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. Narrator - ? 00:11 This podcast is 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. Welcome to Dr. Sean Kane 00:31 HelixTalk. Episode 126 Dr. Khyati Patel 00:34 I'm your co host, Dr. Kane. I'm Dr. Patel, and today with us, we have a guest contributor, Doctor Morgan Anderson. Dr. Anderson actually is an alumna of RFU College of Pharmacy from the very first inaugural class in 2015 so great to have you here, doctor Anderson. Speaker 1 00:54 Hi to you both. Thanks for having me on today, and for Dr. Sean Kane 00:58 the listeners, just to give a little background of why we have Dr. Anderson today. The title of today's episode is Alex. I'll take enterococcal resistance patterns and treatments for $1,000 kind of an ode to the late Alex Trebek, and we're talking about enterococcal infections today. So what better person to have on the podcast than someone who is an expert in all things infectious diseases? Dr. Anderson, just to kind of orient the audience to your background. So you did a PGY one at Abbott Northwestern hospital all the way up in chilly Minneapolis, Minnesota, PGY two at Northwestern Memorial Hospital in Chicago, Illinois. And now you are currently practicing as an Infectious Diseases Clinical Pharmacy specialist at Advocate Aurora health, focusing on two community hospitals in the Chicagoland area. Dr. Anderson, welcome and thank you so much for your expertise today. Thank you. So like many other HelixTalk episodes, we're going to kind of set the stage a little bit with a patient case. So Dr. Patel, maybe you can kick off our patient case and kind of put it into context of why we're talking about enterococcal infections today, Dr. Khyati Patel 02:02 I am very happy to So hypothetically, we have the 66 year old male patient who came to the hospital with obviously, covid, 19 infection. He's complaining of some difficulty peeing, and a catheter was placed on hospital day one. Fast forward, we are on day six, and he's developing some fevers. We see a spike in leukocytes and some confusion. There is a blurred line between possible worsening of the covid, but urine analysis was completed and the reflex culture sensitivity is done to just kind of do a complete workup. So we're waiting on those results. It's not clear that the symptoms have anything to do with the urinary tract infection, and it seems like it's catheter‑associated UTI. Since he was placed on catheter on the hospital day one, we found the organism growing was Enterococcus faecium, and he's not currently on any other antibiotics or has no drug allergies. So I guess now the question on hand is, what is the most appropriate antibiotic to use? We have sensitivity results pending. Dr. Sean Kane 03:10 And Dr. Anderson, I think you would agree that this kind of scenario of covid patient comes to the hospital, gets worse. The number one question that really very few people know the answer for is, is it the covid getting worse, or is there something else going on? And we have the advantage here of having a positive urine culture and new symptoms, we have to treat this, right? But it is all too common that we have these patients that we aren't really sure. Is it worsening covid? Is it worsening bacterial pneumonia? So this is a very common clinical situation, yes. Speaker 1 03:43 So this is definitely a great case to start with, and it's not an uncommon problem in today's hospital environment. I would definitely agree with that. So there's always going to be some gray area, but I agree. I think establishing what antibiotic is most appropriate would be our first place to start. Dr. Khyati Patel 04:02 So I think it's a good thing to start out with providing some background to the audience about the bug itself. We want to talk about the drug, but let's start with talking about the bug. And so what? What is really the species on hand, Enterococcus. It's a gram positive cocci. Actually, originally it was part of the streptococcus genus, but now it's kind of redefined under the Enterococcus genus. And so we're looking at couple different species that are most common, e faecium and e facalis. We'll talk about the differences between these two in just a little bit. Dr. Sean Kane 04:35 So Dr. Anderson, in terms of how common these bugs are, are patient cases actually a very common scenario, right in terms of where we see these bugs infecting patients? Exactly? Speaker 1 04:46 Enterococcus species are the most common cause of nosocomial or hospital acquired CLABSIs, and what a CLABSI is is its central line‑associated bloodstream infection. And they're the second most common cause. Cause of hospital associated infections overall in the United States. So this is definitely not an uncommon issue to encounter in the hospital. And these are second to staphylococcus is the most common cause of hospital acquired infections. So another gram positive that I know you all have discussed before on the podcast, Dr. Sean Kane 05:16 and let's just full stop there for a second. So Enterococcus, I think, doesn't get the credit that perhaps it deserves. We've spent so much time talking about staph, pseudomonas, E coli, as you said, second most common hospital acquired infection and most common nosocomial central line, associated bloodstream infection. This is a really big deal in the nosocomial area, and I think that Enterococcus doesn't get enough street credit for the job it's doing right now, so hence why we're doing an episode on it right? Speaker 1 05:47 It's a unique organism. It's known for its ability to cause a lot of resistance, both acquired and intrinsic resistance can occur with this, and it's good at evading the immune system, so that's how it can stick around in our hospital environments, It tolerates inhospitable environments that maybe other bacteria can't, and it also forms biofilms, so it's pretty sticky, and it likes to hang out and wait, Dr. Sean Kane 06:12 and clearly that's why we're seeing things like central line infections, catheter associated UTIs. It's sticky, like many other bacteria are sticky as well, but that's one of the reasons that we see this type of infection with this particular bug. Dr. Khyati Patel 06:26 Yes, exactly. And really, where does it come from, right? That's a big question. And it is actually natural part of our GI tract, so it's a it's a normal flora. The entero really means, you know, your gut, intestine, so that's where it really comes from. But because it's proximity to genital urinary tract, we get to see a lot of those UTI type of infection, especially in the older, older patients. And as as the the ground has laid out, you know, this is kind of like the most common, second most common infection in the hospital settings. And so we're kind of looking at things such as status post abdominal surgeries, or patients who've got the drains and the catheters and the tubes in the GI tract. Dr. Sean Kane 07:11 Now I think one thing that is really interesting about Enterococcus, so it causes plenty of infections, but unlike Pseudomonas and staph, and perhaps why it doesn't get the street credit that it deserves is that it's fairly rare for patients to have fulminant, incredibly sick disease when they're infected. More common. This is like a sub acute type presentation where a patient feels malaise and just doesn't feel well for a while, as opposed to coming in with fulminant septic shock caused by enterococcal bacteremia, which is interesting that for whatever reason, this particular pathogen doesn't make you as sick as quickly as some of these other pathogens, right? Speaker 1 07:48 And then something to consider is that when a patient does get that fulminant or invasive disease, those cases are actually associated with some of the highest mortality rates of all bacterial pathogens. So for example, if you do get an Enterococcus bloodstream infection, mortality can be seen up to 40% in some studies. So it's a weakly virulent bug, but once it becomes an invasive or fulminant disease, it's definitely something that we have to take very seriously. Dr. Khyati Patel 08:17 So some of the non virulent type of infections with Enterococcus probably seen more commonly on the community side, as we establish as UTI by far. That's the most common one that a pharmacist like I would see on an outpatient setting. But then the GI tract infection, biliary tract infection and trabdominal infections are also common. Dr. Anderson, what kind of like? Primarily nasocomial infections that Enterococcus would cause from your experience, Speaker 1 08:47 great question. So in the hospital environment, we may see this organism occur in wound infections, mostly if it's a poly microbial infection. So it may not be the main player for that infection and that wound, we also see bacteremia, as we mentioned, that can get quite severe, and that's usually a complication of maybe another infection. Maybe it started in the urine and then became bacteremia, or it's a result of central lines or medical devices, as we talked about. And then endocarditis is something that comes to mind. So this is the second most common cause of healthcare associated endocarditis, and in general, if you find Enterococcus in a sterile site, so that would be like blood or bone or somewhere where we wouldn't expect to find normal flora, we need to take it seriously and not consider it a contaminant. Dr. Sean Kane 09:37 And you know, we won't get too much into specific treatment pathways for specific infections, but I think it's worthy of note intra abdominal infections, right? So everyone has Enterococcus in their GI tract. Again, entero means intestine. So many of our empiric regimens for intra abdominal infections, like a ruptured appendix or perforated colon, something like that, many of our regimens actually. Don't cover empirically for Enterococcus, which is interesting because it's all over your GI tract. Maybe Dr. Anderson, you could just briefly comment on what are typical regimens, and why do we not empirically cover very commonly for that community acquired intra abdominal infection type patient, right? Speaker 1 10:17 So that's a great point. So those first line regimens can frequently include cephalosporins, which I know we'll talk about later. Some of the antibiotics that caught that have resistance with Enterococcus include cephalosporins, and so ceftriaxone and Flagyl would be a commonly used antibiotic regimen for an intra abdominal infection, especially when presenting from the community, and that does not provide enterococcal coverage. And one of the reasons for for those regimens being included is that weaker virulence associated with this organism, and the chance that it could just be colonization when it is found. So those intra abdominal infections, when we do get cultures, there's often quite a few things growing, and Enterococcus could certainly be, you know, a member of the party, but maybe not the the most virulent or the one causing this severe disease that's occurring. Dr. Sean Kane 11:08 So it's almost as if we're, we're expecting the body's innate immune system to kind of mop up after we kind of help clear out some of the bacterial burden of the other pathogens. And as you said, for the most part, this is something that the body should be able to deal with on its own. Its own, assuming you have good source control and stuff like that, right? Speaker 1 11:26 And it's something to keep in mind if a patient doesn't improve on a normal and pure regimen that we would use, it's something to think about that maybe Enterococcus is causing more issues than we initially gave it credit for, and maybe we need to switch to something else. Dr. Khyati Patel 11:40 And so we kind of discussed that there's just two more common species of Enterococcus, the Enterococcus faecium and Enterococcus faecalis. And Dr. Kane, you kind of said that this bug doesn't get enough credit for its evasive resistant pattern. So I'm assuming that these are a little bit different when it comes to their resistant patterns. Dr. Sean Kane 12:02 So if I had to pick one of my two favorite species of Enterococcus, and if you can only pick one, which is very difficult to do, but if you had to pick one, mine's going to be e fascium, because this is the big bad boy of the Enterococcus world, right? So like getting punched in the face, that's how I remember that fascium is the bad one. So it's much more likely to have cool antibiotic resistance patterns versus its brother, which is E faecalis. So Dr. Anderson, what are some of the typical patterns that we see when comparing efatium, the bad guy, versus e facalis, the one that is the nicer of the two brothers? Speaker 1 12:38 I love that great way of remembering it. I'll have to use that in the future with students. So I would say E. faecalis is less likely to be resistant. So like you're suggesting not the not the scary brother. I know we'll talk a little bit more about antibiotics in a bit, but to I guess, put it in context for you, 80% of efatium is vancomycin resistant, or what we call vre, vancomycin resistant, Enterococcus, the vast majority of these are also ampicillin resistant. However, with E. faecalis, only 10% are vre, and the vast majority is sensitive to ampicillin. So figuring out which one you're dealing with definitely has implications on your initial antibiotic plan and Dr. Sean Kane 13:23 Dr. Anderson. When we did our Staph aureus episode, we talked about MRSA and MSSA, and how historically MSSA was the thing that was around, and then over time, MRSA, this more resistant bug, kind of came about. So do we see a similar pattern here, where the bad one, the more resistant one, used to be more rare, and now it's becoming more common. Or is it a different story here? Speaker 1 13:49 Yes, I think over time we'll we'll see changes in both directions. But historically, e facalis, or the friendlier one of the two, was much more common, and then E FAS sort of grown in popularity, and is now about 50% of hospital associated infections would be the E fascium species. Dr. Sean Kane 14:09 So basically, it got no respect for a long period of time, and now it's demanding street credit for its cool antibiotic resistance patterns. It's increasing incidence in the nosocomial environment, and it's trying to compete, out compete its brother of, of E. faecalis, in terms of more common, more virulent, better antibiotic resistance patterns. So this is going to be a bug that we're going to be talking about for a long time. Dr. Khyati Patel 14:33 So talking from bugs, I think it's time we move on to the drugs of of this bug. And so thinking how this actually was categorized in the, you know, streptococcus genus. When we think about streptococcal infections, we think about beta lactam antibiotics. And so Dr. Kane, what beta lactams are going to be effective against our Enterococcus we kind of already said, we're kind of pitching that. Emphasize. In, you know, for the resistant pattern. So I'm kind of going to hear that drug of choice is ampicillin. Is that right? Totally. Dr. Sean Kane 15:06 So historically, ampicillin was the drug of choice could be used alone or combination for with other drugs for more serious infections within that category. You know, penicillin has cross sensitivity, so if it's susceptible to ampicillin, penicillin should also work. Same is true with amoxicillin if you're looking for an oral option, or even piperacillin, which is a component of Zosyn, which everybody uses Zosyn all the time in every context that they can so those are things that we can use. But remember, e facalis Generally, is ampicillin sensitive. We said 10% of the time it's resistant, so most of the time it's sensitive, but E. faecium getting punched in the face the vast majority of the time, ampicillin and its similar. Beta lactam antibiotics are not going to work. It's going to be ampicillin resistance, and that is going to be a problem. So we have to have other options. Yeah. Speaker 1 15:55 And that comes from the fact that the penicillin binding proteins, or pBPs of Enterococcus are unique. So many other beta lactams have poor binding affinity and thus poor activity. So we we have this great group of antibiotics that we can use in the beta lactam class. However, that doesn't mean that all the beta lactams are going to be helpful in these scenarios. There is intrinsic resistance to basically all cephalosporins, which I alluded to earlier when we talked about the intra abdominal presentation, and I think that's a really big deal, and that's something that is frequently missed, and we want to make sure that we're paying attention to it when we select our regimens, or if we have a patient with a UTI that was started on ceftriaxone, as commonly occurs, we want To be paying attention if they grow Enterococcus. Dr. Sean Kane 16:42 So Dr. Anderson, I just want to pause here, and I want to reiterate this another time, because it is probably the most important point of this episode. So what you're saying is that in someone that has enterococcal infection, and the common scenario is a UTI, when someone starts a cephalosporin like ceftriaxone, that ceftriaxone won't work against that Enterococcus, because basically all cephalosporins don't work against Enterococcus, right? Speaker 1 17:08 Exactly. So it's something we need to be looking at when we do get those cultures back on these UTI patients. Dr. Sean Kane 17:14 And what's probably even more messed up, Dr. Anderson, maybe you can expand on this a little bit. You're not going to see ceftriaxone on your culture and sensitivity report when that urine culture comes back, right? So it just won't be there. It's not going to say resistant. It just won't be present on that report, right, right? Speaker 1 17:30 So that's the example of it's intrinsically resistant. So the laboratory has no expectation that it could work, so they're not even going to test it or include it on the report. So it's just something you have to know. Dr. Sean Kane 17:40 And I think that's such a big like, gotcha right in medicine, of it would be great if on the report, it said, By the way, these definitely won't work, and we're not even going to test them, but you almost have to know that as a clinician. And perhaps some institutions do provide some context to that. But if they don't, it's kind of a you got to know it kind of thing, right? Right, exactly. Dr. Khyati Patel 18:01 And the other intrinsically resistant antibiotic that you're not going to see on the culture and sensitivity will be a couple of penicillins like oxicillin or naphthalene. These are primarily our anti cephalococcal penicillin. So again, don't use them. Know that inherently. Yeah. And then Dr. Sean Kane 18:20 Dr. Anderson, what about our carbapenems? So carbapenems are our very broad spectrum agents that are beta lactams. It's kind of a mixed picture here, right, right. Speaker 1 18:30 So carbapenems are frequently looked at as the catch all they, you know, cover everything and they'll save the day. However, you do have to remember that most of our enterococcal species will have resistance to carbapenem, so especially those e facium bugs that we'll find So ertapenem has no activity at all for either of these brothers we've talked about. Meropenem has minimal activity for E facalis and is not reliable for E facium and imipenem is the only one that we have known susceptibility rates for their susceptibility for imipenem can be inferred by ampicillin susceptibility. So if it's ampicillin susceptible, you can be confident that imipenem would be an option for that patient, and it has some activity versus e facalis, but usually no activity for faecium. Dr. Sean Kane 19:19 So E. faecium, again, being the troublemaker here, right? So even with our big, broad carbapenems, probably not a great option for that e fascium. So, you know, I think it's great that listeners know, hey, ampicillin resistance is a thing. But probably even better to know, how is it a thing? You know, the mechanism of resistance is really important to know in all of the ID world, and with Enterococcus, it comes down to that unique penicillin binding protein. So Dr. Anderson, maybe you can tell us a little bit more about what is it about penicillin binding protein that can make Enterococcus resistant to ampicillin. Speaker 1 19:54 So it mostly deals with just poor penicillin binding protein affinity. So. So there's overproduction of PBP four and e facalis, or PBP five and e fascium, and that leads to this poor binding affinity with the antibiotics. Technically, they can also produce beta lactamases, which we know can cause issues with beta lactam susceptibilities, but this is usually of secondary significance, so that's not something that that is most often the issue when it comes to ampicillin resistance. But because most of this resistance is due to that reduced binding affinity, ampicillin may actually still be effective if you can get high enough concentrations at the site of the infection. So it's something to keep in mind when dealing with UTIs, there actually is data to support still using ampicillin and a patient with a UTI caused by ampicillin resistant Enterococcus. So that's that's a really interesting study that I enjoyed talking about, because it just shows that with beta lactams, it comes down to that concentration and how well we can reach the site of the infection to overwhelm that resistance. Dr. Sean Kane 21:03 So basically, we can accept the fact that a good amount of mostly e fascium is going to be resistant to ampicillin as a gram positive bug. I think there's a number of different antibiotic classes that aren't beta lactams that we sometimes consider for gram positive infections. And again, this is one of those gotcha moments of we see plenty of intrinsic resistance, or developing resistance, like high incidence rates to some of the antibiotics that we might normally choose for a gram positive infection. So Dr. Patel, are some examples of typical antibiotics that we might use in gram positive infections that are probably not good choices for Enterococcus. Dr. Khyati Patel 21:39 I'm going to go with some of these, like omnipresent antibiotic like clindamycin or Bactrim, right? So going back to how we said some of these staphylococcus oriented penicillin, such as naphthalene and oxacillin, these clindamycin and Bactrim are going to be similar. They're intrinsically resistant. You're not going to find them on the sensitivity pattern. Fluoroquinolones, as we know in general, has lot of resistant reported, as is when it comes to Enterococcus species, though the resistant kind of varies, and so makes them kind of not the good starter type of empiric option for for the infections. Dr. Sean Kane 22:17 And Dr. Anderson, if you had to pick fluoroquinolone, which fuller quinone would you pick? And why, I Speaker 1 22:22 would say Ciprofloxacin is the most active. But like Dr. Patel mentioned, resistance is common, so empirically, especially for UTIs, in general, we don't frequently use them. Now, compared to levofloxacin or moxifloxacin, I would say Ciprofloxacin is most likely to be the one that that may have activity. Dr. Sean Kane 22:42 Now the the other class that comes up, mostly for something like endocarditis, is going to be aminoglycosides. And this is going to be one of those things where you're combining an aminoglycoside plus a cell wall inhibitor to help get that aminoglycoside into the cell itself. What do we know about resistance when we have that kind of combination strategy. Speaker 1 23:03 So we know that tobramycin and amikacin aren't going to be great options. Most, most strains of Enterococcus have a chromosomally encoded aminoglycide modifying enzyme that results in resistance to those options. The ones you'll hear about are streptomycin, which isn't frequently used in the United States, and then gentamicin, which is one we use quite a bit, that can still have resistance. It's called high level aminoglycoside resistance as a result of a modifying enzyme. And I think one important thing to note is that aminoglycosides are not reliable as a monotherapy for Enterococcus, but they can be used in combination, like you mentioned, especially for endocarditis, that increases our bactericidal effect when used in combination. Dr. Sean Kane 23:46 And I think what's cool about that note is that, generally speaking, gentamicin, tobramycin, we kind of group them in the same camp, we dose in the same they have similar levels antibiotic resistance rates depends on the institution, but they're not terribly different. This is one of those instances where tobramycin probably is a bad choice and gentamicin is going to be the more appropriate choice, specifically these enterococcal infections because of, like you said, chromosome encoded genetics, where it's naturally resistant to that tobramycin, but not gentamicin, right? Speaker 1 24:19 And the laboratory should provide that information for you when you get susceptibilities on these organisms to see if it's an option to use in combination. Dr. Sean Kane 24:28 So not everything is a rosy picture, right? Dr. Patel, sometimes things are not treatable with the ampicillin that we like to give. So what would be the next best option that we'd see in these more severe infections? Dr. Khyati Patel 24:41 Yes, and this would be somebody like me who has penicillin allergy, that a good old, cheap, you know, around the corner episode and cannot be used. So with that in mind, you know, vancomycin was developed historically for those patients who cannot take ampicillin because of tolerance or allergy issues. Is but then we have a thing called vancomycin resistant Enterococcus vre, and we kind of mentioned that already, it kind of started to become more relevant in the late 1980s but as we as we discussed earlier, we're seeing higher and higher vre rates, especially in the more stronger type of Enterococcus, the faecium, right? Speaker 1 25:22 So it's currently classified as a serious threat by the CDC in their most recent 2019, antimicrobial resistance threats report that they put out. So it makes up a substantial portion of all enterococcal infections, especially those nosocomial ones we talked about. Although I will say that increased infection control in the hospitals, and antimicrobial stewardship has led to a decreased incidence in recent years, so we are seeing some positive trends from a lot of effort being made in those hospital systems. Dr. Sean Kane 25:55 Finally, some good news when it comes to the ID world, that not everything is doom and gloom with more more resistance and crazier bugs and stuff like that, right, right? Speaker 1 26:05 What we do matters, so it's always nice to see those results. Dr. Sean Kane 26:09 Well, before we talk too much about the mechanism of resistance to vancomycin with vre I think it's relevant that we talk about how vancomycin works in the first place. So very briefly, you know, the way that a cell wall works is you have this peptidoglycan layer, and these layers have cross links, and the cross links basically connect one layer to the next layer. And that's actually what the penicillin binding protein does. It takes one cross link and links it to another cross link, so that all of your different layers are now connected together. It's like developing a brick wall, as opposed to having a bunch of independent layers stacked on top of each other. So with penicillin binding protein, which is where beta lactams work, it blocks the enzyme that makes the cross links vancomycin, it actually binds to where the cross links are supposed to form. And it's basically this like five amino acid sequence that ends up with D, Alla, dialla as the last two amino acids, and vancomycin binds to that and makes it so that the penicillin binding protein can't do its job of making these cross links. Dr. Khyati Patel 27:07 So it's wonderful to revisit exactly how vancomycin ends up working, and I have to, I probably have to suspect that the resistant is targeting this unique five amino acid chain. So Dr. Anderson, can you tell us, how does actually the resistance happen for vancomycin? Speaker 1 27:26 So you can have these, this expression of vancomycin resistance gene clusters, so most commonly referred to as van a but there are other types as well. It changes those amino acids where the cross links form, so that D allidala can become d allidy lac. This prevents vancomycin from binding. It doesn't prevent PvPs from making cross links. And there's also a vre variant that uses D allidy serine. So there's not just one way this happens. There's a couple ways, and it ends up causing an infection. That is bad news, because the remaining treatment options are primarily IV and, you know, may not be well tolerated in all patients. Dr. Sean Kane 28:08 So unlike what we saw with altered binding affinity, with penicillin binding protein, this is an all or nothing thing. You know, you can't give more vancomycin to overcome vre it's just not going to work, right, right? Speaker 1 28:20 Exactly, and it's it's definitely something we need to be aware of, because this is actually something that was shared with staph aureus and can potentially lead to that vancomycin resistant staph aureus. So that's why that dialla delac may sound familiar to listeners. Dr. Sean Kane 28:34 So you mentioned that basically, we have IV options. What are some of the common IV options, and why might we pick one or over the other in certain circumstances? Pros and cons. Speaker 1 28:45 There's a couple options that are IV, as you mentioned. So it depends on the site of the infection, and then it depends on those adverse effects that may occur from those those drugs. So the first one that comes to mind worth discussing would be daptomycin (Cubicin), that works by disrupting the cell membrane, inserts its lipophilic tail into that cell membrane and forms an ion channel. And it's our only vre drug that's bactericidal. So that can put it maybe closer to first place in terms of what you would try for an IV option, when when patients have a vre infection. Dr. Sean Kane 29:23 So of course, the next question is, is it common that vre can also be daptomycin resistant? Is that a thing or not? Speaker 1 29:29 It's something that can occur, but it's extremely uncommon, at least for now. I mean, it requires multiple stepwise mutations, so it's not just one gene cluster that can turn it on like we may see with vancomycin. Dr. Khyati Patel 29:42 And Dr. Anderson, you kind of mentioned that it forms these ion channels, and they're essentially like holes into, you know, making holes into the bacterial cell wall. Does? Does that have an implication as to its side effect in human cells too? Speaker 1 29:57 Yeah, that's a great question. It's good. Poking holes. So it can poke holes in our muscle cells too, and that can lead to rhabdomyolysis. We really need to monitor the CPK in these patients at least weekly, or maybe even more frequently, if they have other risk factors present, to make sure that that's not an adverse effect that's occurring. Dr. Sean Kane 30:18 And one kind of goofy but really interesting topic about daptomycin is how to dose it, right? So it is a weight based dose. We're not going to get into which weight to pick and things like that. But even the number itself, in terms of how many milligrams per kilogram do you need to fight vre Dr. Anderson, what is the magic number here? Yeah. Speaker 1 30:37 So this is a tricky topic. It's FDA approved for four milligrams per kilogram per day for skin and soft tissue infections, or six milligrams per kilogram per day for those more serious or bacteremias. However, since that FDA approval occurred, we've gotten a lot of data to suggest that vre infections likely require much higher doses, so eight to 10 milligrams per kilogram per day, and a lot of that comes down to the mics that we use to cut off to say if the antibiotic is going to have susceptibility for the organism. So in recent years, we've had changes to the mics that we use to determine what dose would be appropriate for the infection. For some of these vre infections, you use higher eight to 10 or even higher doses in milligrams per kilogram per day, however, so non severe infections such as UTIs, weren't included in a lot of those studies that supported those higher doses, and so there is some data to support those initial FDA approved dosing schemes for those UTIs or non severe infection presentations. Dr. Sean Kane 31:46 And I think this is one of those things that many students remember about daptomycin, is that it is not effective for pneumonia. One, Enterococcus doesn't cause a lot of pneumonia anyway. But two, you know, in animal studies, we basically confirm that pulmonary surfactant will bind to the drug, and then it doesn't work in terms of killing bacteria in the lung. They actually even studied it for communicable pneumonia, and it was worse than ceftriaxone. So it's good to know that daptomycin is a poor choice if you're trying to treat pneumonia, plus other stuff, where pneumonia on its own, you're not going to get that lung coverage Right, right? Speaker 1 32:18 So it's a hard stop if they have pneumonia as their source of the infection. And that's one of the reasons why we have to think of some alternative IV options for very infections. Dr. Sean Kane 32:28 And what would another alternative be to daptomycin? Speaker 1 32:31 Then, sure, so linezolid is another one. I think of zyvox would be the brand name. It works by inhibiting ribosomes and thus protein synthesis for the bacteria. Dr. Sean Kane 32:41 And again, the common question here is, do we see lanazolid resistant vre or not? Speaker 1 32:47 Same as with daptomycin resistance can occur. It has been seen via ribosomal mutations, but it's extremely uncommon. There have been some outbreaks that they found of resistant isolates, and that's usually in a healthcare setting where the lineal use is high. So the idea that if you use a lot of the antibiotic, you're encouraging that resistance to occur. Dr. Khyati Patel 33:08 Something unique about this antibiotic that I recall is that it's a bacteriostatic and you know, so maybe for our more sick patients, those who are immunocompromised, we probably want to go with this little drug and not a static drug. So probably that limits the effectiveness there. But what I do recall is that this is available in an oral form, and it's, you know, just two pills a day, good bioavailability. It's available in IV too. So those who got started in the hospital with an IV the transition to PO is also very easy to consider, right? Speaker 1 33:41 And with that standard dosing that that occurs regardless of renal impairment. So for example, in the ICU, where we may have patients with a lot of renal impairment, that I'm sure is a nice, a nice aspect of this drug for you, Dr. Kane in practice, Dr. Sean Kane 33:54 Oh, yeah. You know, if you consider a situation where someone is going to need longer term vre therapy, the decision point between putting in a pic line, basically an indwelling catheter to give IV antibiotics, versus potentially having the option to have an oral therapy. That's a really big selling point, and also a reason why for a very long time, Lange islid was very expensive, is that they knew that their competition was having an IV line and having, you know, outpatient IV therapy given to someone who has an infection. So that oral therapy is a really big deal when it comes to vre treatment for a patient, right? Speaker 1 34:29 But we can't forget this drug also has some adverse effects, right? So on the outpatient side, there's still going to be things that we have to consider when we send them home, especially for those longer courses that that you mentioned may, may drive the selection of this drug. So it's really a balance. So there's a couple adverse effects or drug interactions that we would need to keep in mind. I'm sure Dr. Patel, this is something that you've seen come up too. Dr. Khyati Patel 34:53 Yeah, I get questions all the time about, you know, what is the risk of serotonin syndrome with. Of these drugs, because those those alerts, are already built into our, you know, patient database. So when it comes to Lange allied, it is a weak monoamine oxidase inhibitor, so there is a possibility that it could cause more serotonergic effect, especially in patients who are already on another serotonergic agent. So this flag would pop up. And again, like you mentioned, Dr. Anderson, risk versus benefit. If this is the only drug that patient can go home on to treat the infections, we may have to adjust their other therapies accordingly. Dr. Sean Kane 35:32 And I think, as Dr. Anderson, you were alluding to, one of the challenges here is that, you know, a short course of Lange lid generally, not a huge deal once you start piling on the number of days that you're on Lange list for, we start seeing duration dependent adverse effects, where the longer you're on it for, the more likely you are to see some of these pretty nasty side effects. So what are some of those that come to your mind? Speaker 1 35:53 Sure, so with prolonged use, maybe greater than two weeks or so, we can see bone marrow suppression occur. So that's especially thrombocytopenia. And this is relevant because a lot of the patients with these serious enterococcal infections may have those underlying myelos suppression from those comorbidities that made them susceptible to the infection in the first place. And so it's something that we have to keep in mind when we select this drug. I'd also say lactic acidosis is something that can happen and then with even longer, extended use, so maybe greater than a month or so. It's associated with possibly an irreversible peripheral and optic neuropathy, which is something to be concerned about. Dr. Sean Kane 36:32 So certainly a very difficult risk versus benefit for some patients, in terms of having an indwelling IV line versus having an oral option that could cause potentially irreversible problems if they're on the drug long enough, and especially if they're not appropriately monitored. And I think that's probably the key to most of those side effects, is appropriate monitoring for that patient, Unknown Speaker 36:52 right? Exactly. Dr. Khyati Patel 36:54 And Dr. Kane, I always remembered, if you know, you can't treat an infection with the with the drug, think of tetracyclines, right? Good old tetracycline. So is there a role that a tetracycline derivative kind of plays in the therapy for Enterococcus infection? Yeah. Dr. Sean Kane 37:10 So there is a drug called tigecycline – it's a tetracycline derivative that has kind of its claim to fame in that it treats many, many things, except for Pseudomonas. So it's going to cover MRSA, it's going to cover anaerobes, some of the other non pseudomonal gram negatives. So its spectrum is nice to have, but there's like two big deal issues with tigecycline. One, it kinetically has a very large volume of distribution, so that means that the drug doesn't sit in your blood. It kind of goes to all of goes to all of your tissues and hangs out in your tissues. Now, if you have a bacteremia, that's not good, because you want the drug where the bacteria are like in your blood, but maybe that's awesome if you have a lung infection or an abdominal infection or skin infection, because that's where the drug goes. So it probably is pretty good for pneumonia, skin and soft tissue infections, and it's actually FDA approved for complicated skin and skin structure infections and abdominal infections can be required bacterial pneumonia. So it does have some of these indications, but there's a scary boxed warning that comes along with it. Dr. Anderson, what is that boxed warning that comes to Speaker 1 38:16 your mind? Yeah, so in the phase three and four clinical trials, they actually saw higher mortality with the use of tigecycline compared to other antibiotics. And so when we hear that, that definitely makes you pause and and you want to be really sure that this is the best option for that patient. So the FDA recommends that we reserve use of this for situations in which alternative treatments are not suitable. Dr. Sean Kane 38:40 And I think that with respect to that boxed warning, there's kind of two going theories in terms of why that is. One, perhaps it's lack of pseudomonal coverage meant that these patients are more likely to have a pseudomonal infection. Or two, the very large volume of distribution means that perhaps we didn't do a good job killing the bacteria in the blood, and that predispose a patient to a worse outcome? We don't know the answer, but we do know in comparative literature, there is a scary signal that we're not as excited about tigecycline as we might be given. It's a fairly favorable side effect profile. It is IV only, but there's a lot of reasons to like it, except for the VD issue, the biomed distribution issue, and that boxed warning, right? Speaker 1 39:22 And Tiger cycling actually treats a lot of other types of infections too that sometimes we want to reserve it for. So daptomycin and linezolid tend to be our workhorses when we see these severe vre infections. Dr. Sean Kane 39:35 So speaking of workhorses, there's a number of drugs that are effective for vre that, you know, in preparing for this episode, I don't think I've ever used I've heard of them, but they're definitely not on my go to list in terms of typical therapies that I see recommend things like that. So what are some of these kind of, maybe board esque questions in terms of other therapies for vre Speaker 1 39:58 so one that comes to mind would be. Nurser, and that's a much older antibiotic that's quinapristin, delphopristin. That's one that can treat vre but not commonly used due to a significant number of side effects, but something to consider when you have really complicated infections, and a lot of reasons why you can't use our first line therapies. Other ones would be orbactive, or oridovansin, and then televansan Those are both new drugs that have come out recently that do have vre activity, Dr. Sean Kane 40:29 and then perhaps more up. Dr. Patel's route, if she does see this vre patient who is otherwise healthy, doesn't need to go in the hospital, but they've got a UTI. Dr. Patel, what are some options that that patient could have, that are oral options that is meant for UTIs only, that are not severe infections. Dr. Khyati Patel 40:45 Yeah, definitely, we have to establish the severity even on the outpatient side too. But you know what comes to mind is this yellow and black capsule pill, nitrofurantoin, right? That's what comes to mind. So, yeah, it's very common whenever you find the Enterococcus susceptibility data and it is susceptible, it is a fair game to use. One of the less commonly used oral option is phosphomycin. We don't see IV systemic therapy in the United States, and I don't think po option is utilized as commonly either. Yeah. Speaker 1 41:20 One of the issues with that one can be cost, so it can be hard for the patients to get a hold of, but it is nice because it's usually only a couple doses when you do use that oral fosfomycin, so maybe one to three doses, depending on the patient case. Dr. Sean Kane 41:36 And, you know, we don't have time to cover it today, but there are a number of other instances where there are unique regimens based on where the Enterococcus is. So as an example, we briefly talked about using an aminoglycoside plus a cell wall inhibitor for endocarditis. Or in this one I did not learn in pharmacy school, and blew my mind that we would have a regimen of ampicillin plus ceftriaxone Dr. Anderson, you have to tell me about a double beta lactam approach here. Why would you do that? What situation would that be relevant, right? Speaker 1 42:08 So there aren't a lot of situations in which a double beta lactam is a recommended regimen, especially in a guideline. So especially, you know, we're using ampicillin plus ceftriaxone for some of these endocarditis cases with Enterococcus, and that's, that's a cephalosporin. So ceftriaxone, cephalosporin, which we just talked about, wouldn't actually work for Enterococcus. So it is. It does sort of blow your mind. But this comes down to the PBP, those penicillin binding proteins, and the fact that both of these drugs work on individual PvPs, and when they are given together, they can completely overcome that organism and have activity. So this is a regimen that we consider for patients with enterococci inocarditis, and it can be especially helpful when patients won't tolerate an aminoglycoside, which is part of sort of the more classic regimen when using ampicillin, and so maybe those patients that have renal dysfunction, for example, excellent. Dr. Sean Kane 43:06 Well, we've gone through a lot of different things. I think it's probably time that we go back to our poor, 66 year old guy that came in with covid 19 now has a catheter associated urinary tract infection, and that is growing e fascium Again, the bad guy being punched in the face. So not on any antibiotics yet. We don't know if it's going to be resistant to anything yet. We're waiting for that, but he's sick enough to warrant antibiotics now, pending more information from that lab. So what are some of the things that we need to think about from a likely resistant pattern standpoint, as well as what are our empiric therapies until we know more information? Dr. Khyati Patel 43:44 So Dr. Kane fascin, being one of the more resistant type of Enterococcus, I'm thinking we should probably be looking out for some sort of ampicillin vancomycin resistant here. So kind of keep that in our radar first, and with that, then what would be our treatment options. Dr. Anderson, right? Speaker 1 44:02 So first, when I hear about catheter associated UTIs, I want to make sure that they get that catheter out and they replace it, if, if the patient still requires a catheter. And so that's usually my first question, because source control is a big part of infectious disease therapy. And then, because we're treating the urine, we still could consider ampicillin, it would depend a lot on the patient's clinical status and what else is going on. But that's because of that data that we have that ampicillin or amoxicillin can overcome that resistance, because we can get such a high concentration in the urine, so at the site of infection, but reviewing the three therapies we talked about, so daptomycin, linezolid and tigecycline, I think those are all things that we would also have to consider because we are dealing with a patient that is sick enough to be hospitalized. So daptomycin, I think, would be okay assuming there's no concomitant pneumonia. Linezolid would also be an okay option assuming we didn't have those drug interactions that we had talked about before, and then tigecycline probably not a good choice. And that really comes down to the fact that it doesn't concentrate well in the urine, so it's not something I would want to rely on to treat an infection like this. Dr. Sean Kane 45:14 So Dr. Anderson, I'm going to put your feet to the fire here so you have a sick enough patient who we think is septic from their UTI. So it's not a simple UTI anymore. What are you going to start on this patient until you have more information? Speaker 1 45:28 So for a patient like this, the information we have, I would think daptomycin would be the drug that I would start with. And there are lots of reasons we talked about why that might be the best option, but I think that bactericidal effect, especially in a patient that is hospitalized and has another infection that we're treating, that would be my go to for a patient like this, perfect. Dr. Sean Kane 45:51 And I think we can't wrap up this episode without talking about antimicrobial stewardship, right? So you are going to start your adaptomycin. Let's say what is the next step that must occur the next day or the day after that, once you get your full lab data back in terms of, what is this bug causing the patient's UTI right? Speaker 1 46:11 So that's that susceptibility result that we'll get from the lab. So we want to de escalate, so that's our next step. So we want to follow up and make sure that, you know, do we have any other more narrow or potentially better tolerated options that we could use? So ampicillin, if it is sensitive, then you can use it. And that's something that we would we would want to consider potentially as a step down option when switching to orals, because daptomycin would be IV only. Dr. Sean Kane 46:39 And then how long would you treat this for? So Speaker 1 46:42 I would consider a seven day duration. There's no data to support one specific length of therapy for this particular infection, but I would, I would say at least seven days if it was determined to be a true catheter associated UTI and that we needed to to follow through and give a full course of therapy. Dr. Sean Kane 47:01 So Dr. Anderson, you know, we've covered a lot today. What are some key concepts that you think the listeners should really get out of today's episode? Speaker 1 47:09 So I would say Enterococcus, remembering that it's a gram positive pathogen, it's well known for intrinsic resistance to multiple antibiotic classes, and it causes infections both in the community and in the hospitals. So it's something we need to be aware of, Dr. Khyati Patel 47:24 and we have the two most common types, Enterococcus faecalis and Enterococcus faecium, the Enterococcus fascium. However, the punch in the face bug is becoming a little bit more prevalent, and keeping in mind this has also higher resistance to ampicillin and vancomycin, so we're likely to see more vre infections with that particular bug. Dr. Sean Kane 47:50 And then in terms of some of those resistance patterns, we see ampicillin resistance, mostly because of overproduction of penicillin binding proteins that have low affinity to ampicillin. Then we also see vancomycin resistance because of changing the cross link amino acid sequence from D allidala to dial a D lactate, where vancomycin can't bind to that unique amino acid sequence. Speaker 1 48:13 Another key concept, I would say, is that when you are dealing with a VRE infection, there are a couple different antibiotics that first come to mind, such as daptomycin, linezolid and tigecycline, and daptomycin, being bactericidal, usually is one of your first-line options. And then we have some other oral or IV therapies that that are available that may not be as commonly utilized Dr. Sean Kane 48:35 well, Dr. Anderson, you know, Dr. Patel, and I absolutely appreciate your time today for the listeners that want to nerd out a little bit more about Enterococcus, we've got two great articles referenced on our website at HelixTalk.com again. This is episode 126 so check that out. We're also on Twitter at HelixTalk, and we still love the five star reviews, so keep those coming so that other clinicians are more likely to find us. So with that, I'm Dr Dr. Khyati Patel 48:59 Kane, I'm Dr. Patel, and thank you so much, Dr. Anderson for joining us Speaker 1 49:04 again. Thank you for having me. That was fun. Dr. Khyati Patel 49:07 And as always, listeners study hard. Narrator - Dr. Abel 49:10 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 49:21 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.