Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 146 I'm your co host, Dr. Kane. Dr. Khyati Patel 00:35 I'm Dr. Patel, and today, with us coming back is Dr. Christy Bertram, to discuss our new and exciting topic. Speaker 1 00:44 Thank you for having me. I'm really excited to be here and talk about one of my favorite topics, gram negative resistance and the newer antibiotics we can use to treat these infections. Wonderful. Dr. Sean Kane 00:53 So the title of today's episode is new drugs for bad bugs, six newer antibiotics for multi drug resistant pathogens. Dr. Bertram, we've obviously asked you to come on today because you are an expert in infectious diseases, and welcome back to the podcast. You know, today we're talking about six newer drugs that any inpatient clinician is likely to see in the next several years, if not sooner, to treat some of these newer, multi drug resistant, gram negative pathogens. Dr. Khyati Patel 01:21 I think we owe it to our audience to kind of give a background on what are these multi drug resistance. We call it the MDR bugs are in back in 2013 CDC had published its very first antibiotic resistant Threat Report that highlighted the urgency in the issue of antibiotic resistant with the bacteria. And at that time, the report had said about 2.8 million antibiotic resistant infections happen in the US, and a lot of people died. 35,000 people per year die from these type of infection. That's That's mind boggling in the world of science that we live in today. Speaker 1 01:59 It really is. And in 2019 the CDC updated this Threat Report, and again, they categorize bacteria into three major threats based on the level of harm to humans. So urgent threats, serious threats and concerning threats. And in today's episode, we'll talk about some of these therapies that we can use for these infections. Dr. Sean Kane 02:20 So Dr. Bertram, can you just give us a nomenclature some of these threats that we are likely to talk about today that are part of that 2019, CDC report? Sure. Speaker 1 02:30 So our two urgent threats that we'll discuss are carbapenem resistant Acinetobacter as well as carbapenem-resistant Enterobacterales (CRE) and you may hear the term Enterobacteriaceae used, but this is actually an outdated term; the modern name is Enterobacterales, incorporating a larger group of these organisms. And then the two serious threats we'll discuss are ESBL, or extended spectrum, beta lactamase producing Enterobacterales as well as multi drug resistant Pseudomonas aeruginosa. Dr. Sean Kane 03:09 Dr. Bertram, obviously, one step in terms of addressing this threat of multi drug resistant pathogens is to be better stewards and kind of prevent them before they even happen. And granted, we're not talking about stewardship globally today, but can you just give Can you just give us a sense of some key points in terms of big stewardship opportunities to help prevent these infections? Speaker 1 03:29 Definitely so in terms of antimicrobial stewardship, or ensuring that antibiotics are being used appropriately, including for the correct diagnosis, using the correct drug, correct dose, proper duration and route of administration, we have some different strategies that we can use, including de escalation of our antibiotics when we can so utilizing a narrower spectrum agent, and also ensuring that we utilize antibiotics for the shortest duration possible, while still maintaining efficacy of killing off the bacteria that we're treating. We can also reduce antibiotic prescribing in general, so we know that antibiotics do not treat viruses, so ensuring that we educate our practitioners on making that diagnosis and not prescribing antibiotics when they are thinking that it is a viral infection. And then we can also reduce antibiotic use in agricultural settings, especially in animals and farming. Dr. Sean Kane 04:19 And then, of course, when we have new bad, multi drug resistant pathogens, it's always nice to have drugs that can treat those things, right? So, you know, the focus of today's episode is some of these newer drugs, and newer is kind of in quotation marks. We're going back to 2014 but in the spectrum of ID land, that's actually a fairly new antibiotic, right? Dr. Bertram, yep. Speaker 1 04:40 So we are, unlike many other fields in that we do not get a lot of new drugs approved as quickly as some of the other specialties. So we are very excited anytime a new antibiotic comes to market. Dr. Khyati Patel 04:53 And that's also exciting to see that there has been about what six new ones since 2014 until 2019 That we could use in the inpatient settings for these multi drug resistant, gram negative pathogens. Speaker 1 05:06 Definitely and hopefully, that trend continues. Dr. Sean Kane 05:09 And for the listener, you know, this episode, in part, was developed from a very good review article about some of these and other newer antibiotics, and by Yousef and colleagues, it's referenced on our website at HelixTalk.com again. This is episode 146 so if you want to know more or want to see it in writing, you're welcome to check out that Yusuf article that we'll have referenced on our website. Dr. Khyati Patel 05:30 So now, when we talk about bacteria and the resistance, you know there are multiple different mechanisms of how bacteria develop resistant to antibiotics. The most common one we see for gram negative bacteria is beta lactamase enzyme. It's an enzyme that chemically changes the beta lactam antibiotics, such as our common penicillin, cephalosporin and carbapenems, and kind of renders these antibiotics into something that has no antibiotic effect, like renders them inert. And so there's tons of different type of beta lactamases out there. So the spectrum of activity is very wide. Can you shed some light on this? Speaker 1 06:13 Dr. Bertram, yeah. So, as you mentioned, there are tons of beta lactamases out there that all tend to do a little bit different of the activity and what beta lactams they degrade. But most of the new antibiotics that we'll talk about today are focused on activity that they have for bacteria that produce a very special class of beta lactamases called carbapenemases. And these are concerning because they are enzymes that degrade carbapenem antibiotics. And as a reminder, carbapenems are some of our broadest spectrum beta lactams that we have out there for the treatment of gram negative infection. So this is a very concerning enzyme and something that we're grateful to have some of these newer agents to treat. Dr. Sean Kane 06:55 And just for clarity, you know those carbapenemase producing bacteria, we kind of already mentioned some of these. So carbapenem-resistant Enterobacterales (CRE) that was one of those urgent threats from the CDC. And you know this is going to include things like E coli, Citrobacter, enter back to Klebsiella, serratia Proteus. So it does not include pseudomonas, does not include Acinetobacter, but many of our kind of typical gram negatives are included in that category. We can also see carbapenem resistant Acinetobacter, again, that was one of our CDC urgent threats, and then also multi drug resistant Pseudomonas aeruginosa. This is one of those CDC serious threats that can be carbapenemase producing organism as well. So there are a multitude of gram negatives, and we kind of classify these into cre or carbapenem resistant Acinetobacter or multi drug resistant Pseudomonas. So this is a big deal, as you mentioned, Dr. Bertram, because we do like to have those carbapenems to be able to target some of these gram negatives. And if those don't work, then what else do we have? Speaker 1 07:54 Right exactly? So luckily, we have some of the newer agents that we'll move into. But first, I think we need to start by describing how we classify these beta lactamase enzymes. So one of the most common classification systems that we use is called the Ambler classification system. So there are really four classes within the Ambler system. We label them a through d, and so we'll start with class A. So Class A includes kind of our normal beta lactamases that we think of that commonly confer resistance to antibiotics that we frequently use, such as penicillin, ampicillin. And these are pretty common, so we relatively don't think of them as as big of a deal as some of our other beta lactamases in this class and other classes. So we have different abbreviations, such as tem or tem and SHV or Shiv that we use to describe these beta lactamases. Now Dr Dr. Sean Kane 08:47 Bertram, it's my understanding that even though we have class A, B, C and D, within these classes, we have different kinds of beta lactamases that are very different. So within class A, do we have something different beside the TEM and Shiv type of beta lactamase Speaker 1 09:02 we do so the other subtypes of beta lactamases in class A, including tem and shiv, are what's known as KPC and CTX M. So KPC stands for Klebsiella pneumoniae, carbapenemase, and CT XM is the most common gene that encodes our common ESBL or extended spectrum beta lactamase enzymes, and both of these are very concerning, as they produce multi drug resistance. So KPC enzymes typically degrade our carbapenem antibiotics and our ESBLs, or extended spectrum beta lactamases, they confer resistance to a lot of our beta lactams, including penicillins and cephalosporins. So carbapenems are really the drug of choice for systemic infections of ESBL producing organisms. So I Dr. Sean Kane 09:48 just want to highlight that a little bit. You know, within class A we have kind of a very normal like, at least half of E coli produces a beta lactamase against ampicillin, for example. That's kind of run of the mill. Very normal, very expected. But then also within class A we have these very nasty, fatal activases Like kpcs and ESBLs that are completely different and are treated with completely different antibiotics. Speaker 1 10:12 That is correct. And we'll get into a couple of the antibiotics that we can use for some of the more concerning infections, such as kpcs, to really effectively treat them. Unknown Speaker 10:23 What about Class B? Then? So Speaker 1 10:26 Class B is what's known as our Metallo beta lactamases. And they get their name Metallo because they actually use a zinc in the active site of the enzyme to catalyze this beta lactam hydrolysis. Whereas other beta lactamases Use serine, which is an amino acid in the active site. And there's a variety of different subtypes of Class B, Metallo beta lactamases that exist. One of the common ones is NDM. One stands for New Delhi Metallo beta lactamase one that's commonly found in India and Southeast Asia. We also have Vim and imp, which are some other concerning Metallo beta lactamasas. Dr. Sean Kane 11:04 So then, in terms of class C, what do we have for Class C? And how is that different? Speaker 1 11:09 So Class C is pretty easy to memorize, because the enzyme subtype in class C is called amp c, and this primarily breaks down our cephalosporins, especially our third generation cephalosporins like ceftriaxone or Ceftazidime. And the reason why Class C or amp C is concerning is because amp c beta lactamase production can actually be inducible, which means that bacteria can turn on and off the expression of the beta lactamase enzyme, usually due to the presence of other specific antibiotics that cause the induction of the enzyme expression, and this makes it really tricky to detect on a traditional susceptibility report, because initially, when we get the susceptibility back from the microbiology lab, it may look like our third generation cephalosporins, like ceftriaxone, are susceptible, but as soon as that enzyme is induced, it can quickly flip to resistant, making it a more challenging infection to treat, and unlike the other beta lactamase enzymes, amp C, unfortunately, doesn't have a reliable genotypic molecular test to detect it in the microbiology lab, so we need to be aware of the organisms most likely to harbor amp C when we're selecting an Antibiotic for treatment, Enterobacter cloacae, Klebsiella, or formerly Enterobacter orogenes and Citrobacter frondii are the top three organisms that are considered moderate to high risk for clinically significant amp C production. Dr. Sean Kane 12:31 So Dr. Bertram in terms of Class D, this one kind of put me through a loop, because in class d1, of the main subtypes is oxacillinase. And when I think about oxacillin. I think about Staph aureus between like MSA and MRSA. So can you tell us a little bit more about Class D and what's going on with this oxalinase naming convention for this class D? Speaker 1 12:52 So it got its name due to the hydrolysis of oxicillin, which is an anti staphylococcal penicillin, but similar to Qpc OXA or OXA enzymes typically cause the resistance to carbapenem antibiotics, and these are most commonly seen with species such as Acinetobacter. Dr. Khyati Patel 13:12 Dr. Bartram, you know, talking about all these mechanisms of resistance, and you know its classification, I just have a newfound respect for the bacteria. They're so smart that they're kind of foregoing our technology and basically the mechanisms that we are using to tackle some of these infections that are old. When we are talking about the six new antibiotics, four of the new antibiotics are not quite new. You know, they're in combinations. And one of the examples that we have used in, you know, even outpatient settings is, you know, think about Plano amoxicillin, and you add clabulone to it, and it becomes amoxicillin, clabuelonate and becomes augmentin. So that clabulanet actually is your beta lactamase inhibitor that binds to and occupies the beta lactamases that's produced by the bacteria, and that prevents the enzyme from finding the actual antibiotic, which is the beta lactam, which is the amoxicillin here. And some of these new therapies are using that similar approach. The manufacturers have, you know, selected new type of beta lactamase inhibitors there are combined with some of these broad spectrum beta lactams there already were on the market. So as we say, new, but they're really just combination with the beta lactamate inhibitors. Speaker 1 14:32 Definitely need new beta lactamase inhibitors, since some of the older ones don't work as well against these multi drug resistant strains of the beta lactamase enzymes. So for example, tazobactam, which is the beta lactamase inhibitor found in piperacillin. Tazobactam or zosin, it doesn't work for most of the carbapenemase enzymes. So interestingly, beta lactamase inhibitors, in addition to kind of protecting that beta lactam antibiotic, also reduce the mic. The beta lactam, even if the beta lactam isn't degraded by the bacteria itself. So an example of this is that when you add the beta lactamase inhibitor Avi bactam, to the beta lactam Ceftazidime, it can reduce the mic to an E coli that was already susceptible to Ceftazidime by an additional two to 128 fold, which is very cool, Dr. Sean Kane 15:21 before we jump into our drugs. Here to kind of summarize where we're at, we see lots of new multi drug resistant pathogens out there. Many of them are using beta lactamases to degrade the antibiotics that we have on the market. And our focus today is mostly on those carbapenemase, beta lactamases, where they're breaking down carbapenems. And most of these new therapies are using new or even existing antibiotics in different combinations, especially with these newer beta lactamase inhibitors to try to combat some of these concerning multi drug resistant patterns that we're seeing in the hospital in the community setting. Well, Dr. Richard, why don't we start with antibiotic number one, cefttolazan and tazobactam. The brand name is zerbaxa. This is the oldest of the new ones. So this was FDA approved in 2014 Can you just tell us a little bit about that combination and what it's FDA approved, for sure. Speaker 1 16:12 So the beta lactam is ceftolozane, which is a novel beta lactam cephalosporin antibiotic that we haven't seen before. Unlike some of the other beta lactam beta lactamase inhibitors we'll discuss, ceftolozane was never FDA approved on its own, but it does have intrinsic activity against some of the more resistant gram negative bacteria, like Pseudomonas aeruginosa, tazobactam, on the other hand, is one that we are all familiar with. So this is the same beta lactamase inhibitor that's in piperacill and tazobactam or zosin, but on its own, taso backdam does not have activity for carbapenemase producing bacteria. Dr. Sean Kane 16:51 So Dr. Bertram, in terms of that ceftolozane, is there a cephalosporin drug class or generation that is sometimes assigned here, or is it kind of on its own, because it's never been approved as monotherapy. Speaker 1 17:03 Good question. We tend to think of ceftilizing kind of within its own generation, within the cephalosporin class. Speaker 2 17:09 Okay, and then what is this FDA approved for? So it's Speaker 1 17:13 currently FDA approved for the treatment of complicated intra abdominal infections in combination with metronidazole. So cephtoliz and taso bactam actually does not have any anaerobic activity on its own. So for the treatment of infection, such as an intra abdominal infection, where you worry about anaerobic bacteria, we do need to combine it with metronidazole or Flagyl here, and this is really because the cefttolazan doesn't cover the most common anaerobic bacteria that we see bacteroides species sufficiently enough, even with the taso bactam added. So that is one pearl there is that when you're using ceftolozane/tazobactam For something like an intra abdominal infection, always combine it with metronidazole, and then the other two indications include complicated urinary tract infections as well as hap or VAP. So hospital acquired pneumonia and ventilator associated pneumonia. And the pearl here is that when we're using ceftolozane/tazobactam For hap or VAP, the recommended dose is a little bit higher than the other indication, so it'll be three grams IV every eight hours, as compared to 1.5 grams IV every eight hours for your complicated UTI or complicated intra abdominal infection. Dr. Sean Kane 18:25 Dr. Bertram, I think it's worth just double emphasizing the fact that you do need Flagyl in combination with zerbaxa. Intuitively, when we think about how we learn infectious diseases, we think about pattern recognition and patterns of how different drugs cover different bacteria. And for me, at face value, when I look at ceftil as a and taso back Tam, I'm thinking, well, that taso back tam provides that anaerobic coverage, and in fact, like you said, it doesn't provide enough, and you do need that Flagyl. Addition to it, this is an easy area for a pharmacist intervention to identify when that Flagyl is potentially needed, even though, intuitively you feel like you might not need it definitely. So we have a new fancy drug therapy here. When are we pulling this one out with Dr. Bertram? So I Speaker 1 19:09 would say the main role of ceftolozane/tazobactam is going to be for your multi drug resistant Pseudomonas aeruginosa infections. So that, by definition, multi drug resistant Pseudomonas is defined as any Pseudomonas isolate that has non susceptibility to at least one antibiotic in at least three different classes of antibiotics for which Pseudomonas is generally susceptible to. So this can include your penicillins, your cephalosporins, carbapenems, fluoroquinolones and aminoglycosides. So if you have resistance within three drugs within those classes, you should be thinking about using ceftolozane/tazobactam. Some other coverage that it has is that it does cover our ESBL producers. It was originally thought to have some amp C coverage, but the clinical outcomes data are really lacking for this indicator. Patient and taso backdam just isn't as effective versus emptia, some of our other newer beta lactamase inhibitors that we'll talk about. So really, we think of this drug as more potent for our multi drug resistant Pseudomonas. It also will cover ESBL producers, but it really doesn't cover other organisms that produce carbapenemases, such as our KPC-producing Enterobacterales. Dr. Khyati Patel 20:24 So the next one, Dr. Bertram, I have to say, one of the drug in this one is my favorite. It's a combination of ceftazidime/avibactam (Avycaz). It was FDA approved back in 2015 and I remember learning, obviously, I don't practice, you know, Id an outpatient basis, but ceftazidime as a third-generation cephalosporin. And remember learning this had the cool Pseudomonas coverage. And so this was an old one proved in 1985 very similar to ceftazidime, but not as good of a strep coverage as cefepime. Here. Can you tell us about the Avi bactam? However, that one is a new beta lactamase inhibitor, sure. Speaker 1 21:07 So Avi bactam actually does have activity for most of the carbapenemase enzymes, with the exception of Class B, which is our Metallo beta lactamases. Unlike other beta lactamase inhibitors, it also does not provide anaerobic coverage so similar to what we were discussing with septolazan tazobactam, if you're going to be using Ceftazidime Avi bactam for one of its FDA approved indications, complicated intra abdominal infections, you will need to use it in combination with metronidazole for that anaerobic coverage. The other indications that ceftazidime/avibactam is currently approved for include complicated urinary tract infections as well as hap and VAP, similar to ceftolozane/tazobactam. So out of all the drugs we'll discuss today, I think ceftazidime/avibactam is probably the one that all of our listeners are most likely to see used in current clinical practice, and this is because it really covers a lot of our multi drug resistant gram negatives, really, with the exception of Acinetobacter, I would say its main role is in the treatment of cre infection. So our carbapenem-resistant Enterobacterales. But it does include coverage for Ambler Class A, so yes, BL as well as KPC, it also includes coverage for Class C, which is our AMP C, and it also includes coverage for Class D, which is our OXA enzymes. Dr. Sean Kane 22:30 Dr. Bertram, I'd say, of the antibiotics that we're talking about today. This is one of the ones that I have seen in my practice. And we actually don't have a lot of multi drug resistant gram negatives in my practice site, because it's a community hospital setting. But I have seen this one compared to some of the other ones. So I do think that this is the one to at least keep on your radar a little bit more, because I do think that we're going to see a little bit more of it as we move forward. And it is on the older side of our newer antibiotic spec. In 2015 is when Avycaz was FDA approved. Dr. Khyati Patel 22:58 So fast forward to 2017 FDA approved another combination. This combination was with our older broad spectrum carbapenem, name meropenem, and they added a new beta lactamase inhibitor, vaborbactam, to it. Brand name is Vabomere. So like I said, meropenem, we know it's a broad spectrum carbapenem. It's an older drug you we usually use it in inpatient settings for MDR, gram negative infections and then new pearls about vero back to Dr. Bertram. Speaker 1 23:32 The vaborbactam is a newer beta lactamase inhibitor that we haven't seen before, but it does have activity for some of our carbapenemase enzymes, with the exception of Class B and Class D. So it really only covers classes a and c here in terms of its FDA indications, currently approved for complicated urinary tract infection. But an interesting Pearl is that it does add a bit more coverage to meropenem, primarily for our KPC producing organisms. So again, Class A but it is important to note that it does not provide any better coverage for Pseudomonas or Acinetobacter. And this is a point that I think a lot of even our clinical pharmacists don't realize, is that if you have a Pseudomonas aeruginosa isolate that's resistant to meropenem, the addition of vaborbactam will not restore the activity of that meropenem for a meropenem resistant pseudomonas, but probably the best role is going to be for the KPC producers, especially those that are resistant to Avycaz. Dr. Sean Kane 24:31 Dr. Bertram. I'm just going to point out, you know, we're on drug number three here, and we've yet to have a drug that will cover those Ambler Class B, the Metallo beta lactamases. But the pattern that we're seeing is that there is this one category of, you know, carbapenemases, in this class B, those Metallo beta lactamases. We don't have a ton of drug therapies for those, right? Speaker 1 24:52 That is correct. They're by far one of the most difficult classes to treat. We'll talk about a drug in a little bit here that does have. Some intrinsic or in vitro coverage, but in general, class B is the most difficult to treat. Dr. Sean Kane 25:05 Well, why don't we move on to our number four new antibiotics? So this is imipenem with cilastatin, which is something we already have on the market, brand name of Primaxin, that was way approved way back in 1985 and then they added relobactam to that, and the brand name of that is recarbrio, and that was FDA approved in 2019 so if we just talk about imipenem/cilastatin for just a second, at face value, almost looks like that would be a beta lactam beta lactamase inhibitor. But in fact, the cilastatin is doing something different. Dr. Bertram, can you inform us about that cilastatin component that is always with imipenem. And then what is new with this relebactam beta lactamase inhibitor. Speaker 1 25:46 So as you mentioned, imipenem is always co-formulated with cilastatin, and that is because imipenem, on its own, is readily metabolized by an enzyme in the kidney known as dehydropeptidase, which results in very low urine levels of the drug, so an inhibitor of the enzyme, which is cilastatin, is always combined with the imipenem, so that the drug can really make it into the urine and be effective in the treatment of urinary tract infections. Relobactam is the beta lactamase inhibitor that's combined with imipenem/cilastatin, and this is another novel beta lactamase inhibitor that we haven't seen before, but we can think of it as very similar in structure and activity compared to Avi backdam. So the beta lactamase inhibitor that we talked about with ceftazidime/avibactam, avibactam, it has very similar coverage. Dr. Sean Kane 26:35 And then what is this FDA approved for? In your view, what is the role of recarbrio in treating these multi drug resistant pathogens Speaker 1 26:43 so similar to our other beta lactam beta lactamase inhibitor agents that we talked about today, the FDA indications are the same, so hap and VAP complicated urinary tract infections and then complicated intra abdominal infections. Of note, imipenem does have anaerobic coverage, so you don't need to add that metronidazole on here if you're treating an intra abdominal infection. I would say its niche in therapy is a little bit less clear than that of ceftazidime/avibactam, meropenem/vaborbactam, and ceftolozane/tazobactam, but it does have coverage for Class A so our ESBL KPC producers as well as Class C. So our AMP C producers, I would say that it may be useful for bacterial isolates such as Enterobacterales or Pseudomonas that are resistant to some of our other newer agents that we talked about. It does have high rates of in vitro susceptibility for Pseudomonas. But since this drug is relatively new compared to the other ones. We just don't have as much clinical data yet. Dr. Sean Kane 27:45 So Dr. Bertram, the fifth agent we're talking about today is also approved in 2019 the generic name is cefiderocol. The brand name is Fetroja. And this is a totally different concept than what we've talked about with the first four agents. So can you tell us a little bit about the pharmacology of Fetroja, and what makes it different than everything we've already talked about so far? Speaker 1 28:07 Sure, I think this has one of the coolest mechanism of action out there. So essentially, bacteria need iron to survive and for continued growth, and bacteria produce this moiety, called a siderophor, to really uptake the iron into their cells. So what cefiderocol is, it's a novel cephalosporin antibiotic that actually mimics a siderophor based on its catechol moiety that it has in its structure. So essentially, our cefiderocol antibiotic will bind to iron, and then it tricks the bacteria into thinking that it's just a normal siderophor, and the bacteria will uptake it via passive diffusion, and then that is how the antibiotic actually enters the bacterial cell to do its job and kill the bacteria. So the marketing team versus done a really great job on their website of linking this antibiotic to a similar mechanism as a Trojan horse, where it was tricking the bacteria into taking it up and then doing its job to kill it off. Dr. Sean Kane 29:13 And I just want to highlight you can see the word Trojan in the brand name of the Troja. And also, if you literally go to the website, it says like a Trojan horse. So they are pulling no stops. They're making it very clear of what they are trying to mimic in terms of their marketing scheme here. Dr. Khyati Patel 29:30 And very clever, Fe is iron, and Trojan means Trojan. So it's an iron Trojan. Dr. Sean Kane 29:36 Love it. So, Dr. Bertram, what is this FDA approved for? Speaker 1 29:40 So, cefiderocol is FDA approved currently for the treatment of complicated urinary tract infections as well as hap and VAP. Interestingly, it does have activity for all of the Ambler classes that we discussed. So Class A, including our ESBL and KPC producers, class B, are Metallo beta lactamases, which we haven't seen. A drug yet that has activity against Class B, and it does have activity for Class C and Class D as well. It covers some of our more difficult to treat, non fermenting bacteria, such as Acinetobacter Pseudomonas and stenotrophomonas, but unlike some of the others we discussed today, it does not have any activity for any type of gram positive bacteria or anaerobes. Dr. Sean Kane 30:22 And I actually think that's probably worth highlighting, because again, when I am thinking about pattern recognition with infectious diseases, if I knew that this was a cephalosporin, which it is, intuitively, I would kind of assume that it does have some gram positive coverage, at least strep coverage, and we don't see that with this agent. So again, it would be very easy to make a false assumption that you have gram positive coverage with this, this drug. So it sounds like Dr. Bertram, this is awesome. We have a cool mechanism. We've got all of these FDA approvals. We're covering all of the Ambler classes. We're even covering Acinetobacter and stenotrophomonas, bugs that are really hard to cover. For what's not to love about photosia. Speaker 1 31:02 So unfortunately, this drug has an FDA warning for higher mortality, specifically in carbapenem resistant, gram negative bacterial infections. And this is really related to the randomized trial, the credible CR study that was published a couple years ago. So this study included patients with nosocomial pneumonia, bacteremia, sepsis and complicated urinary tract infections. Of note, about half of these patients did have infections with Acinetobacter bacteria. And in the study, cephidoricol was compared to best available therapy, which usually contained colistin among some other medications, and clinical cure rates were generally similar between the cefitor Recall arm and the best available therapy arm, but unfortunately, 28 day mortality was higher 25% in the cefitor Recall arm versus 18% in best available therapy. And although this was not statistically significant, it was numerically a pretty large separation. Hence, the FDA did put this label on here. Dr. Sean Kane 32:05 So Dr. Bertram, the difference between 25% versus 18% mortality sounds like that would be worrisome. Are there any kind of caveats to that FDA warning and interpreting the data from that credible CR study? Speaker 1 32:19 So in this study, it seemed like the mortality was higher and some of our non fermenting bacterial infections, so specifically, pseudomonas, Acinetobacter and stenotrophomonas. But I really think in general, we just need more data in this area before we can make a definitive conclusion. Dr. Sean Kane 32:39 So in terms of nichin therapy, I'm gonna guess, as we've kind of alluded to, this is great for those Ambler Class B Metallo beta lactamases, because all of the other antibiotics we talked about did not cover those. What else can we use this for in terms of our multi drug resistant gram negatives? Speaker 1 32:55 So it does have activity, as I said, for all four Ambler classifications, which is great, I think the concerning mortality rate in the credible CR study is something that we have to take into consideration when we're using the this agent. In my practice, we have been using cefitor call as more of a first line agent for very serious carbapenem resistant Acinetobacter infections, despite that mortality warning, as this is an infection that we don't really have many effective antibiotics for. But the disclaimer there is that we always use it as part of a combination regimen, so we are very hesitant to use it as mono therapy. Dr. Sean Kane 33:33 And then when you say combination therapy, does that mean colistin, or is there something else that you're combining this with, Speaker 1 33:40 usually high dose ampicillin, cell back down plus or minus meropenem plus or minus Polymyxin B. So usually we're using at least three agents, if not four, for some of our really resistant Acinetobacter infections, and are very critically ill patients. Dr. Khyati Patel 33:57 And last but not the least, new drug we are talking about is eravacycline. Xerava is a brand name, and it was FDA approved in 2018 and the phrase cyclin tells you Yes, it is a tetracycline class, and it behaves very similar to tigecycline or Tygacil. Yeah. Speaker 1 34:16 So this agent is currently FDA approved for the treatment of complicated intra abdominal infections. And in terms of its spectrum, it's something you would expect from an agent that covers intra abdominal infections, so covers most gram positives, gram negatives, as well as anaerobic bacteria, including strep, staph and Enterococcus species. And in terms of the Ambler classifications, it also covers all four classes, including ESBL, amp C, and it does cover Acinetobacter, but the key bacteria that it's actually missing is Pseudomonas. So our avacycline, unfortunately does not have any Pseudomonas coverage. Dr. Khyati Patel 34:57 And as the name suggested earlier, too, I think most of the. New antibiotics we discussed had some sort of that beta lactam, you know, component to it. Just know that this one is constantly different. This is a tetracycline class. Dr. Sean Kane 35:12 So Dr. Bertram, in terms of contrasting this versus tigecycline, what are some big differences that you would highlight for clinicians that are more familiar with tigacyclin. What does eravacycline bring to the table, or what's different about it? Speaker 1 35:25 Think, in general, in some of the studies, eravacycline seem to be a little bit more well tolerated than tigacyclin in terms of especially the nausea and vomiting, and then additionally, the C Diff rates that we've been seeing with eravacycline have been a lot lower, and that may be because it does have some intrinsic activity against the C Diff bacteria on its own. So maybe a better option for some patients that have difficulty tolerating tigacyclin, Dr. Sean Kane 35:51 perfect Well, you know, we've covered six different drugs, all new or new ish, why don't we go through each one of them and kind of highlight one of the most important things that clinicians should know when they see these antibiotics in their future practice. So I'll go ahead and start with ceptolozan tazobactam. The brand name was zerbaxa. This is mostly for our multi drug resistant Pseudomonas. It does not cover carbapenemase producing organisms, even though it has the tasobactam component. And as we mentioned, if you're going to use this, despite that tazobactam, you still need to add metronidazole for those complicated intra abdominal infections, for that anaerobic coverage. Speaker 1 36:28 Yeah, the next one is ceftazidime/avibactam (Avycaz). This is probably the one that our listeners will see used more frequently in clinical practice, but it's primarily used to cover our CRE or carbapenem-resistant Enterobacterales infections, but it also has activity for many other gram negatives, including Pseudomonas. But with the exception of Acinetobacter, Dr. Khyati Patel 36:51 our third agent is meropenem combined with vaborbactam. Vabomere has similar activity to Avycaz but may provide some coverage for certain KPCs (Klebsiella pneumoniae carbapenemase), and just know that if your patient has meropenem‑resistant Pseudomonas, adding vaborbactam does not restore its activity against Pseudomonas, so it's not meant to be used for any infection with meropenem‑resistant Pseudomonas. Dr. Sean Kane 37:23 Then our fourth agent was imipenem/cilastatin combined with relebactam. The brand name was Recarbrio, and this is fairly similar to Avycaz and Vabomere in terms of its coverage. It's a newer agent. Probably we don't have a clear niche in therapy just yet, but maybe in the next couple years, we'll have a better sense of when this agent is more likely to be used. Speaker 1 37:44 Our fifth agent is celetroja, and this uses a unique mechanism of action to enter the gram negative bacteria by using the iron. And it has a broad spectrum of activity against carbapenemase producing bacteria, as well as many other multi drug resistant gram negatives as it covers all of our Ambler classes. But of note, it does not have any gram positive or anaerobic activity. Dr. Khyati Patel 38:09 And last but not the least, eravacycline. Xerava is a tigecycline-like tetracycline, which has a broad spectrum activity against carbapenemase, producing gram negative, gram positive and anaerobic bacteria, but just remember, it does not have any coverage for Pseudomonas. Dr. Sean Kane 38:27 So that kind of wraps up. Our hand selected six new drugs for bad bugs. Dr. Bertram, thank you so much for your time. Again, we do have some show notes, if anyone wants to either read that Yousef, review article about some other newer antibiotics in the market that we didn't cover, and also the CDC antibiotic resistance Threat Report from 2019 both of those are cited on our website, HelixTalk.com we love the five star reviews in iTunes, so keep those coming. If you have topics that you want us to cover, you can find us on Twitter at HelixTalk or even email us in our contact infos on our website. So, Dr. Bertram, again, thank you so much for your time. I really appreciate it. Thank you so much for having me. So with that, I'm Dr. Kane. Dr. Khyati Patel 39:08 I'm Dr. Patel. Thank you again. Dr. Bertram, and into our student audience. Study hard. 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