Hello and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. In today's webcast, we feature two viewpoint articles from Critical Care Medicine. This webcast will be available to registrants on demand within five business days. Log in to mysccm.org and navigate to the My Learning tab. My name is Thomas Zagmani and I'm a Professor of Intensive Care at Cardiff University in the United Kingdom. I will be moderating today's webcast. Thank you for joining us. Just a few housekeeping items before we get started. First, during the presentation, you will have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. Second, there will be a Q&A session at the conclusion of both presentations. To submit questions throughout the presentations, type into the question box located on your control panel. Third, if you have a comment to share during the presentation, you may use the question box for that as well. And finally, everyone joining us for today's webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation. Your feedback is greatly appreciated. Please note this presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are of those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I would like to introduce today's two presenters. Erika Plata is an internal medicine physician and critical care medicine specialist in Barcelona, Spain. She is affiliated with two hospitals in the Barcelona area, Hospital Clínic de Barcelona and Clínica Diagonal. She received her medical degree from Universidad Panamericana School of Medicine, Mexico City, and have been in practice 13 years. Dr. Plata is also a clinical researcher at Walder Braun Institute of Research as a member of shock, organ dysfunction, and resuscitation group of research, which is led by Prof. Ricard Ferrer. She leads the rational life support in sepsis educational training program in the University of Barcelona for healthcare professionals. Since 2019, she has been a consultant for a startup company that is developing a point of care test that identifies severe infection through immune activity to aid emergency physicians to recognize sepsis earlier. The group recently reached the Europe finals in the wildcard program, Munich, Germany, an initiative that awards funding to promising ventures aimed at addressing healthcare challenges. Her areas of interest include critical care medicine, sepsis, immune response, and continuous medical education strategies in sepsis. Captain Ryan Maves is an attending physician at Naval Medical Center San Diego, or NMSCD, and serves as a research director of the NMSCSD Division of Infectious Diseases, and as a staff intensivist in the Combined Medical Surgical Intensive Care Unit. He's an associate professor of medicine at the Uniford Services University of the Health Sciences, and is the Department of Defense Coordinating Principal Investigator for the NIAI-sponsored adaptive COVID-19 treatment trial. He served previously as program director of the Naval Medical Center San Diego's Infectious Diseases Fellowship. He has deployed at sea on board the USS George Washington, and served as a director of medical services at the NATO Role 3 Multinational Medical Unit in Kandahar, Afghanistan. Dr. Maves earned his Bachelor of Arts and Doctor of Medicine degrees at the University of Washington in Seattle, and completed his internal medicine residency and fellowships in infectious diseases and critical care medicine at NMCSD. He's a member of the Society of Critical Care Medicine's Congress Program Committee and Disaster Management Subcommittee. Thank you, Erika and Ryan, for joining us today. Before we begin, could you each tell us if you have any disclosures to note? Erika? I have no conflicts of interest to disclose. Thank you. And Ryan? I also have no conflicts of interest to disclose. Thank you. Thank you. Okay. So I will turn things over to our first presenter, Dr. Erika Plata. Thank you for the invitation to the Journal Club. Today I will present the point of view regarding the best viable evidence supporting the use of PCT guidance in critically ill patients with sepsis. I will refer to procalcitonin as PCT for the presentation. Sepsis is considered a medical emergency, which causes time-dependent organ dysfunction and high risk of death. The fundamental pillars of therapy are the early administration of adequate antibiotics, effective source control, and adequate resuscitation. As these interventions are essential to improve survival, the last update of the Surviving Sepsis Campaign Guidelines, the Hour 1 Update Bundle, it recommends the early administration of prospective antibiotics upon recognition of sepsis and septic shock. I will not discuss these other interventions displayed in the chart because it goes out of the scope of this talk. Even though antibiotics have to be initiated quickly, the use and overuse of antibiotics lead to undesirable effects which limit our viable arsenal for therapy. Multidrug resistance, drug toxicity, pharmacological interactions, drug-associated organ dysfunction, and increased healthcare costs are some of the consequences. In the near future, it is presumed that antimicrobial resistance will become a global crisis and an overwhelming public health problem worldwide, causing more deaths than cancer, diabetes, and road traffic accidents. The actual trends in epidemiology of resistant phenotypes over time is worrying. When analyzing the percentage difference between the early 2000s and the subsequent years, an important increase in resistant phenotypes and carbapenemase-resistant organisms have been observed among virtually all regions. At this time, we constantly face a challenge, and we have a question like, how do I treat my patient in an optimal way following the best available evidence, but at the same time, how can I reduce exposure to broad-spectrum antibiotics? How do I implement a right balance, and is there any evidence-based guidance in the ICU for different clinical scenarios which can guide me to make my decision? There are various strategies for infection stewardship. They are based mainly on prevention, improving early detection, and improving the whole process of care, including an optimal antimicrobial stewardship. It sounds good to the ear, and now is when biomarkers takes place. Procalcitinin is the most studied biomarker in sepsis. Its production is triggered by systemic inflammation due to severe infection in response to various pre-inflammatory signals. Early studies found that most patients who died from sepsis did not decrease their PCT levels below 1.1 nanograms per milliliter. Also non-survivors had a slow decrease or no decrease in PCT levels 48 hours after admission. So, would PCT help remissions to stop antibiotics earlier? In the MASA study, the authors prospectively validated that the inability to decrease PCT levels by more than 80% between baseline and day four was associated with increased 28-day all-cause mortality. We learned from MASA study that PCT is likely to provide unbiased complementary information beyond clinician's confidence or experience when managing patients with sepsis. Here I display the process of care of sepsis. During initial stages of management, the broad spectrum empirical antibiotic therapy should be directed to the potential organisms causing the infection. But subsequently, the treatment should be progressively modified and de-escalated based on early microbiological data, clinical evolution, and other objective markers such as PCT, delta values of PCT action, which reflect response to therapy, and finally, to stop therapy. So far, antimicrobial de-escalation is an important step in the antimicrobial stewardship process. However, this involves a multidisciplinary process to optimize the use of antibiotics. Although an appropriate clinical assessment is crucial for de-escalation, in certain circumstances, physicians need some objective guidance to make their clinical reasoning stronger. Any validated strategy to refine our clinical assessments is very welcome. I'm quite sure about the need for an objective guidance for clinical decisions since often clinicians de-escalate antibiotics based on their clinical judgment that the patient has a febrile course or there is no risk of clinical deterioration of their patients. In this national study, the Diana study, performed in 28 countries, de-escalation was infrequently applied in clinically ill patients with sepsis. Then it seems that clinical judgment is clearly perfectible and as reflected by this study, physicians frequently face management issues. Biomarkers could aid the decision-making process of de-escalation then. Early studies evaluating PCT guidance were performed in the general population of patients with community-acquired pneumonia. In this study, shorter durations of antimicrobial therapy were achieved without adversely impacting outcomes. This study, the PROGAVA study, was designed to initiate and stop antibiotics based on PCT values. PCT-guided antimicrobial de-escalation algorithms are clinical pathways that consider delta values or changes in PCT levels from baseline. And the overall clinical evolution of patients when tailoring antibiotic therapy. Algorithms are based on the previous evidence showing that patients with prevalent evolution and adequate response to antibiotic treatment have decreasing PCT levels. The PERCEP study algorithm was designed to stop antibiotics according to the delta values of PCT when PCT levels decreased more than 90% on day five. In this study, more patients had their antibiotics stopped with PCT guidance and the PCT group had three and a half days shorter median duration of antibiotic therapy for the first episode of infection than control subjects in the intention to treat analysis. The results of this study suggest that a protocol based on serial PCT measurements allows reducing antibiotic therapy duration and exposure in patients without affecting outcomes. This finding has been reproduced in other trials such as the PROGAVA trial. And there are important studies that evaluate in the safety of PCT guidance in the ICU. The SEPSIS study reported improved clinical outcomes and reduced the length of stay with no associated harms in critically ill patients with septic shock. The study was assigned to stop antibiotics. In at least three meta-analysis, PCT guided algorithms have been effective and safe to de-escalate antibiotics in SEPSIS and septic shock with no adverse effects on patient outcomes. This is a study by Yankova and colleagues. The SEPSIS study results show us that the pre-test probability for severe bacterial infection and severity are essential to detect any effect from procalcitonin guidance. In this study, almost all patients had septic shock and benefit on mortality was observed. In another meta-analysis, WIRS and colleagues found that PCT guided treatment in the patient with SEPSIS decreased mortality too. And this finding was consistent in subgroup analysis stratified by site of infection. Combining studies from different phases of antibiotic management may not be appropriate due to the risk of clinical heterogeneity. Thus, in this meta-analysis by Lama and colleagues, the purpose was to evaluate the effect of PCT guided algorithms in different phases of antibiotic use. When only examining PCT guided cessation of antibiotics, lower mortality was detected. The different trials have obtained different effect sizes or no effect depending on the algorithm implemented. When analyzing studies on PCT guidance, it is essential to evaluate the algorithm and the overall process of care given by protocol. Using PCT for the escalation may actually lead to wrong decisions or adverse outcomes when based on a single value of procalcitonin or when implementing an inadequate algorithm. This is also true for available tools at base site. We need a guide to using them. An example of an appropriate process of care can be represented with a recent trial performed in Greece. I personally love this study. And the primary outcome was the rate of infection-associated adverse events at six months, which was a composite of the occurrence rate of any new infection by consumed difficile or multirole-resistant organisms or any death attributed to those infections. In sepsis patients, PCT guidance effectively reduced infection-associated adverse events, 28-day mortality and cost of hospitalization. This trial takes a huge relevance for the topic discussed today as not only PCT guidance is safe as demonstrated in the methanalysis of Yancova or the PRIS-ICU trial, the PUR-RATA trial, Geneva or PERSIP trials, not only PCT-based algorithms improve survival as demonstrated in the SAHPS trial or the methanalysis conducted by WIRS or LAM, but also this study demonstrated that not using any guidance is actually dangerous for the patients. That's why I've rated this study as having the two Gs, Greek and great. Therefore, antimicrobial treatment in sepsis comprises a whole process of antimicrobial stewardship in which PCT could aid during the optimization phase of treatment to reduce exposure to antibiotics and associated costs. And what about cost-effectiveness of PCT guidance? Well, back, Valcount colleagues in this study found significantly lower cost than healthcare utilization in PCT-managed patients. It seems that I'm reaching the end. And now I'll move on to the most important slide of this presentation. There are different keys to success when trying to implement evidence-based PCT guidance in our daily clinical practice. I proposed using delta values in addition to clinical evaluations, the use of simple, practical, and valid algorithms that include PCT in a high-quality process of care, and promoting the compliance with local protocols and quality-of-care improvement programs within our institutions, and multidisciplinary collaboration, the use of algorithms in the right patient. This involves assessing the severity of illness, evaluating the probability of having a bacterial infection, and enhanced continuing education on the right interpretation and implementation of evidence-based clinical tools. As conclusions, those conclusions, sepsis is a time-dependent condition. Causing organ dysfunction and death, so the early recognition and treatment are crucial for improved prognosis. The more severe the disease, the more urgent is the treatment. Think about septic shock and the bare results of trials. Antimicrobial resistance is limiting our current arsenal of treatment, so physicians should avoid the prolonged or thoughtless use of rare-spectrum antibiotics. PCT delta values aid by giving objective data in addition to clinical assessments, and the right interpretation of PCT kinetics is useful to reduce exposure to antibiotics in critically ill patients. PCT-guided algorithms improve mortality and other important secondary outcomes and costs. However, further studies are needed to determine the validity of PCT guidance in certain populations, like trauma patients, renal dysfunction, patients on continuous renal replacement therapies, and cystic fibrosis. Education for compliance and adequate implementation of evidence-based algorithms are essential for this success. And my key conclusion is, please do not order a test, in this case, a biomarker, if you don't know what to do with the results. Well, I have concluded my presentation, and now I will read the polling question one. Yes. In which subgroup of patients is PCT-guided de-escalation beneficial? Okay, it seems like 75% say E, A, and B. Well, the answer is correct, and I expected this answer. The intention of this question is to emphasize the subset of critically ill patients who benefit the most from PCT guidance. Now I will move on to polling question two. PCT-guided de-escalation is useful in patients with sepsis, except for patients. The first answer is with intraderminal sepsis. The second answer is receiving high-volume infiltration. The third answer is receiving low-dose corticosteroids. The fourth answer is E and B, A and B, and the last answer is B and C. Okay, here. Okay, the responses were changing, so, okay. 55% said E is the answer, and 27% say D, A and B. Well, the correct answer in this question is D, A and B, because this is a tricky question because it is focused on recalling the importance of validating adequate cut-offs. Especially in patients with intraderminal sepsis. And thresholds for positivity in other populations, like patients receiving high-volume infiltration. We recently wrote a letter on this topic, and I'd like to say that patients with high-volume infiltration eliminate prococitinin, so the values are not so reliable, but also you have to look at the delta values. And the answer that says receiving low-dose corticosteroids, well, there are clinical trials, including patients receiving low-dose corticosteroids, and prococitinin is validated in this population. So, the correct answer is the answer A and B, so the answer is D. Now, thank you very much, and I will turn things over to Dr. Ryan Mapes. Thank you. All right, thank you so much, Dr. Plata. So, my name's Ryan Mapes. I'm an infectious disease and critical care specialist at the Naval Medical Center in San Diego. And, you know, I'm in the sort of unusual position of giving the pro, I'm sorry, giving the con side of a debate against someone who I fundamentally agree with. And everything that Dr. Plata said about the utility procalcitonin is absolutely correct, and I think, if implemented in this manner, will lead to improvements of care. But what I'd like to challenge you with today is, and it's in my title here, is the word inadequate. Procalcitonin is a start. It is a step in the right direction. But there are a lot of critical things that we, as a community of clinicians, need to do first before we add another blood test, another biomarker to our armamentarium. All right, just my standard disclaimers. I'm an active duty Naval officer in the United States Navy, and these views are mine and do not necessarily reflect the official policy position of the Department of Navy, Department of Defense, nor of the United States government. I have no relevant financial conflicts of interest, and for CME purposes, I may discuss off-label medication or product uses. I also just wanted to say a thank you in a memoriam to Dr. Douglas Gehan. The genesis of these articles that Dr. Plata and Dr. Rickard-Ferrer and I wrote for the Journal for Critical Care Medicine came from a pro-con debate from the 2020 Critical Care Congress. The original speaker was Dr. Douglas Gehan, who is the Medical Director of Trauma Services at the University of Missouri in Kansas City and a professor of surgery who passed away unexpectedly immediately prior to the Congress that year. And I came in as a sort of last-minute substitute, but I wanted to make sure that we acknowledged Dr. Gehan and his work and the loss to his colleagues and his family. All right, so a friend of mine, another infectious disease doctor, has a little term that I like to use on rounds of my house staff, which is called the devil's labs. That is to say, looking at a number of commonly ordered tests with multiple confounders that often lead to misinterpretation. So troponin, BNP, D-dimers, lactate, procalcitonin. Assays that taken out of the appropriate clinical context often lead to confusion. And if we make our decisions based on the lab and rather than on the clinical context may lead us down an undesirable pathway. And procalcitonin is an interesting one where we order it for generally a fairly discreet and pretty well-defined entity, the infected hospitalized patient receiving antibacterial drugs. But that scenario is common. That scenario is common and overlaps across multiple patient groups. So, you know, procalcitonin is a biomarker. Dr. Plata explained this better than I ever could, but procalcitonin production largely is a result of two separate pathways, an inflammatory pathway, which is upregulated by the presence of lipopolysaccharide, other microbial products, inflammatory mediators, such as IL-6 and TNF-alpha. It is on the other hand inhibited in its production by the upregulation of interferon gamma and other cytokines that are associated more with viral types of infections, more of a TH1 type response. Then of course there's constitutive or thyroid-generated procalcitonin, part of the calcitonin and calcium metabolism pathways, which is discrete from and separate from the mechanisms we're describing here. So what are the uses of procalcitonin in the intensive care unit? There's basically three of them. Determining viral versus bacterial pneumonia is an initial decision to initiate antibiotic therapy. Gaging the severity of illness in a given patient used as a prognostic marker. And then lastly, the one that we're really gonna focus on today, determining duration of antimicrobial therapy. How long do we treat people for? All right, so procalcitonin for the diagnosis of bacterial versus viral pneumonia. I could just cut to the chase on this. In 2019, at least in North America, the American Thoracic Society and the Infectious Diseases Society of America updated their community-acquired pneumonia guidelines. And their summary was that, we recommend that empiric antibiotic therapy should be initiated in adults with clinically suspected and radiographically confirmed community-acquired pneumonia, regardless of initial serum procalcitonin level. This is unusual. IDSA recommending that we treat everybody rather than, with a compatible syndrome, rather than relying on microbial testing, right? So what's the data underlying this? Well, this comes from a thing called the EPIC study. This was, we're gonna see some familiar names as we go through here. But this was a prospective study of 3,600 patients in North America, of whom 2,500 were enrolled, and then had microbiologic testing for etiology of community-acquired pneumonia obtained through very rigorous screening. And then what they did was a sub-study here, and this was published in Clinical Infectious Diseases in 2017, where they took people who had confirmed viral atypical bacterial or typical bacterial pneumonia, setting aside patients without a detected pathogen or with mycobacterial or fungal infections. From those, they looked at the pre, I'm sorry, the positive and negative predictive values of different procalcitonin cutoff levels. And this is just a graph indicating what the general ranges were, a median range and then confidence intervals around patients with, as we see, viral pneumonias, atypical bacteria, typical bacteria, mycobacterial, and then unknown patients without a discrete pathogen identified, who were, to be fair, the majority of patients. So what it turns out, and if you figure that a typical procalcitonin cutoff in our clinical practice in most centers is usually about 0.25 nanograms per milliliter, what they found was that the positive and negative predictive value for typical bacterial pneumonia, even using a very low procalcitonin cutoff of 0.1, led to a positive predictive, excuse me, led to a positive predictive value of 49% for determining bacterial pneumonia and a negative predictive value of only 82%, meaning that someone with a procal less than 0.1 admitted to an intensive care unit with pneumonia still had an 18% chance of having a bacterial pathogen as a cause of pneumonia. I think we would all broadly agree in critical care that that is not an acceptable cutoff for us to make many clinical decisions. So this and comparable data have led most of the critical care community to not use ProCal for the initial determination of whether to start antibacterial therapy in pneumonia. All right, so how about as a marker of illness severity? We know that patients who are septic with very high procalcitonins are quite sick, and generally as their procalcitonins come down, they are usually improving clinically. And Dr. Plata presented that data quite beautifully. So this is a multinational observational study of procalcitonin in patients with pneumonia requiring mechanical ventilation. This is just one example of a number of similar studies. And what they found was in the graph on the left-hand slide here, that procalcitonins correlated quite nicely with mortality in patients with pneumonia, and that was true in patients with both community-acquired and hospital-acquired pneumonia. What is interesting, though, is you compare that to the Apache score, and those curves are basically right on top of each other, that we have physiologic and existing laboratory markers that show very, very comparable outcomes to procalcitonin. We also see similar curves on the right with SOFA scores and with other assays. There is similar and comparable data with use of lactate as a prognostic marker as well. How about C-reactive protein? What if we compare C-reactive protein as a biomarker? And there have been studies comparing these two in a randomized trial published in Critical Care Medicine in 2013. What they found is that procalcitonin did pretty well for antimicrobial discontinuation, and much as Dr. Palata described, what we see is C-reactive protein, another more widely available and more rapidly obtained test in many centers, performs just about the same. So that's interesting to see. So what do we need procalcitonin for in this setting? We see that procalcitonins are positively associated with mortality in patients with hospital-acquired pneumonia and ventilator-associated pneumonia and community-acquired pneumonia requiring mechanical ventilation in the ICU. We see that it mirrors C-reactive proteins in infected patients. It predicts mortality about as well as lactate, about as well as Apache, about as well as SOFA. So what's the point of procalcitonin then? Another data point that gives us data that, to be honest, we already had. We already knew these things. But then we get to antimicrobial de-escalation. Now, C-reactive protein data actually does discuss that, but let's take a look at procal as a tool for de-escalation. if we can't use it reliably for determining the initial viral versus bacterial origin of a given infection, maybe we can use it for stopping antibiotics earlier. Well, so antibiotic durations, these tend to be fixed durations in many intensive care units. So where do our durations phantom microbial therapies come from? Well, my theory is that modern antibiotic dosing durations are attributed in part to the work of Gudea, priest king of Lagash in ancient Mesopotamia, in the third century BC, sorry, third millennium BCE. So Lagash, sorry, Gudea, priest king of Lagash built a temple to the then seven visible planets in the sky. This became ultimately the basis both of the Mesopotamian pantheon and the seven day week, leading to the fact that most of our antibiotic durations tend to be multiples of seven based on the days of the week, seven days, 14 days and the like. So there is a competing theory based on human and ape hand proportions and how primate hands evolved where we have five digits. So there is the seven multiple theory and the five multiple theory. So if I say, I wanna treat this patient for 10 days, people nod at me and say, yes, you're a wise, wise infectious disease doctor. If I say, I'd like to treat some for 12 days, I don't like where you're going with this. This is unreliable, but we have one with five and seven and all of our therapies tend to be based on that. So prorata, this is one of the first large studies in the Lancet, looking at a procalcitonin guided algorithm for antibiotic deescalation, using cutoffs of generally 0.25 nanograms per liter. In this case, there's micrograms per liter or nanograms per deciliter as a cutoff for discontinuation of antimicrobial therapy. And what they showed was that there was good outcomes. The patients did well, that there was no real safety signal for mortality and those patients treated using this algorithm had excellent outcomes with less antimicrobial exposure. So this is very promising. There's a follow-up study by De Jong and colleagues in Lancet ID in 2016, the SABS-2 trial. They looked at this over the long-term and not only did they see the initial improvement during the initial hospitalization, but when they followed patients out a year after the randomization, mortality was in fact lower in the patients with procalcitonin guided therapy. So this is clearly good evidence that procalcitonin as a tool for de-escalation is very useful. So how about this study? So Dr. Plata referred to this. This was a retrospective study by Dr. Balk and colleagues published in Chess in 2017, looking at the use of procalcitonin in healthcare utilization and costs in critically ill patients in the United States. And their conclusion, which I've copied here is the use of procalcitonin in the first day of ICU admission was associated with significantly lower hospital and ICU links of stay as well as decreased total ICU and pharmacy costs. So this is very promising, right? We're using spending less money. Patients aren't in the hospital as long. So this is great. We should probably all be doing this. And they lay it out very nicely here in one of their figures, where you see the length of stay decreased from 12.8 to 10.5 days. The total costs went down from 33,000 to 25,000 US dollars. Then inpatient mortality was, it was about the same, but certainly it was not statistically worse. Very, very promising. But then you get to this next part, total by antibiotic exposure, 17.3 days in patients without procalcitonin guidance versus 14.9 days. So about two days, two and a half days less using procalcitonin guidance. That is an improvement. That is a real improvement. That is also completely inadequate. In an era where we have solid data saying that the treatment of, for example, gram-negative bloodstream infections with source control should be seven days perhaps, that community-acquired pneumonia, ventilator-associated pneumonia, five days for community-acquired pneumonia, seven days for ventilator-associated pneumonia, that most bloodstreams other than say staph aureus bacteremia can be treated very effectively with short courses. Why are we still treating people with 14 plus days of antibiotics with procalcitonin guidance, right? This is an improvement. This is definitely improvement, but it is not enough. And it is not enough to fend off that wave of antimicrobial resistance and the resulting public health consequences of it that Dr. Palade illustrated so nicely. So how about this? So this is a trial done by Jensen and colleagues. This was performed in Denmark, published in Critical Care Medicine 2011. This is an example of some of the challenges we have with procalcitonin guidance. So they assessed 1,200 patients for eligibility, randomized to the overwhelming majority of them, and then allocated to procalcitonin-guided therapy or not, looked at mortality, and excluded essentially no one from analysis. So a very tightly conducted study. And what they found was that patients with, and it's important to mention, and Dr. Palade mentions this, the outputs of an algorithm matter as much as the inputs. So patients with declining procalcitonins had decreases in de-escalation of their therapy. Patients with rising procalcitonins in this algorithm had escalations of therapy. And we see the results of this here. In patients with procalcitonin guidance, the total defined daily doses of piperacil and tazobactam in standard of care to short of 1,900 patients. Procalcitonin guidance, almost 3,000 days. Meropenem, same increase from 2,100 to just about 2,500. Ciprofloxacin use went up from 6,200 to 8,300. And the total number of days in the intensive care unit where patients were on at least three antibiotics increased from 57.7% of the standard of care to 65.5%. So the outputs matter. This particular algorithm used in this study led to increases in therapy. Now, one of the counter arguments against this point that I'm making here is that, well, again, the outputs matter as much as the inputs. To which I would say this, if we are only responding to a blood test result when we like the results, why are we ordering it? If we're not going to act when the lab value is getting worse, then what's the point? Why would we order that test in the first place? So there are a number of confounders. Elevated procalcitonin levels are well-described in candidemia, in patients with chronic kidney disease, patients requiring renal replacement therapy, hematologic malignancy, lung cancer, malaria, and dengue, for example. Now, some of these conditions are quite rare in North American and European intensive care units. Malaria and dengue are not terribly common. Candidemia is common. Hematologic malignancies are common. Lung cancers are common. And so we really need to do some more work to figure out how we can best utilize this and any biomarker in some of these commonly seen syndromes in our ICUs. So that being said, shaving two days off of antibiotic exposure is an improvement, and there is solid data saying that there is a survival benefit. So what am I offering is a counterargument, because I don't want to be a nihilist about this. I do think that procalcitonin plays a role. And I will tell you that I order it myself. I order it routinely, and I do my best to act on it. But the key thing, and we talked about stewardship earlier, is before we start relying on another test that gives us the same prognostic data as we already had as a tool to shorten antibiotic therapy, why don't we just use evidence-based durations of antibiotic therapy in the first place? We have good data that five days is adequate for the treatment of community-acquired pneumonia. That says eight here, but guidelines now say seven days for the treatment of ventilator-assisted pneumonia. Five to seven days for pylo. Four days for intra-abdominal infections, and that is level one, randomized controlled trial-level evidence. Gram-negative bacteremia, a week. Chronic osteomyelitis, 42 days, not really the most common thing in the intensive care unit. But in all of these cases, we have evidence that shorter courses are effective and lead to either no worsening of mortality or, in fact, improvements in mortality, just as Dr. Pilata described. So my summary is this. Procalcitonin is ineffective for the initial diagnosis of viral versus bacterial pneumonia. It has little benefit over other established markers of disease severity and critical illness. It may, and I think we've got good evidence that it can, reduce antibiotic exposure in a carefully controlled RCT, but not yet in real life. Although, again, the education, the coordinated multidisciplinary efforts that Dr. Pilata described so well, those are the things that we'll need to make it work, and hopefully we'll get to that point as a critical care community. I think procalcitonin definitely can improve care, but our first priority before another blood test is to use short evidence-based courses of antibiotics before we rely on biomarkers to solve our problems for us. Thank you so much for the opportunity, and I'm very grateful to the society for the chance to speak to you all today. Thank you very much for both of you for the presentations, and this will be the time for some Q&A. One thing which we have seen is that the, and what Erika has recommended, that we look at the Delta PCT. What would be that recommended cutoff for this Delta PCT to convince a clinician to stop antibiotics? Erika, I'll leave that one to you. I can tackle it if you like. Both of you can answer it. I think I've seen 75% reductions. I'm satisfied with source control. I'm satisfied with an adequate antibiotic, and I see patient improvement. If I see people getting better that fast, and I see a 75% decline, I'm usually pretty satisfied with that. I'd be curious to know what Erika thinks. Yeah, it's not a tight rule, but I also use the 8% cutoff. Okay, thank you. So 75% to 80%. One question is that you were mostly talking about the adult population, and most of the data is in sepsis or community-acquired pneumonia. Do you have any idea, is there any data that how procarcitonin could be used in the pediatric population? You know, I think, Thomas, you and I recall from when we gave this live, I think Dr. Ferrer's and my response at the time was that if he and I were responsible for making that decision about a child, something has gone horribly wrong. I believe there is some limited data, but nothing on the scale of the data that Dr. Plata presented. I presented some data in Ketamine, and I presented some data in Ketamine. I understand you anymore. What I know from the PCT literature is that in meningococcal sepsis, it has been used in infants and in the pediatric population, but not, as you say, not in the scale that we've got data in the adult population. Another question came, which I think it's quite an interesting one, that apart from the critical care clinicians who might be ordering the procarcitonin, who else should we educate about the biomarker use? And I think I'm pointing that towards Ryan. Well, pharmacists, absolutely, right? Intensive care pharmacists and ID pharmacists play such a massive role in stewardship, and I will say our hospital stewardship program is really run by our ID pharmacy team. And I think there are different models of stewardship programs that we use. For example, there's ones that are very, shall we say, prescriptive, that will just discontinue an antibiotic or tell the primary team, you can't have vancomycin anymore, for example. And then there are more, I think, collaborative models, which I suspect lead to improved buy-in, where the stewardship team makes recommendations based on best available data. It's 72 hours, there's no Staphylococcus aureus seen in cultures, you should stop vancomycin, or it's okay to stop vancomycin. And similarly saying, hey, your patient is off vasopressors, they've gotten five days of effective therapy, their oxygenation's improving, and their procarcitonin is now 0.1. Consider stopping antibiotics. A lot of that is driven by our pharmacy team. And I think that they are completely integral to making a system like this work. Certainly curious what Erika's thoughts on that are, though. Well, in my opinion, I think that the general practitioners are actually involved in the initial stages of sepsis. Like many patients, at time of presentation are on the medical wards or in the gynecological wards, I don't know, like outside the ICU. So I think that at least it should be a general knowledge regarding the use of biomarkers, because they are going to order the test at time of presentation, even though the patient is transferred to the ICU later. Thank you. I think that is leading to a number of questions from here. One is that if we think that the PCT guided antibiotic course is on average one and a half, two days shorter than the standard care, that's about five, six doses of tacitin, meropenem, name your antibiotic choice. Is that really significant for the development of antimicrobial resistance? Or could we just use common sense? And as Ryan said, the five and seven day rules. Ryan should answer first to follow the order. I think you'll get very similar answers from both of us though, right? I mean, it's not the, just so everyone realizes, the kinetics of procalcitonin upregulation takes six to 24 hours after the onset of infection. So that first procalcitonin is just a baseline moving forward. So yeah, six, it's six to 24 hours Yeah, six doses left of piperacillin-tazobactam really make a difference. You know, I think there's a couple, there's an analogy we can look at here where we look at the studies of balanced crystalloids in sepsis versus normal saline. And we see that there is a, you know, a meaningful but not massive decrease in renal replacement therapy in patients who are resuscitated using lactated ringers or plasma light or a comparable fluids. And although those absolute numbers are small, they accumulate over time, especially when you're dealing with an intervention that is so common as crystalloid resuscitation. Well, the same thing is true of antibiotics, right? Shaving two days off of someone's exposure to a broad spectrum antipsudamonal beta-lactam in that individual patient is likely to make a huge difference. Probably not in that individual patient. But when you consider the tens, hundreds, millions of doses of antibiotics given, the cumulative impact is quite large. So I do think that it makes a difference. And shaving two days off. My only catch that I would toss in there is you referred to standard courses of therapy. I would, the word I would use is usual courses of therapy, right? Because again, if we're shaving from 17 days down to 14 days, that is not a spectacular improvement. That is just less bad. What I would want us to focus is on standard of care durations of therapy. And if we are giving what I would consider an evidence-based standard of care, five for community-acquired pneumonia, seven for hospital-associated pneumonias and so forth, then the biomarkers start to play a role in, okay, can we start shaving off? And also I would say kind of deep-seated infections, complicated intra-abdominal infections, bone and joint infections where physical examination and other things are not necessarily as reliable as we like. Biomarkers are very useful in that setting as well, at least in my clinical practice. Erika. Thank you. Well, I totally agree with Ryan. And also I would like to add that, for example, if we recall those studies on prophylactic antibiotics, for example, the studies on the oral flora ecology have shown us that even a single dose of antibiotics are significant to selection of resistant phenotypes. So in the case of critically ill patients with sepsis, to minimize exposure to antihistaminal agents in at least one dose, I think is beneficial for patients. And probably we should endorse also the implementation of the recommended short duration of antimicrobial therapies, like recommended in the guidelines, like Ryan has said before. But this is when education takes place, right? Like we have to make people to adhere to the current protocols and current recommendations on short duration of antimicrobials. And I don't know, like improve our practices in the short range of the treatments. Like instead of using seven days in the range of five to seven, we should use probably the five and also supporting our decision on pre-conceiving values. Absolutely. Thank you. So I think you have answered the question which came that, is it clinical improvement rather than clinical improvement and considerable decrease in the procalcitonin level for antibiotic discontinuation? So I think what you are saying, it's probably both if you are combining a biomarker with your evidence-based standard of care and the clinical improvement. Is this correct? Yes, you have to combine both like your subjective clinical assessment and also adding some data that tells you actually the real state of the patient. Absolutely, could not agree more. I don't think that we can do a webcast in 2021 where we don't mention the word and disease COVID-19. So what do you think, where does procalcitonin sit in this case? Especially if the hospitals adopt using steroids and using IL-6 receptor antagonists, all of which can blunt the usual or other usual CRP response that the people and providers are quite familiar with. Ryan. Oh, all right. Is there any data available at all? It's an awful situation, right? I've used it for de-escalation. I try to discourage antibiotic use in patients admitted with COVID-19 to the ward unless there is something significant on their imaging that a classic low bar pneumonia and I see gram positive cocci on their sputum gram stain just because we know that bacterial pneumonia is so infrequent in most patients admitted with severe COVID-19. Surviving sepsis does recommend empiric community-acquired coverage in patients who require mechanical ventilation. This is the challenge is that most bacterial community-acquired pneumonia, as far as we can tell, often has a preceding viral component. And so you have all the TNF-alpha and IL-1 and IL-6 being upregulated in response to bacterial infection. Then you have on the other side, the interferon gamma and the like being upregulated as a response to viral infection. And so procalcitonin levels become a question of which side wins, right? And then just as you described, Thomas, what happens when you give an IL-6 inhibitor to it? I have no idea at that point, right? I have no idea. My personal practice in someone who is on mechanical ventilation is to MRSA-PCR, sputum culture from a deep tracheal aspirate. And if antibiotics are started, deescalate rapidly based on culture and Gram-stain and more conventional means. And I have found that reasonably successful, but I am sure that I am overusing antibacterial drugs in that very specific setting. And procals have, so far I have been, I will say frustrated with the results of it in this particular setting. Thank you. Erika, do you have any experience? Well, I would like to say that, well, even though co-infections are actually rare in COVID-19 at the beginning, like co-infections, in critically ill patients, well, there are reports in which almost 30% to 40% of patients acquire ventilator inhibitors or associated pneumonia for long courses, for long durations of mechanical ventilation and for long stay in the ICU. So probably, I don't know in the setting, I actually don't know in the setting of immunomodulating treatments, but it would be interesting to validate those values of PCT to reduce antimicrobial exposure in all those patients receiving empirical treatment for ventilator-associated pneumonia, which are a lot of patients after the day 14 of ICU stay, or I don't know. And probably it will be useful in that subset of patients. Thank you very much. Yeah, no, I would say someone who's 14 days out, who's finished their dex, who isn't on TOSI anymore, I think that's a great example. Yeah, I could not agree more. Yeah, so I think in this PROCON debate, we've got an agreement on a number of things, one of which is that we definitely need more data on this to use it better than we can. That concludes our Q&A session. And I would like to thank you, Erica and Ryan. And obviously, I thank the audience for attending. Again, everyone who joined us for today's webcast will receive a follow-up email that will include an evaluation. So please take that five minutes to complete the evaluation because your feedback is greatly appreciated and helps us to improve. And on a final note, please join us for our next Journal Club, Critical Care Medicine, on Thursday, April 22nd. And that concludes our presentation today. Thank you.

Journal Club Critical Care Medicine

procalcitonin guidance

critically ill patients

sepsis

early recognition

treatment of sepsis

antimicrobial resistance

PCT biomarker

antibiotic treatment decisions

PCT-guided algorithms