Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. My name is Evelyn Luo, a clinical pharmacy specialist in the medical ICU at North Shore University Hospital in Manchester, New York. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to My Learning tab to access the recording. Thanks for joining us. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter, following hashtag SCCM CPPJC and hashtag PharmICU. Please note, the disclaimer stated that the content to follow is for educational purpose only. And now I would like to introduce our speakers for today. Each will give a 15-minute presentation followed by Q&A. Our first presenter today is Alisa Govelli, a PGY-2 critical care pharmacy resident at Espeneza Health in Indianapolis, Indiana. She will present on the difficult to treat non-fermenting gram-negative bacteria in ICU setting. Our second presenter is Neha Mehta, a PGY-2 critical care pharmacy resident at Brigham and Women's Hospital in Boston, Massachusetts. He will present on continuous versus intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis, the BLINK-3 randomized clinical trial. And our third presenter is Abigail Cochran, a PGY-2 critical care pharmacy resident at UPMC Presbyterian Hospital in Pittsburgh, Pennsylvania. She will present stress ulcer prophylaxis during invasive mechanical ventilation. And now I will turn things over to our first presenter, Alisa Govelli. Wonderful. Thank you, Evelyn, for that introduction. As she had mentioned, my name is Alisa Govelli, and I'm the critical care pharmacy resident at Eskenazi Health, which is a safety net hospital here in Indianapolis. The study I looked at looks at cephadiricol and difficult to treat gram-negative bacteria, specifically in the ICU. Although this antibiotic got its infamous name from its mechanism of action, current literature regarding its efficacy in this specific patient population is yet to be confirmed. So cephadiricol is a fifth-generation cephalosporin that acts as a, quote, Trojan horse in its ability to bind to the iron channels and facilitate its entry into the bacterial cell. It also is designed to evade other mechanisms of resistance, including beta-lactam degradation, as well as efflux pump regulation. I wanted to orient you to a variety of different resistant gram-negative bacteria in which the study I will be discussing will look at non-fermenting gram-negative bacteria, in which this includes difficult-to-treat pseudomonas, CRAB, as well as stanotrophis multifilia. Another commonly seen resistant bacteria that is not included in the study, but still clinically relevant in practice, is CRE. The IDSA did come out with a guidance statement in 2023, in which I've highlighted each of these roles of therapy for cephadiricol here. As you can see, they do recommend limit use of cephadiricol specifically in CRAB, unless refractory to other antibiotics or allergies as well. Also, combination therapy is recommended for both CRAB as well as stanotrophis multifilia. In terms of existing literature, the first study I want to review is the APEX-MP study that looks at miripenem versus cephadiricol, specifically in healthcare and ventilator associated pneumonia. This did demonstrate non-inferiority, looking at mortality as well as microbiologic eradication. There also is a credible CR study that looked at best-available therapy, which is mostly colistin-based, compared to cephadiricol, in which this was specifically in difficult-to-treat gram-negative bacteria, including those that are carbapenem-resistant. They looked at this for pneumonia as well as bloodstream infections and complicated UTIs. Cephadiricol did achieve a higher clinical care, microeradication, as well as lower relapse, although they did see a higher mortality, both at 14 days and 28 days. When looking at each of these organisms and these outcomes, they did see that the patients infected with the organism of CRAB had the highest mortality. There also is a real-world application study of cephadiricol, in which this included patients across six U.S. medical centers and included 112 patients receiving cephadiricol therapy. The primary outcome was clinical success, in which this was achieved in 68.8% of these patients. They also evaluated on-treatment nonsusceptibility of cephadiricol, in which this was in 5.4% of these patients. Cephadiricol was also evaluated monotherapy versus combination therapy, in which there was no difference in terms of the primary endpoint here. With these in mind, there is mixed mortality regarding data for difficult-to-treat grim negative bacteria, especially after the CREDIBLE-CR trial, in which they did see a significant increase in mortality in the cephadiricol group. There was also variability in comparative groups, so thinking back to the study of the CREDIBLE-CR, it was mostly colistin-based. Then there's also lack of ICU-specific data, knowing that some of these studies previously discussed included some degree of patients in the ICU. Yet, there still is also uncertainty with on-treatment resistance as well for cephadiricol. This brings us to the hypothesis of this study, which is to evaluate the efficacy and safety of cephadiricol compared to best-available therapy for difficult-to-treat non-fermenting grim negative bacteria in the ICU. This was a retrospective multi-center cohort study conducted in nine ICUs, including one burn unit. They matched patients one to two based on the difficult-to-treat non-fermenting grim negative bacteria, in which this was isolated either from the blood or the lung, although infection site itself was not necessarily matched amongst these groups. They also attempted to match ICU location, so burn versus non-burn ICU, although they did disclose that they ran out of patients, so they had to match four burn patients in the cephadiricol group to four patients that were non-burn ICU in the best-available therapy group. Inclusion criteria included adult patients with a difficult-to-treat non-fermenting grim negative bacteria with an identified infection site. So, this is the lung or the blood. They did exclude patients that had multiple difficult-to-treat non-fermenting grim negative bacteria pathogens identified, or if treatment duration was less than 48 hours, or this was unknown, given this was a retrospective chart review. Difficult-to-treat for these organisms are listed here. So, for Pseudomonas and CRAB, this was defined as a resistance to all fluoroquinolones, as well as all beta-lactams, except for those newer beta-lactamase inhibitor combinations. For Stenotropus multifilio, this had to be resistant to Bactrim. Looking at the outcomes here, the primary outcome was clinical cure at 15 days, which was defined as an absence of antimicrobial treatment, as well as an absence of clinical and biological signs of infection. Secondary endpoints include clinical cure at 30 days, relapse rate, and ICU mortality, and the safety endpoints included any antimicrobial-related adverse drug events observed. Quantitative data was expressed as a median with an IQR, and qualitative data was expressed as a number with a percent. They also looked at adjusted odds ratios estimated using bidirectional stepwise regression, in which this was determined with three preselective compounders. These included assessment of degree of immunosuppression, organ transplant location, ICU location, and then other endpoints assessing the degree of hemodynamic stability, as well as organ failure. They also utilized an alpha of 0.05. In terms of baseline demographics, here you can see there was a significant increase in the Staphylococcal group in terms of previous antibiotic lines of three or more. This was also the case if any of the groups in the Staphylococcal received a newer beta-lactam beta-lactamase inhibitor, in which you can see 37% of these patients were already exposed to this, compared to the best available therapy group at 11.1%. This also shows specifically which medications each of these groups were exposed to, so looking at both colistin, ceftazidime, and avivectin, as well as the aminoglycosides, these were significantly higher in terms of exposure in the Staphylococcal group compared to the best available therapy group. Difficult to treat Pseudomonas was the most commonly identified organism in this study, and in terms of infection site, this was most commonly seen as pneumonia, as opposed to bloodstream infection. I'd also like to point out that there was a high degree of polymicrobial infection, so other organisms that these patients were infected with. As you can see, this was 81.5%, as well as 66.7% in these groups, respectively. In terms of treatment in the best available therapy group, most of these patients received ceftazidime avivectin, followed by colistin, and then also ceftolazanetazobactin. Specifically, in the Staphylococcal group, some of these patients did receive combination therapy with either IV or inhaled colistin. Looking at the results, the primary endpoint was clinical care at 15 days, in which you can see there was no significant difference between the groups. This also applies for clinical care when looking at 30 days. Although there was a significant increase in relapse rates in the Staphylococcal group at 29.6%, compared to 7.4%. We also saw longer days mechanically ventilated in the Staphylococcal group at 93 days, compared to a median of 59 days. I'd also like to point out that ICU mortality was no significantly different between the two groups, in which this ranged from 52 to 54%. When looking at these adjusted odds ratios, the only one that was significant was the relapse at an adjusted odds ratio of 10.06. In terms of adverse drug events reported, there were no significant differences between the groups, and some of these events that were reported would be expected knowing the use of broad spectrum antibiotics in this setting. Overall, the author concluded that there was no significant improvement in clinical care or mortality. They also attributed this higher relapse in the Staphylococcal group, possibly due to these patients considering Staphylococcal as rescue therapy, given that 37%, so a good portion of these patients, were already exposed to beta-lactam, beta-lactamase inhibitor combinations prior to the study. Overall, strengths of this study include that it was multicenter. It did exclusively look at ICU patients. They also looked at pathogens, which were difficult to treat non-fermenting gram-negative bacteria, which is obviously the potential role for this medication, and then also they matched organism and attempted to match to ICU location. They also looked at similar outcomes to previous studies, in which there are still gaps with mortality, as well as relapse rates. Some other weaknesses that were seen in the study include it was observational in nature, as well as a small sample size, in which there was no power calculation. They also only looked at infection sites as pneumonia, as well as bloodstream infections alone. And then also, there was difference in previous treatment at baseline, with more patients in the Staphylococcal group receiving at least three or more antibiotic lines, as well as an overall higher baseline and resistance in the Staphylococcal group, which really limits our overall interpretation of the results. And essentially, between these groups, we're comparing apples to oranges, and so it's really hard to assess this, although this may also increase our external validity, knowing this may be the potential role in therapy for Staphylococcal, in which they are refractory or resistant to newer beta-lactamase inhibitors in the first place. I'd also like to point out that not all burn patients were matched, and so they have unique considerations as well, including their degree of immunosuppression in this burn patient population, as well as an inflammatory state, in which it's making it more difficult to even recognize signs of infection, and these patients even have their own sepsis criteria. Additionally, once they're out of that initial 48-hour period of hypovolemic shock, they also are hypermetabolic, and so this is something that would be concerned from a drug clearance perspective, and it may be potentially unclear whether patients after a burn injury are adequately dosed, or if this dosing needs to deviate from the general patient population. And then also, combination therapy was unclear per organism, and this is stressed in the IDSA guidance statement from 2023. So overall, my conclusions highlight that there was no significant difference in clinical care, both at 15 days and 30 days. There was also a similar mortality between the two groups, although this was still higher, so about 52 to 54 percent, compared to the credible CR trial that was about 39 percent, although this would be expected knowing we are exclusively looking at patients that are critically ill, and specifically in the ICU. We also saw longer days mechanically ventilated in the sephidiochol group, although this may be multifactorial. It's unclear if these patients had other conditions contributing to their respiratory failure. Did some of these patients have ARDS or volume overload? It's really hard to draw this conclusion from antimicrobial choice alone. And then lastly, there was a significant increase in relapse, which also still raised some possibly hesitancy, but also contributes to the existing data out there as well. So looking at this study compared to our previous literature, we did address the gap of mixed mortality data and provided additional insight in the ICU patient population. We also looked at a variety of different comparative groups, so in this study, the best available therapy mostly consisted of those newer beta-lactam, beta-lactamase inhibitors, compared to previous studies that were mostly colistin-based. We also looked at patients exclusively in the ICU, although there's still uncertainty with on-treatment resistance. So in terms of future direction, I believe that a clinical application of this study is that there is still mixed mortality data out there, but this did provide additional insight specifically in this patient population in the ICU. Given that there were significant baseline differences within these two groups, this may demonstrate that sephidiochol has a specific role in therapy for patients that were either already exposed or resistant to newer beta-lactam, beta-lactamase inhibitors. Given we didn't see any significant difference in clinical care, and this may be a potential role in therapy given that this was a significant difference in the groups. In terms of future directions or considerations for additional studies, I'd recommend conducting subgroup analysis on other factors that could impact the severity of infection. So the organism itself may be stratifying whether they were in a burn ICU, especially if they're unable to match appropriately, as well as mono versus combination therapy. And then also looking at metallo-beta-lactamase expression, knowing that this can be common and difficult to treat student bonus as well. I'd also like to see similar outcomes in future studies that have well-matched groups, looking at infection site, number of previous antibiotics, ICU location, and resistance profiles. And then I also recommend looking at the occurrence of on-treatment resistance, given this is still a gap in literature. And then also looking at CRE infections, since this was the one difficult-to-treat organism that was not included in this study. And so with that, I'd like to take us to our first poll. And so my question for you all is, is that federical on your institution's formulary? So the options are yes, no, advocate for adding, or no, would still not add at current state. Okay. So it looks like the majority of people already do have sepidercal on their formulary. So it was approved in 2019, so that kind of makes sense. And just for perspective as well, we do have it on formulary here at Eskenazi Health, but it is restricted to an ID consult, and then they have to have proven infection with the organisms we discussed today. So I'm curious if these are similar restriction criteria for those of you that did answer yes. And then my second question is, would you feel comfortable using sepidercal in this patient population? The answers are yes as monotherapy, yes as combination therapy, or no. Okay, so it looks like most of you answered yes for combination therapy, and so I do agree. This is something that I discussed, you know, is unclear in this study, although the IDSA guided statements do, at least as of current state, do recommend this for both CREB as well as stenotrophic mesothelia, so I think this is one area in the literature that could be further evaluated in terms of some of the other organisms as well, such as difficult to treat pseudomonas. All right, and with that, I'd like to open it up for any questions you may all have. I have a question, so in our institution, Siderico is non-formulary, and it's related to ID. We usually use it for MDM, gram-negative infection. I'm just kind of curious, why this study, specifically study for non-formulating gram-negative bacteria infection? Yeah, so that is a good point. Thinking about the FDA approval, you know, indications, it's specifically approved for nosocomial pneumonia as well as complicated UTI, and so I guess those are kind of with the caveat that, you know, based off of the data, we can extrapolate that specifically, like you mentioned. Difficult to treat gram-negative bacteria is kind of where we can consider, so I feel like it would be reasonable to still extrapolate that from different sites of location, and then specifically thinking about this study. They did include bacteremia, but ultimately assessing where was that source of the bacteremia as well. All right, well, if there aren't any other more questions, I'd like to just thank you all for listening. Thank you. Thank you, Alyssa. Now, I would like to introduce our second presenter, Nihad Madar. Thank you again. Just to reintroduce myself, so my name is Nihad Madar. I'm a PGY2 critical pharmacy resident at Brigham and Women's Hospital in Boston, and today we'll talk about continuous versus intermittent antibiotic infusions in critically ill patients. So focusing mainly on our beta-lactam antibiotics, but these antibiotics are divided into three main classes, penicillin, cephalosporins, and carbapenems. They work by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins, making them effective against broad range of gram-positive and gram-negative bacteria. Clinically, they are essential for treating various infections, such as pneumonia, meningitis, and urinary tract infections. Notably, broad-spectrum beta-lactams like piperacillin, tezobactam, meropenem, and cephapenem are often used as our first-line empiric therapy for critically ill patients in the ICU. Looking at our pharmacokinetics of beta-lactams, these antibiotics exhibit time-dependent killing, meaning it's crucial to maintain the drug concentrations above the minimum inhibitory concentration, or MIC. This necessitates more frequent dosing, and pharmacokinetically, prolonged or continuous infusions is preferred over our conventional bolus administrations. Here I have a figure demonstrating the effects of traditional, prolonged, and continuous beta-lactam infusion dosing regimens on the concentration time curve. The traditional, or the red line, starts with a high concentration that rapidly decreases. The prolonged infusion, or the blue line, maintains a moderate concentration for a longer duration, and the continuous infusion, the green dotted line, maintains a steady concentration above the MIC level throughout the dosing interval. This illustrates that prolonged and continuous infusions can maintain drug levels above the MIC for a longer period, which is beneficial for the time-dependent killing of bacteria by maximizing the duration that the drug concentration remains above the MIC during the dosing interval. Additionally, when thinking about our critically ill patients, we also need to consider factors like increased volume of distribution, hypoalbuminemia, and organ dysfunction, which could lead to renal and hepatic failure. These factors significantly impact how we use our beta-lactam antibiotics, requiring adjustments in dosing and administration to ensure efficacy and avoid toxicity. Briefly just looking at some of our guideline recommendations, the surviving sepsis guidelines suggest that the use of prolonged infusions or continuous infusions for beta-lactams due to the potential of experiencing significant changes of pharmacokinetic parameters during sepsis and septic shock. However, this is a weak recommendation based on moderate quality of evidence. Looking at some previous trials, so our first trial here, so Delhontany and colleagues, or the BLINK-2 trial, looked at adult patients with severe sepsis in the ICU, where patients received either continuous infusion or intermittent infusion using piperacillin-tazobactam, meropenem, or ticercillin clavulonate. For their outcomes, they saw no significant difference between the two groups in a live ICU-free days at day 28, which is their primary outcome, as well as additionally seeing no differences in some of their secondary outcomes listed here as well. Monti and colleagues in 2023 conducted the MERCI trial, looking at adult patients admitted into the ICU requiring new antibiotic treatment with meropenem. You can see the dosing they used here in the intervention column, but overall when they looked at their primary composite outcome of all-cause mortality and emergence of pan-drug resistant or extensively drug-resistant bacteria at 28 days, they found no statistical significant difference between the two groups. Additionally, in their secondary outcomes listed here, they found no difference between the two groups as well. Overall, this still leaves us with the question that if there is a benefit to the continuous beta-lactam infusions, when pharmacokinetically, we would think there would be. So we'll start with our first polling question here. Do you or your colleagues currently use continuous or intermittent beta-lactam infusions for currently ill patients? So continuous, intermittent, neither are a combination of methods. So overall, seeing the biggest group having a combination of methods, which makes sense Typically, depending on the scenario, it would be appropriate to have a conventional style, whether it be like a fusion over 30 minutes or maybe a longer infusion when patients are more stable. So now moving into our trial, continuous versus intermittent beta-lactam antibiotic infusions in critically ill patients with sepsis or the BLINK-3 trial. So their study objective was to determine whether continuous infusions of beta-lactam antibiotics using piperacillin-tazobactam or meropenem results in decreased all-cause mortality at 90 days in critically ill patients with sepsis compared to intermittent infusion. So looking at our design, this was an international open-label Phase III randomized clinical trial conducted in 104 adult intensive care units across multiple countries. Their inclusion criteria, they included patients that were adults, expected to be in ICU until at least the next calendar day, documented site of infection or strong suspicion of infection, treatment with piperacillin-tazobactam or meropenem commenced within the previous 24 hours. At least one organ dysfunction criteria met in the previous 24 hours, and administration of the antibiotic by intermittent or continuous infusion considered equally appropriate by the attending physician. Their exclusion criteria is here listed below. Moving into our intervention. So in the study, they defined a daily dose of beta-lactam antibiotics, which piperacillin-tazobactam was dosed at 14 grams and meropenem at 3 grams. As a reference, however, the 24-hour beta-lactam antibiotic dose was ultimately determined by the attending clinicians. All participants received at least one beta-lactam antibiotic infusion dose prior to the open-label randomized treatment. Post-randomization, participants were assigned to either continuous infusion where the drug was administered over 24 hours or intermittent infusion where the drug was administered over 30 minutes. Looking at our primary outcome, so it was all-cause mortality at 90 days from date of randomization. And then their secondary outcomes consisted of clinical cure by day 14, which was defined by the completion of beta-lactam antibiotic treatment course without recommencement of antibiotic therapy within 48 hours of the same infectious episode. In addition, they also looked at new acquisition and colonization or infection with multi-resistant orgasm or C. diff infection up to 14 days after randomization, and additionally, all-cause mortality. Additionally, they looked at tertiary outcomes listed here, and then their adverse events were defined as drug reactions thought to have a causal relationship to the study-assigned administration method. Going into our statistical analysis, so they had a target sample size of 7,000 patients to provide a 90% power to detect an absolute difference of 3.5% in all-cause mortality with an alpha of 0.05. They allowed for a 5% withdrawal slash loss of follow-up. For their data analysis, they used modified intensive treat analysis with logistical regression. They presented their data as odds ratio and 95% CI, which secondary outcomes used a similar logistic regression, and then tertiary outcomes used a linear regression, and additionally, they used a controlled family-wise error rate for secondary and tertiary outcomes using the Holm-Buffari correction. Additionally, they did two subgroup analysis. For the first one, they used their adjusted analysis for the primary endpoint, looking at covariance such as sex, Apache 2 score, admission source, and beta-lactam type. And for their second adjusted analysis, they looked at 90-day mortality in these five pre-specified subgroups of pulmonary infection, beta-lactam type, age, sex, and illness severity using the Apache 2 score. Briefly looking over the screening and randomization, so they ultimately almost excluded 22,000 patients where 19,154 met exclusionary criteria, mostly most patients due to received antibiotic for greater than 24 hours, and then 2,681 patients that were eligible but not randomized due to mostly declined to participate. Looking at our baseline characteristics, I just included some important ones here for the sake of time, but you can see between the two groups, the median age was roughly 62 years old, most patients being male, weighing about 80 kilos. The most source of ICU admission was accident from the emergency department. The median time from ICU admission to randomization was roughly 25 hours. Their median Apache 2 score was 19, and overall majority of patients had a primary site of infection that was pulmonary source. Looking at our results, so for the primary outcome, you can see that all-cause mortality in 90 days was statistically, they found no statistical significant difference between the groups, but when they did their adjusted analysis, they did find a statistical difference. For their secondary outcomes of clinical care at 14 days, they found a statistical significant difference between the two, however, for their other outcomes, they did not. Looking at their tertiary outcomes, you can see listed here, they found no statistical difference between the two groups, and then additionally, for their subgroup analysis of mortality at 90 days, looking at those five variables, they found no statistical difference between the two groups. When looking at adverse events in the study, they had 10 adverse events that were documented in the continuous infusion group, compared to six in the intermittent infusion group. Notably, one serious adverse event in the continuous infusion group was potentially linked to higher meropenem concentrations, leading to severe encephalopathy, which led to aspiration pneumonia, cardiac arrest, and eventually death. Overall, for the authors' conclusions, so they observed a difference in 90-day mortality between continuous versus intermittent infusions of beta-lactame antibiotics did not meet a statistical significance in the primary analysis, and then additionally, the competency rule around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients. Moving into the critique of the trial, so overall, first looking at our patient population, overall looking at our characteristics, which was overall well-balanced, however, the trial did not consist of severely ill patients, as indicated by the medium Glasgow coma scale of 14 in both groups, suggesting patients were awake and conscious, maybe a little confused. The median APACHE-2 score was 19, which the authors state correlates to a 90-day mortality rate of approximately 22%, while overall high, more severe and critically ill patients, especially in the medical ICUs across the country, might have higher mortality rates. Additionally, while the primary infection site being pulmonary in about 60% of our patients, there was an endpoint assessing patients who were free and alive, however, other characteristics such as duration of mechanical ventilation for those who required it, and instances of patients being extubated, then re-intubated, would also help us better assess the patient population. Additionally, potential variables that might have been also important to include is specific ICU locations, whether patients were in the medical, surgical, burn trauma ICUs, would also provide a better insight into the patient population. Additionally, details on pressers and inotropes, including number of patients on multiple agents, would also help us assess the severity more accurately. And then lastly, the open-label design introduces bias as both clinicians and participants were aware of the treatment being administered. And then switching to looking at our intervention, so overall in the Blink-3 trial, they ensured patients received appropriate levels of medication by using the daily dosages that align with standard medical practice and administering one infusion before a randomization to boost drug levels. However, including microbiology and MIC data would have been important to assess the appropriateness of broad-spectrum antibiotics like menopenum and paprazolin-tazobactam in the study itself. If you dig in the supplementary materials, they do report that 40% of the primary infections were unidentified, while the other remaining 60% were gram-positive, mainly MRSA, and then 70% were gram-negative, mainly Escherichia species, but the lack of MIC data limits determining the utility of these antibiotics. Additionally, the trial did not report renal function markers such as creatinine clearance, which are crucial for our antibiotic dosing. This suggests patients either likely had good kidney function or were dosed accordingly by the physicians. Additionally, the median treatment duration was about six days for both groups, suggesting that broad antibiotics might have been unnecessary as less severe pathogens were likely involved. And lastly, allowing the switch between menopenum and paprazolin-tazobactam could introduce confounders and bias related to differences in drug efficacy and clinician judgment, impacting the treatment consistency and potentially the interpretation of the outcome. Looking at the endpoints that they had collected, so they used an appropriate outcome of all-cause mortality at 90 days, which is clinically relevant and patient-centered. However, given the median treatment duration of about only six days, assessing potentially 28-day mortality might have been more appropriate to capture the immediate effects of the intervention. In addition to their primary and secondary endpoints that looked at clinical efficacy and mortality, other beneficial endpoints that could have been assessed were relapse or recurrence of infection, clearance of cultures, incidence of further organ dysfunction or collecting even organ perfusion markers, and readmission rates. Although the primary outcome did not show statistical significant difference, the adjusted analysis indicated potential clinical benefit. This suggests that the continuous infusion may reduce mortality when considering covariates such as sex, Apache 2 score, source of admission, and beta-lactam type. This is important as it accounts for additional factors influencing patient outcomes, highlighting the possible benefit of continuous infusion on mortality when we consider these variables. And then overall, looking at our statistics, this was a well-powered, very large trial that used a combination of fixed and random effects in their primary analysis, which improves their precision and generalizability. And overall, they use the appropriate statistical test to evaluate their outcomes. So going into our second polling question today, so what is the main reason for choosing your preferred method of beta-lactam infusion at your institution? Is it better clinical outcomes, ease of administration, institutional protocols, or pharmacokinetic and pharmacodynamic considerations? Yeah, so it's a pretty mixed bag, which I feel like makes sense that definitely every institution can have their own specific reasons for using potentially a continuing varying infusion modality, depending on how large the institution might be or how small. So this overall mixed bag makes sense. And so overall, it concludes, so continuous infusions of beta-lactam antibiotics did not show a statistical significant reduction in 90-day mortality, but it may offer a potential clinical benefit. Overall, literature suggests that prolonged or continuous infusions are generally preferred for our critically ill patients with sepsis due to their time-dependent killing pharmacokinetics. However, continuous infusions present logistical challenges, such as increased monitoring and the need for a dedicated IV line. These practical issues, along with the lack of confirmed superiority over prolonged and intermittent infusions, often make the latter more practical. Though there is a potential for a compelling argument for the use of continuous infusions, continuing with prolonged or even intermittent infusion might be more practical without strong superiority data for continuous infusions. And with that, I conclude my presentation. Be happy to answer any questions that the audience might have. Thank you. Thank you, Niha. I have a question. It's that the continuous infusion primarily was conducted in ICU. And the patient, when they discharged to ICU, the continuous infusion wasn't continued. Do you think that will affect the result of the study? I think that overall, I think depending on, so in the ICU, we definitely have a lot more monitoring going on in the ICU. So overall, whether that be with nursing, additional people looking at the continuous infusions. However, I think switching when patients were left and departed the ICU, I still feel like that would overall still have continuous monitoring, especially depending with a whole team involved. So I could potentially see both ways. But I feel like that overall, it might have not impacted the results that much, especially when they were looking at 90 days, which overall, when the median duration was only about six days, I feel like it might have not impacted the results that much, especially when most patients were only on it for five to six days. The study did not show any statistical difference for mortality for 90 days. But this shows a clinical cure. How would you apply that to the clinical practice? I think it would do, I think it would be difficult to apply this continuous infusions to clinical practice. It would be more difficult from a more practical standpoint. I feel like it would be hard to implement continuous infusions of beta-lactams into the ICUs because of the amount of already continuous infusions that might be running, especially with patients who are acute and they're having multiple oppressors and fluids, potentially even other medications that are continuous infusions, like amiodarone. I think it would be difficult to implement continuous infusions overall. And even with this trial, the authors speak about potentially having this benefit in this population. I feel like it would overall be harder to implement, just from a more practical standpoint. Thank you, Neil. That concludes our Q&A session. And now I would like to introduce our final presenter, Abigail Cochran. Hi, everyone. My name is Abigail Cochran. I'm a current PGY-2 in critical care at UPMC Presbyterian Hospital. Today, I will be discussing the trial stress ulcer prophylaxis during invasive mechanical ventilation, re-evaluating the inhibition of stress erosions, also referred to as the revised trial. To give some background, stress ulcer prophylaxis is recommended in the following patient populations. High-risk populations is the first bullet point, mechanical ventilation greater than 48 hours, coagulopathy, traumatic brain injuries, and major burn injuries. Patients who are at moderate risk are ICU patients with multi-trauma, sepsis, acute renal failure, an ISS score greater than 15, and high-dose steroids. The optimal stress ulcer prophylactic agent in mechanically ventilated patients is currently unknown. There has been much debate over the years with many trials over the past 30 years coming out. I included two key landmark trials, the SUP ICU trial, which was published in 2018. It was a large multicenter randomized controlled trial with around 3,300 patients that evaluated proton pump inhibitors versus placebo. The primary outcome showed no difference in mortality, and the secondary outcome was PPIs reducing GI bleeding versus placebo. The second trial is the PEPTIC trial, which was published in 2020. It is another large multicenter randomized controlled trial that included around 27,000 patients that looked at PPIs versus H2RAs in preventing stress ulcer prophylaxis. The primary endpoint showed no difference in mortality, and the secondary endpoint showed that PPIs are more effective in reducing GI bleeds than H2RAs. I have our first polling question. Does your ICU utilize a protocol to initiate an acid-reducing agent in mechanically ventilated patients? Yes, no, or unsure? So it's split. 53% say yes, and 47% say no. I feel like it's not surprising to me that some institutions do not, while other, maybe larger hospitals do. Okay. So now I will go into my evaluation of the revised trial. This study had its purpose to evaluate whether PPIs are beneficial or harmful for stress ulcer prophylaxis in mechanically ventilated patients. It was an investigator-initiated multicenter randomized placebo-controlled blind trial. It was conducted across 68 hospitals in eight different countries, and patients were included from July 9th, 2019 to October 30th, 2023 if they met the following criteria. Patients were included if they had mechanical ventilation in the ICU that was expected to continue beyond a day after randomization, were 18 years or older. They were excluded if invasive mechanical ventilation had been initiated greater than 72 hours prior to randomization, received greater than one daily dose equivalent of a acid-suppressing agent while in the ICU. Acid suppression was specifically indicated or contraindicated other than stress ulcer prophylaxis. Patients received dual antiplatelet therapy, or patients were on antiplatelet therapy and therapeutic anticoagulation. The primary efficacy outcome is clinically important upper GI bleeds in the ICU at 90 days, which is defined as overt GI bleeding with evidence of hemodynamic compromise or leading to therapeutic interventions in the ICU, or resulted in a readmission to the ICU during that hospital stay. The primary safety outcome is death from any cause at 90 days, and the secondary outcomes are ventilator-associated pneumonia, C. difficile infections while in the hospital, initiation of renal replacement therapy, ICU and hospital mortality, and lastly, patient-important upper GI bleeding. And this is defined as requiring a blood transfusion, being on a vasopressor, diagnostic endoscopy, having a CTA, or surgery performed, or if the GI bleed resulted in death, disability, or a prolonged hospitalization. For the statistical analysis of this study, the primary efficacy and safety outcomes were analyzed using the Cox proportional hazards, and this adjusted for the receipt of pre-hospital acid suppression. It utilized a intention-to-treat protocol, and the mortality outcomes were adjusted based on their baseline illness severity score through the APACHE-2. It was estimated that around 4,800 patients were needed to achieve 85% power with an alpha of 0.05, based on a difference of 1.5% in the primary outcome, which the study did beat power. Around 6,000 patients were screened, and around 4,900 were randomized. The intervention group is pantoprazol 40 milligrams IV diluted in normal saline given once daily, and versus placebo, which was IV normal saline given once daily. In each group, there's about 2,400 patients. In general, the baseline characteristics, patients were majority male at 58 years of age, with a mean APACHE-2 score of around 21, which is a predicted hospital mortality of around 40%. Both groups had similar pre-hospital acid suppression use and steroid use prior to randomization, and the majority of patients were receiving inotropes or vasopressors. The primary outcome showed that there was no significant difference in clinically, or there was significant difference in the clinically important upper GI bleeds at an incident rate of 1% in the pantoprazol group and 3.5% in the placebo group, with an absolute difference of 2.5 and a hazard ratio of 0.3 that did not cross one. For the safety outcome, there was no difference in 90-day mortality at around 30% incidence in both groups. For secondary outcomes, for the incidence of ventilator-associated pneumonia in the ICU and C. diff infections, there was no significant difference in the pantoprazol versus placebo. There was, however, a difference in the patient-important upper GI bleed while in the ICU, with an incident rate of 1.5% in the pantoprazol group and 4.2% in the placebo group. For the author's conclusion, in patients undergoing invasive mechanical ventilation, pantoprazol resulted in significantly lower risk of clinically important upper GI bleeds versus placebo, with no significant difference on mortality. The strengths of this study are that they included the patient-important upper GI bleeds, which is not something that other landmark trials included. It is the largest randomized control trial of PPIs versus placebo, and it accounted for pre-hospital use of an acid-suppressing agent, which other landmark trials did not include. They blinded the adjudication of primary outcome, which decreases bias, and enrolled eight countries and 68 hospitals, which increases the generalizability of this study. The limitations include no guidance on the duration of pantoprazol to reduce a GI bleed, and the use of only the IV formulation of pantoprazol, so no enteral version of PO, pantoprazol, omeprazole, or esomeprazole. It also excluded patients on dual antiplatelet therapy and those who used antiplatelet therapy and therapeutic anticoagulation, which decreases the applicability of this study to these patient populations. And lastly, no consideration for enteral nutrition. Previous studies have shown, or have implied that enteral nutrition may be productive for GI prophylaxis, so I think that would be something really interesting for the study to have included and noted. Key takeaway points are that PPIs are effective in preventing clinically-significant upper GI bleeds. There is no increased risk of developing ventilator-associated pneumonia or C. diff infections in the hospital, and no statistically-significant differences in the mortality endpoint, which disproves the two landmark trials of PEPTIC and SUP ICU trials, which trended towards increased mortality in certain PPI subgroup analysis. Now we have our second polling question. Which agents do you utilize for stress ulcer prophylaxis in your ICU? H2RAs, PPIs, other, or really varies by risk factors, which agent do you use? So the majority say PPIs or varies by risk factors, which doesn't surprise me. All right. Here are my references. And thank you guys for taking the time to listen to my evaluation of the revised trial. I can now answer any questions you may have. Thank you, Abigail. Question. The limitation you mentioned about entire tube feeding in the study, it seems like they didn't mention about that, and also the steroid use. If you have to think that those information are available, that will be good information for me to have. With the current practice, that most of ICU patient, we fed the patient even before 48 hours after that intubation. So how will you think that you will change for the next study that you want us to look into? Yeah, so this study did not really mention enteral nutrition other than it did report the amount of patients who were on enteral nutrition in both groups, which is about 90%. So in the future, I think this study does a great job showing that PPIs are superior to other agents and that it's safe to use. So in the future, I think really getting the timing as to when to start stress ulcer prophylaxis to stop and to, in regards to enteral nutrition, as it can be, as studies have shown, it's protective. In regards to steroid use, I didn't see in this study that it really mentioned steroid use other than pre-hospital use for a week prior. In the results, it doesn't really mention that. So that's also something that could be evaluated whether patients need to be prolonged on stress ulcer prophylaxis while they're on that. Thank you, Abigail. Thank you for our presenter today and the audience for attending. Please join us for the third Friday of the month from 2 to 3 p.m. Eastern time for the next JournalCon Spotlight on Pharmacy. That concludes our presentation today. Thank you for having us.

Pharmacy

Critical Care

Cephalosporins

Beta-lactam

Septic Patients

Stress Ulcer Prophylaxis

Mechanical Ventilation

Drug Formularies

ICU

Webcast

Pharmacology

Infection

Pulmonary

Antibiotics

2024

Professional

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