Dosing Consult: Daptomycin

[Music] Hello wonderful antimicrobial audio files, and welcome to Breakpoints the Society of Infectious Diseases Pharmacists podcast. My name is Jeanette Bouchard and I am a clinical pharmacist liaison at Deisson, or the Duke antimicrobial stewardship outreach network in Durham, North Carolina. Today we'll be continuing our dosing consult series. This class of episodes was kicked off with our May 2022 episode on Cephtriaxone dosing. If you haven't listened to that episode already, I highly encourage you to do so. We've also had other great episodes focused on Linnezle and Silphamethoxysl, Trimethyprim and dosing in obesity. And so these dosing consults are just a really great way to start on our Breakpoints content, and according to our Spotify metrics last year, many of our new listeners would agree. Today's episode is going to be a good one because it will be all about a drug that we use pretty often in the hospital system, as well as on the outpatient side for O-PET. And I feel like I get a lot of questions about this particular drug when it comes to dosing, and I think a lot of pharmacists that I work with also feel the same way. I think some of my first questions I ever received starting at a new institution had to do with this drug, so we will be discussing all things dosing related to Dapdomycin. And with that, we have the gift of being joined by two excellent guests to break down this topic for us. I'm sincerely honored to be hosting our two experts today, Dr. Jim Rhodes and Molly Steed. First, I'll introduce Jim Rhodes. So he completed his Doctor of Pharmacy degree at the University of Florida in a Master of Science in Clinical Investigations at Northwestern University. He also completed four years of postgraduate training, including a pharmacy practice residency, a specialty infectious diseases residency, and a two-year fellowship in infectious diseases pharmacotherapy, focusing on clinical outcomes and pharmacometrics. Dr. Rhodes is currently an associate professor at Midwestern University, where he serves as a clinical and didactic instructor in infectious diseases therapeutics and clinical pharmacokinetics. In 2018, he joined the Midwestern University Pharmacometric Center of Excellence. In 2020, he released a user interface for the optimal data analysis, non-parametric machine learning algorithm, which is available in R. In 2023, he became the Fellowship Director at Midwestern University College of Pharmacy, Downers Grove Campus. He currently serves as the ID Fellowship Director at Midwestern University and is engaged in clinical translational research at Northwestern Memorial Hospital, where he practices clinically and acute care infectious diseases in antimicrobial stewardship. He actively participates in infectious diseases organizations, publication peer reviews, extramural funding reviews, and continuing education content for clinical pharmacy specialties. So welcome Jim. Hey there everyone. Next up, we have Dr. Molly Steed, so she earned her Farm D in 2005 from the University of Wisconsin School of Pharmacy. She continued her training at the University of Kentucky, where she completed a PGY1 pharmacy residency of PGY2, infectious diseases pharmacy residency, and the scholarship of teaching and learning certificate program. Then she worked as an infectious diseases clinical pharmacy specialist in adjunct clinical assistant professor at the University of Maryland, before setting off to Wayne State University in Detroit, where she was able to complete an infectious diseases pharmacotherapy research fellowship in the anti-infective research laboratory under the tutelage of Dr. Michael Ryback. In addition to her translational laboratory research training, she also taught in the infectious diseases pharmacotherapy module at the College of Pharmacy and Preceptive Pharmacy students, PGY1 pharmacy residents, and PGY2 infectious diseases pharmacy residents at the Detroit Medical Center. In 2011, she joined the faculty as a clinical assistant professor in the Department of Pharmacy Practice in her current clinical practice site at the University of Kansas Medical Center and she is actively involved with the antimicrobial stewardship program and rounds with the infectious diseases physicians on the consult services. So Molly, welcome. Hi. All right, so now that we know all about how qualified you guys are to talk about this topic, we are going to try to break down this topic for our listeners and we're going to start with general principles of PKPD of Daptomycin, as well as current clinical uses. And once we have more of a solid foundation, we're going to dive into some of the many questions we pharmacists receive about this drug. To begin, even though our listeners likely have some degree of familiarity with Daptomycin, Jim, can you refresh our memories and give us a good foundation on Daptomycin? And some of the pertinent principles we should keep in mind as we walk through some of these questions today? Absolutely. Thanks again for having me. So you adapted Mycin. It's a LIPO peptide, antibiotic, sort of a cyclic 13-amino acid, LIPO peptide, and it was initially sort of developed and then shelved in development when the manufacturer sort of realized that there were some serious toxicities that were being explored. That product was then picked up by Cubus pharmaceuticals and further developed using a different dosing strategy. And that previously Cubus and branded, the uses that you'll see for this clinically are usually things like bloodstream infections from gran positive organisms, endocarditis in particular. We see a fair bit of Daptomycin used for, as well as skin and soft tissue infections that you might see caused by things like Staphorious. In development, they did test and evaluate the PKPD relationships. So Daptomycin is known to be a concentration dependent antibiotic with higher concentrations both with the effect of the C-max to MIC, as well as AUC to MIC being associated with killing in the neutropenic thia infection model. Bill Craig and Dave Andes did some of that work early on back in 2004. And what was identified there was a relationship that was pretty strong for both AUC and C-max. However, AUC is sort of the index that we normally think of as being the PKPD driver of efficacy for Daptomycin. An interesting side note is that it was explored in terms of development for community acquired pneumonia. So you might see if you look back at some of these papers, pneumococcus being evaluated as a target pathogen, but it was discovered very quickly in clinical studies that Daptomycin was inactivated by lungs or factant, and therefore not a very effective option for the treatment of pneumonia. So that was an abandoned pathway there. But to that sort of a, I think, a high-level overview of Daptomycin, we see it used in our facility as well as in the outpatient setting. Most often, we tend to use it for patients who are intolerant to Vancomycin for grand positive infections or folks for whom Vancomycin or an alternative is not appropriate. Right, and it's DOST once a day normally, which I think is one of the big reasons providers are like, "This is the better option as we send people home," because we don't have to dose it multiple times a day, which we often have to do with Vancomycin, which is a great advantage that Daptomycin has over Vancomycin for O-PAT reasons specifically. Molly, do you have anything to add? Yeah, that was a great overview. The only thing I would add is about Daptomycin's protein binding, because as we know, this is a very highly protein-pound drug. Usually, the number side is about 93 percent protein-bound, but you know, it can vary a little bit depending on what study you look at. But the Daptomycin bounces on and off the proteins very, very quickly, so much, much quicker than a lot of other drugs. So some people, including myself, like when I work with this in the in vitro models, you know, it acts like there's more free than actually 7 percent. Sometimes, just because it's jumping on and off so quickly. So highly protein-bound, definitely if you have a patient that is, you know, severely protein-deficient, they're possibly going to have more free around than somebody who has a lot of good albumin and everything like that. So just keeping in mind, because everything that was talked about with the AUC, we're still talking about free AUC, right? That's totally AUC. And with it being so highly protein-bound, sometimes that can play into this a little. Great. Great. Thank you for that awesome introduction. I think we've touched on a lot of different variables that will help us with the discussion to come. So I'm going to pivot to Daptomycin dosing, specifically as this is a dosing consult. And in the context of differing organisms. So Molly, I want to start with you because you have done some work in this area of Daptomycin dosing. So can you talk to us about if we should be dosing differently for different organisms, such as methamethystyl and resistant staphoresis or MRSA or vancomycin resistant enterococcus or BREs? Okay. So absolutely yes. We're going to be dosing very different based on these organisms. So as Jim so eloquently pointed out, this is predominantly a concentration or AUC to MIC, you know, pharmacodynamically driven drug. And when we look at staphoreas, usually we'd be using it for MRSA. But when we look at staphoreas versus entrococcus B, MIC is actually buried by about 8 to 16 fold. So when you're talking about staphoreas isolates or MRSA, 90% of the staphoreas isolates have Daptomycin MICs of 0.5 or less. And then when you move into entrococcus fecalus, the vast majority of them are going to be at 0.5 to 1. And when you get to EFICI and there's going to be a vast majority at 2. So going from 0.25, which is where the vast majority of staphoreas are to 2 with entrococcus, you know, phycium or VRE. Those are very, very different bugs, very, very different MICs. You're going to need very, very different doses to treat. For staphoreas, if you have a pretty simple infection, you know, skin and soft tissue, UTI, you can certainly do something that's with the dose that got it approved by the FDA. Some are about 4 to 6, makes per kig. Since this is concentration dependent or AUC dependent, there are a lot of studies even with staff workers, especially with high inoculum difficult to treat infection. like endocarditis that the bigger you go on the dose, the better the patients tend to do, right? So for staphoreus, our high doses typically considered greater than or equal to 8 milligrams per kilogram, and sometimes you get better efficacy with high inoculum or difficult to treat infections. So for staphoreus, you know, 4 to 6 for easy infections can go up to 8 or higher that's considered high dose. Now, it is completely different when you get into entrococcus. And I don't know how this happened, but some people think that high dose for entrococcus includes 8 and it does not, okay? It absolutely does not include 8. So there have been multiple, multiple studies, both in vitro and microibax lab. Some are done by one of my co-fellows, Ashley Hall. Some others were done by Brian Worth, but show when you're in the in vitro setting, only 10 milligrams per kilogram and up for dapdomycin has sustained bacterial logical activity, only 10 milligrams per kilogram and up prevents the emergence of resistance. So 6 and 8 makes for cake for dapdomycin, they don't cut it. They're not high dose. You need to be above 10. And then we've seen this clinically as well. So in the study that I was really fortunate enough to do with Nicolas Sprit and Nymish Patel, where we mind the huge VA database, when we looked at all cause mortality, 6 and 8 were the same. You didn't split until you got to 10 milligrams per kilogram or above. So really for dapdomycin, high dose and the dose you need is 10 milligrams per kilogram and about 8 does not cut it. And there's been a few studies since then as well, one by Changatol in 2017 that showed a similar result where really needed to be above 9. So, high dose for staff can be 8 enough, but when you get to enter cacus, it has to be greater than or equal to 10. So Yeah, I think that's a very nice summary of sort of the literature in this space. The only thing I might add to that additionally is the considerations that have been brought forth in recent years. I think clinicians who are practicing in the hospital, at least over the last five years or so, have probably seen the break points of all. It feels like almost weekly in terms of, is this enturocacus susceptible, which is susceptible to this dependent? I'm just going to call pharmacy, right? And so the idea behind this I think was nicely summarized by Romney Humphries in a review in AAC. And the challenge I think is that some of this data that Molly has cited and I think has been used in re-evaluating the interococcus break points has identified some PKPB targets. So some very nice work from her as well as collaborations with the Hartford group, Joe Cutty and the fellows there. And what they found was that there was sort of a free AUC to MIC target around 27 or so. That was associated with better outcomes. Again, this was sort of mixed group across I think three different studies. And the challenge is that you really can't achieve those targets when the MICs are four or greater. And so that sort of prompted CLSI to look at this and sort of lowering the MIC break points in a rapid stepwise fashion. The other piece I think to this is MIC variability. So if you were to pull this review article by Romney Humphries, you know, a lot of the simulations that we do, I'm sort of in the modeling world, we do a lot of Monte Carlo simulations. We're excited about things like, you know, AUCs and simulations. But we don't often consider the pharmacodynamic target, the MIC ability. And so there are some serious technical challenges with measuring the MIC, getting an accurate MIC assessment. And so when you think about, you know, if you're targeting these organisms like anorococcus is an MIC of four, really an MIC of four, is it higher, is it somewhat lower. We usually think of plus minus one dilution, but there's actually a fair bit of variation in the depth of my S and MIC. And so I think that underscores the issue of maybe aiming a little bit higher for things like anorococcus with your dosing that makes a lot of sense for staff warriors, you know, your standard dose ranges usually fairly acceptable. Maybe talk of things like PK when we get down to the nerdy stuff. Yeah. And just for our listeners clarification, when you say anorococcus, do you mean all anorococcus, e-feecium, e-fakealis? Great, great question. So that break point in particular was for anorococcus, e-feecium. Fakealis has a slightly different break point and this can be confusing. So usually it's a little bit easier to achieve better exposures and the MICs tend to be lower for fakealis over feecium. So feecium really is, you know, sort of the bad boy in the hospital setting and we sort of continue to see that over and over. But I think Molly could even elaborate a little bit on what she saw in some of her data that combinations with things like beta lactams and other drugs seem to have better outcomes and fakealis over feecium. So is that a function of just the bug? Is it a function of synergy? I think that question is maybe somewhat unresolved. Yeah and actually I was going to talk a little bit about synergy in the nerdy corner at the end. But I've been wondering for a while too, just with, you know, the studies showing that we really can't achieve the pharmacode dynamic target for MICs of four. And I look at all the studies and nobody, my knowledge has done the study where they actually look at outcomes are survival by MIC. And we have pretty high mortality still with enterococcus back dream, we are bad infections. And I always wonder like are those the really high MICs or those the patients that don't do well? Because we think we're getting there, but we're really not getting there. I don't know. Yeah, we can definitely say that for our I feel nerdy at the end. That's a great I feel nerdy content. I also love the idea of enterococcus BCM being the bad boy of the hospital that makes me giggle mainly because here at breakpoints we like to personify our microorganisms on our infographics. And so I feel like that's an infographic coming to us soon. All right. So we talk about these higher doses with enterococcus specifically more for the BCM side and using these 10 milligram per kilogram doses. Now I think another really common question that is heard around the hospital community. And honestly, I always find myself looking into this particular question. What weight should we be using in patients with obesity? So I work here in the southeast corner, been in the southeast corner for majority of my career at this point. And this question constantly comes up of what should we do in order to get that 10 MICs per gig because because you start to end up with these really high doses that make pharmacists, providers really nervous. So what can you tell us about dosing in obesity without demison? Yeah, I'm happy to jump in here a little bit. This is an area of significant interest in development that the manufacturer was able to identify that weight was an important factor. But the population PK model considered a variety of different things including sex-based differences and clearance. Temperature was a factor interestingly. Perhaps temperature is a surrogate for things like sepsis and infection status in the patient. So I've rited different factors, but it seems that again, the daptomycin clearance, which is important if you're trying to target an AUC because it's a function of dose and clearance, right? And so if you're trying to maintain a specific AUC, you want to know what's driving clearance. And in the case of daptomycin, creatinine clearance or renal function is a huge factor when it comes to the drug elimination. So you kind of fast forward to how we estimate, you know, creatinine clearance. And so weight is certainly a factor. And most of the time, total body weight is what we tend to use. The problem with total body weight when we come to making an estimate of clearance is that obese patients tend to get more credit than their due. Their kidneys are, for example, in 120 kilo-patient. The kidneys are not twice as good as a 60 kilogram patient. And so as a result, if you end up dosing based on total body weight, you're going to naturally give a higher exposure to the obese patient than the non-obes patient, just using a nigg-per-kig basis. And so folks like Almatype and others have been doing an incredible job over the last 15 years or more of trying to raise the issue of identifying the right dosing weight. And should we be perhaps using a fixed dose of daptomycin? We actually looked at some of this data at our facility and we implemented a fixed dosing daptomycin strategy back in 2014 or something like that. I think it went away when Epic came along and sort of blew up our EMR. But we were doing that for a number of years and we didn't have bodies in the streets. So again, you have a fairly narrow range of clearance. They can go up and down by, you know, 20 to 40 percent, perhaps. Some of that's going to be driven by critical status, but obese patients generally and what the evidence has shown is that they're going to be at higher risk for overexposure. So you want to be monitoring those individuals a lot more carefully. The flip side of that is that there was a nice paper that was just published in Pharmacotherapy. Almatype was a co-author on that, but Katie was the lead on that was her project that was actually funded by SIDP, Early Career Research Grant. And they enrolled patients and they evaluated the pharmacokinetics in these individuals and they compared weight-based dosing versus fixed dosing strategies. And they found that if you want to try to maintain similar exposures, you know, either using a weight-based or a fixed-do strategy, the fixed-do strategy does a better job of maintaining similar exposures across the weight distribution. So I would say that thinking about this, what is 10 mixed per gig going to be for your average American patient, you know, 800 to a thousand milligrams probably, right? Again, if you're capping at the high end, you're probably avoiding some of that overexposure in your obese patients. So thinking about those sorts of choices and about the risk of toxicity, especially if your patient happens to have concurrent kidney disease, or having rapidly fluctuating renal function. Those are some factors that you might want to consider when you're thinking about, okay, I'm just gonna do this based on total body weight or maybe I want to consider doing a fixed dose strategy. - Great, yeah, and we'll link that new article in our show notes for people to reference to. I think by the time this podcast comes out, it will be out for about a month or so, but it is a very recent article that came out with Amit and Katie as co-authors, titled Fixed Dose, Staptamysin, an opportunity for pharmacokinetic and pharmacodynamic optimization and Staflokakis-Orius infections. One of the figures that really popped out to me in this article is figure two, just because it looks at the probability of achieving three different PKPD targets based off of different AUCs in the 10-meg per kig dose versus the Fixed Dose versus the Fixed Pre-Mixed Dose, which will get a little bit into those pre-Mixed bags that are recent to our Deptamysin market. But it's almost like a comical figure because all three look exactly the same in terms of probability of attainment for all three of these targets. So they have AUC greater than or equal to 666 and then AUC 666 to 939 and then they have a C-min greater than 24.3. And the bars are almost nearly exact across most of all three of those categories. So really great paper to kind of look at this approach of fixed-based dosing and definitely encourage our listeners to give it a read. All right, with that, I think we kind of answered this question but I do want to touch upon it. So Jim talked about in our patients who are obese, kind of weighing not overdosing and maybe using this fixed dose strategy to kind of showcase that it might be okay, just AUC-wise to use that fixed-based dosing. Jim has had quite a bit of clinical use of it but there is less clinical data with this strategy that's available for our listeners. But related to that, another question is how high is too high? Which I'm assuming based off of the discussion we just had that 750 might be closer to the cut off at least for stafel-coccal infections. But usually when I get the question, it's when pharmacists are trying to make per-kig dose to adapt to my身 and it's hitting like a 1,500 milligram range or a 1250 range and there's a lot of institutional protocols that cap it off at 1250. And so do you guys have a max dose that you think about in your brain when dosing adapt to my身 or a dose that you wouldn't necessarily go above or are you moving, Jim might be moving more towards just 750 so he doesn't even ever hit 1,500 as a thought. - I'll just kind of throw up my hat in the ring here. I'll probably get some tomatoes as I'm walking down the street for own in my direction. But I start getting a little nervous when I start seeing a gram. I'm like, does this patient really need a gram of dapto? And then I wanna ask that question to be thoughtful about it. If there are factors that are driving me towards that, for example, if you've got a higher MIC, you know, endococcus, are we doing the right thing by just giving them mono therapy? I guess that's a question I think about too. And then again, if we're just sort of doing this, is this a patient where ID is consulted? I think Molly had some nice data too. The ID consultation is an important factor when considering BRE Bacteremia. But, you know, if you're dealing with staff bacteria, that's sort of a no-brainer. ID should be involved. BRE Bacteremia, I think similarly, you should probably think about having an ID consultant way in on the case. And again, if you're looking at going over a gram of dapto, is are you leaning on dapto harder than it should be leaned on? I would just echo, I think, with all the stuff with fixed doses or dosing on an adjusted or ideal body weight with obesity, I think it's much more straightforward with step four, it's just because the MICs are so much lower and we're just having a much better chance of getting our pharmacodeinemic targets and getting where we need to be. And we've already touched on that, like, technically we shouldn't really quite be able to get there with endococcus with dapto and my Cs of four. So I get a little more worried with capping the dose or doing like an ideal body weight when we're treating like a really bad entro-occal infection. And I've seen a lot of hospital protocols where across the board it's ideal body weight or adjusted body weight, but then it gets to endococcus and it's like, no, you use that actual body weight for the entro-occus. So I think we still need to tease out a little bit about like, what can we actually accomplish with endococcus and where should the break points actually be? And people are just kind of hedging their bets and trying to just more is better and just a little safer when we're not quite sure how we're to get there with endococcus. Yeah, endococcus being a different beast is important to take into consideration, but I agree with you guys where anything with staff orias, you can just, I mean, you're shooting for like an eight mag per keg or four to six depending on the type of infection that you have. And so we shouldn't be hitting those high, high doses for most patients. And so with that, so our fixed dosing in this most recent paper, we talked about 750 milligrams. So what recently come out that I've noticed via questions from a lot of my community sites is there are these new premixed bags and based off of whispers that I hear, now I don't work necessarily on the front lines of hospital so I don't have that kind of price data, but they are priced pretty competitively in terms of the vials. And so these pre-made bags are ready to use bags. There's no compounding involved so you don't need to worry about any sort of depth of mice and waste and they come in a number of different sizes. So there's a 350 milligram, a 500 milligram, a 700 milligram, and a gram. And so I have been tasked by a lot of my hospitals to come up with a dosing table to fit the doses into these pre-made bags, which as you can imagine because the current standard for dosing is in-depth amycin is a mag per keg. So it's very difficult to make a table where you have mags per keg and people in weight in keg and then what dose, what bag you would do and showcasing how much above or below your dose that you're shooting for. So it's a very complicated table. So what are you guys' thoughts on these pre-mixed bags and when it comes to trying to make a table to fit patients into these bags? - You know, what I would say is that that table two in the most recent paper from Katie Olme and Ovet, I think is very instructive. So if you're trying to shoot for weight-based dosing, the probability that you're going to have efficacy versus if you're doing fixed dosing is very, very similar. And they provide some nice, creatinine clearance cutoffs. You're going to have to, I think, modify and adapt these to your patient populations, but it does fit in somewhat nicely with some of these fixed combination or fixed bags that are put together. What's not on the table, I think they might be some consideration for things like dialysis and what have you. That's just going to push out the interval to every 48 hours instead of every 24 hours. But the doses are all here. So I think that folks should consider this, think about the probability of having exposure that's efficacious as well as potentially those who might be at risk for accumulating dapto and having maybe some of those CDK elevations that we sometimes see in practice. Yeah, I think that's a good point. This article definitely came a little late in my game when it came to making these tables. I think I made my tables like a couple months ago. But it would have been great to have this table available just to provide a little bit of expert guidance or data to support where I'm making these tables because unfortunately, the company did not come out with something like this. So they just came out with the fixed dosing and these community hospitals want to use something that's going to be easier on their compounding staff. They want to use something that's going to be competitively priced. So not wasting all of this depth of my sin. We were already doing a similar strategy. I think in most institutions, whether you rounded to the nearest 50 milligram or 100 milligram to use up those bottles appropriately. And so this table, I think really Shed's light and allows you to fall back on the fact that even though it's not exactly six milligrams per kilogram or eight milligrams per kilogram that these bags are fitting into, the targets are appropriate in this paper and that gives you a little bit of confidence when it comes to creating these tables and also confidence to be able to show, I know a lot of providers end up signing off on like dosing conversions when you're creating protocols in hospitals and you're like, we're gonna automatically change doses from a pharmacist and so you have to showcase that to a lot of providers in order to get approval. These data and table two are supportive of these dosing tables to make it a little bit easier to create those and feel confident in your dose. Again, Qdos to this team that put out this paper, but it's a really clean look and I think it'll really help a lot of institutions who want to use these pre compounded bags in their institutions to make it easier. So we have talked about Daptomycin dosing with different organisms, Daptomycin dosing and obesity. We've dived into fixed-based dosing, especially with our very recent article about it and then also touched on these pre-made bags, which I think are something that a lot of institutions are starting to see and starting to question, try to figure out how they're gonna fit into their institution. So the last topic that I wanted to take a moment to discuss in terms of Daptomycin is monitoring toxicity. So we play around with whether or not we're gonna talk about toxicities and managing drug interactions in these dosing consults because they're not, a lot of times not necessarily related to the dosing, but I think in this particular case, toxicities are related to the dose of Daptomycin. So I want to start us off right out the gate with CK monitoring and if that's necessary. So Molly. Can you give us your take on it? Yes. So before I kind of give my take, I just want to take a few steps back just for anyone that maybe knew just to make sure everybody's on the same page with the vast number of things that can affect the CPK. So this is not some very specific measure that we're looking at that is just going to account for depdomycin toxicity. It can be elevated for many, many reasons. That are going to be very common in a lot of our patients that are in the hospital and sick enough to need depdomycin. So it can go up in viral illnesses, cardiac or renal disease, if they're in any kind of crazy metabolic state, inflammation, surgery, so many, many things can cause this to go up. And a lot of people that have been in practice for a while will tell these stories like, yeah, you know, we were short nurses and my ICU patient didn't get turned when they were supposed to and the next day their CPK shot up. And you know, is it that or is it adapted? My son, when I was at the University of Maryland, we had a very large percentage of patients with HIV that were not on medication or were not controlled. So they were walking around with uncontrolled HIV. They had a constant viral infection. They were in a constant state of inflammation and their CPKs were through the roof. We'd get a baseline. We started my napto and be high at baseline. It'd go higher and we didn't do anything because of course it was going to be high. So it begs the question, if you're not going to do anything, why are you getting it? Right? It's recommended to get it at baseline. So you know where it is and then to monitor it throughout therapy to see if it goes up. And we're hoping this will be an early indicator of rabidomylicis or actual muscle damage. So do we need to get it? Certainly we know that increased elevations in CPKs are dose-related or are adapted mice in dose exposure or semen related. That's been shown very clearly in the literature. Because rabidomylicis is such a rare adverse effect to my knowledge, I've never seen any data showing that is actually dose-related. Certainly the elevation in CPKs, I have not seen the data for the rabidomylicis. So that's like kind of the second thing. And then the third thing is I think when we're looking at depdomycin toxicity in rabidomylicis and CPK elevations, we're pharmacists, right? So we want to hone in and we want to be like, we want to focus on the drug and we want to be like, you know, is this causing this? But I think depdomycin, if it's playing a part in rabidomylicis, I don't think it's just the drug. I think it's probably pretty multifactorial. You know, we focus a lot on dose. Some studies have certainly hinted that duration probably plays a part, but no one's come right out and said it, kind of like Leneaslid, but probably higher risk if you're on it for longer. There was a really cool study recently by Yamada at all that actually tried to elicit the mechanism of depdomycin induced muscle toxicity and muscle cells from humans. And unsurprisingly, it was by membrane damage, but they actually found that it was much higher in hypoxic conditions. So is this going to be much more common in our patients that are in sepsis that are not getting good profusion that have diabetic foot infections? You know, there's probably other factors playing in as well. And there's a really cool case control study in CID really recently by Garuio at all where they actually found that protein binding was a big predictor of some of these rare adverse effects because there was more free drug. They also found that an elevated CRP at baseline. So inflammation at baseline was probably a pretty big predictor. So you know, we try to save measures CpK and do this. It's not that straight forward. There's probably a lot of factors playing into it. So I don't think CpK should be all or nothing. I think maybe legally we kind of have to do it a little because it's in the package insert. But I think for me, you have to look at the whole patient. If you look at everything that's going on with them, do I have another reason that it's high? And I think the trend probably is more helpful than the absolute values. Like if you're cruising along and you're great and then it just shoots up and you don't have another reason why then maybe I'm in trouble. If it's high and it just stays high, you're probably just kind of going along as is. So I don't I'm sorry, I don't have a clear answer, but I think maybe legally we have to get them, but the trend's probably more important. And I would love to see in the future more literature looking at other risk factors because I think we just have hyper focused on CpK and there's probably a lot more going on as who is actually at risk for progressing the lab though. Yeah, I would echo those those sentiments, you know, from a medical legal standpoint, certainly continuing to do at least once we've got CpKs is considering sort of the recommendations makes a lot of sense. You know, it's one of those things I think that we do add up an abundance of caution given what we know about the drug and it's sort of its pharmacology. And you know, the other piece is that CpKs are not the only toxicity that we know about with Daptomycin and that could be concentration related or exposure dependent. So the other thing is the asynophilic pneumonia, right? So we sort of see that that tends to occur late in the course of Daptomycin treatment and it seems to be about, you know, seven days or so, maybe a little bit longer into the course of treatment. And the thought there being is that the free drug concentrations increase within the long space due to sort of interactions with what we talked about earlier, the longs or fact, altering the biology of the response. And so the immune system becomes activated in response to this, you see use and philocnamalutic place. So there's not really great exposure metrics for this, right? It's something that you monitor for in patients and then you're going to stop Daptomycin if you suspect you're a synophilic pneumonia. So really monitoring and looking for, you know, changes in the clinical signs and symptoms of what's happening in the patient, you know, nuance that we're sitting of oxygenation status and things like that. But that's primarily the main toxicity we think of. So, you know, I think Raptop certainly being very rare, maybe benign transient increases in CPK are like warning shots across the bow that we take seriously. But, you know, we'll monitor and ESL philocnamalutia. We're going to stop treatment and sort of initiate appropriate management. Yeah, I was going to say the number of times I've seen ESL philocnamalutia from Daptomycin is way more than I've seen Raptop from Daptomycin. And like Molly was, wait, both of you said, I think from a legal standpoint, just because it's in the package insert, people feel the need to monitor CPK. But I will say that whenever it does have start to have like elevations from baseline, after you get that baseline, like Molly said, you can kind of attribute it to other things that are going on with the patient. And often it does just get attributed to other things going on with the patient. And we don't stop Daptomycin most of the time. And so in my personal practice, I feel like it is a little bit of a waste because you're just going to explain away the elevation anyways and continue on Daptomycin. And the only time I've truly ever stopped Daptomycin is with ESL philocnamalutia. Now, after you have a patient who has come in on Daptomycin, ESL philocnamalutia, say they come back in a month later, similar infection, or they need Daptomycin again, would you re-give them Daptomycin again, or would you be more hesitant because they've had that episode in the past? I'm a little bit conservative, so I would not. As I say, my general inkling is to be conservative and use a different drug. Oftentimes we can use a different drug when Daptomycin is involved. So being more conservative is definitely the approach I would also take. I don't know, Molly, if you also feel the same. Yeah, I vote that too. Yes, we're all the same page. Yep. Awesome. Yeah, so those are the two main toxicities that I wanted to talk about. Big questions we get. I feel like ESL philocnamonia is not something like you learn about CPK so much in school, and it's on every single checklist when you're a student or a resident to like look for, make sure you get the level, and no one emphasizes ESL philocnamonia, and then you get the first patient and you're like, whoa, that's a thing that happens. And so I do think shedding some light on that other toxicity is important. And taking note of Jim's notes about when you can kind of see that happen in patients. All right. I think that rounds out our discussion about Daptomycin here at Ducing Consoles. We try to keep it brief. So that way you can fit this in on your commute into work. If you have a 45 minute commute like I used to have, I do want to move onto our segment that I like to call I feel nerdy. So I feel nerdy is meant to be a safe place for our panelists and nerd out over their favorite ID topics, quirks, fun facts, sometimes just stories that you want to tell about patients or something that's happened. So for today's edition, I would love to know your favorite teaching point for Daptomycin when you're teaching or on rounds with any learners that you have. So we can start with Molly. How about that? Okay. So one of the things that I think is really interesting with Daptomycin is that it's been studied a lot in recent years for synergy. And we've talked a lot about, you know, can you push the dose this high? What do you do in obesity? And I think looking at potential combination with synergy provides a really nice kind of off ramp or a side ramp to get into kind of a different lane when you're in these situations and maybe use a lower dose and still get hopefully good outcomes for your patients. But so I'm like a super, you know, lab nerd. So this is like super, super nerdy, but this is where I go when I think about the stuff with so it was just so nerdy. And certainly there's some really cool data with Daptomycin backdrome combination therapy and staff that you know I did when I was at Ryback. It actually is super effective. There's also some really cool new data with the appdome façade mice and if you're curious kind of go look that up, but I'm just going to focus on the beta lactams because it's just really interesting how staff worries and enterococcus are very, very different. So the combinations of Daptomyin beta lactams have been studied in vitro and clinically for both staff worries and enococcus. But what beta lactam you need to use in each scenario is very, very different because it's based on their PVPs. So Warren Rose has actually published two really good articles in AAC one in 2013 and one in 2016 where he looked at PVP selectivity of various beta lactams and how likely they were to be synergistic with Daptomycin for stack orias. And what he actually found is PVP one selectivity and potent was what was most important. So actually the best antibiotic technically to use for DAPTO plus beta lactam for separation is actually a miro-pendom. Now I'm not saying we're clinically going to do it, but if you just look in the lab and in like in vitro stuff that's actually by far the most potent and then you know there's a few other ones that are somewhat selective that hit like you know one through three like naphthalene and septarylene and stuff like that that are still good you still get a positive effect but they're actually not as good as miro-pendom just putting that out which is very interesting. Solar clinical studies look at septarylene and we look at naphthalene we look at all of those and everything like that but when we move over to entro-cockus because entro-cockus is so smart right it is just like such a smart little dude so there you actually have to saturate all the penicillin binding proteins to actually get the synergistic effect right because entro-cockus is super smart so if you saturate one or two it just aburculates the other ones right so you actually have to saturate all of them so there your most broad penicillin binding proteins are actually going to be the ones that are going to have the most efficacious as far as synergy against entro-cockus so that's going to be more like ampicillin, amy-pendom and this couple of things like that so they are not created equal and we actually are not looking at the most optimal combinations when we look we've been studying these combinations clinically so some of that translates in vitro-suctant quite make it up to clinical practice but aren't they super smart these bugs are so smart they are so smart right I love that very very smart as a side note my PGY1 I had a very very special opportunity who Lou who is on this podcast a couple of months ago about line locks she got me in with Ryan Shields at his lab at UPMC and I did a study on combination therapy with deptomycin and bankomycin and septarlene and kind of pairing them all and running time kill studies in his lab which is a great PGY1 opportunity appreciate him so much for that but I read Warren Rose's paper and I saw that like Mara Penum was one of the better options and we were like clinically this will never fly so we're not even gonna study it no one's gonna do this so we did like combination with oxycylin septarlene and then deptomycin and also bankomycin with a different combination so I have a funny for our listeners I'm showing them my mousepad that I made for me and Ryan when I was in his lab he's a very big grim negative guy and so he at one point said to me I don't want to like gpc's but I'm getting suckered in during my little stint with him so it was a fun time and I really like that because that's probably one of my favorite things to to teach a lot of my residents as well so Jim do you want to round us out with your rifle nerdy oh sure you know that was by the way Molly that was awesome thank you for for sharing that that's a great teaching point when it comes to you know stuff that you know I focus on usually being a bit of a pk nerd myself I like to try to get the students to think about just sort of if you're trying to think about the pkpd and if you're going to achieve your target or not let's say you're targeting let's say 27 right as a free auc to myc for anorogoccus you can do some back at the end of a lot of math using pop pk making a best guess about what your clearance is assuming that they don't have augmented clearance but I just looking at the pot values of you know you have a pot clearance of 0.75 that doses 500 your auc to myc is going to be 666 interestingly they're about and if you take the protein binding into account you have 10% that's 66 so there you go you're already above their free auc to myc target obviously the variability comes in in terms of where that patient's clearance really is and I think that the nerdy aspect for me is that the upshot from the most recent paper that we sort of been discussing throughout this entire episode is do we need to start doing tdm for depth of myc and I think that's really the going to be the nerdy teaching point in question that we start to ask more and more going forward for depth of myc and is do we really need to peg the tail on the donkey for this patient's clearance and if we do let's start talking about the tdm so that's my minor nerd point but I think that there's more room for this in the future to really understand what's actually happening under the hood for our patients I love a good tdm I feel nerdy even though really hard to translate into most clinical practices but I love discussing it especially since we use daptomycin outpatient so much and we have this grayish area when it comes to fixed-based dosing and then also the n-arococcus realm so it's definitely something that's fun to consider and something maybe we'll have a episode two of daptomycin in the future when we start to get data about tdm and depth of myc and all right so thank you guys both so much for finding the time to do this it's always so hard in the summertime with everyone's lives and so we really appreciate you guys coming out and sharing your expertise with us I've learned a lot of things with this conversation and maybe have some new teaching points that I can use in the future for some of my residents thank you so much for having us thank you so much for having us it's been a blast I really enjoy our conversation today yeah great so thank you everyone for listening to breakpoints the society of infectious diseases pharmacist podcast I have been your host Jeanette Bouchard and our featured speakers have been doctors Jim Rhodes and Molly Steed breakpoints was created by Julianne Justo Aaron McCreary and Jason Pogue this episode was produced by myself in Megan Clatt it was edited by Emily Plouche and peer reviewed by myself and Eileen at his cally the transcript was edited by Bezma Hassani and Anna Zo our production team includes Justin Moore and Mary Hutton the executive producer of breakpoints is Aaron McCreary and our theme song was recorded by SIDP member Steve Smoke and you can subscribe to breakpoints on apple podcasts Spotify or wherever you get your podcasts thank you for listening and helping SIDP achieve our vision of safe and effective antimicrobials for now and the future