Hello, my name is Sunesh Shah. I'm an infectious diseases pharmacist here at the University of Pittsburgh Medical Center. Today we're going to go over the novel antimicrobials, specifically a focus on novel beta-lactams for the treatment of gram-negative bacteremia in the intensive care unit. By the end of this presentation, the viewer should be able to compare the spectrums of activity of the newly approved broad-spectrum antibiotics to be able to select an appropriate empiric agent for a patient with drug-resistant gram-negative infection, and to identify common mechanisms of resistance in gram-negative bacteria. Typically, when beta-lactamases are taught, often the Ambler classification is used, and they're broken up into four categories. You may be a little bit familiar with these already, but there's a class A, class B, class C, and class D. Class A consists of ESBLs, so SHIVs and TEM variants. These are often seen in certain enterobacter alleles, commonly E. coli and Klebsiella pneumoniae. Class A carbapenemases would consist of things like KPCs, E. coli and Klebsiella pneumoniae, or again, where we often see these. They're not uncommon in the United States as far as KPCs go. They are currently considered to be endemic. Otherwise, metallo-beta-lactamases are emerging in the United States. They can be seen in Klebsiella pneumoniae, E. coli, pseudomonas as well. These would consist of things like epenemases, New Delhi metallo-beta-lactamases, things like that. Cephalosporinases, these are commonly referred to as AMPC organisms. We'll get a little bit more into those. Often, it's assumed that these organisms may harbor this enzyme and because of that, sometimes you may want to avoid certain antibiotics. For instance, ceftriaxone, having inducible resistance is something you'd want to avoid in somebody having Enterobacter aerogenes infection or Citrobacter infection. Oxacillinases, they are commonly found in non-lactose fermenters in the United States, so things like pseudomonas and Acinetobacter. We'll get into which agents are going to be active against these as we progress throughout this presentation. As you can see here, there's different beta-lactamases that will be targeted by different antimicrobials for the novel agents. I'll refer back to this slide as we progress. You'll see it many times to become comfortable and very familiar with it, but I think it would serve as a nice reference. The green is going to represent susceptibility that's anticipated to be over 90 percent. The yellow is going to present intermediate susceptibility between 30 and 90 percent, and red is going to represent intrinsic resistance or no antibiotic susceptibility. They're listed as follows for KPCs, metallobeta-lactamases, for OXA48-like enzymes, carbapenem-resistant pseudomonas, which can have various mechanisms of resistance, but it's usually due to OPRD and carbapenem-resistant Acinetobacter as listed. Like I said, we'll go through this as we progress. It's also important to recognize that it might depend on which country you might practice in, in terms of the local epidemiology for the different carbapenemases. Like I said earlier, the KPC carbapenemases are endemic in the United States, but in certain parts of Southern Asia, such as India, it might be more common that you'd see metallobeta-lactamases. For Europe, it's very variable depending on which country you're in in terms of which mechanisms of carbapenem resistance that you might be dealing with. The article on the left is a report published in the Journal of Antimicrobial Chemotherapy from Greece regarding an outbreak of Klebnumo-producing carbapenemase. When this was treated with Ceftaz-AV, it actually selected out for VIM-producing isolates, which is a metallobeta-lactamase. This may be due to the selective pressure, since Ceftazidime AV-Bactam harbors no activity against metallobeta-lactamases, and it was selected out for. Interestingly, on the right is an article specifically for United States hospitals where it's been shown that the epidemiology of carbapenemases for KPC-producing organisms has been shown to decline versus metallobeta-lactamases have been shown to incline. At present, currently, KPCs are the most common form of carbapenemase-producing enzymes that result in resistance. But in the near future, we might see that metallos might overtake that based on this report. The antimicrobial pipeline is delivering. In 2014, Ceftolazate-Tazobactam had come to market, followed by Ceftaz-AV in 2015, Marovapor in 2017, which is predominantly used for its KPC activities. We'll see Imipenum ribactam in 2019, which has KPC activity, but it's also a very useful agent for pseudomonas, and in 2020, Cephideracol, and more recently, Solbactam duralobactam, which is more of an acinetobacter drug, and we'll talk about all these. But to start things off, we'll start with Ceftolazate-Tazobactam since it's first on our list. As you can see, based on its spectrum, it is intrinsically resistant to many of these carbapenemase-producing organisms, but it's a very useful drug for carbapenem-resistant pseudomonas. So Ceftolazate-Tazobactam, like I said, is considered a first-line agent. There's many reasons why that is. It can overcome multiple resistance mechanisms in pseudomonas that would otherwise render things like cefepime, peptazo, ceftaz, and meropenem-resistant. Meropenem-resistance is usually through OPRD. Ceftaz, for instance, and peptazo are usually through hyperproduction of AMPC enzymes, and Ceftolazate-Tazobactam is gonna be able to overcome all of these mechanisms. Additionally, we have clinical data, which makes it a very attractive agent of our novel agents. It's the earliest one for drug-resistant pseudomonas, and various studies have been listed. It's hard to quantify what the resistance rate actually is following treatment with this agent. This is because there's different infection types, dosing, definitions of resistance that really vary across studies. So the two studies I'd like to share on efficacy for Ceftolazate-Tazobactam, the first one's a real-world study that compares polymyxin and aminoglycoside-based regimens to the agent Ceftoltazo, and they look at toxicity as well as in-hospital mortality. What they find is that the agents, the aminoglycoside and the polymyxin group had more toxicity, and there was a trend towards increased in-hospital mortality relative to the Ceftolazate-Tazobactam group. This was a real-world study again, but on the right-hand side is a randomized trial that compares Ceftolazate-Tazobactam to meropenem for the treatment of nosocomial pneumonia. Overall, there was no difference in the endpoint of mortality, and again, when stratified by subgroups for ESBL-producing pathogens, for ESBL-producing enterobacterioles, or pseudomonas aeruginosa, there's no difference really seen from a statistical standpoint between groups. So, not only does this show us that Ceftolazate-Tazobactam is a reasonable treatment option for MDR pseudomonas, but it also shows us that it might have some clinical utility for ESBL-producing pathogens. So, a couple points to keep in mind from a dosing standpoint. So, Aspect NP, which is the randomized trial we just talked about, they used a dosing regimen of three grams every eight hours. The drug has shown to have better pulmonary concentrations for those with nosocomial pneumonia in prior studies, which is why that regimen was used. Historically, others had been using 1.5 grams Q8, but again, you may want to be a little bit more aggressive with dosing in most infections, but particularly pneumonia. Our team here at Presby had also had cases of endovascular infections where we pushed the dose as well to three grams Q8. In addition, we've also had instances where we've used it in post-hemodialysis dosing. So, somewhat similar to things like Cefazolin or Ceftazidime where you could do post-administration dosing on dialysis days only, but that should only be considered for maybe less severe infections, I think. So, with this information, it's important to go back to the guidelines to see where Ceftolazantazobactam falls in the IDSA recommendations. So, Ceftolazantazobactam, Ceftaz-AV, and Imipenumrelabactam as monotherapy are largely considered the treatment of choice for drug-resistant pseudomonas or DTR pseudomonas, which they refer to as difficult to treat. But all that being said, it is important to take into consideration that although guidelines may consider Ceftolazantazobactam and Ceftazidime-AVbactam equivalent, it's important to be very aware of some of the literature that goes into it. Ceftolazantazobactam overcomes, again, multiple mechanisms of resistance in pseudomonas versus Ceftazidime-AVbactam only really overcomes one. So, we actually took a look at this at our center. So, this is a cohort of adult patients who were treated for over 48 hours with Ceftazidime-AVbactam or Ceftolazantazobactam for the treatment of drug-resistant pseudomonas. These were patients who either had bacteremia or pulmonary infections in order to try to keep the cohort a little bit more homogenous. And what we found was that after testing by broth microdilution for follow-up cultures, and again, this was a real-world study, there was more resistance that was seen in follow-up with Ceftazidime-AVbactam relative to Ceftolazantazobactam. So, very important to keep in mind, again, this might be attributed to Ceftaz-AV really only being able to overcome mutations in AMPC versus Ceftolazantazobactam can overcome many different mechanisms of resistance. So, let's talk a little bit about Ceftazidime-AVbactam. It is a broad-spectrum agent. It's less targeted than Ceftolazantazobactam. It does have activity against carbapenem-resistant pseudomonas. It also has some OXA48-like activity. This might be more so due to the Ceftazidime, though, than the AVbactam. And it's also active against KPC-producing pathogens. So, again, going back to the IDSA guidelines, it is considered to be a potential agent for the treatment of drug-resistant pseudomonas. It is active through AMPC hydrolysis, but, again, this is really the only mechanism where the AVbactam is adding enhanced activity to the Ceftazidime. And, again, it's also very active against KPC-producing activity, so class A beta-lactamases. So, Ceftazidime-AVbactam has been studied against meropenem in nosocomial, including ventilator-associated pneumonia, and reproved. So this was a study performed across 23 different countries. Patients were assigned to receive Ceftaz-AV or meropenem. It was mostly in Terebacterialis patients, as you can see, but some patients with pseudomonas were also included. I thought it was interesting in this study that, although it didn't reach statistical significance, there was also a lower response rate or a trend towards a lower response rate with the Ceftaz-AV relative to the meropenem, so something to keep in mind, but, overall, this was shown to be non-inferior. So in terms of our real-world data, Ceftaz-AV has been studied for carbapenem-resistant in Terebacterialis. This first study is in CID on the left-hand side that shows a clinical success rate around 55% and a survival rate around 81%, so somewhat interpreted to be a little bit better than some of our previous agents that might have been a little bit more toxic. Otherwise, a larger series published in AAC in 2018 looked at risk factors for failure with Ceftaz-AV, maybe Bactam, and the clinical response rates are shown where it looked like pneumonia had some of the worst rates for success. This was also seen in regression models where pneumonia and receipt of renal replacement therapy were risk factors for clinical failure, and this could be because of the poor ELF concentrations seen with Ceftaz-AV, maybe Bactam, so something worth keeping in mind. Meropenem-Vapor Bactam is an agent that is highly active against Klebsiella-producing carbapenemases, so very similar in its spectrum to Ceftaz-AV in that regards. However, unlike Ceftaz-AV, it's a little bit more targeted for what it is. It has no activity against metallobatelactamases or OXO48-like activity. Vapor Bactam offers nothing for pseudomonas compared to meropenem alone, and same thing with Acinetobacter. The Vapor Bactam is not active towards anything outside of the meropenem itself. So its role is really just to inhibit KPC-producing organisms, so again, very similar to Ceftaz-AV where it also has KPC activity, but it doesn't restore carbapenem activity outside of that. So these are the results from the TANGO-2 randomized trial. It's 77 patients with CRE infections who were randomized to receive either meropenem, Vapor Bactam, or best available therapy. Within this study, there was one patient in the best available therapy group who got Ceftazidime AV Bactam, but otherwise, these are more so historical agents, so things like aminoglycosides, tigacycline, and polymyxins. And as you might expect, treatment-related adverse effects and renal adverse effects were 24% and 4% respectively for the meropenem Vapor Bactam group versus the adverse effects were higher in the best available therapy group at 44% and 24% respectively. But otherwise, the efficacy was shown to be similar for the meropenem Vapor Bactam. So given we have both Ceftazidime AV Bactam and meropenem Vapor Bactam that are active towards KPC, one question that may come up is which one should we use, right? And there's not a lot of data to answer that question, but one piece of evidence that I'd like to bring forward, it's a study in AAC by Renee Ackley and colleagues. And what they found was that in this multicenter retrospective study of patients with CRE infections who got Ceftazidime AV or meropenem Vapor Bactam, there was a trend towards more increased resistance with Ceftazidime AV Bactam compared to meropenem Vapor Bactam as shown by increases in MICs as well as emergence of resistance. But unfortunately, given the sample size, these numbers were not enough to show statistical significance. It's also worth noting that those in the Ceftazidime AV Bactam arm did receive combination therapy more than those in the meropenem Vapor arm. The clinical significance, however, that I don't think is fully elucidated. But remember that Ceftaz AV may not be the best in terms of achieving adequate ELF concentration. So at least for pulmonary infections, I would certainly favor merovapor. And in terms of limiting treatment emergent resistance, I think merovapor might have its advantages there as well. So I think many would regard it as the drug of choice for KPC infections. That being said, the IDSA doesn't list a very clear preference here in terms of agent for Ceftaz AV, merovapor, and emiral for CRE. And it's kind of not a clear cut recommendation since this is in the setting where carbapenemase testing results are not generally available. But otherwise, the next agent we'll talk about that has KPC activity is imipenem relabactam. So this agent, in addition, also has activity against carbapenem-resistant pseudomonas that we'll talk about on the subsequent slide. So relabactam is a unique beta-lactamase inhibitor where for pseudomonas, it makes it less prone to efflux. And this is important because OPRD loss or efflux pump mediated resistance is largely what confers carbapenem resistance in pseudomonas, which is why these are paired together. In addition, it also restores Ambler class A and C enzymes. So again, it's going to have KPC activity. If you have AMPC pseudomonas, which is also known as PDC, they are the same thing. It's also going to restore that activity as well. So those are the two mechanisms for pseudomonas. Porin or efflux loss, as well as AMPC-derived cephalosporinase. So for imipenem relabactam, there's two studies worth noting. The first one on the left is Restore-ME1, which it really only included 31 patients, but, and pseudomonas was identified in even fewer of those patients. But that being said, it was a study comparing imipenem non-susceptible pathogens who got imipenem relabactam or colistin plus imipenem and favorable outcomes were observed comparatively between groups at around 70%. Similarly, Restore-IMI2 was not specifically of patients with carbapenem resistance infections, but 264 patients who received imipenem relabactam versus 267 received paparisil and tasobactam for pulmonary infections. And the primary endpoint of 28-day mortality was not statistically different between groups. So in terms of pseudomonas, we have two real-world studies. I think the data is a little bit less limited for its utility in KPC infections. But for pseudomonas, again, two real-world studies, I have them both depicted on the slide. On the left is a cohort of 21 patients who received imipenem relabactam, but only 16 of them actually got it for the treatment of pseudomonas. And of note, one of these 16 patients had developed a pseudomonas infection that was non-susceptible to imipenem relabactam. So that might give you a little bit of an idea of the incidence of the development of resistance to this drug. Although again, the numbers are small. On the right-hand side, depicts the evolution of resistance of imipenem relabactam following treatments in five out of 19 patients who were exposed to the agent. Whole genome sequencing was performed and it was actually found to be due to eflux pump mutations that were collaborating with each other. So I wanted to bring up a patient case scenario if it helps you think about these agents a little bit better in real-world practice. So you have a 51-year-old patient with a history of a COPD and MDR pseudomonas colonization who comes in with respiratory failure and requires mechanical ventilation. Of note, you look back in his history and you see that last month he was managed with two weeks of ceftolazantazobactam for possible pneumonia. So there's now concern for possible pseudomonas aeruginosa that is resistant to ceftolazantazobactam. There is concern for pneumonia. So the team asked for input from the critical care pharmacists. So as you think about this case, I would like to bring one study to your attention. It's highlighted in the reference section at the bottom of the slide. But basically what was done here was that for treatment of multidrug-resistant pseudomonas, patients were managed with ceftolazantazobactam and then follow-up isolates were later characterized. And what we can see is that ceftolazantazobactam seemed to not only confer resistance to potentially other agents, but also ceftazidime AV-bactam, the MIC had gone from four to a dilution of 64. So very important to keep in mind. However, imipenumerella bactam seemed largely unaffected. So this might be a scenario where you would think about using imipenumerella bactam since ceftazidime AV-bactam may also confer pseudomonas resistance in somebody who was exposed to ceftolazantazobactam. And that makes sense, right? Because the mechanism of resistance for ceftolazantazobactam is thought to be due to over mutations in AMPC, which again can also confer to ceftazidime AV resistance. But imipenumerella bactam is more equipped to overcome that. The next agent is cefitericol. So this agent has broad-spectrum activity towards KPCs, metallobetalactamases, although, you know, when you look, usually the MICs run a little bit close to the break point. It's also active against OXF48-like organisms, carbapenem-resistant pseudomonas, and controversial, but we'll talk about its role in Acinetobacter infections as well. And its mechanism is thought to be through iron transport mediators in the cell wall through penicillin-binding proteins. So it's thought to be very similar to the Trojan horse, where these iron transport mediators will uptake cefitericol into the bacteria itself. And like I said, it is broad-spectrum in terms of its activity, activity against KPCs, various metallos, including imipenemase, VIMS, NDMs, L1s, which are primarily found in stenotrophomonas, as well as oxacillinase carbapenemases. So based on the break points for this, different organizations will recommend different break points for this antibiotic. So for pseudomonas, Acinetobacter, and Enterobacter aleis, it differs by CLSI, FDA, or UCAST. The UCAST break points are going to be a little bit more strict generally. For pseudomonas, it's less than 2, versus for CLSI, it's 4. So difference between the United States and European guidelines. For Acinetobacter, there are actually no break points by UCAST. We'll talk about why that is. It's one of the findings in the clinical trials, which is credible. Actually found some failure with Acinetobacter, so we'll talk a little bit more about that on the subsequent slides. Enterobacter aleis, the MIC is around 4 for CLSI for the break points. And these are usually where the MICs fall, which is around 4 in metallobetalactamases. So keep that in mind that you might see some discordance because of that with UCAST, where you might see something called susceptible by CLSI, but non-susceptible by UCAST because of the difference in the break point when you're dealing with the metallobetalactamase. Otherwise, resistance can occur through iron transport mutations based on the mechanism, which are as listed. Metallobetalactamases, although the risk factor there is travel outside the United States. Same thing with PER mutations. SHIV and AMPSY, there's a few cases of AMPSY overexposure through cefepime mediating resistance. Cefedericol, there's two randomized trials worth discussing. The first one is the APEX-NP trial, which is a randomized study comparing cefedericol to meropenem. These are in patients of nosocomial gram-negative pneumonia. The MICRO is as listed. So Klebnumo was the most common organism, not necessarily drug-resistant. C. dimonis and Acinetobacter, as well as E. coli. All-cause mortality at day 14 was 12.4% with cefedericol and 11.6% with meropenem. And again, this is more of a clinical trial-based study. Something that was a little bit more real world is on the right-hand side, the CREDIBLE-CR study. And like I said on the previous slide, this is where the controversy for its use in Acinetobacter might come into play a little bit. So for patients over 18 years, they could have a hodgepodge of infections. It could be nosocomial pneumonia, bacteremia, or even UTIs that they included. Patients got cefedericol versus best-available therapy, which largely consisted of colistin-based regimens. Mortality was 36% in the cefedericol group and 29% in the best-available therapy group. And overall, they found a non-inferiority here. But at the same time, bear in mind that 50% of patients infected with Acinetobacter experienced mortality, which was compared to 18% in the best-available therapy group. So do keep this in mind. Again, it was compared to colistin-based regimens. So there's more to come on this discussion. And on the contrary, there was a real-world study conducted at Italy between January 2020 and 2021. This is published in the AAC by Falcone and colleagues. But what they did was they looked at carbapenem-resistant Acinetobacter baumannii, and specifically bloodstream infections, as well as ventilator-associated pneumonias, just to make things a little bit more heterogeneous, and compared cefedericol-containing regimens to colistin-containing regimens. These were often in combination. But what they found was that there was a lower mortality rate with the cefedericol-containing regimens when compared to the colistin-based regimens. This was seen for bloodstream infections. And again, there was a trend seen for ventilator-associated pneumonia as well. So this is in contrast to what was noted in the randomized trial known as CREDIBLE. In terms of metallobatal actamases, again, remember, cefedericol is active towards them. But the MICs do run closer towards the breakpoint. That being said, there is some guidance from the IDSA that does recommend using it as a preferred treatment option for areas where metallobatal actamases are common. The other one of note here is ceftaz-AV plus astreinam. And we'll talk about that one on the subsequent slides. So the big thing to note with the combination of astreinam, and it's currently in combination with ceftazidine-AV-bactam, although think about the combination as astreinam with AV-bactam. The reason being is astreinam is what's active against our metallobatal actamases. However, organisms that harbor metallobatal actamases can also often be co-harboring other carbapenemase or betalactamase-producing enzymes, whether these be KPCs or AMPCs or ESBLs. So that's the thought process towards where the AV-bactam is going to come into play here. Yes, astreinam is going to be what inhibits metallobatal actamases, but the AV-bactam is going to be what inhibits KPCs and other betalactamases. And again, we talked about this article a little bit already, but bear in mind metallobatal actamases are on the rise in the United States. And we need to keep them in mind for patients presenting with critical illness. So again, the astreinam is what's active against metallobatal actamases, but it's going to co-harbor other enzymes, whether these be ESBLs, KPCs, or AMPCs. On the right-hand side is kind of a real-world example. It's a phenotype that you might see. So your hints here are that if you're suspecting a metallobatal actamase, the ceftaz-AV and the merovabr are going to be drug-resistant, since these are intrinsically resistant to metallobatal actamases. However, other agents, such as astreinam, may be active or intermediate, but they should harbor, they'll often harbor some activity. Sometimes, however, you might see that the co-harboring enzyme, whether it be the AMPC, or KPC, or ESBL, may inhibit these, and they might be resistant. But if you see something where astreinam has some activity, but ceftaz-AV, merovabr are both inactive, especially in a patient with travel history, although maybe not so much anymore in the United States, that should cue you in towards thinking about a metallobatal actamase. So like I said, the regimens to think about for metallobatal actamases are cefeterocol versus astreinam with ceftazidime, maybe Bactam, per the IDSA guidelines. Like I said, however, the MICs are a little bit elevated with cefeterocol for metallobatal actamases. The data is a little bit more limited there, too. There were some isolates incredible for metallobatal actamases. But generally speaking, I really like to think about the astreinam ceftaz-AV for those infections, the reason being is, again, the MICs run much lower with that regimen. And we also have reasonable clinical data. Here's one that I wanted to share. It's a prospective observational study of patients admitted to three hospitals in Italy and Greece. And patients, again, had bacteremia due to a metallobatal actamase-producing organism. They were treated with either ceftaz-AV plus astreinam or other active agents. Sometimes within these countries, or oftentimes they were susceptible to things like Cipro or TMP sulfa, which usually isn't the case here. In terms of the type of metallobatal actamase, 82 were due to NDMs and 20 due to VIMS. But overall, we can see that there was a survival advantage towards using ceftaz-AV plus astreinam with this regimen. And again, this was patients with bacteremia, so very clear-cut, very homogenous in terms of infection. So just a hypothetical, what if you had a patient with a ceftazidime allergy? In other words, I think what I'd like to think about here is, could you use other agents? Could you not use astreinam-AV-bactem? So the other betalactamase inhibitors that are active, so relabactem is also quite active. A little bit less so than astreinam-AV-bactem, but imiral with astreinam was 72.5% susceptible. So very worth thinking about. If you had somebody with a ceftazidime allergy as well, the astreinam is still reasonable to give. I know historically, it's been thought about that there is some cross-reactivity, but there's a case series out there where patients who had tolerated ceftazidime would also tolerate astreinam without evidence of cross-reactivity. So a quick note on stenosrophomonas. These harbor an intrinsic metallobetalactamase known as L1. So with that, astreinam is not hydrolyzed by L1, and AV-bactem is going to inhibit L2. So astreinam-AV-bactem might be a reasonable option when stenotrophomonas is not susceptible to first-line agents such as trimethoprim, sulfamethoxazole, or fluoroquinolones, or even like tetracyclines. You might want to start thinking about astreinam-AV should you come across that less common scenario. Sefideracol is also active against steno, so also worth thinking about. But bear in mind the clinical data for this sort of thing is not there at the moment, just because most often TMP sulfa is going to be regarded as a drug of choice. Finally, I wanted to mention sulbactam-derlabactam. The niche for this is with its activity against carbapenem-resistant acinetobacter. Remember, for acinetobacter when administering something like ampicillin-sulbactam, it's the sulbactam that really harbors all the activity towards acinetobacter baumannii. And so when given with derlabactam, the mechanism of action here is binding to both PPP1 and PPP3. But the derlabactam is going to neutralize the beta-lactamases that might otherwise hydrolyze the sulbactam, so they work together. And derlabactam in and of itself is designed to inhibit class A, C, and D beta-lactamases, so ADC-type beta-lactamases, which would be class C. Those are AMPC-producing beta-lactamases that are found specifically in acinetobacter. And oxacillinases are typically what confer carbapenem resistance in our acinetobacter, and derlabactam is designed to help overcome that as well. So sulbactam, derlabactam was studied in the randomized trial known as ATTAC. These were patients with nosocomial pneumonia or bacteremia secondary to carbapenem-resistant acinetobacter. These patients were randomized to receive sulbactam, derlabactam, or colistin. Both arms in the background got imipenem, cytostatin is adjuvant therapy here. And this was a non-inferiority trial, and sulbactam, derlabactam was found to be non-inferior. Overall, though, these rates seem to favor the novel agents when compared to colistin with imipenem, cytostatin. So with all this, some questions still remain to be unanswered. Others have thoughts. Since the way it was studied, does imipenem need to be given with sulbactam, derlabactam? I'm not so sure that that's the case, but I do think it's reasonable to give combination therapy for drug-resistant acinetobacter. So we talked about a lot of this already, but just as a summary, I wanted to kind of go over what could be considered for first line here. And again, this might differ from the IDSA guidelines, but for KPCs, I would think about merovabir as our first-line agent. For metallos, I would think about astreonam, avbactam as our first-line agent. For carbapenem-resistant pseudomonas, think about ceftoltazo. And carbapenem-resistant acinetobacter, think about sulbactam, derlabactam. So a few take-home points here. Novel beta-lactams are very useful as a therapeutic option for previously untreatable infections. Understanding where they fall in therapy for each one is going to be key for managing patients with these very difficult-to-treat infections. So knowing the mechanism of resistance, evolving epidemiology is going to be key for optimizing treatments. And more studies are certainly needed for each of these. They're all relatively new as far as our timeline for having antibiotics at all goes. All right, so thank you so much for listening. If you have any questions, my email is on the slide. Thanks so much.

Sunesh Shah

antimicrobials

beta-lactams

gram-negative bacteremia

carbapenemases

resistance mechanisms

novel agents