy, it doesn't really move the bar a lot. And so the little triangle shows with a stewardship program, time-defective therapy was shorter than just having the rapid diagnostic test result and hoping everybody knows how to make the changes. So this is our study from OSU. Eric Wentzer was our PGY-2 resident. And we looked at the management of staph bacteremia. And we knew from previous work, 40% of patients weren't getting an ID consult. So we wanted to look at really requiring an ID consult, but there weren't enough ID physicians. And so we looked at, how could we do this? And like, well, we have pharmacists present 24-7. Why don't we operationalize it through our pharmacy department and have pharmacists be the driving factor? And so this was vetted through our medical staff. And we created a bundle-based approach driven through pharmacists. So again, you know, the stewardship program steered the ship, but we needed all hands on deck. We needed to operationalize the rapid turnaround of the test results. So we had a rapid diagnostic test in play to identify staph bacteremia. But what if it comes back at 2 in the morning? Do you just sit and wait till 8 o'clock to go look at the results and go, oh, I see they're on wrong therapy? That's a missed opportunity. So we wanted to operationalize it, and we did it through a staff bundle. And so we looked at time-to-effective therapy, ID consults, repeat blood cultures, and a TEE. So just imagine the evening shift pharmacist at 2 in the morning making some of these decisions. And that's exactly what we did. So the stewardship team educated the entire pharmacy department, and these were pre-populated in Epic. So we actually got another publication of how do you make this work in Epic? That's a different presentation, but that's published. And so we looked at really combining the efforts of our IT department that helped us populate this. So it was really a scripted reply. You know, if the 2 a.m., the night pharmacist is getting this rapid diagnostic test result, and they're waiting and sending an alert to Epic, which they were to look at twice a shift, twice during their shift, they'd get the result and say, oh, it's MSSA. They're on vancomycin. I see the guideline states they should be switched to nafsalin or cefazolin. And then they would call the physician and say, per the guidelines of our medical staff, this should be changed. And then they could initiate that change. It was really an amazing effort, and it actually worked. So that was our goal, is to operationalize this. And so all four quality care components, we showed a statistically significant improvement by operationalizing this in Epic through our pharmacy department, went from 68 percent compliance to 92. There's not too many things we do that you get 92% compliance. But most importantly, we looked at, you know, there's a couple papers that show if you get an ID consult for staph bacteremia, the outcomes are better. So when we first looked at this back in, I think it was 2009, we actually showed worse outcome with an ID consult. I remember presenting that to our ID team and they were quite taken back and I was like, now just a minute, there's more coming to the story. The story was, yeah, if we don't consult ID until day 9 or 10 of failed therapy, guess what? Those patients did worse because they were on wrong therapy for 9 to 10 days. And a lot of those tended to be our surgical cases where, you know, consulting ID is not amongst their first thought process. And so that was part of the challenge. And so we knew we could do better. And you know, you educate and you teach and, you know, kind of goes in one ear and right out the other. And so we looked at really operationalizing the management of this through all pharmacists. And it actually worked. Most importantly, we showed a six-fold decrease in mortality. And I think what's real important is, you know, some people really perceive stewardship as the right antibiotic at the right time, at the right dose, at the right duration, which it is. But it's far more than that. You know, if you're giving vancomycin and your, you know, goal is to make sure the trough is okay, but it's actually not the right antibiotic or it's given delayed time, it won't make a difference. It's the whole component, you know, the right diagnosis, the right organism with a rapid diagnostic test, and then the right antibiotic given at the right infusion time for the right duration. It's the whole package that makes a difference in patient outcome, not just the right drug alone. And so that's really what I think our process showed. It's a process improvement project that took the efforts of many, many people. So you know, it wasn't just stewardship looking at, you know, restricted antibiotics and making those calls. And, you know, what I feel is most people think the stewardship program is the program of no. No, you can't have this. No, you have to get, you know, approval by us. And it just sets up brick walls. People hate being told no, and they don't like having to go through all these barriers. And you know, I just looked at this project. It was such a significant impact, and, you know, we were able to drive up the ID consults almost 100%. TEEs, we were very effective at ordering to begin with. But really imagine that, you know, the pharmacist being the trigger for suggesting a TEE. So you know, this was all a long process, getting cardiology on board with this guideline. And it was really a monumental effort by many, many people, but it was driven by stewardship. And that was really our passion as you continued to see a really difficult infection mismanaged over and over again due to multiple failures throughout our healthcare system. And some of it was simply not getting the results rapidly to the physicians trying to make decisions. So we found that this process improvement really did improve our management of staph bacteremia. All right. And then there are many other papers that have done the similar. This is the one from Michigan where they used MALDI-TOF with stewardship to impact the management of bacteremic patients and canademic patients. So they had 256 in the clinical outcomes analysis in the pre-intervention group. So it was a pre-post study. And really if you look at their bar graph, they show the pre-intervention time to effective identification was 84 hours, then with MALDI implementation, 55. You know, just think of that. We found it game changing when we implemented MALDI. So MALDI identifies the organism from any site, which was nice. Many of the others that Amanda went through were blood culture driven tests. MALDI can do from BAL, sputum, urine, wounds. It doesn't tell you susceptibility, but it does identify the organism. So one of our first ways that we implemented the use of MALDI, you know, at first we were thinking, oh, it will help us deescalate people off vanco. But actually it didn't because you knew it was staph, but you didn't know if it was MRSA, MSSA. But what we did find is in our utilization for acinetobacter, for BALs out of our surgical ICU unit, you know, most patients were getting admitted and getting put on peptazovanco, kind of the universal combination around the world, I think, for ICUs. But if you had a BAL and it grew acinetobacter, we absolutely knew vancomycin wasn't going to do anything for that, but neither was peptazo. And so that's a different study that we published from OSU. And we quickly switched them at that point in time to our two most optimal agents, which at Ohio State was minocycline and colistin therapy for the treatment of acinetobacter. Now there are some other options, but at that point in time, that was our most effective option. So the role of stewardship with a rapid diagnostic test can be so powerful when you work together. All right, so they showed a mortality benefit as we did in our early use of a rapid diagnostic test. So I think this is really empowering data. You know, I think the first question we asked is how many have a rapid diagnostic test, and 60% of you said you don't. How do you get these expensive instruments into your micro lab? Studies like this that actually show a mortality benefit, to me, is the way you explain this to your CEO. Never expect your micro lab to try to cost justify these on their own. This is an expense that sits in their budget, and how many still work with silo budgets in their hospital? You know, you've got the micro lab budget, the pharmacy budget, they don't cross over, and nobody wants to take a big hit. But when you come together as a team and say, you know, this is what it's going to do for our patients. Yes, this is $100,000 in our budget that wasn't there to get this instrument in and have this test be available, but look at the potential impact. And then you use these studies that show that. And CEOs, I think, are getting it, especially now that stewardship programs are mandated. You've got to have something that differentiates you from your competitors, and I think a rapid diagnostic test is one of those. You know, cardiology has mastered the door-to-balloon time as a marketing campaign. Door-to-balloon time. I mean, you see, you know, billboards around Columbus on that. So if you have your heart attack, have it here, because we're door-to-balloon time faster. You know, what's the stewardship message? Oh, yeah, we don't have any. You know, what about time-defective antimicrobial therapy? I mean, Marin showed that one study. There's actually one now that actually use that, time-defective therapy. To me, that's the ticket to market these, and you really need a catchy campaign, because that's what resonates with the CEO. Everybody's asking them for something. But this, to me, is really powerful, and the studies clearly show that there is a major impact on patient care. So you're all intensivists. You know, those patients are the high-price-ticket patients. A lot of our early antibiotic use, we could cost-justify some of the new antibiotics just by getting them out of the ICU one day faster was enough to cost-justify some of these. So now you're looking at trying to cost-justify a rapid diagnostic test. Some of these studies showing a mortality benefit by time-defective therapy, you build upon the studies that Marin's done so eloquently many years ago. Mortality benefit if you get appropriate therapy faster. But now you actually have a diagnostic tool to tell you the organism, where when Marin did those original studies, those weren't even on the market yet. So now we have a tool, but we're not using the tool 100% across the board, and we all know why. So now that we know these tests are there, now we have pneumonia panels, I mean, it's really hard to figure out what's right, but that is our job. And so all these studies can help empower us to make that financial case to our CEOs. So this one, just combining stewardship-bundled approach on de-escalation. This is Brandon Bookstaver's study looking at this, and again, it's just another example of looking at the gram-negative bloodstream infection panels with a bundled-based approach to de-escalate. You know, de-escalation is one of the hardest things, especially if you didn't have a culture. You know, what are you de-escalating it based on? It's opinion, signs and symptoms. You know, how am I supposed to tell you to de-escalate when we don't even know what we're treating? Pneumonia. I don't know the organism. I think you should probably stop your antibiotic. Based on what? My opinion versus yours? That doesn't go over too well, and it's hard. But now if you have a definitive organism, it makes the discussion much easier. Miron went through that case where they were able to de-escalate from muropenem because they actually knew the organism. It was E. coli. Sure, muropenem will work. It's excessive. We need to preserve those carbapenems. So, you know, when you have the organism identified, you can actually accomplish that. And so they showed a pre-implementation period. So you see a similarity to all these studies. It's kind of pre-rapid diagnostic test, post-rapid diagnostic test. The difference in this is they had two post-interventions. They implemented MALDI-TOF, and then they implemented the Filmorae blood culture diagnostic test. And again, remember I told you MALDI identifies the organism but doesn't tell any susceptibilities. The blood culture rapid diagnostic test gives you markers so you can predict resistance. And they showed significant improvement in appropriateness of the empiric antibiotic selection to begin with, but they showed significant improvement in the ability to de-escalate. So for combination antimicrobials, 2.8 to 1.5 days. The anti-pseudomonal beta-lactams, you know, those are what are so highly overused, from four days to two and a half. So not only is it good stewarding of an antibiotic, there's also probably cost implications in that. The carbapenems, you know, we always try to advocate, you know, carbapenem sparing if you can. So this allowed them to go from four days to 2.5, pretty significant differences. So again, just another study showing with a combined effort between implementing these with the microbiology lab, the stewardship, kind of steering the ship and helping guide the clinicians in the ICU to de-escalate. You know, it's always great to have that team-based approach and, you know, go, hey, it's day four. We know what the organism is now. Let's de-escalate. Let's see if we can do this. And stewardship can help guide that. This is one of the earlier studies as these multiple different venues were being released to try to look at quality-adjusted life years saved by a rapid diagnostic test. And it was most significant with the molecular rapid diagnostic test with stewardship interventions. So if you don't have stewardship and you just have the micro lab implement a new test, send the email out that nobody reads, it just doesn't work. The results are somewhat complex to understand. And then, you know, physicians are slow to understand the uptake of these. You know, what's the sensitivity, specificity? They get burned once on trying to follow the results because they didn't really understand them and then they'll never use the results again. So someone really needs to help guide how you're going to use these. And it's a learning curve. So who's going to do all that education? I think it falls to the stewardship team. And then a constant reiteration as the results come out to make sure they're being followed appropriately. All right. So this is just from a newer paper, kind of a statement on rapid diagnostics. Use of a rapid diagnostic test can significantly improve the management of patients with infectious diseases. So we've shown you several studies. You know, when you couple it with stewardship, rapid diagnostic tests show a greater impact on outcomes. The most important outcome in my mind is mortality. I mean, you can save a life when you know what the patient actually is infected with and you get them on effective therapy. So although most of them have been done with bloodstream infections, we're now seeing data with pneumonia panels and it makes a bigger impact. So I think as ICU clinicians, you know, I look at the number of cultures in our hospital, you know, the lion's share urinary tract, and then respiratory follow second and third are blood cultures. So although the blood culture results are very powerful, the newer panels allow us to capture far more patients. So proceed with caution. The tests are fast, but you have to make sure you know how to apply the results. So let me show you a couple examples. So here's a traffic sign in Washington, D.C. So you see the little arrows there from 7 to 9.30. Make sure you're in this lane going that way Monday through Friday, except holidays. Name the holidays that apply. Yeah, that's a little hard. Do they mean President's Day or just like Christmas and Easter? Who knows? Monday to Friday, 4 to 6.30, all the lanes go that way, except those holidays that you can't really define. Then all the other times, what are those? Two go that way, one go that way. Now if you go past this at 60 miles an hour, can you digest what that whole sign says? Yeah. So if you don't, you know, you might not have to worry about it because you're probably in a head-on collision. So this reminds me of a rapid diagnostic test report because here was the first one we implemented at OSU in 2009. We had Cepheid's Rapid Diagnostic for Staph Bacteremia, and I remember this discussion so well. Our microbiologists came to the weekly stewardship meeting, you know, just kind of like as an aside, oh, yeah, there's this new rapid diagnostic test for Staph Bacteremia, except it's really expensive. I was like, what do you mean by rapid? Oh, in an hour, you would know MRSA, MSSA, coag negative staph. I'm like, an hour? So you had to grow the organism first. That took generally about 24 hours, but from that time point, one hour. I was like, do you know what it costs to manage Staph Bacteremia? Oh, my goodness, we could cost justify that instrument in a heartbeat, and that's exactly how our journey with rapid diagnostic tests started back in 2009. But the microbiologist also has guidelines of how they can report results based on how the languaging is FDA approved for the rapid diagnostic test, and comes and shows us this will be the report. I was like, oh, my gosh, there's no way anybody's going to understand this. You have a gram-positive cocci. If I did a survey of fellows, I'm pretty sure some still would not know what organism that might imply. It's negative for Staph aureus. It's negative for methicillin-resistant Staph aureus. What might that be? It's positive for Staph aureus, but negative for methicillin-resistant by DNA. Negative for Staph aureus, positive for methicillin-resistant Staph aureus. I did a little analysis because actually our microbiologist said, well, physicians will understand that. They're physicians. I'm like, hmm, I beg to differ. So I went around and just covered up the right side and said, hey, can you just look at this real quick and tell me what the organism is? And you just watched them reading it and trying to understand. It was the traffic sign. Is this the holiday? Is it 4 to 6.30? Which lane am I supposed to be in? And I said, yeah, I didn't think this would work too well. Some actually couldn't even figure it out. And they just said, why don't you just tell us what it is? It's like this report is telling us what it isn't. It's a guessing game. And so we had to simplify it. And so what was really important, if this was just implemented through the microbiology lab, the report on the left is what would have come out. So that did come out along with the interpretation. So there was an asterisk, interpreted by stewardship. That is what your organism is. It was game-changing. And we published the outcome of utilizing this in clinical infectious diseases back in 2010. So when you make the case for stewardship, it is team-based approach. I'm never going to tell our ICU physicians what they can and can't use. We're going to make the decision based on the microdata coming out of our unit-specific antibiograms. Thank you, microbiology lab, because that's another monumental amount of time. But what is present in our medical ICU is very different than what's present in our surgical ICU and very different than the hospital-wide antibiograms. If you want to provide best of care, you need to know the organisms in your hospital and in your ICU units. So it's a collaborative effort of making this all known. So our antibiograms are all available in Epic. But we've also learned, when you're in Epic, if you have to jump out of Epic and go to a different program to go try to find those antibiograms, how many actually do that? That'd be zero, because it's too disruptive to the workflow as you're trying to enter orders. So they have to be embedded into the screens in Epic, and that's where our IT pharmacists just make such a difference in helping us develop these. So they're clinically useful at the point of prescribing. So what is the ideal diagnostic tool? There's a lot of things we want. We want rapid results. I want it faster than an hour. So you saw some of the pneumonia panels are a couple hours. That's good. Could we do better? And that's what every diagnostic company is trying to get. We ideally want these at point of care. Imagine in your outpatient clinics, all the patients coming in asking you for a Z-Pak because they have a cold and they don't have time to be sick, pressuring their doctors to prescribe antibiotics. Imagine if you could do a throat swab, kind of like for the rapid strep test, and go, just give us 30 minutes. We'll know exactly if you have a viral infection or bacterial. Powerful. Those are coming. Those are coming. That's game-changing. Empowering you as physicians and pharmacists to actually know the organism. Is it viral? Is it bacterial? What is the organism? And then ultimately, susceptibility. It's coming. It's coming soon. So that is the name of the game. But I think it's amazing that the majority here don't even have what's available right now. So hopefully, we've really provided you with a lot of opportunity to see the potential of all of these agents. So really, at the end of the day, it's about detecting clinically relevant microorganisms. Part of the concern, am I going to just identify pathogens that are contaminants? And could we potentially over-treat patients because we know how everybody feels compelled to treat everything that grows, right? And that's not a good thing either. So that's where you really have to work with your microbiologist to understand maybe we're not going to report all of this because it's not clinically relevant if the copies per unit are too small. That's where I think Amanda's slide really was very valuable. When it comes out different than what we're used to seeing, is anybody going to understand what copies means instead of colony-forming units? That's an alerting curve. That is our job. And then clinically actionable timeframe. So that's where we recognized if we want to improve the management of staph bacteremia, we just did a survey. How many of those cultures turned positive after 8 p.m.? It was a fair share. So who's going to look at that rapid diagnostic test result as it's alerting you in Epic with all the other alerts at 1 in the morning if there's nobody there to do anything about it? Or the approach is, oh, there's the alert, but we'll let the team, when they come in in the morning, manage that. That can be seven hours of mismanagement. And that could be the difference in someone's life because they're on wrong antibiotic therapy. So we have to make that effort and strategize how do you maximize the utilization of these tools. Just getting them available is not enough. That isn't the answer. It's got to be a strategic approach. And it's not just one person that's going to make that happen. So as we implemented these, we're working with our ICU physicians, clearly working with our microbiologists, team-based approach, multidisciplinary to get the most out of these because they are more expensive. But I think we showed you a lot of the potential and the impact on patient care that these can make. So Maren, I'll turn the last polling questions over to you, please. Sure. Why don't we just go through these polling questions real quick, and then we'll answer some of the audience questions. So again, how confident are you in your knowledge of rapid diagnostic tests for sepsis now? And we're not going to see the results, but we've got a second question coming up. And how confident are you in your knowledge of rapid molecular diagnostic tests for pneumonia? I think what we can start doing now is handling some of the questions that we had. And there are actually some interesting questions. I'm going to start out reading some of these. So I think this first one, Debra, maybe for you, as far as costs go, is there an estimated difference in institutions that utilize rapid molecular diagnostics versus traditional micromethods? So I think in a lot of my work around the US and looking at hospitals trying to implement a rapid diagnostic test, the challenge for some of the smaller institutions is, well, how could we justify these if our volume of cultures is fairly low? We're 300 beds. We're not 1,400 beds like Ohio State. And it's a very valid question. So what I recommend always is sometimes in smaller communities, there's a central micro lab that's doing cultures for multiple hospitals. So collectively, there's enough cultures for that lab to provide that. And then the key is, how does it get communicated to each of the hospitals that are sending their cultures to that lab? And you look at the one that will give you the biggest bang for your buck. So staph bacteremia, we know, is a really complicated infection and has horrible consequences if mismanaged. So when you look at it in your own hospital, you look at how many are positive in one year. And your micro lab can start providing that data. How many blood cultures do we see in a year that are positive for staph bacteremia? You work your economic analysis backwards. So maybe that's not going to be the right one for you. Then you look at one of the respiratory panels. How many patients in your hospital have pneumonia? And you work with your micro lab to find, where would the potential impact be greatest? And do you have the manpower to execute a strategy that can make sure the results are applied rapidly? And that's how you can do it. So it takes really a collaborative effort of many to try to pinpoint where it's at. What I have found is sometimes in the smaller community hospitals, this question will go to the ID physician. He's like, oh, well, I see all the staph bacteremics here. And actually, the microbiologist or the infection preventionist will tell them, actually, you don't. So sometimes people's perception is different than reality. And you watch an infection preventionist will go, actually, this one group of physicians manages it themselves. And the ID physician actually didn't know that because their perception was that they were managing all of them. And so they knew the N in their hospital. But the N was actually greater. And we were able to advocate getting in a rapid diagnostic blood culture test in that one hospital. So it really is individualized. And as a collective team, usually you can come up with which test would be most beneficial in your hospital and start with one and implement it really well. There will be bumps in the road. You've got to try to strategize how to address the results rapidly. If you have residents, PharmD students, a lot of them can be guided to help with this. So there's a lot of different ways to approach it. But those are some of my suggestions. Great. Thank you. And we've got one for Amanda now, I think. Can these rapid panel tests be performed after antibiotic therapies initiated? I mean, we've all been taught that you want to try to get your cultures before antibiotics are started. But what about these rapid diagnostics, Amanda? They can, of course, but realize that the antibiotics do have a good impact on what we recover. So whether we'll be recovering the live organism or just remnant nucleic acid is a challenge for us. And that's part of why we're having these discussions with our physicians before we implement these tests. All of these considerations need to be taken into account when you order the test. What kind of sample did we get before the test was sent to the lab? But they do have that really powerful ability to pick up organisms and detect organisms where we might not have picked them up in culture. So there's a lot of advantages. And really, a follow-up question to that is, what are sensitivity and specificity of the pneumonia panels that we talked about today? They're really in the high 90s. So that's a really good benefit. Of course, if the patient has been treated with antibiotics, then there is a discrepancy between what we'll find in culture. So that'll impact the sensitivity or specificity, actually. And I know, at least in our micro lab, when it comes to quantitation, our micro lab won't even report respiratory organisms below 10 to the 2, because oftentimes they're contaminants. There's a question here on the copies. And the question is, how does the copy count affect treatment decisions, as opposed to simply saying yes or no, the organism's there or it's not? Yeah, that's a great question. As we've started to explore the utilization of these panels, we've gone to our pulmonary and critical care teams and asked them, how are you going to use these results? What's the best way to report them? Our physicians were really interested in having the actual quantitation there. So that'll drive our decision between which test we pick. And then it was very helpful to offer that translational piece, this copies detected. What does that mean for culture? Because I think most people are used to making their clinical decisions based on those culture numbers. So we're going to offer that as a translation piece, as you suggested with the MRSA and MSSA. Just make it very clear as to what those results translate to. I think that copies per mil will be confusing. And although it's a little bit of an off-topic question, I'll ask the question here, since it was asked by a couple of people. Do you use procalcitonin levels after antibiotic initiation de-escalation to guide stewardship? Debbie, what's your answer to that? No, we're not. It's available, but I think there is a meta-analysis that's been done of the value of using procalcitonin. In Europe, they've used it forever. They've got beautiful algorithms. In the US, there's a lot of variability. We aren't using it. Tom Feil at Akron General Hospital in Ohio has a nice paper showing the value of procalcitonin along with stewardship and rapid diagnostic tests as a bundle and has had great success. So I think it really depends on your strategy of how effective it can or can't be. I think there's a lot of data that has been published in Europe that shows great value. I work in South Africa, limited resource country, except when it comes to procalcitonin. I mean, they get PCTs every day on everybody. I'm like, you probably could afford some of the antibiotics if you stop getting PCTs on everybody, but it's embedded in their practice. So it's interesting how it varies around the world, the value of it. So that's our approach. Good. And then we have a question here. If the pneumonia panel is negative, do you feel confident in stopping antibiotics in critically ill patients? So it really gets to the crux of the issue here. I can just tell you that even within our lung transplant group, I mean, more and more they're relying on these diagnostic tests in terms of treatment decisions. So within our medical ICUs, we're very aggressive about de-escalating antibiotic therapy based on these types of testing results. And as confidence increases, I think, within your own institutions with using these kinds of results, you'll be able to sort of do the same thing. But let me just ask both of you, have you seen clinicians actually changing their therapies based on these types of data? So the pneumonia panels are fairly new. So my answer to that is no, I haven't seen them utilized with an outcome analysis. But the respiratory panels have been around. And John Basso published this study with one of his residents a couple years ago, implementing the respiratory panels in the emergency department. So it would tell you viral versus bacterial. How cool is that, right? Did it make a difference? So they did calcitonin, the respiratory panel, and found even with the results, it absolutely did not change antibiotic therapy. So you'd have a negative PCT, you'd have a positive viral panel, and they still sent them out on antibiotics because the physicians really didn't understand the sensitivity and specificity of the test. So it was a test. It told you it was viral, but I don't know if I can really believe it, so I think I'm just going to give the antibiotics anyway. And that's exactly what they did. So it was without stewardship, just implementing it in an ED, hoping they all understood it. I'm sure someone put a memo out of how to interpret it, which nobody reads. And the end result was there was absolutely no difference in antibiotic prescribing. So that's one that I'm aware of where it never made an impact. And I think it's because they didn't really trust the test. They didn't, you know, it's new, like how reliable is this? I don't know, I'll never see the patient again, they're not coming back. So the comfort level is just give them some antibiotics. So I think it'll be really interesting to see what these pneumonia panels do as we have the ability to test sputum in a larger range of bacterial targets, if that'll give more confidence to then avoid antibiotics. I see a great study coming soon. Right, and that's one of the other questions here. Are there more studies coming out on pneumonia panels that will better help to justify the cost? And I think the answer is yes, they will be coming. And then there's a follow-up question. As a pediatric critical care physician, what is the applicability in pediatric critical care? And are there studies currently on the way? I'm not aware of specific pediatric studies, but I guess one way of answering that, the data really shouldn't be different compared to an adult. I don't know, Amanda, if you want to tackle that or? I don't think so. The tests are designed to work for most patient populations and not specific to adults or pediatrics. Yeah. And I'm recently partnering with Nationwide Children's Hospital in Columbus with NICU stewardship in South Africa. So I've been over there working with them. So again, I do adult medicine. But there's a brand new study looking at pediatric use of antibiotics in prophylaxis. And it was, I think, 58% inappropriate use, like in something that basic. So pediatric stewardship is an untapped market that, A, there aren't enough pediatric clinicians and pharmacists to go around. Neonatal stewardship is another important avenue. So in my work in the last year, I'm realizing they have a very high need. The only thing that is a major difference is most neonates have what they call culture negative sepsis. I'm like, what the heck is that? It means 85% of neonates will never grow an organism. So it's like voodoo medicine. You just go by symptoms and a lot of subjective opinion of how long you give these antibiotics. It's even harder. So a test that was more utilized in that population would really be welcomed. And this sort of addresses or a follow-up to an earlier question. Are there any situations when the rapid test is positive but the cultures are negative? And how do you use that information to determine the most appropriate antibiotic selection? So I think we already mentioned that patients who get antibiotics before the cultures are obtained are much more likely to have negative cultures. I mean, there have been a number of studies, particularly looking at organisms like strep pneumo, where you can't identify strep pneumo as a cause of pneumonia after the antibiotics have been started. But when you do a PCR, it's one of the more common pathogens that are identified. And I guess at that point, if you have an organism like strep pneumo identified, nothing else is identified, and you're dealing with a pneumonia case, it really should be an opportunity to de-escalate for that particular pathogen. So I see this as really being one area where these rapid microbiologics can help us. The antibiotics were started quickly. We don't have culture data available to us. Any thoughts on that? I think that's something we've had a lot of conversations about at our institution. And that's where stewardship really has to be part of the team. We know we're going to see these discrepancies between PCR and culture. And what does that mean? Does that mean your therapy is effective, or does that mean you can de-escalate? Because that was potentially just leftover nucleic acid, and it's not really there. So I think it really does need a good eye to interpret these results. And then the other, I know when we implemented MALDI-TOF, you start identifying organisms we've never heard of before. We have the MALDI-TOF list of, what is this? I'm Googling it. I'm like, I've never even heard of this. And you have to be prepared to interpret, like, is this something we're supposed to treat or not? So you enter into uncharted waters sometimes with the rapid diagnostic test, but it really shows the codependency of each other. I mean, you can't really roll these out on your own. You need each other to help understand the significance of some of the results. So this, I think, is a very important question. This person asks, when should you employ these rapid diagnostic tests? Should it be when the patient initially presents with a suspicion of infection, or should you just wait? Start your empiric therapy. If they're not getting better after several days, then go ahead and administer the rapid diagnostic test. We always want your sample before the antibiotics. If you can do it, that's the best way to go. We understand that, of course, there's urgency, and you have to get those antibiotics on board, and we'll work with what we've got, but we'd always rather have it ahead. But I guess what this person's getting at is, do you want to just start your empiric therapy and give it a shot and wait several days? And if they're not improving after two or three days, then send off the rapid diagnostic? That's a great question. I would say if it's a BAL specimen, hopefully we'll get that up front. I think there's a lot of value in that specimen type. I think we're a little bit unsure what to do with sputum. These tests are so new. Did we get a good sample? Is it the right time for the patient? Could they be treated empirically? I think more studies need to be done to take a look at that. Deborah, did you have any comments? My approach would be no, I would not wait. I mean, you know, there's so many studies, and Maren, you've published most of them, time-defective therapy, the impact on mortality if you have inappropriate therapy. You know, if you don't know what they're infected with, how are you going to change your therapy? And so, no, I think it's implementation of the test at the decision-making to start antibiotic therapy, you know, because if you don't really think they're infected enough to get a rapid diagnostic test, then why are you starting antibiotics? To me, that doesn't make sense. So if you are going to pull the trigger to start an antibiotic, then you've made a clinical decision, I believe this patient's infected, and therefore I'm going to start, and I'm sure you're not starting one antibiotic, you're starting two, maybe three, then you need to be empowered to have the knowledge of what are they infected with. That goes back to diagnostic stewardship. Can't just start antibiotics and then, you know, just because. And so to me, it would make no sense to wait. And I would agree with that 100%. So here we have another question on, do these tests, the rapid microbiologic tests, actually provide susceptibilities? The diagnosis may deescalate or these tests may help to deescalate, you know, but can they really help to guide organism-specific treatment? So they only offer resistance markers. They won't give you a true susceptibility. So I think you can do some guidance from that point of view, but you'll need the full susceptibility. Yeah, and that's where it becomes important to have stewardship help guide what these mean. So I'll just give, for example, when we implemented varigene gram-negative blood culture, and it would tell you you had a CTXM E. coli. So if the surgeons had a positive blood culture for E. coli, telling them it's CTXM, no clue. They're like, I don't know what that means. Like, what am I supposed to do with that? And so we would switch them to a carbapenem if they were on ceftriaxone, and that was one of our examples. So it does not tell you susceptibility. You have to understand what that marker implies and then guide them. So we would have algorithms, and there's many published studies now that have put out these algorithms based on the markers that are identified on the blood culture results. So again, that's somewhat of a limitation. Those rapid susceptibility results are coming soon. That's kind of the holy grail of rapid diagnostics. That's really what you want, the whole package of information, not just organism with resistance markers and you got to figure out what you have to, it's like that stop sign. What does it mean? And you have to have a pretty good knowledge of ID and micro to figure that out, which everybody doesn't. So again, that's what stewardship helps with the interpretation, and that would be our phone calls our residents would be making is that's what the CTX would imply. We won't know for three to four more days, but we would recommend you change your therapy. So it is a learning curve. And I think also, unfortunately, for PCR-based testing, especially for gram negatives, there's only a limited number of markers we can detect these days, and that really doesn't give you a comprehensive view of your susceptibility profile. So that is a limitation of this PCR-based approach. Okay. We have another question here. How much do the respiratory and or pneumonia panels rely on getting a good specimen, for example, a good BAL before you can confidently say no bacteria that you're just dealing potentially with a virus or something? Yeah. The sample type is imperative. We love to say in the laboratory, junk in, junk out. We can't rely on the results unless we get a good sample. So that's... Yeah, I think, I mean, just to illustrate that fact, just spending the last two weeks in the medical ICU, we've had situations where the influenza nasopharyngeal swab was taken in the emergency department where they're negative, and then we do a BAL on that patient and they've got influenza. So we see that about 20% of the time, just because the sample isn't collected appropriately. Well, it looks like the lights have been turned off, so it seems like they're kicking us out of this room. So I just want to thank everyone for showing up this morning. I want to thank both Amanda and Deborah for being here. Thank you.

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