Good afternoon, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Zach Smith, and I'm a critical care clinical pharmacy specialist in the Medical Intensive Care Unit and PGY-2 Critical Care Program Director at Henry Ford Hospital in Detroit, Michigan, and 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. We'd like to thank you for joining us today. Before getting into the presentations, a few housekeeping items. 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 during the presenter's presentation and at the Q&A at the end of the presentations. You 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 CPP JC and hashtag PharmICU. A disclaimer before the presentation, the content that will be presented today is strictly for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15 minute presentation followed by a Q&A. Our first presenter today is Dr. Alina Gallant. She is a PGY2 critical care pharmacy resident at University Hospitals Cleveland Medical Center in Cleveland, Ohio. She will present on the efficacy of weight-based anoxicarin dosing for venous thromboembolism prophylaxis in trauma patients, a systematic review and med analysis. Our second presenter is Dr. Marinda Graham. She is a PGY2 critical care pharmacy resident at Geisner Medical Center in Danville, Pennsylvania. She will present on high-dose dexamethasone and oxygen support strategies in the intensive care unit patients with severe COVID-19 associated acute hypoxemic respiratory failure, the COVIDICUS randomized clinical trial. And our third presenter is Dr. Molly Bray. She is a PGY2 critical care pharmacy resident at Detroit Receiving Hospital in Detroit, Michigan. She will present on the comparison of eight versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults, a randomized controlled open-label trial. And now it's my pleasure to turn it over to the first presenter. Thank you so much, Dr. Smith, for the introduction and good afternoon, everyone. As mentioned, my name is Alina Gallia and I am a critical care PGY2 at the University Hospitals Cleveland Medical Center in Cleveland, Ohio. And I just wanted to preface that this institution is a level one trauma center and I am currently completing my trauma ICU rotation this month. So I felt it would be fitting to evaluate the efficacy of weight-based anoxaparin dosing for venous thromboembolism, prophylaxis in trauma patients. By the end of the presentation today, I hope listeners are able to understand some background relating to trauma patients' risks for venous thromboembolism or VTE, review previously published literature relating to VTE risk and prophylaxis, and then evaluate today's systematic review and meta-analysis. To start out, I did wanna mention that trauma is a leading cause of morbidity and mortality worldwide and that VTE is among the primary cause of preventable death in this patient population. To understand why VTE is so prominent in our trauma patients, we'll go back to the basics of Virchow's triad with hypercoagulability, stasis, and our endothelial injury. Trauma patients have each one of these risk factors for VTE, putting them at the highest risk as noted in the middle of this Venn diagram. Additionally, trauma can activate a prothrombic state as functional protein C levels and antithrombin levels are decreased, and then a higher injury severity score and the delayed initiation of VTE prophylaxis due to the risk of bleeding may also put patients at a higher risk for VTE. Now that we reviewed why this patient population is at higher risk, we can start to discuss the agents to use in the previous literature. Our low molecular weight heparins are the agents of choice in trauma patients due to reasons that will be discussed in some upcoming slides. And then after review of some previous studies, researchers did know that the dosing requirements for VTE prophylaxis are known to be higher, but there's been no consensus on what this optimal dosing regimen truly is. While there are other agents to be used for VTE prophylaxis, today's focus will be spent on anoxaparin. And before getting into today's article, I just wanted to lay a foundation for what dosing strategies have been used previously. So we do have a fixed or our standard dosing for anoxaparin, which is 30 milligrams subcutaneous which is 30 milligrams subcutaneously every 12 hours. And then our weight-based anoxaparin, which is dosed at 0.5 to 0.6 milligrams per kilogram every 12 hours. As I mentioned previously, our low molecular weight heparins are the preferred agent in the trauma population. There was a randomized double-blind trial published in the New England Journal of Medicine back in 1996, which compared heparin subcutaneously Q12 hours to anoxaparin 30 milligrams Q12 hours. And outcomes included the incidence of deep vein thrombosis and bleeding events. And there was no difference noted in either outcome. So researchers did make the conclusion that anoxaparin was actually more effective in preventing VTE after major trauma and was just as safe as heparin to utilize. In this study, in addition to the fact that low molecular weight heparin's bioavailability is better, has a longer half-life and has an increased activity against factor Xa and has a lesser effect on platelets, result in less bleeding, which made these agents the preferred option for VTE chemoprophylaxis in our trauma patients. There was another study that was a prospective cohort study which reviewed standard-dosed anoxaparin, so our 30 milligrams every 12 hours, and the correlation of anti-TENA levels. The outcome of interest here was the occurrence of any VTE. And results showed that 50% of patients actually had low trough levels and more DNATs occurred in those patients. So authors concluded that standard dosing just wasn't enough for half of these trauma and surgical patients, and that those patients did end up having an increased risk for DVT. So I wanted to take a minute to review our first polling question before getting into today's article of interest. So I just wanted to gauge whether the audience had an institution-specific VTE prophylaxis practice management guideline or protocol for trauma patients specifically. Looks like majority of viewers said yes, and my institution does have our own VTE risk assessment and order set, and we do have a subsection for trauma admissions as well. So their dosing can be a little bit different than our general population. Now for today's study, which is looking at the efficacy of waste-based anoxaparin dosing for venous thromboembolism prophylaxis in trauma patients, a systematic review and meta-analysis. The clinical question at hand was if weight-based anoxaparin was more efficacious at achieving prophylactic anti-factor 10A levels than our standard dosing. Patients that were included into these studies were at least 18 years of age or older, admitted under a trauma service, and received VTE prophylaxis with anoxaparin. And those that were excluded received VTE prophylaxis with a different agent, had a BMI greater than 30 kilograms per meter squared, or had a single trauma pathology, as authors thought that these patients would be a source of bias as they may be at higher risk for VTE due to their mechanism of injury or delays in chemoprophylaxis initiation. Our outcomes for this study was, the primary outcome was the achievement of an anti-factor 10A level within prophylactic range, which was set to be between 0.2 to 0.6 international units per milliliter. And then our secondary outcomes included anti-factor 10A levels outside of that prophylactic range, so either sub-prophylactic or super-prophylactic. And then the incidence of VTE and then the rate of leading events as well. For the statistical analysis to test statistical heterogeneity, I-squared, which described the percent of variation across studies due to heterogeneity rather than chance was conducted, and then chi-square as well. Researchers deemed low heterogeneity to be an I-squared of less than 40%. And then if substantial heterogeneity, so anything greater than that 40%, a random effects model was used to assess the outcomes. For our primary outcome, this was evaluated utilizing odds ratio and a 95% confidence interval, while our secondary outcomes were evaluated with risk ratios or risk differences if zero events were found. The primary outcome of that target prophylactic range occurred more often in our wheat-based dosing strategies compared to our standard dosing. And with that odds ratio of 5.85, the odds of achieving that prophylactic range level is almost six-fold greater in our wheat-based dosing compared to our standard dosing group. And then for our secondary outcomes, there were significantly more sub-prophylactic levels in our standard dosing. So as you can see, 60% compared to our 14% in our wheat-based dosing group, which is consistent with that previous literature that I mentioned earlier. And then this had a risk ratio of 3.97, which demonstrated the risk of sub-prophylactic levels were increased almost four-fold in our standard group compared to our wheat-based group. Supra-prophylactic levels occurred more often in our wheat-based dosing, but there was no significant difference in either bleeding events or VTE events, as noted by the low or non-existent risk difference between these two outcomes. The author concluded this systematic review and meta-analysis has demonstrated that wheat-based dosing regimens for VTE actually increase the odds of achieving prophylactic anti-factor 10A levels and decrease the risk for sub-prophylactic levels, which ultimately suggests that the standardized dosing regimen provided inadequate VTE prophylaxis and our wheat-based dosing may actually improve prophylaxis. So now to transition into my own evaluation of this article. As for the study design, there were 190 articles screened with 24 articles assessed for eligibility and a total of four articles included. I felt there was a limit to the articles being included, which could potentially skew our outcomes. And then to mention that all four of these studies were all underpowered, leading to a lower quality of evidence and validity to the results and outcomes. And then as for the study population, patients with a BMI of greater than 30 kilograms per meter squared were excluded. And to me, this influences the generalizability, which will be discussed in the following slides. But additionally, the renal function cutoffs were also inconsistent between the studies as some had a cutoff of an EGFR less than 60, and then others had a cutoff of a creatinine clearance less than 30, which may play a factor in the high heterogeneity between the studies and articles that were included as well. For clinical relevance, the patients with low body weights or high body weights would require dose adjustments to our standardized regimens as directed by our institutional specific protocols. But these studies that were included didn't even include these patients. And the mean weights ranged anywhere between 72 to 90 kilograms, and the mean BMIs ranged from 24.8 to 30. So looking at this, we would know that these patients that were excluded from the trials could not really be generalized to what we see in clinical practice. And then the outcomes, I felt appropriately assess the clinical question and even assess the safety aspect of utilizing a different dosing strategy than what was used in clinical practice by evaluating the risk for VTE and bleeding events. I felt this study did have some limited external validity primarily due to that exclusion criteria I mentioned earlier, and then the single trauma pathology as well. And then as for bias, I felt that the authors did a really good job of including an assessment for potential bias, but they did find that three out of the four studies included had an overall severe to moderate risk for bias. And those came from confounding factors as well as patient selection or missing data completely. As we digest some of this information, we can go into our polling question number two, which was whether your institution utilizes weight-based anoxaparin dosing strategies for VTE prophylaxis in your trauma patients. This is a really interesting result as 36% said yes, 36% said no, and then there was some response for sometimes it depends on the clinical scenario. From my experience, we personally don't use weight-based anoxaparin at my institution, but it is something that I would be interested in looking at in the future. So let's summarize with some takeaway points. The systematic review did provide some evidence for weight-based dosing as patients did have more anti-factor 10A levels within range, but I'm just not satisfied with the results, especially due to the high heterogeneity involved in the studies. So there's very little clinical applicability to me at this moment in time. To know that this is the first meta-analysis to evaluate the efficacy of weight-based anoxaparin dosing strategies, and it just was not robust enough for me, but I believe that if we do have an improved study design, potentially a randomized controlled trial, including those higher risk patients or those with extremes of weight, that could eventually provide us with some more robust evidence and support to make this more clinically applicable. Thank you so much for attending, and I will now take any questions that you may have. Great job, Dr. Glenn. It looks like we have two questions in the question box so far. So were patients included in this meta-analysis or any of the individual trials populations that had traumatic brain injury or spinal cord injury? I do know that one of the studies specifically excluded those patients as they do have a higher rate or a higher bleeding risk, so I also think that that could potentially be an area that would be needing more research to make this more applicable for those patients as well. Thank you. Thank you. And then the second question, I'd like to hear your thoughts on, you know, you have this surrogate endpoint of anti-TENA activity and the finding of a meta-analysis pooling more patient data together and the inability to show a difference in VTE outcome. So what are your thoughts on achieving a laboratory value at a significantly higher rate but ultimately not making a difference clinically in the diagnosis of VTE? Yeah, I think this was something that I kind of struggled with when doing this whole evaluation for the journal club. So I felt like it was almost challenging since, like, how do we know that the prophylactic range, I feel like it's almost a little bit subjective and then also it not making an actual clinical impact. I had a little bit of a hard time kind of wrapping my mind around that as well. Okay, and we probably have time for one more question. So the last question is, how high did the noxiparin doses go within the studies that were included and based on, you know, the different trials and regimens that were included, is there a regimen that you would personally implement in practice if you were deviating from the FDA-labeled dosing? Yeah, so it looks like for the weight-based dosing, most of them did stick true to the around 0.5 milligrams per kilogram. There was one study that included patients with a weight greater than 100 kilograms and they used 50 milligrams twice a day. And then I feel like our institution-specific protocol does a really good job of breaking it down by weight class, so those with a BMI greater than 40 would get the 40 milligrams twice a day. And then as for going off-label, I would probably lean more towards, like, the 0.5 milligrams per kilogram twice a day if I was doing the weight-based noxiparin. And then checking those target peak levels as well. Great, thank you. That concludes our Q&A session. Thank you, Dr. Glant, for the excellent presentation. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. So how many attendees are viewing this webinar with? Just me, 2 to 5 people, 5 to 10 people, or greater than 10 people. And now I'd like to introduce our second presenter, Dr. Miranda Graham. Hello, my name is Miranda Graham. I am a PGY2 Critical Care Pharmacy resident at Geisinger Medical Center in Danville, Pennsylvania. Today, I'm going to be presenting to you on the COVITICUS randomized clinical trial. I have nothing to disclose for this presentation today. To dive into the background for why the COVITICUS trial was performed, it's important to understand that optimal steroid dose in form of respiratory support strategy is not currently agreed upon. I've listed answers from a couple of different organizations, including the National Institutes of Health, Society of Critical Care Medicine, and World Health Organization. As you can see, all three organizations do support a dexamethasone six milligram once daily strategy, but duration varies by the organization. Additionally, the NIH does suggest that a higher dose dexamethasone strategy may be appropriate in patients who have higher levels of respiratory support. For respiratory support strategies, generally high flow nasal cannula is supported over non-invasive ventilation, except for the World Health Organization, which currently does not have any recommendation due to uncertainty of data. When the COVITICUS study was designed, it ran from April of 2020 to January of 2021. In that timeframe, there was other literature that came out, including the RECOVERY, CODEX, and RECOVERY-RS trials. The RECOVERY trial and CODEX trial were both open-label, randomized clinical trials reviewing different dexamethasone dosing strategies. The RECOVERY trial looked at what we now consider our standard dose dexamethasone of six milligrams daily, while CODEX looked at a higher dexamethasone dosing strategy of 20 milligrams daily for five days, followed by 10 milligrams daily for five days. The RECOVERY trial found that there was a lower incidence of 28-day mortality in critically ill patients, and the CODEX trial found that there was an increased number of ventilator-free days for participants. The RECOVERY-RS trial was an open-label, adaptive, randomized clinical trial that evaluated a couple of different forms of respiratory support strategies, including CPAP, high flow nasal oxygen, and standard-of-care oxygen therapy. In the RECOVERY-RS trial, they found that CPAP showed reduced composite in vasomechanical ventilation, or death within 30 days, compared to standard-of-care oxygen. This led to the hypotheses of the COVITICUS study, for which there are two. Firstly, that corticosteroid therapy could reduce mortality of severe COVID-19 patients. And secondly, that CPAP, or high flow nasal oxygen, non-invasive respiratory support strategies could reduce the need for mechanical ventilation. To dive into the methods of the COVITICUS study, let's review the inclusion and exclusion criteria. Participants were included in the COVITICUS study if they were aged at least 18 years, admitted to an ICU within the last 48 hours for either confirmed or strongly suspected COVID-19, and participants with acute hypoxic respiratory failure. For key exclusion criteria, it was participants who had long-term corticosteroid therapy and patients who had active and untreated bacterial, fungal, and parasitic infections. What was unique about the COVITICUS trial is that it was a 2x3 factorial design, meaning that participants ended up being sorted into a total of six different groups. The three different oxygen strategies that were reviewed were standard-of-care oxygen, CPAP, and high flow nasal oxygen. The dexamethasone dosing strategies were considered a standard-dose dexamethasone and a high-dose dexamethasone. It's important to note that standard-dose dexamethasone was implemented on September 17, 2020, after the recovery trial results were published. Initially, the standard dexamethasone arm was no corticosteroids because at this time when COVID-19 was just coming around, steroids were not universally agreed upon. For the high-dose dexamethasone arm, the dosing strategy that the authors decided to do was a total of 20 milligrams daily from days 1 to 5, then 10 milligrams daily from days 6 through 10. The way they blinded this was by supplying it either as an extra 14 milligrams to participants or as a placebo. Participants who were not going to be double-randomized into the different oxygen support strategy arms were those who required invasive mechanical ventilation, participants who had hypercapnia indicating the requirement for non-invasive ventilation, patients who had a contraindication to nasal cannula, or participants who had intolerance to the three modes of oxygenation study. For those participants, they were simply randomized either into the high-dose dexamethasone arm or the standard-of-care arm. There were two primary endpoints reviewed in the COVITICA study, the first being for a high-dose dexamethasone, looking at time to death from all causes up until day 60, and for the oxygenation strategies, time to invasive mechanical ventilation criteria fulfillment within the first 28 days after randomization. Of note, participants did not need to be intubated in order to have been considered to meet that primary endpoint of meeting the criteria for fulfillment. There were numerous secondary endpoints reviewed in the COVITICA study, and I've highlighted a few of those here for you, including change in SOFA score for high-dose dexamethasone, overall survival at day 60 for oxygenation strategies, and for both of these, healthcare-associated infection at day 28, number of ventilator-free days alive at day 28, and both ICU and hospital length of stay. For the results of the COVITICA trial, there were a total of 550 participants ultimately randomized into either of the study arms. This met the study goal for 550 participants, assuming a 60% cumulative 60-day incidence of all-cause death to achieve 80% power. When diving further here, you can see how we have our six different participant groups. This did meet the study criteria goal to have 110 participants per different oxygen support strategy group, combining both the high-dose dexamethasone and standard-dose dexamethasone groups in each oxygen support strategy arm. When evaluating our first primary outcome, looking at time to death from all causes up until day 60, looking between standard-dose dexamethasone and high-dose dexamethasone, it is important to note that this outcome was not statistically significant. Looking at the absolute risk difference, it was negative 0.8%, with a 95% confidence interval of negative 8.3 to 6.5. Also of note here, the study authors did describe how there was no significant interaction with randomization strata observed between participants who were and were not invasively mechanically ventilated. When evaluating the second primary outcome, which was time to meeting the criteria for ventilation within the first 28 days after randomization, comparing high-fluoronasal oxygen and CPAP to the standard-of-care oxygen therapy, there was no statistically significant change in the cause-specific hazard ratio between either of these arms. The study authors also noted that there were no significant interactions noted between the two different dexamethasone interventions. For all secondary endpoints and for the post-hoc analyses, there were no secondary endpoints in this study that were found to be statistically significant. A post-hoc analysis did not find that 60-day mortality was mediated by dexamethasone dosing regimen or receiving invasive mechanical ventilation, and another post-hoc analysis did not show a period-by-treatment interaction for time-to-need invasive mechanical ventilation for any of the oxygenation support strategies described. The study authors concluded that there was no significant difference in 60-day survival for patients treated with high-dose dexamethasone compared to standard-of-care. Additionally, they also concluded that none of the primary oxygenation support strategies reviewed had a significant impact on 28-day risk of invasive mechanical ventilation requirements. For the critique of the COVIDICA study, I have a few different points I'd like to address. First of all, this study had a bit of a lack of adherence to the allocated oxygen support strategy. This was found in 57 participants, which accounts for 17%. Part of this that the study authors attributed it to is that not all centers were experienced with CPAP therapy compared to high-flow nasal oxygen. Additionally, there were 58 patients who fulfilled criteria to be invasively mechanically ventilated, but these patients were not ultimately intubated. However, they were considered to reach this primary endpoint for our oxygen support strategies. Because this study was performed between April of 2020 and January of 2021, this was when a lot of things were changing with our COVID dosing strategies, with our different therapies, and even with prone positioning. This was something that was not recorded in the study, and while other different interventions were recorded in the study in their supplemental appendices, they did not necessarily account for this in their statistical methods. Another important point to note is that the study was performed in France. The study authors noted that in France, the dexamethasone that was given intravenously was by dexamethasone phosphate, of which 16.6 milligrams of standard dexamethasone is found in 20 milligrams of dexamethasone phosphate, which could lead to difficulty with generalizing this to other hospitals, depending on the product that's used. And lastly, the study may have been considered underpowered. Because it was started when we didn't have a lot of data, they were looking at an effect rate for 80% power on the assumption of 60% all-cause death at 60 days for dexamethasone. They did reach that. However, the Recovery-RS trial effect rate found an 8% difference in intubation rate at day 28 with CPAP strategies. If this study, the COVITICUS trial, were going to try and find that 8% difference found in the Recovery-RS trial, they would have required the study to include 585 patients per group for 80% power, which they simply did not have. When interpreting the results of the COVITICUS trial, I do agree with the authors that the results were not statistically significant. However, I do feel that the statistical analysis methods utilized were appropriate. For clinical significance of these results, I don't feel that they are clinically significant. There are other studies that have been performed that concluded a standard dose dexamethasone regimen is appropriate for certain patient populations. Additionally, one thing I think was unique about the COVITICUS trial was the design they utilized to evaluate those alternative non-invasive respiratory support strategies. For practice sites that have limited access to different kinds of non-invasive respiratory support, these results do strengthen that providers could utilize what strategies are available. But, due to the lack of adherence to the study protocol, I would interpret those results with caution. My key takeaway points for this study are that the study design was appropriate given the information available at the time it was designed. However, if redesigned today, I would provide analyses on other concomitant therapies, considering remdesivir therapy, tocilizumab, whether patients were proned, and even considering patient COVID vaccination status. I also feel that there were some issues with adherence to the study protocol, as we described, with certain centers not being familiar or comfortable with using the different oxygenation support strategies. I do feel that, while the results might be valid, both primary endpoints were not significant. For institutional practice changes, I feel that my institution will continue our current practice of standard dose dexamethasone for most patients, and we will continue our current practice of provider-driven oxygenation support strategies. For next steps or questions in this area of research, I think we could consider analysis on different non-invasive respiratory support strategies in hospitals that are familiar with both high-flow nasal oxygen and CPAP. I would agree that if a repeat study were performed that analyzed these respiratory support strategies, in the future, they could account for additional information not supplied in the COVIDICUS trial, and I think they should continue all patients on the standard dose dexamethasone regimen. With this, this leads me into my two polling questions for this study. For my first question, which of the following is not true regarding the limitations of the COVIDICUS trial, that the study dates were from April 2020 to January 2021, all centers were equally experienced in CPAP and high-flow nasal oxygen, prone positioning was not recorded, and there is a lack of adherence to the allocated oxygen strategy. I'm pleased to see that most people picked up on that B is not the correct answer choice here. Unfortunately, not all centers were equally experienced in CPAP and high-flow nasal oxygen strategies. And then for my second polling question, this is simply a true or false. So true or false, high-dose dexamethasone showed a significant increase in 60-day survival of ICU patients with COVID-19-related severe acute hypoxic respiratory failure. And the correct answer is false, as the majority of participants have found. The results of the COVIDICUS trial were not statistically significant. With that, I will conclude my presentation. Thank you for your time, and I will take any questions that you may have. Great job on the presentation. We have a few questions from the audience. The first question is regards to the baseline demographics. Is there any information on the percent of patients who met criteria for ARDS during treatment? That's a really great question to ask. I believe this was supplied in the Supplementary Appendix. However, I do not recall the exact percentage of patients who met the criteria for ARDS. I can certainly evaluate that and get that back to you if that is appropriate. Okay, and thank you. The second question is kind of looking at the literature as a whole on this subject matter. So, you know, you explained the findings of no difference. There's a trial, the CODEX trial, that had some support for using higher doses. How do you kind of integrate all these trials together? And ultimately, you know, in your own clinical practice, is there a way you would select different dosing regimen other than the standard dexamethasone six milligrams based on patient specific factors? At our institution, the majority of patients do stick with the standard six milligrams dexamethasone dosing. Patients who we do consider higher dosing strategies are patients who are on like steroids before they came into the hospital so that we can give them a higher boost than they would have had previously. We also have had providers who do prefer to give the higher dexamethasone dosing strategy. Additionally, patients who have meet the criteria for septic shock and need to have like stress dose steroids, we found that it's basically provider judgment and clinical judgment at this time at our institution. Okay, thank you, Dr. Graham for that excellent presentation. And that concludes our Q&A session. I'd like to introduce our final presenter for the day, Dr. Molly Bray. Thank you, Dr. Smith. My name is Molly Bray. I am a PGY2 critical care pharmacy resident at Detroit Receiving Hospital with the Detroit Medical Center in Detroit, Michigan. And today I'll be discussing the article titled, Comparison of Eight Versus 15 Days of Antibiotic Therapy for Pseudomonas aeruginosa, ventilator-associated pneumonia in adults, a randomized controlled open-label trial. To provide a bit of context and looking specifically at ventilator-associated pneumonia or VAP as I'll refer to it, it accounts for 25% of infections in intensive care unit patients, but the optimal duration of therapy has not yet been determined, particularly when it comes to ventilator-associated pneumonia caused by non-lactose-fermenting gram-negative bacilli like pseudomonas aeruginosa. Two large reasons that we are concerned about the duration of therapy are infection recurrence as we want to fully treat the infection before we discontinue antibiotics and drug resistance as we don't want to create difficult-to-treat organisms. There are two major guidelines that address duration of therapy for PA VAP. The 2016 IDSA guidelines on the management of hospital and ventilator-associated pneumonia recommend a seven-day rather than a 15-day course of antibiotics for VAP, but provide the caveat that a shorter or longer duration may be indicated based on clinical, radiographic, and laboratory findings throughout the course of illness. This is based on systematic reviews in which they found a decrease in 28-day antibiotic-free days and a reduced rate of recurrent ventilator-associated pneumonia due to multidrug-resistant organisms. However, with non-lactose-fermenting gram-negative organisms such as pseudomonas, shorter antibiotic courses were associated with more recurrent pneumonia. Likewise, the 2017 European guidelines recommend a seven- to eight-day course of antibiotic therapy rather than 14 days for VAP in patients without risk factors such as empyema or lung abscess with good clinical response, including patients with non-lactose-fermenting gram-negative organisms such as pseudomonas. Their review found no difference between short and long courses of antibiotics in regards to mortality, duration of mechanical ventilation, or intensive care unit length of stay, but there were more antibiotic-free days and secondary infections from multidrug-resistant organisms were lower with the short course regimen, although there were a limited number of patients in non-lactose-fermenting gram-negative organisms, limiting the applicability to this specific population. There are two studies that have specifically examined the duration of therapy for P-AVAP prior to the current study. When looking at the subset of P-AVAP in the PneumA trial, they found pneumonia recurrence to be significantly higher with an eight-day course of therapy than with a 15-day course, but found no significant difference in the 28-day mortality, although the subgroup was not powered to find this difference. A relatively recent Cochrane review looked at two studies in their subset of non-fermenting gram-negative bacilli pneumonia and found a significantly higher odds ratio of recurrent pneumonia with a short course of antibiotics of seven to eight days versus a long course of 10 to 15 days, but did not find a significant difference in 28-day mortality. With obvious discordance in the evidence, Bugle and colleagues published the comparison of eight versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults in intensive care medicine in May of 2022, which was funded by the Hospitals of Paris Clinical Research and Development Department. This study was thus designed to assess the non-inferiority of a short duration of antibiotics, which they defined as eight days versus prolonged antibiotic therapy of 15 days in P-AVAP. Inclusion criteria included patients who were at least 18 years old and they had to have a documented diagnosis of P-AVAP, which included clinical suspicion, including at least two criteria of a fever, leukocytosis or leukopenia, purulent tracheobronchial secretions, and a new or persistent infiltrate on chest radiograph, as well as confirmation by a Pseudomonas aeruginosa positive quantitative culture from a respiratory sample. Exclusion criteria were pregnancy, any immunosuppression, current antibiotic therapy active on Pseudomonas aeruginosa for pulmonary infection, any procedure of withdrawing life-sustaining treatment, and chronic pulmonary colonization with Pseudomonas aeruginosa. For their methods, antibiotic therapy was initiated after respiratory sampling, and the choice of initial antibiotic therapy was left to the discretion of the physician according to usual practices. Investigators were strongly encouraged to convert the initial regimen into a narrower spectrum therapy based on culture results in antimicrobial susceptibility testing as the study went on. Patients were randomly assigned in a one-to-one ratio stratified by center to eight or 15 days of therapy, and they were screened for a multi-drug resistant pathogens on admission and once weekly until discharge. Their primary outcome was the composite 90-day mortality and PA vac recurrence, and secondary outcomes included the duration of mechanical ventilation, the ICU length of stay, the duration of antibiotic exposure, number and types of extra pulmonary infections, and multi-drug resistant pathogens. This was a non-inferiority study with a specified 10% non-inferiority margin of the primary endpoint. They assigned an alpha value of 0.05 and needed 600 patients enrolled to meet 80% power to detect a difference in their primary endpoint. They analyzed their primary endpoint as intention to treat, and their subsequent sensitivity analysis was per protocol. Some baseline characteristics in this study were evenly matched across groups, but others were not, which the study attempted to adjust for in their sensitivity analysis. Some of these demographic characteristics that were not evenly matched were higher percentages of hypertension and heart failure in the 15-day group specifically. As far as main diagnosis at admission goes, there were some differences in these baseline characteristics as well. So we see that there were higher percentages of neurologic impairment and acute respiratory failure in the 15-day group, while more patients who were in the post-operative period fell into the eight-day group. Lastly, for reason for ICU admission, there were more patients needing catecholamines at inclusion in the 15-day group, and there was a higher median PF ratio to begin with in the eight-day group. Here we see empiric antibiotic therapy choices effective against pseudomonas, with the majority of providers in this study choosing Zofan as their initial antibiotic therapy, with second and third most popular choices being cefepime and ceftazidime in this study. In regards to their primary outcome, they did not find any significant difference in either their intention to treat population, as we see in the first row, nor in their sensitivity analysis, as we see in the second row. When looking at PAVAP recurrence alone, they once again found no significant difference between the groups. And when looking at mortality alone in the Kaplan-Meier curve, although there may be a trend toward higher survival probability with 15 days of therapy, the difference between groups was not statistically significant. In regards to secondary outcomes, there were no significant differences between the groups either, although there was a slightly higher percentage of patients in the 15-day group developing multidrug-resistant organisms. But in regards to duration of mechanical ventilation, the duration of ICU stay, exposure to antibiotics during ICU stay, and the number of extra pulmonary infections during the ICU stay, there were no statistically significant differences. The authors concluded from this study that eight days of antibiotic therapy did not show non-inferiority to 15 days in the treatment of PAVAP, and that the eight-day group was actually almost twice as likely to have PAVAP recurrence. There was also no significant difference between the groups in terms of multidrug-resistant pathogen acquisition. Some strengths of this study are that it examines relevant clinical outcomes rather than any surrogate markers in regards to infection recurrence, mortality, and drug-resistant pathogen development. This study does have some external validity, particularly in terms of inclusion criteria where the diagnosis of PAVAP required both subjective and objective evidence of infection, and it has some internal validity as well by excluding patients who would have confounded the results, although this may have decreased their external validity. Lastly, empiric antibiotic therapy was physician-driven rather than fixed, particularly in the case of a 30-center study such as this. Local susceptibility patterns may vary, and the physician was allowed to choose antibiotic therapy that they believed to be appropriate based on local data and the clinical history of the patient. However, there were many flaws in the design of this study, and there are some limitations that I would like to point out. This was an open-label study which may have introduced bias when examining the patient and considering whether they were receiving active antibiotic therapy or not. However, it would be very difficult to do this as a blinded study as a patient receiving placebo would not be ethically being treated, and it would be difficult based on local susceptibility patterns choosing an antibiotic or just having a fixed antibiotic in this case. Additionally, the study had to be stopped after 24 months due to a slow inclusion rate unless it did not even meet the power to detect a significant difference in its primary outcome, which is a major limitation. Some of the differences in baseline characteristics were particularly large, and although they did adjust for these possible confounders in the sensitivity analysis, some baseline characteristics such as heart failure, initial P-to-F ratio, and catecholamine use could affect outcomes. These differences may have occurred in part due to the size of this study, but future studies may need to control for these variables to reduce confounding. In addition to this small sample size, 32 patients were wrongly included as they did not meet eligibility criteria and were subsequently analyzed in the intention to treat population due to duration of mechanical ventilation being less than 48 hours prior to enrollment, not ensuring that they did not meet the definition of VAP or not having TA VAP at all. These patients were excluded in the sensitivity analysis, but their initial inclusion weakens the true sample size and thus the validity of the results. In addition to patients who were wrongly included, approximately 20% of patients in each group did not adhere to the assigned duration, with the majority of these patients having a longer course than expected. The majority of these extensions were justified by TA VAP persistence as documented by the original causative baseline pathogen or pathogens appearing in a lower respiratory culture obtained between the end of treatment and 72 hours after end of treatment, or an extra pulmonary infection. This was also adjusted for in the sensitivity analysis, but once again was a major confounder for what the true duration of therapy was for these patients. Additionally, it's unclear if these patients were experiencing symptoms or not still, or if the pneumonia was still only in the culture. It is also unclear whether or not these patients were considered in the PA VAP recurrence group in the secondary outcomes, limiting the utility of this outcome. Once again, there were cases where the duration of therapy was modified to adapt to the clinical picture, but these patients were analyzed in their originally assigned group, which may have confounded the outcomes. Lastly, it is difficult to determine from this study the time that patients were truly on appropriate antibiotics if the antibiotic choices, each culture and sensitivity result was not provided. We don't know exactly how quickly each patient was put on appropriate antipseudomonal coverage, if the organism was susceptible to that drug, or if the patient missed any doses for any reason, thus it's difficult to determine truly appropriate therapy and duration of therapy. To summarize, there appears to be a higher rate of composite mortality and VAP recurrence with eight versus 15 days of antibiotic therapy based on this study, but many confounders were involved in this outcome, so the results should be taken with a grain of salt. There is a trend toward less multi-drug resistant pathogen emergence with eight versus 15 days of antibiotic therapy, although other potential reasons for multi-drug resistant development, such as recent hospital stay and IV antibiotic use, social situation at home, such as residing in a nursing home, or previous history of multi-drug resistance and cultures were not considered and adjusted for. Lastly, as there's no clear benefit from adopting a specific duration of therapy, according to this study, choice of antibiotics and duration of therapy should still be based on local susceptibilities, biomarker evidence, and the overall clinical picture of the patient, keeping in mind the risks and benefits of each duration of therapy and adjusting the antimicrobial plan as needed. So with that, I just want to assess a couple of polling questions based on everybody's practice. The first question is, what is an appropriate duration of therapy, or what do you believe to be an appropriate duration of therapy when treating Pseudomonas aeruginosa ventilator associated pneumonia? And this is kind of what I expected too. So we do try to lean toward a shorter duration of therapy based on all the reasons listed in guidelines in previous studies. But really when we're assessing the patient, we need to take a look at the patient. How is their clinical progression? Are we at, when we're at the bedside, are they actually looking better? Do we see biomarkers that may lead us to believe that the infection has resolved or not, the culture evidence, and really just looking at the patient as a whole and adjusting the antibiotic duration as appropriate. And then question number two is, what is the empiric anti-pseudomonal agent of choice at your institution? So, I see the majority say cefepime here. That is the major workhorse for anti-pseudomonal coverage at our institution here. And I've seen institutions use zosyn quite a bit, too, as the anti-pseudomonal coverage of choice, with obviously the difference in those two being what types of gram-positive organisms they cover as well, so there are slight differences in the treatment. And I don't even—we don't use ceftazidime, or imipenem and meropenem do tend to be too broad as the carbapenem for our initial choice of pseudomonal—anti-pseudomonal agent in general. With that, I'll say thank you so much for attending, and I'm happy to take any questions at this time. Great job on the presentation, Dr. Bray. We have a few questions in the chat, so the first question you kind of touched on, did the trial indicate differences in the empiric active therapy between groups, and were there any mentions of combination therapy empirically? And do you know if there's any difference in those two groups? Yeah, so they—as far as differences between the groups go, there weren't any major statistically significant differences between the groups in their empiric antimicrobial therapy choices. And some of these patients, since they weren't included until they had a positive pseudomonas culture result, some of these patients weren't even initially started on an anti-pseudomonal agent right off the bat, so some patients were even started on things such as Augmentin to begin with, which doesn't have that anti-pseudomonal coverage. And I know that there is some practice based on the local susceptibilities and patient history to potentially consider double anti-pseudomonal coverage, and they did not address that in this study either when looking at the effective empiric antimicrobial therapy. In this study, looking at the total population, the numbers do add up to 100 percent, suggesting that only—each patient was only on one of these anti-pseudomonal agents. But otherwise, like I had said, they didn't discuss what the patient cultures looked like either, so it was difficult to tell if patients were on truly appropriate therapy based on the susceptibilities of their agents too. Thank you. And the second question, you kind of alluded to in your limitations and your takeaway, but as you mentioned, the trial had higher rates of reoccurrence, it was underpowered, and there's this signal of numerically higher rates of mortality, so what things do you use in your clinical practice and based on this new evidence to extend beyond eight days? So what things are you looking at where you might extend beyond the contemporary eight days based on this trial? Yeah, as far as extending beyond the contemporary eight days, I know especially they mentioned with the amount—they had to have been on the ventilator already. It was difficult to say—they didn't necessarily mention when or if these patients had been activated too, but especially looking at respiratory characteristics and saying, like, what their vent settings are, if they're requiring less help from the ventilator in terms of respiration, especially with a pneumonia, as far as if a fever is resolving or if the leukocytosis is resolving, if the patient is more awake and alert as well. So those are some things that I would look at to see if a patient needed an extended duration of therapy, and then continuing to monitor cultures as well just to make sure that we're treating appropriate organisms too and that they didn't develop another organism. For instance, if they started to develop a MRSA pneumonia instead, that might not necessarily make me extend the duration of the antipsytumonal therapy, but we may have to extend the duration of therapy in general with an appropriate agent. So those are just some things that I would look at. Thank you, Dr. Bray, for that great presentation. That concludes our Q&A for the third presentation. I'd like to thank our presenters for these great presentations today and for the audience participation in asking these presenters questions. Please join us November 18th from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy, and that concludes our presentation day. Thank you for joining us.

Journal Club Spotlight on Pharmacy

webcast

Dr. Alina Gallant

weight-based anoxaparin dosing

venous thromboembolism prophylaxis

Dr. Marinda Graham

high-dose dexamethasone

ICU patients

severe COVID-19-associated acute hypoxemic respiratory failure

Dr. Molly Bray