My name is Charles Delacruz. I'm on the faculty at Yale School of Medicine in New Haven. I'm delighted to participate in this panel with my colleagues, Dr. Christina Crothers and Dr. Rich Wundering. So I'll start by talking about the treatment of strategies for nosocomial pneumonia. My only conflict is I've been involved in an ATS guideline on viral diagnostic and some of my granting support. So the objective I was given was to review the clinical practice guideline recommendations for patients with hospital-acquired and ventilation-associated pneumonia. So we know that HAP and VAP are one of the most common nosocomial infections. It's the leading cause of death to hospital-acquired infections, especially with VAP, increased mortality up to 50%. A significant economic burden for this infection. During COVID, people have reported that having COVID-19 increased the risk of having VAP. This is a study from the UK using the routine microbial culture plus a more sensitive TaqMan multi-panel pathogen array showing how this compares to non-COVID. Our colleague, Dr. Wundering and his group recently reported in a preprint that mechanical ventilated patients with suspected pneumonia using a machine learning approach found that patients who have unresolving secondary pneumonia end up with poor outcome. And you can see in this graph comparing non-COVID and COVID patients that there are significantly higher patients have at least one pneumonia that is VAP. And on the right, increased number of patients with multiple VAP in the COVID-19 patients. The earlier studies also suggested that these COVID-19 was associated with increased risk of VAP, despite not being associated with the duration of mechanical ventilation. Here you can see the different kind of organisms that they were able to detect. You can see the more common associated organisms to hospital acquired in VAP. Pneumonias, for example, are pseudomonas. You can see Klebsiella in cyan color and also Staph aureus. So by definition, we know that HAP is pneumonia that is after 48 hours after admission and that was not present during the time of admission. Ventilator-associated pneumonia develops typically after 48 hours after endotracheal intubation. And then in the guideline, they mentioned about ventilator-associated tracheal bronchitis. And so the initial approach is to think about the impaired treatment of HAP and VAP. And for this, we need to think about the risk factors related to multidrug-resistant. If the patient, for example, do not have any associated risk factors for multidrug-resistant organisms, on the left-hand side, you can see broad-spectrum antibiotics against both pseudomonas and atypical gram-negative organisms, as well as coverage for MSSA is recommended. However, if your patients have risk factors both to either MRSA or MDR pseudomonas, broad-spectrum has strong recommendation, even though the quality of evidence at the time in 2016 was low. So for impaired treatment of HAP, there are, for patients who have no risk factors, and these are patients with no prior antibiotic therapy in 90 days. More importantly, if the hospital and the unit have low rates of MRSA, and they've had negative screening or no prior infections, in addition that the patients do not have significant risk of death requiring ventilator support of septic shock, these are the recommended impaired treatment. And on the right-hand side, you can see here are some of the antibiotics that we typically use for our patients, including peptated tazobactam, cefepime, and others. And most of these antibiotics here have appropriate coverages for MSSA. For patients who have structural lung disease, it was recommended to consider two anti-pseudomonal coverage. So to target antibiotic therapy, we really need to know about our local pathogens. The use of antibiogram is quite important. Ideally, this is unit-specific. And so we typically round in our ICU with the most current updated antibiogram for our patients. And the second sort of take-home message from the HAP-BAP guideline was really to target the risk factors of the patients. This was because of an earlier study showing different ICU units have different percentages of pseudomonas and acinobacter in different countries. And so for impaired treatment of HAP, MRSA anti-pseudomal coverage requires the recommendation as listed here, based on their risk for mortality, likely MRSA, and also on the right, high risk of mortality and exposure to antibiotics in the past 90 days. You can see in the top are some of the more common antibodies that we use in our hospital for these patients. And then in the bottom here, depending on the risk for MRSA coverage for these patients. Impaired treatment for VAP also is split between the suspicion for MRSA and anti-pseudomonal coverage. And many of them are now familiar in using some of these regimen. And I'll just move to the next slide. And so the impaired treatment for MRSA that you're suspected for your patients in the hospital, these are the risk factors for HAP and VAP. And these include 90 days of antibiotic therapy, the past 30 days, the unit rate that is significantly high in prevalence, or you do not have this data and the need for ventilator support or patient in shock. And typically the coverage that we all know is the use of vancomycin or lasanilate based on strong recommendations from the guideline. Impaired treatment for pseudomonas pneumonia also has their own list of similar risk factors, including 90 days antibiotic use, lower thresholds for unit rates of resistance. But for pseudomonas infection, it is important to consider patients who have structural lung diseases like bronchiectasis and cystic fibrosis. And typically, although weak recommendation, dual initial therapy is recommended for anti-pseudomonas agents. Dual therapy for these pseudomonas agents include what's listed here, one antibiotics on the left-hand box and then one on the right. And typically it's a combination. Again, this is a weak recommendation, but initial recommendation for initial broad-spectrum coverage, empirically, is to consider this option. And there are some studies in the past where there's some, that show the extended use of infusion for short infusion of antibiotics. And you can see here that extended continuous infusion versus short infusion, that is around less than 60 minutes, was associated with lower mortality. And this has been sort of reported in the setting of patients also with dialysis. And that these extended infusions associated with better drug target attainment, which likely responsible for the lower mortality. There's recommendations and guidelines against the use of monotherapy with aminoglycoside. And this is mostly because of the poor penetration of the antibiotics to the lung, which also requires high P concentrations associated with nephrotoxicity and ototoxicity because of the limited studies. Unless it's needed, it was recommended against. However, we need to refer to the local susceptibilities and the biograms given that maybe there might be a shift towards other antibiotics. And if your hospital has more susceptibility resistant to fluoroquinolone, this might not be good either. So with all these antibiotics that empirically start for your patients, it's important to consider timing for de-escalation and waste. And for patients who, for example, without any of these multi-drug risks and risk factors, you're confident about a negative good quality respiratory studies. And also that your patients are clinically improving. And for this, consider removing second antiseptomal coverage, removing MRSA coverage if the nasal screens are negative. And ultimately, converge to a single broad-spectrum antibiotics that has MSSA coverage based on the antibiogram. It is important to target your therapy based on the available culture data and sensitivities for your patients. As a clinical utility of MRSA, for example, using the nasal screening to rule out have been shown in many studies, including some meta-analysis looking at the role of MRSA to rule out this pneumonia. Specificity actually for MRSA nasal swab VIP, for VIP is actually fairly high. And the negative predictor value also very high. Dr. Wunder's group have also shown that the use of this method using MRSA screening was able to decrease use of antibiotics as well as maintaining clinical outcomes. And duration of therapy over the years, we have now cut down the length of antibiotics use from 14 days now to down to seven days. And this is because of the studies with strong recommendations that seven days is enough for both HAP and VAP. There's certainly variables that need to be considered in terms of duration, depending the patient's improvement. But overall, seven days for both HAP and VAP is enough. And so if your patients are not improving clinically or radiographically, it is recommended to revisit the diagnosis and maybe there's an alternative, additional antibiotics or alternative pulmonary diagnosis that needs to be considered. So this is a meta-analysis that show that short-course antibiotic therapy is not better than having a longer course of antibiotics based on mortality. All organisms, be it cram-negative organisms or MRSA, the recurrence of pneumonia. This, however, was noted to have, especially for cram-negative organisms, some increase of recurrence of this in that population. And given the risk-benefit, it was recommended by the committee to consider the shorter course. And with the shorter course, obviously, the mean at 28-day antibiotic-free days are significantly higher. So a recent study sort of looked at this again, comparing eight versus 15 days, look at non-inferior trial randomized open label. This is actually quite a lot of problem with this study because they were having a difficult time recruiting. And also they had a composite endpoint of mortality and also VAP from pseudomonas recurrence. What they showed was that 25% of the patient, and compared to 35% of the patients with the shorter course reached the endpoint of recurrence and mortality. And there were no significant mortality differences between that sort of recapitulate some of the earlier studies to suggest that there is recurrence of pseudomonas in the patient with shorter course, sort of eight days of therapy. The question here is really, what do these recurrence do clinically? And currently, at least in this smaller study, albeit with a lot of caveats, there were no increase in mortality lengths of stay or ICU lengths of stay that was noted. And this is suggesting that the recommendation from the guideline at this point is still appropriate. So we need to discontinue antibiotics once we start. The guideline, although weak, recommended the use of procacitonin and with clinical improvement. However, I think this is less likely to be useful now because many now hopefully are using the standard practice of using seven days of therapy in our hospital. The use of CPIS is not suggested to be used for discontinuation of antibiotics. So COVID-19, we found that people are using a lot of procacitonin, obviously. And overall, if the procacitonin remains low, it is reassuring to discontinue antibiotics based on low procacitonin level, which is what we know with regards to influenza virus. So low procacitonin, which is what it's used for, you can rule out bacterial infection. The issue is that if the procacitonin is high, does it diagnose super infection? And we have others have shown that in the setting of viral infection, including influenza, and in this case, COVID-19, that procacitonin, if high, does not necessarily mean you have super infection with a bacteria organism. And you can see that pure viral infections, you can see procacitonin as high as more than 10. And this is sort of superimposed in terms of this violent plot with patients who have COVID-19 and bacterial super infection. It's really hard to determine. In fact, procacitonin actually had a better error under the curve to predict renal insufficiency, mechanical ventilation, and really mostly severe disease rather than super infection. And so the use of procacitonin really does not help in diagnosing bacterial infection, nor does it help in deescalating, for example, at this point. So additional consideration for your patients. What if they don't respond to IV therapy alone, or maybe they have highly resistant pathogens, which you'll hear about a little bit later. So the guideline for VAP due to gram-negative organisms that are susceptible only to both either glycosides or polyamics, it was suggested to use both inhaled and systemic antibiotics rather than systemic alone. This is a weak recommendation. And so there's some studies that suggest that, for example, inhaled glycoside, for example, the amikacin phosphomycin study for 10 days with endpoint using the CPAS, there were no difference between the groups, no mortality differences, despite having fewer positive tracheal cultures. In the bottom, the vaporized study using tobramycin twice a day for eight days compared to placebo, plus the standard IV antibiotics. Treatment failure compared to both groups were similar. Again, this study did not show any mortality benefit, but at the same time, they had poor enrollment and it was terminated earlier. And so at this point, I think it's hard to say whether it has clinical benefit, although the recommendation is on the weaker side. Aerosolized colistin have shown, do meth analysis here, improve microbial and clinical response despite not having any effective mortality in nephrotoxicity, quality of evidence is poor. And then for other organisms, such as acinetobacter, carbapenem-resistant pathogens, the use of intravenous polymyxin IV form was suggested compared to the adjunct inhaled colistin, for example, in this case. Just one point to mention is that I mentioned ventilator-associated tracheobronchitis. From the recommendation in the guideline, it is not recommended to use any antibiotic therapy at all, as we've seen some people who use this in their practice. So unless they have pneumonia, there's probably no need for antibiotics. So lastly, we need to strategize into preventing VAP. There's a recent update through the SHEA-IDSA and also our infection control group. And this lists avoiding intubation if possible, minimizing sedation, having PTOT, providing oral care with toothbrushing. I think one of the differences is that the recommendation is without chlorhexidine. Some of the study did not really show any positivity results. In fact, I think it's not recommended by this group. Changing the circuit, elevating of head of bed. And then additional approaches, as mentioned in the last, on the right-hand side. In the bottom, the selective decontamination of gut is really not really used in the US, and especially in population, they use it more in Europe, and we're reportedly lower incidence of MDR in other places. So in terms of risk for VAP, we really need to have a comprehensive view. And this study actually was kind of interesting where they looked at the incidence of hospital-acquired pneumonia and incidence associated with what we know of as older age, male, pre-existing lung disease, as well as the role of tube feeding, suctioning, mechanical ventilation. But it also highlighted patients who are poor. The non-tertiary general hospitals, like many of our hospitals, also with higher bed-to-nurse ratio and higher numbers of bed per room, especially during the time of COVID, and then in places where caregivers are with the patients. And so these are some of the risks that we don't think about, but also can add to the risk of these hospital-acquired pneumonias. So in summary, this summarizes some of the clinical practice guidelines that we know from 2016. I know there's some works on updating this guideline soon. And the MRSA and pseudomonal risk factors is quite important in guiding our therapy and in the importance of antibiotic stewardship. And lastly, November 12 is World Pneumonia Day. And so hopefully people understand that pneumonia continues to kill many in the world. And so I think we hope that you can pass this around to other people for awareness. Thank you very much for your time. Thank you. Polymyxin B versus polymyxin E, any difference in effectiveness? Or does one have an advantage over the other? I think most of the time I don't think there is. I think polymyxin B is what's been used more often. You know, we don't use it as often because we try to avoid some of these MDR organisms. And so I think it's also, in our hospital, it's hard to get into formularies for polymyxin and stuff like that. So we move on to Dr. Christina Carothers, who's a faculty at University of Washington and the VA site as well. Oh, okay. Thank you very much. So I don't have any conflicts of interest to disclose. So I hope that we'll learn a little bit about identifying risk factors for MDR organisms and mechanisms of resistance, some data on recent clinical trials of novel antibiotics and indications for the new therapeutic agents in nosocomial pneumonia. And I'm going to skip my background slides as these were covered nicely by Dr. de la Cruz and kind of get right into the question of beyond the guidelines, when should novel antimicrobials be used? And so some of this depends, as you've just seen, on the local incidence of pathogens. In your ICUs, you saw from the study that Dr. de la Cruz cited, there's a wide variability. So understanding your own local antimicrobiogram and whether there's high prevalence of some of these very resistant organisms. Also, is the patient been previously colonized or infected by some of these MDR organisms? And do they have particular risk factors for MDR organisms that increase the probability for some of these very highly resistant pathogens? So that includes prior broad-spectrum antibiotic exposure within the past 90 days, a longer period of hospitalization and the presence of indwelling devices. Additionally, detection, if it's isolated in culture or some rapid diagnostics that might indicate the presence of these organisms early would be other indications to think about whether some of these novel antimicrobials are needed. And you'll hear more about the rapid diagnostics in the next talk. So what organisms are we concerned about in HAP and VAP? Of course, there's MRSA. And then the CDC has defined sort of a serious threat from Pseudomonas aeruginosa with difficult-to-treat resistance, beta-lactamase-producing Enterobacterialis, and carbapenemase-resistant Enterobacterialis and carbapenem-resistant Acinetobacter are in the CDC urgent threat category. And unfortunately, the frequency of isolation of these organisms is increasing worldwide. So I have an audience question for you guys. So which one of the following would be an appropriate antibiotic selection for a patient with VAP at day 10 of mechanical ventilation for ARDS with Klebsiella pneumonia growing in BAL culture? She has acute kidney injury with a creatinine clearance of 42. The MIC to ceftriaxone is over two, and the following is the susceptibility profile. So it's resistant to astreonam, sensitive to cefepime, resistant to Cipro, sensitive to gentamicin, resistant to imipenem, resistant to meropenem, and resistant to epiptazobactam. So the choices are cefepime, meropenem-vabrabactam, ceftaz-abubactam, tedazolid, ceftolazone-tazobactam, or let's see what ID says. Okay, so on the next slide, I've heard you get 15 seconds to answer. So get your response things out, and ready? Okay. Okay, so we have a good range of responses here Most the most chosen answer was actually cephapeme and then we have cephtas abibactam as number two and then B, E, and awaiting ID consultation kind of tied. So this is good. This is good to have a good range of responses And so we'll go through kind of what the correct answer is as we go through the talk So It's a my choice would have been cephtas abibactam or I wouldn't have faulted you for saying well Oh wait, what ID consults and the antibiotic stewardship team recommend? Okay, so the agents that I'm going to talk a little bit about are ones for gram positives Televansin and Tizazolid and then focus on these six gram negative agents So First let's start with staph aureus and the sort of gram positive agents What are potential indications for using some of the more going beyond vancomycin and linazolid one could be with staph aureus It has reduced susceptibility to vancomycin and so this can occur due to cell wall alterations plasmid mediated genes or MIC creep and we see that MIC can kind of increase to Vancomycin in that four to eight range has been termed visa or vancomycin intermediate susceptibility And this has been associated with worse outcomes in patients with with HAP and VAP But it's unclear if that's due to confounding in the studies because of the overall severity of illness of those patients And so one indication for thinking of alternatives to vancomycin would be if the MIC is over two Particularly if there's a poor clinical response So Tizazolid is one alternative to vancomycin and linazolid And so since it's active against gram positives was not the agent of choice in our question The vital study was a randomized non-inferiority phase 3 trial that compared tizazolid for tizazolid to linazolid for gram positive pneumonia It had 726 patients who are mechanically ventilated with HAP or VAP And they were randomized to the two treatments About 30% in both groups had MRSA and 50% had mixed gram positive and gram negative infections And so the overall result was that tizazolid was non-inferior to linazolid for 28-day all-cause mortality However, non-inferiority was not demonstrated for investigator associated clinical clear cure But there was in kind of exploratory analyses no explanation for this difference in clinical cure Televansin is another alternative. This isn't a new agent But there's some a new study looking at kind of post hoc analysis of patients who had an elevated vancomycin So I'm mentioning it here The attained study as you see was done in 2011 and compared to televansin and vancomycin It wasn't recommended sort of strongly in the guidelines that Charles has talked about Because the populations overall had a pretty small percentage of patients with MRSA VAP And also patients who had a creatinine clearance of less than 50 had a higher mortality if they were treated with televansin However, a recent post hoc analysis of this study of patients with staph aureus who had a vancomycin of over one Found that tizazolid, sorry, televansin had a non-significantly higher cure rate and survival compared to vancomycin and similar AEs So it's FDA approved for staph aureus HAP and VAP, but not for other causes and the recommendation will be to Reserve televansin for those who can't receive vanco or lenazolid and to have normal renal function So it's important to note those agents that are not recommended as first line in gram-positive HAP and VAP include daptomycin, ceftaroline, ceftibropol and tigacycline Particularly tigacycline was noted to have higher mortality in analyses of pooled studies in HAP and particularly in VAP patients and It's actually just approved for CAP not approved for HAP and VAP So, let me shift gears and talk about gram-negative Pneumonias and so here it's important to think about mechanisms of resistance in gram-negative bacteria And some of the common ones that we see in organisms that do cause HAP and VAP include loss of porins that'll generate resistance to carbapenems, beta-lactamases that I'll go into a little bit more detail on the next slide and then increased efflux pumps that can affect pseudomonas and Acinetobacter, they really generate very broad spectrum resistance to quite a number of antimicrobials So the beta-lactamases can be divided into serine and metallo beta-lactamases depending on the amino acid substitution at the active site On the left you see the serine protease beta-lactamase here With AMPC which is often inducible and so an organism may appear susceptible initially, but develop inducible resistance So if the cefepime MIC is less than 2, cefepime is an acceptable alternative Otherwise a carbapenem would be indicated and it's commonly seen in those organisms listed here the extended spectrum beta-lactamases Are also highly resistant and this here the proxy is the presence of ceftriaxone MIC greater than 2 So in our patient who had a ceftriaxone MIC greater than 2 even though it appeared sensitive to cefepime on the on the susceptibility panel Cefepime would not be recommended given this because there's likely the presence of an ESBL and so carbapenem would be recommended However in the Klebsiella pneumonia carbapenemases oxosilanases and the New Delhi metro beta-lactamases These generate carbapenem resistance And so this is an indication to consider Some of the newer antibiotics and this can be seen in a number of enterobacterialis and acinetobacter So, let me go through several of the studies now that have that have focused on these novel agents and provide you some information On the antibiotic and then the clinical trial and so ceftaz abibactam Is the third-generation cephalosporin that we know plus a beta novel beta-lactamase inhibitor It's active against some ESBL producing organisms amp C's and the KPC producing enterobacterialis But importantly it's not active against metallobeta-lactamases and it is indicated for hap and vap and the reproved study Compared patients who treated with ceftaz abibactam versus meropenem For 7 to 14 days in a hap-vap population had almost 900 patients There were 527 who were in the clinically evaluable population Pseudomonas, sorry Klebsiella was present in 37% of the patients and pseudomonas in 30% and about a third had vap This was a non-inferiority trial that found the primary outcome was clinical cure at 21 to 25 days post randomization and it was similar in both groups And so this was the agent that I chose in our patient under question Another agent to consider is ceftolazone tezabactam This is a novel fifth-generation cephalosporin With combined with a beta-lactamase inhibitor. It's active against pseudomonas aeruginosa including extensively drug-resistant pseudomonas Amp C and extended spectrum beta-lactamase producing enterbacter alice But it's not active against carbapenem producing enterbacter alice And it also has limited activity against acinetobacter and stenotrophomonas Notably it has decreased efficacy in patients with a creatinine clearance of less than 50 So if you remember our patient she had a creatinine clearance of 42 So that was why this agent wouldn't be recommended in her And it can be associated with increased transaminases, renal impairment, and diarrhea. It is approved for HAP and VAP So in the Aspect NP study they compared ceftolazone tezabactam to meropenem again for 8 to 14 days of treatment in HAP and VAP patients They had 726 patients who were block randomized by type of pneumonia and age over 65 they found Extended spectrum beta-lactamase producing enterbacter alice in about 31% of patients Pseudomonas in 20% of patients and overall this was a pretty sick population with 71% who had VAP and 92% of the patients were in the ICU They found the 28-day mortality was similar in both groups 24 and 25 percent And the test of cure was also similar at the end of treatment and similar rates of adverse events And so again, this was also a non-inferiority trial showing that ceftolazone tezabactam was non-inferior to meropenem So imipenem celastin relabactam Relabactam is another agent that has a sort of broader spectrum activity It has a novel beta-lactamase inhibitor plus our known carbapenem here It's active against extended spectrum beta-lactamases carbapenem resistant enterbacter alice and kpc producing enterbacter alice Given the imipenem component need to be concerned with seizures and it's also approved for HAP and VAP The restore IMI study compared this to pip tezabactam In a population that had about 50 percent of patients who were invasive on invasive mechanical ventilation and two-thirds in the ICU Klebsiella and pseudomonas were common organisms and it was found to be non-inferior In terms of all-cause mortality at 28 days, which was the primary outcome And overall the there was favorable clinical response at follow-up and similar adverse events And Cepdiracol this is actually a very broad spectrum agent. It's a Cytophore cephalosporin antibiotic and it has really a wide range of activity Against ESBL carbapenemase resistant enterbacter alice as well as pseudomonas and acinetobacter So there were two studies that have looked at this one in kind of a more general population of patients with HAP VAP and Nosocomial pneumonia the Apex NP study compared lenazolid plus cepdiracol or an extended infusion maripenem And they found that overall it was non-inferior with 14-day all-cause mortality similar between the two groups Credible CR was a study that looked at cepdiracol versus the best available treatment for carbapenem resistant gram negatives Carbapenem resistant gram negatives and this was a mixed population of different infections not just HAP and VAP But about half the patients did have acinetobacter And the clinical care was similar in the 59 patients who did have HAP and VAP at seven days But there were more deaths in the cepdiracol arm and most of those occurred in the patients with acinetobacter And so this is again a very broad spectrum agent that should be reserved for use in sort of these more highly resistant gram negatives And lastly maripenem vaborbactam Is a novel non-beta-lactam plus beta-lactamase inhibitor with a carbapenem that we know It's active against multi-drug resistant enterbacterialis including carbapenem resistant enterbacterialis It's notable it's approved for HAP and VAP in Europe, but not in the U.S And so that was why I didn't choose this in our patient under question Although if you're in Europe, that would have been an okay choice, too So the Tango 2 study compared maripenem Vaborbactam to best available treatment for carbapenem resistant enterbacterialis It was a relatively small study again with mixed different infections, not just HAP and VAP And they have 47 with confirmed carbapenem resistant enterbacterialis Overall, they found increased clinical cure and decreased mortality when compared with best available treatment And the treatment related adverse events and the renal related adverse events were lower for the maripenem vaborbactam group So a lot of these studies have been non-inferiority trials kind of with mixed populations And so even though they're you know as a sort of non-inferior to the standard agents It doesn't mean that we should use them and so to help decide, you know Are these really indicated? One of the sources of information that you can go to are these annually updated guidelines from IDSA That have just come out. There's version 1.0 and 2.0 that each focus on different highly resistant gram-negative infections And they provide recommendations in here that are useful and they plan to kind of update these annually And finally I just have to have a couple words on antibiotic stewardship This is a whole talk in and of itself But I think that's the other component of knowing when to select these agents And so, you know waiting for your ID consult and what the antibiotic stewardship team says I think is also the right thing to do Because we want to use the right drug at the right time with the right dose for the right bug and for the right duration And I think the things that we can do in terms of key opportunities to improve antibiotic use in nosocomial pneumonia As clinicians kind of working with these patients at the bedside include the diagnostic consideration So reviewing the findings after we start therapy to confirm has pneumonia been diagnosed or is there another etiology going on? And then in terms of considering empiric therapy Are there multi-drug MDR risk factors present that would warrant coverage of MRSA and other MDR gram-negative organisms And try and keep the novel agents in reserve and review with your antibiotic stewardship team appropriate indications And as sort of mentioned in the last talk, you know, think about definitive therapy What should the spectrum be in the duration? And so de-escalating therapy after 48 to 72 hours if you don't identify multi-drug resistant organisms target therapy to the organ organism detected And then treating generally for seven days and assessing clinical response So, I hope you learned a little bit about mechanisms of resistance and MDR organisms and nosocomial pneumonia some of the recent clinical trials and indications for some of these novel agents And so thanks very much, and I think I might have one minute for questions Mark Thanks for reviewing with regard to the inducible resistance Do you or any of the other speakers know how long it actually takes to come out? So if you had given 17 wrongly And you know and then id comes back Fixes it would that first few doses be affected or does the inducible resistance happen very quickly? My impression is it can happen fairly rapidly, um, and i'm wondering if uh, Rich or charles have other comments on that Thanks, yeah I think that's a good question. You mean failing even on some of the novel choices? um I'm, not sure. I mean potentially considering a combination You know combination therapies of some of the novel agents and using colistin and inhaled Antibiotics sort of giving as many combinations as possible as side effects allow I don't know if there's any statistics of of probability of success though Okay So Thank you, and I think our next speaker is dr wondering who we've all been referencing so far so thanks rich So All right, thank you, uh, these are my conflict of interest and I do have some particularly with bio miru who makes some of the Rapid diagnostic tests that i'm going to talk about in helix bind, which is a potential competitor So i'm going to start with a case presentation, uh 77 year old, uh previous liver transplant on immunosuppressive agents had breast cancer Type 2 diabetes stage 3 chronic kidney disease who was admitted for worsening renal function That actually was starting to improve somewhat She had no recent admissions, but four days into her hospitalization. She has fever to 104 and cough uh respiratory distress on the floor leading to non-invasive ventilation and so Was moved down to the medical intensive care unit You can see the chest x-ray at that time With a clear-cut infiltrate Her previous Chest x-rays did not show the this on on admission Uh, she got to the unit developed a fib and and that resulted in some hypotension and need for intubation Her white count was 23 000 when she got there. Her lactate was four her creatinine as I say had actually Improved with the treatment on the floor and so This is the first audience response question. What antimicrobials would you start for this episode of vap? Cephapim lenazolid trying to avoid nephrotoxic drugs ceftriaxone monotherapy peptazo and vancomycin With some renal insufficiency are you going to avoid the vancomycin and just do peptazo or Do you consider this an immunocompromised host and go with meropenem? vancomycin and voriconazole So Enter your responses here I will tell you paracentesis had been done and Or an attempt at paracentesis and there was no peritoneal fluid All right, so get a nice split almost one third one third one third With nobody choosing ceftriaxone monotherapy So this is her x-ray so the patient was admitted overnight the residents had started Antibiotics in in the morning repeat chest x-ray now shows that she has a worsening pulmonary infiltrate But cultures were no growth to date. She had a respiratory viral panel. That was positive for rhino enterovirus We'd done a non-bronchoscopic bal that showed 90 neutrophils and intracellular and extracellular microorganisms of pjp And afb were negative legionella pneumococcal Antigens were negative and galactamannan was low So are you still happy with your antibiotics despite still being hypotensive and? now a worsening infiltrate That's a rhetorical question. So I want to have you answer that but I think this case illustrates the issues of the need for rapid diagnostic testing so that you can know whether that worsening infiltrate means you guessed wrong with whatever antibiotic choice you made previously? Or is this something that's just the natural progression of this infection? And so the question is how rapid is rapid? So I'll give you a poll here. Within 24 hours before the second dose of antibiotics, within two hours, 24 to 36 hours, or four to six hours? What would you consider rapid? Something that you can make clinical decisions on that you think would help your patient. So I think the only incorrect answer here was 24 to 36. So nobody did that. Some of you are more lenient with 24 hours. I think from a practical standpoint, before the next dose of antibiotics, within two hours, four to six hours are all somewhat equivalent here. But I think that's the idea. You want to start empiric, but you want to get something right as soon as possible. And this is the data that actually shows what the standard is. This is one of the studies that's out there that looks at how long it takes to get your results back for both the identification of the pathogen in black, but then also the antibiotic susceptibility in white. And I've kind of highlighted Pseudomonas. It's hard to read there. But basically, we can kind of have a suggestion that Pseudomonas may be causing the pneumonia within 48 hours, but the antibiotic susceptibility in three quarters of your patients won't be known for at least 48 hours. And if your institution is like ours, it's flipping a coin to know which beta-lactam you're gonna be susceptible to. So I think that that makes me uncomfortable. I hope it makes all of you uncomfortable as well, that it just takes too long to rely on antibiotics. And so there's this big unmet need for rapid molecular diagnostics. Excuse me. In the U.S. right now, there are really three main available systems for this that many of you have the potential to have in your hospital. There are some more that are in development. There are clearly site-specific kinds of things and a lot of work being done in this area to come up with it. But there are limited panels. The Cepheid Gene Expert System is probably in every one of your hospitals as a test for TB. And they have kits that look at staff and they have this carbapenem-resistant panel. Both of these would be research use only for pneumonia. And then there are two approved multiplex systems that are FDA approved. One, the Curitis Univero. The other, the BioMiro BioFire system. I'm gonna, we have more experience with the BioFire system from, and I'll actually talk about a comparison, but they're generally equivalent. This is the BioFire panel. And what you see on here are many of the bugs that you wanna know. Does the patient have asinitobacter? Do they have pseudomonas, Klebsiella's? This one has a few more strep. The Univero has steno, which this one does not. And the BioFire has viruses. This is the old pre-COVID one, so it doesn't have the COVID. The current one has SARS-CoV-2. And I'll point out, they have resistance genes as well. So two critically important ones that I think make a huge practical difference. One is obviously MRSA, so you can detect both staph aureus and you can detect the MEK-A and MREJ polymorphisms. The other one that I think is critically important is the CTXM at the bottom there. That's your test for the extended spectrum beta-lactamases that you just heard about in the last lecture that would make a change in how you would treat patients. Now, we had validated this BioFire panel for suspected pneumonia just before COVID hit. And I'll point out the negative predictive value is almost 100% in our BAL samples here. And so this is extremely good at ruling out particular pathogens. As I say, this was on our BAL samples. And that brings up the next clinically relevant question, and that is, which is the most common sample you use for diagnosis of VAP? Because the benefit of these rapid diagnostic tests will depend somewhat on this. So do you use endotracheal aspirates with quantitative cultures? Non-bronchoscopic BAL with quantitative cultures, bronchoscopic BAL with quantitative cultures, a protected specimen brush, or endotracheal aspirates without quantitation, so the one plus four plus? So this is not uncommon. So there's a small percentage of people here who are doing bronchoscopic BAL, and that's typical in North America. In general, in Europe, it would, especially in certain areas of Europe, you'd see a big difference there. But it makes a difference on the advantages of your rapid diagnostic test. And this is, I think, a great study. This is a British study in anticipation of a randomized controlled trial. They evaluated the two multiplex PCR panels, the BioFire and the Curitus, compared to usual culture. And in the graphic, you see the number of results per category, and what you see is that the number of negative cultures was actually higher, or negative cultures was higher than negative rapid diagnostic tests. They roughly performed equivalent as far as the Univero and the FilmArray in the time to results was actually well within what we would call rapid. The Curitus a little bit longer, BioFire a little bit more than an hour. There's some failure rates with these rapid tests. So Curitus was a little bit higher failure rate. But I'm a little bit concerned and disturbed as somebody who really likes these rapid diagnostic tests by finding three, four, five or more pathogens with the rapid diagnostics. And that's something that I hear from other centers that use these more routinely. And I think that has to do with the sample that you use. And so most of these were endotracheal aspirates or even sputum. And only 9% had a BAL or non-bronchoscopic BAL. And I think that one of the points about all this is that it still depends on your sample. You can't use a rapid test to exclude colonization or non-colonization, including the quantitation that you get in the BioFire. So it still comes back to getting a good sample. And if you don't get a good sample, you run the same risk of detecting, colonizing bacteria with a rapid test as you do otherwise. And so it solves some things, but it doesn't solve others. Now they did a very interesting analysis in this paper. They used Bayesian latent class analysis, which is a method that's recommended and frequently adopted in studies in which the diagnostics reference standard is really acknowledged to be suboptimal. And we've known for a long time culture is not a gold standard. There's way too many false negative cultures. And they actually used this Bayesian analysis, and I have highlighted what routine microbiology sensitivity is, and it's pretty pathetic. It's really very low in many circumstances. So you have the problem of colonization causing false positives, and you have an issue with false negatives as well. And it actually, their conclusion based on this analysis is that, in fact, the PCR tests are clearly superior to routine microbiology, and they ought to be the gold standard that things are compared to. And I would suggest that's probably true. If you look at the false positives for the rapid diagnostic tests, they're actually more likely to be true positives in false negative cultures. That's especially true if you're doing a good sample like a BAL. It's a little bit less clear for endotracheal aspirates. I think you also have to realize that a negative multiplex PCR does not mean that the patient doesn't have pneumonia. So you may have an off-panel organism, and I'll show you some data on that. And these panels all have a limited spectrum, and there are things that they don't pick up. And so you won't replace culture. There are sampling errors with any sample that you get, whether it's even a tracheal aspirate, if you get deep enough to get something from deep in the lung. And then there's the whole response to antibiotics. So cultures turn negative with antibiotics. PCR turns negative with antibiotics as well. So if you're treating a patient, and you have the right antibiotic, it may make your PCR negative, just like it makes your culture negative. The real interesting thing is what happens when you have a PCR positive, culture negative? Is that cure? Is that somewhere in the process of actually improving? And there's a phase where you're culture negative, but PCR positive. And you have to remember, PCR can pick up dead organisms, and you don't have, whereas culture requires positive. And I'd emphasize again, this is still not pink by numbers. You can't just take a result and say, okay, this is pneumonia from this microorganism. You still have to look at the whole picture. We pay a lot of attention to the percent neutrophils in our BAL. And if you've got less than 50% neutrophils, you really have to question whether the patient has bacterial pneumonia, even if you have a positive PCR. And you can kind of see our data on neutrophils on the right there. So I'm gonna do the easy one, at least what I think is the easy one, Annette, how do you handle suspected MRSA? What's your clinical strategy for this? Do you treat only if it grows on culture? Do you treat high-risk patients until the culture becomes negative? Do you only treat if the nasal swab is positive for MRSA? Do you continue empiric treatment if high-risk, even if culture negative? Or treat just with gram stain? So the majority would treat high-risk patients until culture negative. I think that's probably the, this ratio looks about right for the other times that I've used this question as well. So most of us feel a little bit uncomfortable with a gram stain, still haven't necessarily bought into the nasal swab and clearly have concerns about it. I'm gonna show you what I, there are only two randomized controlled trials of the use of a rapid diagnostic test. We did one of them, and it was with the Curitus Skin and Soft Tissue PCR, which we internally validated, so it was research use only without internal validation. We did a study with patients who had suspected MRSA on, who had a BAL. The attending and fellow had to be committed to continuing anti-MRSA treatment. We have a lot of vancomycin treatments started by residents in the middle of the night when there's really no good indication for vancomycin, so we excluded all of those. We excluded any patient who had another potential source of MRSA, so skin and soft tissue infection at the same time, suspected line infection. And critically important, we made sure that the primary team was willing to stop treatment based on the results. And I think that's the key to using any of these rapid diagnostics. If you're not gonna believe the results, then don't spend your money on the test. And we had some attendings who were uncomfortable at the beginning of our study and asked us not to enroll the patients. That became less and less as we went through the study. Our primary endpoint was decreasing the days of anti-MRSA treatment. We powered it for exactly what we talked about, going from 72 hours to more like 24 hours. So beating the, waiting for culture, because we were already pretty good at stopping if the culture was negative. Secondary endpoints were safety. So if you didn't use vancomycin or linazolid now, were you using more of it later in the hospital course? And you've just allowed MRSA to proliferate. Do you have more other hospital acquired infections, more organ dysfunction? Now looking at downsides of vanco and linazolid. And then length of stay and mortality. This is the results, the top line result there is that we actually decreased the duration of initial MRSA treatment by that roughly 48 hours that we were aiming for. And that ended up being statistically significant. We did show that there was an ongoing effect, that in fact through the next 28 days, there was even less vancomycin used in the patients who had gotten randomized to a rapid PCR. No worsening of duration of mechanical ventilation, ICU length of stay, hospital length of stay, if anything all of those tended to be better with the rapid PCR group. No difference in adverse effects of renal failure and thrombocytopenia. Little bit of a decrease in nosocomial pneumonia and we actually showed a trend toward a decreased mortality and that is consistent with the literature that a diagnostic test that results in fewer antibiotics is associated with lower mortality. So we validated that. We, our faculty and fellows were comfortable with rapid diagnostic testing and basing decisions on that and then COVID hit. And as I say, we had just validated our, the multiplex PCR panel. Before that, we rapidly made an order set and had it available almost the entire time that we had COVID and continue to have COVID. And these are the results for VAP in these patients. So patients who were ventilated for more than more than 48 hours, who had COVID at a rate as the reason for intubation. We did 246 BALs, only 18 of our patients never had a BAL, so never had suspected VAP. But half of them had negative cultures. What we did demonstrate is persistence of previous pathogens. New VAPs in 72, super infections, so a new pathogen on top of the old pathogen and ends up that COVID has a huge increase in the proportion of VAP patients of 44% and 20% of those had a second and a few with a third. So, but this is a very consistent finding. About 50% of suspected VAPs actually do not have it confirmed by quantitative cultures. So lots of polymicrobial and monomicrobial. Staph aureus was our most common pathogen followed by Pseudomonas. But we saw a lot of strep in other things. We saw non-fermenters that were actually pretty crazy like not only Burkholderia and Steno but Elizabeth Kingeria. So no rapid diagnostic panel is gonna have all of those. And a lot of polymicrobial stuff. But importantly, only 6% of our cases were actually detected by PCR alone. So we still needed the culture for those off panel. But it gave us a very rapid test. And by using PCR, by narrowing the spectrum, what we found is that in the first 14 days after intubation, the pneumonias in those cases were almost always susceptible. Only about 20% were highly resistant pathogens. 49% of our initial gram negatives in the first two weeks of mechanical ventilation could be treated with Cefazolin or Ceftriaxone. So if you use narrow spectrum antibiotics, avoid antibiotics, you actually can use narrow spectrum. And we had to develop a score. And so this is a neuro-antibiotic therapy score, NAT score. We were planning a randomized controlled trial of community-acquired pneumonias. So we set Ceftriaxone azithro as a score of zero. If you used monotherapy, you got less than zero, minus numbers, positive increasing by how broad the spectrum was. And what you can see is when we had a positive culture, we still used mainly community-acquired pneumonia agents. As you got later and later in the course, it got more and more highly resistant. But negative cultures, we stopped antibiotics, narrowed. There were other non-pulmonary infections that we still had to use the antibiotics to diagnose as well. But it was a clear-cut response to therapy. And this is the answer for this case. This patient actually had a biofire that was positive for strep pyogenes and H. influenza. So despite being an immunocompromised, hospital-acquired, worsening radiographic infiltrate patient, we treated with Ceftriaxone. He was extubated within 72 hours. He actually completed his seven-day course with oral antibiotics. So you can make decisions based on these rapid diagnostic tests and patients are safe when you use them. So in summary, I think molecular diagnosis should be used to direct all anti-MRSA therapy. I think it's so good, we shouldn't be using a lot of empiric vancomycin and linazolid. The early warning of ESBLs in the introbacteriales I think is critically important. That means jumping to imirapenem rather than a cefepime or a peptazo. That would be a lot of the empiric choices. Detection of pseudomonas and acinetobacter have very important clinical antibiotic implications. For us, none of our acinetobacter is susceptible to carbapenem. So we are jumping to some of these other agents right away. Pseudomonas is a big deal and some of the resistance mechanisms are helpful there. But we still have a long way to go both with the technology and the clinical validation of benefit. Thank you very much.

nosocomial pneumonia

HAP

VAP

COVID-19

broad-spectrum antibiotics

multidrug-resistant organisms

rapid diagnostic testing

novel antimicrobials

pathogen identification

improving patient outcomes