work that you and your colleagues in NETEC do at Nebraska, and of course our friends at Emory, NYU, and elsewhere do, is, you know, the critical importance of that, I think, is a thing that we've only learned and relearned over the last two years. But even post-acute phase of the pandemic, with concerns about cases of Marburg, and early in the monkeypox outbreaks, when NYU and other units were actually activating their biocontainment units for these patients, we're constantly reminded of the importance of this. But also, this is a thing that's very dependent on systems. There has been some discussion about the establishment of this new system of care, the NSPS, the National Special Pathogen Systems of Care, and also about expansion of some of our containment units. Is there anything you could share with us about that? Sure, so first, if you really wanna know a lot about NSPS, there's a great summary document on the NETEC website, and on the ASPR websites, you can access back and forth with that, which really goes into a lot of detail. But if you go in and look at those respect clinics, as they've existed over time, you really have 10 regions, and you have people that are hundreds, if not thousands of miles, particularly towards the western part of the country, from the closest regional center. And so, in 2020, there was clear recognition that we just don't have enough bed access preparedness and proximity for care for patients when something like this happens. And so, the NSPS is really building out a strategic plan that's going to last over several years to include a larger tiered hospital sector, if you will, that kind of pyramids down, where you have all of your thousands of frontline hospitals that are really kind of in that identify, isolate, inform arena. And then, a goal of having kind of this downstream, couple hundred hospitals, eventually, that really are within two to four hours of any single frontline hospital throughout the country, so that there is a regional resource actually within reasonable proximity in which you can potentially transfer patients, move patients needing bed availability or higher level biocontainment, expert care, or a laboratory safety, I can't talk, availability. And so, it's really trying to build this out so the whole country kind of is spiderwebbed in a network that can handle these cases from anywhere and to really help provide clinicians with a broader sense of research. Now, there are other gaps within that, right? So, this program also is looking at the opportunity to change education and ensure that we have that broader education and training that NETEC has started with and provided an enormous amount of over time through these outbreaks, but really, again, to get that out more to more and more frontline hospitals and more of the hospitals in these tiered scenarios. I'm having better overall regional coordination. So, if you see a outbreak or epidemic, but maybe not quite at the pandemic level yet that is really starting in the US, the regions can coordinate in a more functional and structured way and then really trying to figure out how to manage surge activity in the midst of all of that regionally and nationally. And so, again, a very large strategic plan to really expand the skilled expertise of clinicians, the capacity of hospital systems to handle these, and to make sure that within a reasonable amount of transport time, there is clinical expertise available for emerging special pathogens or re-emerging special pathogens, if you will. Yeah, and just a quick plug for the NETEC courses. We were very fortunate just last week at Wake Forest to host NETEC for a kind of first responder course for us at Wake. We're not a respect, we'd be one of the initial assessment and receiving centers, but obviously the practical challenges in quick transport means that many centers would need to at least maintain a basic capability to care for a patient under investigation, at least for the first 24 to 48 hours. Thank you very much. Thanks, Paul, and it was great to participate. I appreciate the invitation. So, Dr. Gaglani, so we talked a lot about kind of rapid, non-culture-dependent mechanisms, but I'm a fairly traditionally trained ID doctor, and I love going to the lab, and I like to look at plates, and I like to show off to the fellows, and I grab a plate and say, this is obviously serratia. And the thought of giving it pains me, it pains me. But on the other hand, it's 2023, right? And we gotta move with the times. So, is there a way that we should be thinking about integration of kind of classical culture methods with the new rapid molecular methods? Or, you know, if I get a respiratory PCR off of an intubated patient and it says, you know, Staph aureus, MEK-A gene present, indicating methicillin resistance, and there's a semi-quantitative value that says that there's a lot of it there. Is that enough? Am I done? Do I really care what the culture shows anymore? Thank you for that question, Dr. Meeves. So, when we really look at the PCR test, any positive PCR, the way, any positive PCR assay, the way we look into it is it can potentially represent an infection, or it can also represent a colonization. And so the way I see the PCR studies, and there are multiple studies actually looking into the direct utility of PCR studies for the respiratory specimens in the ICU, is mainly to make sure that we are covering empiric organisms while we wait for the culture data. So, you know, if somebody has an acutely ill, critically ill patient on mechanical ventilation, comes to the ICU with a positive PCR, and I'm actually worried about pneumonia, I will start him or her on vancomycin or the nesolid. However, like I mentioned, it doesn't really rule out an infection. So PCR should be, in my opinion, used as an adjunctive to cultures. It's not going to replace the culture data per se, because definitely the culture data still remains the standard of care. The issues we see with the culture, they're time consuming. So it takes up to 48, 72 hours for its growth, and that's why the PCR studies being rapidly available are used more for antibiotic stewardship perspective and empiric antibiotic guidance while we determine what happens in the culture. And you made a really good point about the semi-quantitative approach, like the same thing we can compare with cultures as well. Other things I see for cultures with culture negative is when you actually want to see overall if the patient had prior antibiotic usage or when were those cultures obtained. So culture negative does not really rule out an infection. However, you want to see all those aspects and then keeping the patient's clinical presentation itself in mind is how usually I approach it. Thank you very much. That's fantastic. Thank you. Dr. Caudrey-Rodriguez. So, you know, you and I have talked about procalcitonin in the past, and I have, with attribution, I'll say plagiarized your slides on one notable occasion. There's a big picture of you in it, though, to say this is who you thought you were getting. And then I had a picture of myself out in the middle of a camping trip looking like a hobo. So there's got to be a right way to use procalcitonin, right? I mean, there has to be a right way. What would it be for you? Like, if you were able to design an institutional procalcitonin protocol, what do you think that would look like? Would it be physician-triggered? Would it be sort of automatic? What components would you want to have in there to kind of maximize the utility of what could potentially be a very useful tool? Ryan, thank you very much for the question, and thank you for this opportunity to present on a topic that is close to both our hearts. I think, first, I would say that if the protocol is for implementation purposes for actual clinical practice, I would want to base it as much as possible on existing evidence and existing data and less empiricism. And I'll tell you what I mean by that. I think, first, I would probably get an idea of what is the level of understanding about procalcitonin at my institution. I would then perhaps educate the clinicians or the users of the test on the current evidence, because there's a lot of evidence out there on so many topics, and it's difficult for clinicians to keep up. So why not curate and provide the evidence as there is? And once you gauge that there is a certain level of education and understanding of the test, then actually design the protocol. And at least if we're looking at the evidence thus far, I would say there is not a strong evidence to support the use of procalcitonin to guide the initiation of antibiotic therapy for either laryngospectract infections or sepsis. And so still go by your gut, go by your gestalt. But at the same time, ordering it on admission does provide you the opportunity to look at trajectories of procalcitonin levels as compared to on day two or three or four, that has actually found to be useful in decreasing antibiotic exposure, which is everyone's objective without causing harm. And so I think one could make an argument to kind of blanket order on admission for anyone who is being started on antibiotics. But with the education of the users, of the end users, to perhaps not hang their hat on that test for the purposes of initiation of antibiotics. That will open up opportunities for someone down the road, because it may not be the same clinician who has initiated who's gonna discontinue, right? We work in a sort of multi-provider type of environment. And so to increase, and so I would want a protocol that works, but also that people are gonna use, that there is high adherence to. And so that's a really important point. It's been really difficult to interpret some of the data thus far because of the variable adherence. And in the clinical trials, lack of adherence is not always a terrible thing because it tells you that clinicians were given the opportunity to override the protocol. But that has made it difficult to understand the attribution of procalcitonin to the outcome. So keeping that in mind, ways to improve adherence, again, education of clinicians about the evidence and about the utility and about the cutoffs for different disease states, to engaging stewardship programs. Most hospitals today have stewardship programs, engaging stewards who may be ID docs, pharmacists, to really help the clinician to interpret the results, to order it when they think it's helpful for the purposes of enhanced discontinuation when appropriate. And I think in that vein, we should also get a good sense of what usual care practices are at your institution. Because it's 2023 and there's the shorter is better mantra. And as we're going to shorter courses of therapy for various disease states, one wonders whether we're gonna get much bang for our buck today by ordering a procalcitonin to further reduce antibiotic duration. And ultra-short durations of therapy for critically ill patients have not been tested. And so I can't guarantee that there's no harm there. And so these protocols have to be careful in, again, being very evidence-based, so as not to invoke ultra-short therapies that haven't been tested. No, I mean, I'm reminded that in the dawn of the penicillin era, the duration of treatment for bacteremic pneumococcal pneumonia was two days of penicillin. But that was at a time when you had to, not to get graphic, but recycle penicillin because it wasn't widely available yet. So Dr. Kuda, I am very excited about the idea of therapeutic drug monitoring. But I have also never been able to order it for a beta-lactam. So where are we on evidence for that? I mean, obviously for vancomycin, for bromine and glycosides, this is a well-established practice. But I looked in Epic and I can't find a line to order therapeutic drug monitoring for oxacillin, for example. But it seems hugely important, especially with the heterogeneity, augmented renal clearance competing against extracorporeal devices and extracorporeal circulation, competing with altered volumes distribution. All of these things make our doses feel so arbitrary. So is there any, what kind of data do we have for therapeutic drug monitoring for beta-lactams, at least in North America? I know there's an evolving European body of literature on it. And does it seem to work? So I will fully admit that I'm a little bit biased about this topic because I'm spoiled at MIT clinic. Yeah, yeah. For the first overall kind of summary, we're really in the infancy of understanding the right way to use beta-lactam levels. There's been a lot of work out of Australia by Jason Roberts and his research group. And the sort of summary of all of that seems like it's probably a good idea. We can probably improve outcomes by improving the overall time to MIC of these antibiotics with a focus on sort of the broader ones. So, you know, your pivosalantase, bactam, ceftepime, and meripetam are kind of where the focus areas are. On larger scales, we don't actually have a lot of evidence that says that definitively monitoring beta-lactam leads to improved mortality or shorter ICU stays or less resistance down the line. And that's really where things are working towards at this moment in time when we consider the sort of the scope of the literature. When it comes to us being a little bit spoiled, Dr. Erin Barreto is launching a huge study. It's called the Bloom Initiative. And she's working with Jason Roberts and she's also working with a couple of centers in the US. So there's one in Florida, and I believe one in maybe Philadelphia that all have internal lab capabilities of monitoring ceftepime, meripetam, and pivosalantase of bactam. So what we essentially did is we scoured the literature to say, do we even know what a target level is? It's easy to say, yes, I want X above the MIC, but when you're targeting an empiric, you know, I don't know if this patient's infected at all, it's probably a gram negative, what's kind of my worst case scenario. So you've got your minimum efficacy threshold, but then the question is, what's the minimum toxicity threshold? And the answer is we don't know. So we know that ceftepime neurotoxicity is a clinical entity. We do not know the level at which that occurs. And I think we're going to start seeing a lot more understanding of adverse effects of antibiotics because as we're all very aware, the data on the actual negative impact of antibiotics in the ICU is poor. And I think we underappreciate the sort of unforeseen consequences of antibiotics just in terms of drug toxicity itself. So that's another sort of area that we're hoping to get more illumination on as opposed to kind of this black box that we're just seeing right now. So the way that we've launched this at Mayo Clinic is any patient in the intensive care unit who is on meropenem, piperacilontazobactam or ceftepime, the pharmacist for the unit has sort of the decision-making capacity to say, I think we should get levels or not. We launched this out in a couple of phases. The first phase was any kind of extracorporeal replacement therapy. So CRT or ECMO, those patients were prioritized. The secondary rolling out was looking at extremes of weight. So patients above 120 kilos and those less than 50 kilos. So we could really try to target who is the most useful person to be doing these levels in. This was started last May at Mayo Clinic. And now we have rolled it out to really anybody that anyone in the ICU thinks is a reasonable person to check levels on. They're working through the initial a couple of publications out of this right now. But one of the things we found was that actually a lot of our impure dosing was pretty good. We had target attainment above 60% of the dosing enroll in a majority of the patients in the ICU in that first couple of days. We think part of this is because we have a practice and have a long standing practice of being very, very aggressive in our dosing in the first couple of days. But more interesting, it's been really helpful to sort of say like, okay, this person weighs 250 kilos and is on meropenem for a horrific MDR pseudomonas. And to really trust that our mechanism of drug delivery is achieving what should be an adequate level for effective treatment. So I think as things continue to move forward and where this literature is, I think it's really gonna be the extremes of body size, the patients that are on CRT and those kinds of things. But also, like I mentioned in the talk, augmented renal clearance. It's really helpful to know from a drug standpoint, apart from this checking of ankle level and hoping that you're gonna catch it with a couple of ankle levels, but it's an option. So I'm really optimistic that we are gonna start seeing some of those longer term outcomes data for the utility of TDM. But at this point, it's too early to kind of roll all the way out. I will say there are labs that you can do send out testing to across the country. So if you're dying, no, on one of your patients in your unit, if you get ID to do a send out for you, they can send them to our lab. There's a couple of other clinical labs in the country that will process outside. But the problem with that is you're looking at like a week turnaround, which is not helpful. We have a six hour turnaround for when the levels are delivered to the lab. So we have a much more actionable timeframe to do these things. So I would say it's not ready for prime time, but I think it's going to be and I'm really excited to see where it goes. Yeah, that is gonna be super interesting. And you know, in augmented renal clearance, I think those of us who do mainly medical critical care is not an entity we see a whole lot of, right? It's mainly, I attended our neuro ICU at Wake and it is a much more common entity over there. But I was reminded when you're mentioning a vancomycin levels, when I was deployed to Afghanistan, how we would have these young guys who are getting, you know, two Q6 of vanc and we're barely making their drops with that. So yeah, it turns out to go into the gym twice a day and having normal kidneys does not do your vanc dosing any favors. It does not. Right. Well, that feels like a good place to wrap this up. So friends, so first of all, to everyone in the audience, thank you so much for attending today. That concludes our Q&A session for now. But please feel free to drop me a line. I don't wanna speak for my colleagues, but I suspect that if you do have any questions, most of us are pretty easy to find. That does conclude our Q&A session. Thank you to the audience for attending and thank you to SCCM for the chance to put this together. Again, just to remind everyone,

infectious diseases

patient care

preparedness

healthcare systems

PCR assays

therapeutic drug monitoring