Hello, good afternoon, good morning, and welcome to the 51st Critical Care Congress. This is a continuation of the Clinical Pharmacy and Pharmacology section's year in review, focus on infectious diseases, less is more. My name is Melissa Santibanez. I am a critical care clinical pharmacist and assistant professor at Nova Southeastern University College of Pharmacy in Florida. I have no real or potential conflicts of interest related to the subject matter of this presentation besides genuine interest in critical care infectious diseases. This session will aim to review the newest pharmacologic strategies related to infectious diseases, namely describing updates to the ID literature in the ICU related to, number one, the impact of active anti-pseudomonobetalactam use on bacterial resistance to other anti-pseudomonobetalactams, and number two, on the management of clostridioides difficile infections. Each of these selections of topics and literature is focused on a global theme of less is more as an antimicrobial stewardship strategy in the ICU. So the first topic to cover in this session is whether resistance to anti-pseudomonobetalactams confers success in the presence of resistance to other anti-pseudomonobetalactams. And this was a study published in Pharmacotherapy in 2021 by Lodis and colleagues. It was an exploratory hypothesis-generating retrospective cohort study in the Kaiser Permanente group in Southern California across multiple sites in that network. The purpose of the study was to evaluate the effect of anti-pseudomonobetalactam resistance on certain clinical outcomes, and namely in patients with a pseudomonas aeruginosa hospital-acquired or ventilator-associated pneumonia who were initially treated with a susceptible agent, beta-lactam agent. The four susceptible anti-pseudomonobetalactams defined and used throughout this study were piperacillin-tazobactam, ceftazidime, cefepime, or meropenem. Before moving into the specifics about the trial and what its findings were, it's important to note that in 2012, the Clinical Laboratory Standards Institute updated the breakpoints for pseudomonas aeruginosa for piperacillin-tazobactam and the carbapenems, two of the four anti-pseudomonobetalactams that were included in this study. All study sites included adopted these revised breakpoints immediately, and so for all patients from 2012 through the end of the study period, these revised current breakpoints were utilized. And those breakpoints are reflected here in the bottom half of the slide. As you can see, for both piperacillin-tazobactam and the carbapenems, the breakpoint was lowered pretty significantly from what it was before. Patients were included in this study if they were adults admitted to the intensive care unit at one of the study sites with a monomicrobial pseudomonas aeruginosa HAP or VAP over the seven-year time period, and if they received any one of the four susceptible anti-pseudomonobetalactams within two days of index culture. And index culture was either a respiratory or a blood culture. Polymicrobial infections, patients who died within two days and those with cystic fibrosis were excluded, considering the intricacies and specific management of that particular infection. And only the first infection was included, so patients who developed secondary or tertiary infections, even within the same hospital stay, only the first infection was included as the index infection. And for data analysis purposes, the patients were stratified by the presence of anti-pseudomonobetalactam resistance on that index culture. So they were either stratified into a zero or a greater than or equal to one resistance group. And resistance was defined as either frank resistance or intermediate resistance on that culture. And the study had multiple primary outcomes, the main one being a composite outcome of in-hospital mortality or transition to hospice, but also looked at 30-day mortality and discharge to home. Now, a little bit over 550 patients were included in the study, with well over three-quarters of them falling into the group that had no evidence of anti-pseudomonobetalactam resistance on index culture. And the primary outcome was observed, the composite outcome of in-hospital mortality or transition to hospice, in about 30% of patients. Now, the unique aspect of this study's statistical analysis is that it utilized a technique called inverse probability of treatment weighting. And this is a technique that attempts to create similar groups out of dissimilar groups, so very much like a propensity score matching, in order to determine whether a treatment or exposure was associated with a particular outcome or effect. So these groups were created through weighting, and then that removes the effect of any confounders that otherwise may have influenced the outcome. And each subject is weighted by the reciprocal of the probability of receiving the treatment that they actually received. And at the end of this process, a multivariable logistic regression was used to determine the association between anti-pseudomonobetalactam resistance and the primary composite outcome. So this figure depicts the percent standardized differences, both before and after the IPTW treatment weighting analysis. On the y-axis, you can see a variety of variables that were otherwise considered to be confounders had the treatment weighting not occurred. And on the x-axis, the percent standardized difference. The open circles depict effects seen before the adjustment, and the closed diamonds reflect relationships observed after inverse probability of treatment weighting, after adjusting for those confounders. And it's crucial to note that after the IPTW analysis, the standard difference for all variables was defined to be less than or equal to 0.2 or 20% here on this graph. So it's important to see that all of the dark closed diamonds, they fall well below this 20% standardized line of standard difference, with the exception of the severity risk score called COPS, or comorbidity point score version two, which is based on 12-month patient data. And it's a comorbidity score that the higher the score, the more likelihood of patients having death due to that comorbidity. This was the only variable that fell out of the 0.2 or 20% standardized difference range. The other variables were clustered fairly closely together. There were no extremes observed after adjustment for confounders. So you're able to say that the propensity score matching used here was successful. Now focusing on the primary analysis again, after the adjustment for confounders using inverse probability of treatment weighting, the odds ratio of patients experiencing that composite outcome of in-hospital mortality or transition to hospice was not statistically significant between groups based on resistance. But for patients who did have one or more resistance pattern observed, there was a statistically significant effect on 30-day mortality, with more patients dying within 30 days if they had at least one resistance pattern. The discharge to home outcome was assessed using a hazard ratio, and there was a statistically significant difference observed here, namely in that more patients with no evidence of resistance patterns were discharged to home. Now this table was taken from the supplement of the study, and it looks a little bit busy, but it also looks like an antibiogram. And it's a reflection of the individual beta-lactam resistance types that were observed in these isolates compared to what treatments the patients actually received. So what we can see here is that in this first column is the reflection of the antibiotic treatment that was received, and across the remaining columns is whether there was no beta-lactam resistance, one or two types of resistance patterns seen. And of the 553 patients and isolates, you can see that overwhelmingly more of them did not have evidence of any antiseudomonobeta-lactam resistance type. But of those who did have at least one beta-lactam resistance, the most common resistance was to meropenem. For patients who had two types of resistance patterns observed, the most common type was a resistance to both cefepime and piperacillin-tazobactam. In conclusion, this exploratory analysis suggests that the full antiseudomonobeta-lactam susceptibility profile should be considered when selecting therapy for patients with a Pseudomonas aeruginosa HAP or VAP. So now that we've reviewed the findings of this particular study, it's helpful to look at what clinical questions remain to be addressed and questions that were not fully addressed by this study as designed. So if you can type in your responses into the live chat box, you can go through this particular item first. What additional clinical questions related to antiseudomonobeta-lactam resistance were not addressed by the study? Was it effect on clinical cure rates, effect on non-pulmonary infections, effect on patients with recurrent infections, or all of the above? I'll give you a second to type into the chat. And quite honestly, it's all of the above. This was a study that was focused on strictly pneumonias and HAP and VAP, so strictly pulmonary infections, monomicrobial in origin. It excluded patients who had recurrent infections within that same hospitalization, and the outcome selected was more prognostic and mortality-related as opposed to clinical. So looking at clinical cure rates and whether this specific knowledge of what is the full antiseudomonobeta-lactam susceptibility profile of a particular isolate, how that affects clinical cure rates for pneumonias, as was studied in this trial, but also beyond the pulmonary infections to see if this is an observation that fits the gamut of antimicrobial stewardship recommendations across the board. I would like to thank you for your responses to that question, and we'll wrap up this part of the discussion by looking at some limitations and potential for future expansion of this particular topic. So we just addressed the importance and effect of looking at a mortality-based outcome versus a more infection-related outcome when it comes to clinical effect of this particular strategy. The use and inclusion of just a single infection type, so it's not clear whether this antiseudomonobeta-lactam resistance strategy will have the same observed effect in patients who have polymicrobial infections, whether it's multiple organisms causing an infection in the same site or different organisms causing different infections across the body simultaneously. Additionally, the study did not determine, it was not able to determine the effect of the individual antiseudomonal drugs on these clinical outcomes of interest, especially of the newer agents like Avicaz or ceftazidime avibactam or Cervaxa, ceftolozanetazobactam. And we know that this is important because some of our patients already have an intrinsic resistance to Cervaxa and sometimes Avicaz as well, even though they have never been exposed to these agents before. So this will affect our less-is-more type of stewardship mentality and de-escalating therapy in the future. The potential for confounding in that we can infer that patients who had the presence of at least one type of resistance to antiseudomonal drugs had a higher severity of illness. And this was confirmed by the fact that those patients who did not have any resistance patterns were significantly more likely to go home within 30 days as opposed to those who did not. And finally, the update to the pseudomonas breakpoints that was addressed before and how now in the nearly 10 years since those updates were made, how that is affecting clinical outcomes, that remains to be seen. Okay, and with that, we will move into the second focus of today's session, which is the 2021 Focused Update to the Management of Clostridioides Difficile Infection. This Clinical Practice Guideline Focused Update is a conjunction of both the IDSA and SHEA and a panel representing both organizations. And it was aimed to update the 2017 C. diff treatment guidelines, especially for fidaxomicin and beszalotuximab. So these focused updates are looking more at the standpoint of recurrent infections and what is the role of some of these adjunctive therapies. So because this was a focused update to a practice guideline, I arranged the sub-areas of this topic into the actual content updates that the guideline presented, the first of which having to deal with initial C. difficile episodes and what is the role of fidaxomicin as opposed to vancomycin. This was one of the major areas of update in the 2017 guidelines. And the panel experts found with moderate certainty of evidence that fidaxomicin is recommended over vancomycin PO. However, vancomycin PO remains a suitable alternative. Before moving into the next set of updates, because they focus on recurrent infections, thought it good to ask a question related to what are these risk factors for C. diff recurrence. So if you can type your answers in the chat box for this question, we'll go through some of these options. Which baseline characteristic is a risk factor for C. difficile recurrence? Is it advanced age over 65 years, previous use of fidaxomicin, having severe C. diff on the initial episode, or having an initial episode requiring mechanical ventilation? There are actually two correct responses here, the first being advanced age and the second being having a severe initial episode. And thank you for your responses to that question as well. It leads us into C. diff update number two. For those individuals with a recurrent infection, should fidaxomicin be used versus vancomycin PO? And the recommendation was, based on a low certainty of evidence, that fidaxomicin is recommended over vancomycin PO. So now it's recommended for the initial episode and for this first recurrence. Vancomycin PO, whether standard dosing of 125 milligrams POQ6, or as a pulse dose regimen, remain acceptable alternatives for that first recurrence. And then there are additional recommendations for second recurrences and beyond. And the final category of C. diff-related updates also looked at or focused on recurrences, but now trying to determine the role of beslatuximab, which back in 2017, that guideline revision from the IDSA mentioned beslatuximab for the first time and having a role in preventing further recurrences. But it was not quite clear at that point what exactly was the niche for beslatuximab and at what level of recurrence is it most effective. So the question asked was, in patients with a recurrent C. diff infection, should beslatuximab be added to the standard of care antibiotics, whether fidaxomicin or vancomycin PO, as opposed to using the standard antibiotics alone. And the recommendation was in favor of beslatuximab adjunctive to the standard of care antibiotics, although this was based on a very, very low certainty of evidence. And it isn't in every patient. It's in those who have risk factors for C. diff recurrence in the next six months. And those risk factors are, again, that advanced age above 65 years, the presence of a severe infection, which is defined as a white blood cell count greater than or equal to 15,000, or a serum creatinine greater than or equal to 1.5 milligrams per deciliter. And finally, patients with a history of immunosuppressive drug use or immunosuppressive conditions, including chronic steroids, patients with transplant or anti-rejection drugs, and other conditions. So to start putting all these recommendations together, this table summarizes the focus guidelines recommendations for initial and recurrent infections, both the first and second and thereafter, and for fulminant C. diff. The initial episode is recommended to use fidaxomicin over vancomycin PO. And for the first recurrence, fidaxomicin monotherapy, again, is recommended over vancopo. And if that patient, since it's the first recurrence, if they have the risk factors for recurrence, there is a recommendation to add on IV bezalotuximab, one dose, in addition to that standard of care antibiotic. Second recurrences and above, can consider using fidaxomicin monotherapy, again, with the bezalotuximab if those recurrence risk factors are there. And these patients have already had two recurrences, if not more. So most of them are likely going to require use of bezalotuximab. But then there's also recommendations here for initial use of vancomycin tapered dose regimens, and fecal microbiota transplant, which is recommended to be used when patients have at least had two recurrences, or three total infections with C. diff. So these focused update recommendations promote a less-is-more stewardship philosophy by streamlining the treatment recommendations based on evidence for initial episodes, and at least the first recurrence to be consistent with fidaxomicin in all cases, as opposed to having multiple therapies. Again, there is a potential to add on adjunctive therapies once patients have at least one recurrence based on their likelihood to have a recurrence again. But the limitations with these recommendations mainly center on this distinction between a recurrence versus a treatment failure, and when a prior episode is not completely or thoroughly treated, and then leads to a follow-up episode, which is now a recurrence. So what is the effect that these two types of occurrences have on one another? There's also limited data on bezalotuximab's efficacy and benefit when used with fidaxomicin. So considering that fidaxomicin is now the preferred agent for initial episodes, as well as first recurrences, adding bezalotuximab, the full benefit remains to be determined. And on that note, the impact of having multiple adjunctive strategies for patients who are having recurrent infections, including bezalotuximab, but also fecal microbiota transplants for those who have at least two recurrences. And of course, the ever-present cost consideration, considering the expensive acquisition cost of bezalotuximab, and even fecal microbiota transplant compared to vancomycin PO, or even in some institutions, fidaxomicin. So this concludes the infectious diseases less is more portion of our CPP year-in-review session. And I would like to thank you for your attention. My email address is provided there should you have any additional questions. And I look forward to the live chat discussion during Congress. Thank you all for your participation.

Critical Care Congress

Clinical Pharmacy

Pharmacology

infectious diseases

anti-pseudomonal beta-lactam

CDI