Dosing Consult: Amoxicillin/Clavulanate

[Music] Hello and welcome to Breakpoint, the Society of Infectious Diseases Pharmacist Podcast. My name is Megan Klatt and I'm an infectious diseases and antimicrobial stewardship clinical pharmacist at the University of Kansas Health System in Kansas City, Kansas. Today is a day that I've been very excited about for a while now. Today we are going to explore the wonderful world of a Moxasil and Clavulone dosing. Back in October of last year, our Breakpoint's Instagram ran on pole to get listener feedback on what antimicrobial should be up next for a dosing consult series. And over half of our respondents picked good old Mox Club. So a shameless plug to follow us on Instagram and yes, we do listen to you all and appreciate your feedback on episode topics. But before I dive into our content today, I need to take a second to once again promote the upcoming infectious diseases pharmacist day. The annual infectious diseases pharmacist day will be held on Thursday, May 22nd. This day recognizes the importance of ID pharmacists in promoting appropriate antimicrobial use in the contributions they make to patient care, education and research. This year's theme is innovation and ID pharmacist leading the way. Please check out the website www.sidp.org/idfarmistestay to access the advocacy toolkit, promotional content for social media, and this share your story contest where you could be the winner of a free one year S.H.P membership. Deadline for the Share Your Story submission is Friday, April 25th, and we invite all submissions that highlight the work of pharmacists. Already back to a Moxasil and Clavulone dosing. We love using beta lactams for common infections, and a MoxClav is no exception to this rule given its activity against mainly gram positive, but also a mix of gram negative and anaerobic bacteria as well. However, while the addition of Clavulone or Clavuloneic acid, depending on your persuasion, was a definite net positive for the in microbial spectrum of activity of a Moxasil and it is not without its challenges, particularly as it relates to a wide variety of combination products and formulations which one do you choose, as well as tolerability concerns and looking at uDiary up, etc etc. So for today's episode, we are going to attempt to run the spectrum of PKPD for a Moxasil and Clavuloneic acid. What is that ideal ratio for different infections can and should we give a jump to a Moxasil in for certain cases and much much more. It is my absolute pleasure to introduce two amazing expert panelists to answer these questions. Doctors Pierre, Giorgio Cujoui, and Navanisse Naryan. Dr. Pierre Giorgio Cujoui is an MD clinical pharmacologist who works at the University of Bologna, Italy. His scientific activity is focused on pharmacometrics and quantitative pharmacology. In this area, he is responsible for developing population pharmacokinetic and pharmacodynamic models aimed at studying the adequacy of drug regimens. Central to the research activity is the study of pharmacokinetic pharmacodinemic relationships in special populations and in relation to new biomarkers of response to therapy in the field of anti-infective and anti-neuoplastic chemotherapy. He is the author of over 100 publications in international peer-reviewed journals. Welcome Pierre to breakpoints. Hi, nice to be here. Thank you. I'm thrilled to have you on the podcast today. Your expertise in PKPD will be an absolute asset when we dive into that data. And joining Pierre is Dr. Navanisse Naryan. Dr. Naryan is a clinical associate professor in the Department of Pharmacy Practice and Administration at Rutgers University Ernest Mario School of Pharmacy. He jointly practices as an infectious diseases clinical pharmacist at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. He is also an adjunct associate professor in the Division of infectious diseases at Rutgers University Robert Wood Johnson Medical School and adjunct faculty and TB consultant for the Global Tuberculosis Institute at Rutgers University Medical School. He serves as an advisor for and voting member for the CLSI and Immacrobial susceptibility or AST subcommittee and co-chair of the AST Breakpoint Working Group. So excited to have you on the podcast today enough. Thanks, Megan. Appreciate being here. Absolutely. It's so wonderful to have you join us. Your insight on breakpoints will be extremely useful when we dive into dosing of this fun agent. So let's get started. A quick refresher and history lesson on a mox clap. Clavionic acid was originally isolated from streptomyocytes clavula gerus in 1970s and in the early 1980s the mox clap became the first beta lactamate and beta lactamase inhibitor combination available for clinical use. By itself, a moxacillin has activity against various streptococci and anercocci species. While the addition of clavionate expands the agent's activity against beta lactamase producing organisms like penicillinase producing staph aureus, amophilis and moraxella as well as certain E. coli, clavcella and proteus species and anerobs as well. Today, a mox clap is typically used for the treatment of disease states like otitis media, cap and bacterial sinusitis. But it can also be used outside of those clinical scenarios and we'll discuss how we can optimize dosing in those particular settings. Lastly, we all love our pediatric friends, but unfortunately today we're going to really focus and hone in on adult dosing where that typical dosing of a mox clap is 875 milligrams of moxacillin in 125 milligrams clavulane every 12 hours or 500 milligrams of moxacillin and 125 milligrams of clavulane every eight to 12 hours and both of those are oral regimens. Pierre will tell us a little bit more later in the episode about intravenously administered a mox clap once we get there. All right, so with that lead in now, can you tell us a little bit about the PK PD of a moxacillin and clavulonic acid and how we came up with these magic ratios of seven to one and four to one a mox to clav for most infections and adults. Yeah, no, I'm happy to go through that. I like your history lesson because I think it's more into sort of be grounded in that and a lot of honestly what we're going to talk about and at least the perspective I have really stems from sort of that historical perspective of the development of a mox clav in where all these things came from. So we know a moxacillin is a oral beta lactam, clavulonic acid is a beta lactamase inhibitor. A moxacillin has generally good bioavailability, especially in contrast to how we think about a lot of other oral beta lactams, but this is sort of an exception to that general rule of having four bioavailability. You see some estimates across different studies 70% 80%, but it's quite good in general, but the notable thing about that aspect is that there's actually satchable absorption and satchable absorption rate constants, meaning that once you get to higher doses, the absorption starts to slow down and saturate, and even the bioavailability can decrease at those much higher doses. So clinically, for me, it just means that you have to sort of weigh the risk and benefit of giving much higher doses, because it's not like you're getting a linear return on that dose in terms of exposures. So the higher you go, you have that bioavailability reduced. Clavulonic similarly also has a lot of variable absorption, and so there's a lot of variability across the exposures you get with that. And so I think those are all things that should be kept in mind as we sort of talk about dosing and what scenarios we should use it. In terms of how it's eliminated, it's also another relevant sort of feature. A moxam, like most beta lactams are extruded unchanged in the urine, so they could quite high concentrations in the urine. Clavulonic on the other hand has some metabolism, but there is still a decent chunk that gets expreated unchanged. Some estimates can show up to 40 or 50 percent. But overall, the big takeaways that the urine concentrations can be quite high and meaning like over 100 fold higher in the urine compared to the serum for both drugs. Like a lot of beta lactams, a half-life is quite short. It's probably around an hour. And so all of these I think end up being pretty relevant clinical factors. And so that was all the PK, the pharmacokinetics, just sort of describing how it's distribution throughout the body. The pharmacodynamics, it's also notable. So like all beta lactams, the PK PD index, so how a moxasillin works and it exerts its activity is the percent free time above MIC. So if you can maximize how long those concentrations are above that important threshold, the MIC, you maximize its antibacterial activity. And so that's the metric. The question becomes, well, how much is enough or how much is good. And for enter bacterialis, which I know people spend time talking about, it's not really well established. But there is good data and sort of extrapolation from homophilous influenza as well as streptococcus pneumoniae. And generally, which is kind of consistent with how we think about penicillinants in general, we think about 30% free time above MIC as sort of a stasis endpoint and about 50% free time above MIC as a cytol endpoint. And so this has been shown across those organisms and how we generally think about that. For clavioine, it's a little bit different, but there's obviously some similarities. For clavioine, it's basically the percent free time above a threshold. And we're talking about beta-lactins at threshold with the MIC, but here it's sort of an independent concentration threshold. And so having 0.5 micrograms per ML is sort of that critical threshold that you want to imagine. maximize how long the concentrations are above that concentration and that's specifically for enter bacteriaries. And so the question is, well, how much time in a day, let's just say, do you want to be above that threshold is probably around 30 to 50% so similar to a mox in terms of just the numbers of the values. And one important thing, which will have a lot of relevance in terms of how we dose and use this is that pharmacodynamic target is different. Depending on the organics, so for enter bacteriaries, it's 0.5 microns per ml. And then you're trying to maximize 30 to 50% above that in terms of tie. For homophilsin influenza, it's lower. It's easier to get above a concentration because that critical concentration or critical threshold is 0.12 microns per ml. So about like a fourfold difference. Those ratios, I think, was the next aspect. I'll at least say it didn't come out of nowhere, although it sort of confuses me a little bit when I think about it's like a million different combinations and ratios. But like I said at the beginning, I think that history lesson is a good place to start. So if you go back decade and decades, the first formulation kind of was clean. It made sense. It was two to one. It was 250 milligrams of a mox and 125 milligrams of claviline. But that amount of a moxicillin over the years based on clinical need, based on severity of infections, resistance pattern, changing susceptibility, et cetera, that a moxicillin component went up. And we'll talk about the claviline in a second. But if you look at just regular moxicillin, the standard doses were or became over time, 500 milligrams, 875 milligrams. So did it make sense to leave the moxicillin in a moxid clavit 250? Right. So then you have your 500 slash 125 and your 875 slash 125 sort of as a result, based on needing higher a moxed. But the thing is the claviline part stayed the same at 125. And I would say if you think about what it was intended for, that makes sense, right? It sort of fit for purpose. The purpose wasn't to treat multi drug resistant, you know, enter back droves, right? It was to help counteract the beta lactamases that were produced by homophilsin, volensin and more excella, right? In terms of respiratory infections. And so you have a beta lactamase inhibitor that protects you against those beta lactamases that are easier to cover from a beta lactamase inhibitor standpoint. But then you're cranking up the dose of a moxillin to handle more drug resistant or non susceptible strep new low. And so that just stayed the same. And then the mox just kept climbing up. And that's where you get all these magical combinations in ratios that that we see today. And then the last step is the most recent formulation, which is that 16 to 1 ratio, which is the 1000 milligrams to the 62.5 milligrams of clavulane and the dose being two grams of moxicillin 125 clavulane, but that's specifically designed to overcome drug resistant strep new mo, which is based on PPP mutations and lower affinity. So it's once again clavulane fine, just keep it as is to sort of help empirically cover those other things that produce beta lactamate, but just keep going up and up and up on the mox dose for that PPP certain mutations that you see with strep new mo. Yeah, that's really fascinating. And again, kind of takes it home to why we're talking about this today is that this drug was originally designed for cap sinusitis, those sort of organisms. But like any drug, we use it outside of that particular space. And so how to optimize the dosing in that setting really becomes key when you start playing outside of those organisms. The way I think about it is it's helpful to sort of anchor your mind is when we're using a mox type, at least oral mox type, I know what the village think about oral mox type, when you're using it for enteric gram negative infections, I think of it as a repurposed drug. Like that's not what it was for. It was a repurposed drug. So the way it was designed the way it's dosed, that may or may not actually translate to this free purpose indication. And so if you put that as like a mental framework, at least it makes me feel better that it's complicated to free purpose it, that it's not sit nicely for that purpose, because that's not what it was for. Right. Exactly. Yeah. Why we're having this conversation today. Otherwise, why would we be here? Wonderful. That was a really great overview. And again, love a good history lesson. I feel like I've learned a lot already. But now I want to hit you with the difficult questions right off the bat. You actively serve on a CLSI breakpoint working group. I know you have all the juicy details now. So let's talk a mox type, MIC distribution and breakpoints because a lot of our discussion today, particularly as you alluded to with the grand negatives is optimizing dosing to get sufficient exposure at certain MICs. Yeah. I'll start by saying I'm a happy volunteer. And it's really an honor. I work with some really phenomenal people. I co-chair the breakpoint work group with Mike Sattlin. And it's really enjoyable. And I'm happy to give any insights that I can. Because I think there's a lot that we can adapt to how we think about these things. And honestly, I'm glad when you're saying that even before you said breakpoints, you said the MIC distributions. Because I think that's a really good starting point to help understand how these breakpoint assessments and proposals get developed. So the 10 second primer on development of breakpoints is there's multiple sources of data. MIC distributions and micro-biological characterization of the wild type population as well as resistant populations and the genotype, phenotype interaction in terms of what the MICs are for certain genotypes. That is like step one. The next step, which is the sort of most contemporary step. And you know, I think what we enjoy, especially as best pharmacist is the PKPD aspect. And that is really in my mind, the translational piece that helps bridge that microbiological characterization to the clinical world. And then the third is really any clinical data that could help inform and help validate. Because at the end of the day, these are clinical breakpoints to be used in patients. And so any type of clinical validation would be helpful, although the strength of that data is always challenging. But like you said, the MIC distributions right away gives you a big clue as to the differences across organisms. So if you look and I'll use just some prototype organisms to help illustrate this. But if you look, you know, there's publicly available databases like JMI century surveillance program. I think you have to make a log in, but it's freely available. And so you can look at MIC distributions and I'm sure many people have it. But more like a side. I heard it's love it. Love that site. If you haven't actually gotten the profile, you absolutely should. I recommended to everybody every single ID pharmacist position. And like you have access to the site, right? Yes, it's like my second favorite thing to show after the micro free on CLS size, like website where you can see the M100, which shows you all these breakpoints. So everything I'm saying in terms of breakpoints, it's freely available. If you Google CLS side, micro free, it'll come up and you can see all these tables that I'm talking about. But if you think about the fit for purpose organisms, like come off, it's influenza, strep pneumo, more, etc. The MIC 50, the median MIC, right? The MIC 50 is less than equal to one. And then the MIC 90 is two or even less than equal to one in terms of more acceler. For E-coling side, CLS, the MIC 50 is eight and four. And then the MIC 90 is greater than E. It's so the off scale in terms of what the JMI Century program measures. And so the central tendency of the distribution of those entire gram negatives are multiple dilutions higher than the central tendency of that actual sort of a mox, clav, targeted organisms like homophilous strep pneumo and more etc. So that big difference right there just tells you there's a potency difference, right, between the two. And then there's the epidemiologic cutoff value. On this side of the Atlantic, we call it the ETV and then on the other side, they call it the E-Coff, but terminology wise, it means exactly the same thing. And me and Pierre can kind of debate which the Krunenborg revision we like better. Exactly the same. Those try to characterize the cutoff of where the end of the wild type distribution is. So it's sort of like a prelude to a break point, but it's just an epidemiological description. It's not a break point. The ECV for E-coli is 16 for PLEBSI LSE for proteus, it's four. So the enterobacterialis, those prototypical enterobacterialis lives in the high end, right, four, eight, sixteen all all over there. Homophilous because we also looked at homophilous for break points, it's two probably as estimated. So it's the same day. It's just that distribution for these homoclav organisms are to the left and lower and then this enterobacterialis is the right. And so the break points, so for enterobacterialis, the break point, it is less than equal to eight, eight clash four. For homophilous, it less than equal to two slash one for strep pneumo, it's less than equal to two slash one. There's a whole different conversation about where you set break points relative to the wild type distribution. But that I think is a great way to do it. hopefully should just give a sort of eye opening look as to the differences of those organisms and the potency of a Mox live across those wild type distributions. For sure, it definitely gives some insight, like you mentioned, as to the differences across those spectra of bacteria. All right, Pierre, you have a menace, which I'm very jealous about. So you abide by UCAS breakpoints. UCAS updated their anorebacterialis breakpoints as it relates to a Mox cloud. I think was back in 2023. And from what I'm reading here, they really no longer recommend or seem to recommend a Mox cloud resistant infections. The oral formulation. Can you speak to that bit? Right. In fact, the Mox cloud is not used for systemic formulation anymore in the oral form. And in Italy, I can tell you that the Mox cloud in hospital is only used high B. The oral formulation are used for mild or autitis media or community acquired pneumonia, healing, patient with it without any kind of comorbidity, so the most safe condition. And for all other severe infection, a Mox cloud is only used IB. Apart from, of course, urethra infections, which I would mention before, are sustained by granulonicate pathogens, easily targeted by a Mox cloud. Because the ad is fully susceptible. But these ad not that really have a problem, I mean, when you use a Mox cloud in the community. In terms of even after those connections, maybe we can speak a bit better on it, which is the best dose of the connection of positive infection, from a significant infection. We will dive into that for sure. And yeah, when you look at that, you cast a rationale document. They really focus a lot on a paper that I want to pull up. It's from Deviled in Colleagues and Published in Jack in 2016, where they look at different Mox cloud dosing regimens, perform a PKPD analysis, and essentially provide information as to the probability of target a team. And so now, can you summarize that study for us? Since that will lead into some of those conversations about how to optimally dose Mox cloud when you're dealing with enter back to rallies where your MRCs are a little bit on the higher end. Yeah, I could be happy to. I mean, this was a crucial study when we're looking at the break point assessment, when actually Paul Edelstein broached this topic and presented those one of the studies he presented on to raise its issue. And to even just go back when I said the enter back to rallies, the break point for Mox cloud is less than equal to eight slash four. It's a specific nuance where there's some context added to that. So the comments specifically associated with that and say, for IV fine, but for the oral formulation, the application of those break points are really for UTI or infectious or in your nurse source as well as oral step down quote unquote or at the specific languages for a completion of systemic infection. And so there's an important nuance there. And that nuance really feeds into this study that you mentioned. It was a really well done study. It's a PK study. And the goal of it is to really just characterize the the pharmacokinetics of oral Mox and create a model. So being able to quantitatively describe that pharmacokinetics across the population of patients. And then you can assess the probability of hitting those important PKPD targets like you mentioned. And so they used 40% free time above MIC as their A Mox target like we talked about before. I think the context is important. They enrolled about 30 healthy male volunteers. And so it just keep that in mind because the PK can vary between healthy volunteers, patients, and even critically ill patients. And we know that there's variability across that. But it across these approximately 30 male healthy volunteers, they gave them a bunch of different dosing regimens of a Mox. They drew a bunch of blood samples. They measured those concentration and they were able to sort of characterize the PK at a population level. And what they found was there's a big takeaway is to hit a high probability of targeted team. And I think that's an important definition about 95%. So meaning they wanted not just an A, they wanted like an A plus in terms of through probability of targeted team. The cutoffs they notice was when you're giving 875 BID, the sort of cat to the MIC that you can cover in order to maintain a 95% probability of targeted team was 0.25 micrograms per M. If you're giving 500 TID, 500 three times a day, the highest MIC that you can cover to hit this high probability of targeted team is 0.5 micrograms per M. And if you're giving 875 or 1 gram TID, then it's 1 microgram per M. So as you go up in the dose and the frequency, you can cover a higher and higher MIC. And that's what we think of as quote unquote the PK PD cutoff or the PK PD break point. What's the highest MIC you can cover with that dose in order to maintain a very high probability of hitting your target? On the other hand, for 5 yuan, the 125 milligrams that we know, if you're giving that BID or TID, the percent of time that you're spending above that concentration threshold of the 0.5 micrograms per M. That we said, it was less than 20%. So didn't really do well. And so that is an important take with based on the things that we said. And kind of that surprising because that's not what it was calibrated to. And the last probably important takeaway is that they also notice this nonlinear delete absorption. So hitting on some of those earlier points about the PK that's a satchable absorption rate. So you can still increase the exposure. And so you can still increase the free time above MIC with higher doses. But it's sort of a bit slower in terms of that rate of absorption. Thank you so much for summarizing that study. Pierre, do you have anything to add? Yeah, it's just a consideration about the most cloud and the target now correctly mentioned. The target that for most of the time is 30 to 40, 50% the time above the MIC. But we have to underline that this time, it is that suboptimal for any better. So especially for severe infections. So this time it could be okay for community aquanel infection, those type of no severe, no spetanizing infection. But for severe infections, so we should go for higher target. So 100% about the MIC or even 100% for telling the MIC deserve a target for example, any bit an act of news in critical contaction. So it would consider a so less aggressive target of 34 or even 50% of the MIC, which is I should say spoptimal. It's actually in the presence of local epidemiology aggressive from a microbiological point of view. Constituation, additional considerations, they think that from a certain coordinate part of the ocean should be taken into account. And they said both two are the instead of increasing the dosages using a suction dosage instead of using porous as one gram every or 12 hours. It is better to increase the frequency to trying to optimize this no performance pd target. This is my opinion. You pair agree with you. The half life is an hour. And so like once again, if you stay rooted in the development, you know, having this Q12 regimen, it's because it's the supposed to be an outpatient option, right? And I don't know the data off the top of my head. But there's a big difference in terms of adherence rates with TID versus BID. And so like it's not designed for these like tough infections, at least the oral peer to your point. I think especially for folks that are comfortable with these pkpd simulations, every assumption you put into this simulation in the model is just an important consideration. What's the target is a 30% 40%, 100% what are you trying to hit when we say probability of targeted attainment, right? Then it's also what's your threshold? A good probability. Is it 80% is it 90% is it 95% like you cast I know uses 95% COSI. It's a little bit more flex, but maybe 90%. So it just it varies like what's your definition of a good probability, right? In terms of thresholds and there's there's a lot of interchangeability of those sort of parameters, right? In terms of the phase of therapy, is it initial parity? Debt down. So there's a lot of just things to consider because if you tweak those a little bit, those pkp cutoffs will change. And I think that's important. It's not these aren't set in stone, these pkpd cutoffs. So when we look at all the data, we keep that in mind as to being fit for purpose. Yeah, absolutely. I think that's a really good background for our conversation about applying this to clinical practice and making these decisions for our patients at the time of deciding oral step down or or transitioning to a different antibiotic for discharge. So that was fantastic. Let's summarize this thus far. We have different MIC distributions for different organisms as it relates to a MoxCLAB, whereas organisms like homophilus and moroccella tend to have MIC distributions that are one to twofold lower than our NRB which tend to be higher. And then we have these pkpd studies that suggest with standard dosing that 875, 125, Q12 hours, we may not be achieving the necessary exposure to meet those MICs that we tend to see for anorebacterialis. So we could consider pushing that dose, but what dose do we select? And how do we make that tolerable for our patients? And honestly, should we even be recommending a MoxClab in serious infections if we're unable to achieve that necessary exposure? So let's talk about those situations and start first with our grand positives, which might be the less controversial of the two. So Pierre, can you walk me through how you would decide optimal dosing of a MoxClab oral in setting a grand positive organism? So less so a bacterial sinusitis or acutotitis media situation, but more so more difficult to treat infection, let's say a grand positive osteomyelitis or a bacteremia. In general, for grand positive infections, high-dose moxocinin should be useful for any infection where some of the compus chimonic carbohydrates needed. That is the basic concept. This is simply because of the last, let's say, 20, 30 years, that the hypogoclinic moniastrates with reduced susceptibility, then it's as a merge. And when I say reduced susceptibility, I say, MLC greater than 0.4, right? One or even greater than one milligram per meter. And so this stress start to emerge and the diffused worldwide. And in some countries, some of the immunosicul studies show that even 50 to 60% of those streptococs, the monistrates, the type of NIC greater thing. So if we look with this scenario in mind, if we look what could guidelines say, well, they see that they recommend the combination with a mox cloud of 875, 1.23 milligrams, twice daily, which means 1 gram every 12 hours, or 500 milligrams three times daily, which is another option. The same, the nice guidelines which have to pay based guidelines very followed here in Europe. So that's basically the same strategy. So 500 milligrams every day, plus or minus a macroevalent. Of course, these, these dosages are insufficient. We have to clearly state this. Our insufficient considering both the microbiological point of view. So the fact that has I told you resistance rate of streptococcus demons are increasing. What what happened, a chemical kinetic point of view, which is the length. And speaking about community of what the morning because the long is a set of infection where an idle feed it can't be out of like moxacillin doesn't penetrate very well, doesn't penetrate very well. So for this reason, many tertiary care hospital and in many countries, adopted high dose of moxacillin strategies, including for it and hearing the larger views. Many years, those just still cover moxacillin, as a title is one gram every six hours or 2.2 gram every eight six hour IV road value, don't have a V road. So a container is only one gram every six hours already. Standard dosage could be used when for instance, streptococcus pymony coverage is not needed. So for instance, by the bones, where streptococcus pymony is not the cause of the agents there. So I let a great doesn't throw to make sense here, but make on that that they would prepare a moxac have one gram every six or even years, even in this context. Also taking into account that for instance in a skin, skin structure infection, a moxacillin having a no running of distribution, doesn't penetrate one into skin as a skin structure and so you have to consider, of course, the microbiological aspect, but even the patient, the pathophysiological condition, the side of infection, which makes all the difference because one thing that having a bacterium is the bacteria in the bacteria in the other called little difference scenario is that for instance, the ammonia works or even in fact, you need the bones that they can can speak about that another important answer to anything that may raise your interest in our interococcal infections. Well, for interococcal infection, for the sake of precision, let the lactants for a visiting susceptible interococcus, either insulin, not a moxacillin, simply because the MSC range for a visiting time, lower for interococcus, with respect to a moxacillin. And in this scenario, here, Google guidelines that recommend a visiting or a moxacillin after the dose of quadgrams daily, IV dose, of course. In recent years, there has been an increasing interest in oral antibiotic as the switching from IV to oral dose, so it could make sense, but in some particular select patient. So namely, those stable formal clinical condition and often appropriate period of IV parental antenna, and switching to oral dose could be, could be pursued. So in this case, the moxacid dose could be used, but those is at 1 gram per six hours, so for a brand day, all that, probably in conjunction with other antibiotics, such as occipital lynacid, but it is at quite particular situation, I wouldn't stress too much of this, a scenario of interococcal infection, because in my experience, interococcus, interococcus, infection should be treated in IV, of course, because of a serious infection. You mentioned before, bone injury infections, well, this scenario is particular because from the cake point of view, I have to say that the moxac clav being an eye-juptal antibiotic, it penetrates poorly into the bones, so penetration is very limited, and in case for instance, of ostomatellitis, so it is substale by the mediscelling susceptible to the occipital lynacoccus, so hemensis, they, well, the moxacinin is not a jacked choice for oral treatment, so other options, for instance, using lipoflopsicin, which is susceptible to MSSA, lacerin, lacerin, as you've seen, this is very interesting argument for the oral management of bone injury infection, not the moxacillin. So, just to conclude on this overview on the positive infection, I would say that administration of moxacillin with the wider ratio of 71 appears to be sufficient overall, in terms of glambulonic acesic exposure, it is not so compelling in this type of infection, there are also formulation with wider ratio, of course, this apply only to gram positive infection, in the glimicative infection, the need for high glambulonic acesic is, of course, different. Thank you for that insight. To summarize for the audience for gram positives, we really do want to be using a moxacillin instead of a moxacillin clavulonic to get those higher moxacillin doses whenever possible, and of course also to spare unnecessary clavulonic exposure. I think you also made a good point with anurococcus specifically that we want to be a little bit wary about using moxacillin, particularly for bone-injointed infections, where not only are we concerned about maybe the higher MICs with a moxacillin versus ampacillin, but also penetration into the bone as well. Now, if you did have a situation and went to really needed or wanted to use a moxacillin clavulonic, maybe it's a mixed infection, let's throw in a gram positive and heck maybe anurococcus as well. If you really needed to cover those organisms, do you add additional moxacillin to the standard 875, 125, BID, or what kind of regimens have you concocted in the past? Yeah, that's a good question. I guess I'll start saying that because this is more or less a repurposed drug for that, I've seen, referred from colleagues and seen around all types of needle concoctions to sort of make things, make things right and fit, and there aren't a lot of studies, so that a lot of this is not like we evidence based, but maybe more sort of experience based, and you have to take that with the grain of salt in terms of the validation of that sort of broached, actually, he me madder, she was a guest recently, I think too, right? So she's a phenomenal human being at UVA and she was a big help, especially from the clinical aspect when we're looking at immunopenicillin breakpoints, she did a very thorough review, looking at sort of oral moxac clav and anurobacter alleything infections and a lot of the studies, diabetic foot infections, maybe one or two on complicated and tribdominal infections, complicated skin and soft tissue, infections, things where there were anurobacterialities found, but all those were way later in terms of approval, so there were like in the early 2000s, right? And a moxac was, you know, a couple decades before that was approved, so all this is sort of awful able fashion for that purpose and all of them were used as step down therapy, so they were not like let's give them oral mox clav right from the joke, and I think that context is is important because even how you would try to develop a preclinical model that translate it is different in terms of step down therapy, right? If you give even one ID dose that changes the whole calibration of the whole of what the efficacy or ET bacterial activity is going to look like even in a model, if you then follow it with something that's less potent but in oral asian. And so when you look at the price of those, a lot of times they were giving the 875 BID because that's convenient. And you don't see a lot much beyond that. If you're really using it for a gram-negative infection, like enter-bacterous infection, I think taking the context is important, but then if you look at that PKPD view, you need higher doses, right? And it's not just higher doses, you need higher frequency. So like in the developed study, 500 TID was not the same in terms of its PKPD targeted team. It has eats 75 BID. It did a little bit better. So all those a little bit lower of a dose, it wasn't like completely interchangeable from that PKPD simulation standpoint. It had a bit of a higher cutoff, so it covered one dilution higher in terms of the MIC. And so it maybe it's not enough to just give a higher dose. Like, oh, we'll give one gram BID or two grams BID. The problem is it necessarily the Mox dose is too low. It could be the frequency is not low enough, so you're not maximizing the free time of MIC, as well as the aspect of the clavulanate dose. Right? That 125 milligrams is not designed to hit such a high concentration threshold that you need for interactuality. It's designed for lower constriciate thresholds you need for the beta acrimates produced by things like more accelerome, homophilsine, flungie. And so can you do 875, 125 TID? I don't know, sure. Why not? But like if you really are desperate at that point, you should probably be very thoughtful about the choice that you're making for the negative that you're trying to treat at that point, because it also might be sort of a mood point, because if they've gotten a week of ID therapy and they're sealing Chipper and about to go home, then maybe you're just giving them sort of not a placebo, but just something to send them all on to make yourself feel better if you give them the 875 BID. So you could give a higher frequency. I do think it's reasonable from two perspectives. One is that 875, 125, you give more than that, which is a Mox-cylone alone from the Mox-cylone component. So we know giving a Mox-cylone at those doses is okay. The 500 milligram formulation of a Mox-5, you give that TID. So you also know that giving 125 of clavine TID is also okay. And now you're sort of just like putting that together. And so 835 TID is not unreasonable from that perspective, right? If you think about it in each of its components, right? All safe, all approved, even on label, in terms of those doses from individual components. There's not a lot of data. I know that there was, there was a nice paper a few years ago, you know, at least just getting some expert opinions sort of collated that was publishing OFID looking at uncomplicated gram negative blessure infections. And I think I'm pretty sure it was 875 TID that they recommended, acknowledging all those things that we talked about. Was there any data as evidence based for that? No, but there is none, so you can't change that. So at least you can try to get some opinions. The other thing to think about, which is not like validated from a daily dose of claviline eight on label is instead of giving 835 TID, would you double up, you know, the 500 125 and give two tablets and then give that TID. So you get, you know, a gram slash 250 of claviline eight. I'm not specifically advocating for that. It's just something I know folks have done. And from a strict micro PKPD standpoint, it makes sense, because you're increasing the claviline eight dose to help you against those enter back to rallies, produced beta lactamases, which you would need more. And you're giving it TID, right? And so that makes sense. Obviously, the downside is, you know, tolerability issues, right? You cranking up the claviline eight is a tolerable, is there any data? So you don't know of any data or sufficient or rigorous data if that for that. But that's definitely something at least that takes consideration the fact that if you're trying to use claviline eight for beta lactamases produced by these enter vector rallies, you probably need a higher exposure of that claviline eight, you know, because what you have now, that's geared toward easier to counteract beta lactamases produced by each flu and more acela. So that is maybe something to be considered. If folks do this very routinely, it will be great to see data published on that. And I would encourage that. I mean, this is the reason why if you have a certain practice and you have enough to even just throw out there to share your experience, it benefits a lot of folks. And so academic research isn't just for the sake of it. It really helps crowdsource in information and data to help give some evidence pool to things that people might be thinking about doing. But I would just say that, you know, if you're to the desperate point where you're trying to give two tablets of 500 slash 125 TID, then, you know, you should just be thoughtful about should you just be something else that's more reliable or even almighty therapy if you don't have an adequately treated invasive gram negative infections because the reliance on that regimen for serious interactrials infection is really a data free cell. And so you have to be thoughtful about the risk and benefit of that. And don't just go to P.O. just for the sake of it. Be thoughtful about what you, what your outcome goal is at that point. That's a great point. Like we just shouldn't switch because we're trying to find something that's the most convenient for the patient and not what is the most optimal in terms of their regimen. So hopefully I'm going to attempt to summarize this for our audience. If you are attempting to use a MoxClab for a gram positive and aren't necessarily concerned about needing that extra boost of clavulane for a beta-actamase producing organism, the suggestion would be to increase your frequency. So give it Q8 and then try to bump up that a Mox dose to give it as high of exposure as you possibly can. If you're using it for an enter back to rallies, one, you should be assessing your MIC and thinking is this even reasonable for this particular organism. And then again, try to increase your frequency, keeping in mind that you have to be aware of your clavulane concentration and that might increase risk of tight effects with the patient. But there appears pernav and Pierre, I'd like to get your thoughts on it as well. In terms of doubling that clavulane concentration, a lot of the data that we've addressed or talked about has been 125 with the dose. Now I've kind of alluded to this, but Pierre, what are your thoughts on giving two tablets of 875, 125 or doubling up on the 500, 125, giving two tablets of those? Have you run into tolerability concerns? Does it make sense for you to boost the clavulane acid dose and what situations? Yeah, the problem with the MoxClab is the clavulane, can I say the so if you don't need tabulane acid, don't you? This is why for positive infections, older guidelines are commanded only a Moxicilin and even in children, only a Moxicilin is fine for curing or archid status media or even community acquired pneumonia in patient without comorbidities. You add the tabulane acid for covering germ negatives that the better lactamase to use glycum negative because the better lactamase to use glycum positive are quite in existence. So the problem is that and as Nath told before, so yeah, of course 3,000, 84 times 80 is better than 3 times 80, it's better than 2 times 80, of course. I could say that if I have to say for instance, during a immune-etracting infection, I'd normally go with a narrow ratio. So 4 to 1 rather than 7 to 1 or even it's not to mention the the hyena of B2 which makes less sense in curing this type of infection. So multiple windowsing 4 to 1 ratio should be a good choice if you want tabulane negatives in with the Moxicilin. And one point that you brought up that OFID paper that looked at uncomplicated, the cream negative bacteria emus, looking at the MIC and trying to figure out one. I'll just throw out the challenge with doing that is just a few. One is you might not have MICs because some you know get a Moxicilin testing directly and you sort of extrapolate. There's one challenge there. The second is it depends on your automated panel or is it a distest and you might not have an accurate MIC. And so there's a lot of variability in these automated system measurements. You're not doing a reference methods where you can feel much more confident in that MIC being the MIC. And so even if you get what I'm called a low MIC within the susceptible category, it could be a dilution higher, right? What you can feel safe about in most cases is that the validation at least shows that the MIC you get is properly falling into the right category. So taking the MIC at its face value is really challenging to do because the unreliability of that particular point measure. And then the other point is when I mention tolerability issue, talking about GI tolerability, because the IV dose, the clavilane dose is 200 milligrams, and you're giving that at least three times a day. So, it's probably fine, but does that mean it's going to be okay on your tummy, which I talked to my daughter about? Maybe not. So that's a different date, right? So, systemic colorability is a different question than like taking a whole bunch of clavilane and entry. Yeah, absolutely. And that's a great segue, Pierre. Why don't you talk to us about the IV formulation for those of us in the US that are longing for this product, but don't have it? Yeah, yeah. Actually, in Moxic Clav, 90% of the use is the PIDIB in a hospital, that's the true. So, I can tell you, which have the clinic and scenario, the typical IV use of a Moxic Clav. So, the first is by no way acute non-acorficizing, skin-ish and soft tissue infections such as no sugar subnitis or enreciplease. The other is non-apsychosis and community-carb pneumonia, of course, as we thought, in which especially in enderletation, for instance, where there is a race for aspiration pneumonia. And the two substances is another scenario when you need both the and the anaerobic coverage and the vocal coverage. And so, I Moxic Clav is for this scenario. And another area is die-top-earning-track infection, but with microbiologically documented pathogens. The dose of an Amoxic Clav IV is quite high. So, we use 2.2 grams every 8 hours. This is the only available dose. So, it is a ratio of 2,000 milligram of the Moxic lene can show 100 milligram of the pleanic case. So, it is a 10 to 1 ratio. In most severe cases, we can go even with 2.2 every 6 hours. So, high dose. I would say that these 2 doses are the only one we use for IP for the IP treatment of this infection that I told you. Do patients tend to tolerate the IV and Moxic Clav well at those doses? Yes, of course, there is a variability in terms of pharmacokinetic exposure, because in a hospital, you have patients from 30 and so on to 9 years old. So, difference in terms of final drug accumulation, it has of course happens. Of course, it is not that being the monic term in terms of assessing the patient's concentration, but it makes that it could probably be a wide variability of exposure. But in general terms, I have to say, it is well-terligated. More than the Royal treatment. That is really interesting. It's so fun to hear ID practice can differ globally, and again, jealousy, you have that product. So, I want to move on to some rapid fire questions starting first with dosing and obesity. The ID group had a stand for produces guidance on antibiotic dosing and obesity. Their latest update to that was back in 2022. It's a really great reference, and they suggest for obese patients using a dose of a Moxic Clav, 1000 milligrams, Mox, and 125 milligrams of clavulone every 8 hours. So, do you agree with those recommendations on a Moxic Clav dosing in obese patients? In obese patients, the last five or six years, three or four population of hemococinetic stands that address this question, explicitly, and all found that the course CMACS is reduced, the Pro-Moxic Clav, but no specific recommendation, different from the standard dosage in obese patients should be used. Last year, in antimicrobialism, it came up therapy. The paper was published on the day being that those are in a recommendation or what antimicrobial in obese patients. And I think they added that stating that for obese patients, an Moxic Clav dose of one gram per decade to six hour all right dose is okay, it's fine. And that makes sense because a Moxicin clavulonic is an hydrophilic drug, and so obesity doesn't impact too much on drug disposition. So, in an area, of course, we have to take into account the adjust body weight when we make the adjustments for either critical antibiotic, but we don't need for higher dosages in this type of situation. So, I think that one gram every six, eight hour, eight hour dose is a reasonable dose of just inner beast patients. Yeah, I agree. It's hard to argue with that guidance documented. So, thorough and well referenced and looked at. And it's just a great resource of really encourage folks to certainly look at that. The other, I guess, the additional piece of perspective to help give some reassurance, because it seems very counterintuitive in someone with a large body size to just give the same dose. And I think the sort of properties of the drug being a hydrophilic drug is important because that is sex like the distribution of what sort of compartment stays in. But the other study that I seen is another PK model, because it's actually important to say that the developmental study was in called non obese patients or non obese subjects that they say. And so, they didn't have a wide distribution of weight. And so, in their model, weight was not an important covariate, but that kind of makes sense because you know, large distribution to see and understand the association. But and in those study that looks specifically in obese patients, their probability of targeted attainment and the sort of PK PD cutoffs were very aligned with the developed study. And so, it just kind of shows you that if you're giving this dose of the 1 gram TID, you're getting similar probability of targeted attainment, even in that sort of special population of obese patients. And that sort of perfectly aligns with what Pierre was saying in terms of probably not needing to do that, but the general rule of thought for beta-acquins is just give higher end of expected dose ranges, but not doing anything sort of extra special off the shelf type of thing that you might think about for other antimicrobials. No, that's really helpful. I shouldn't try to last my patients with a Mox Clav just because their BMI is 40 or something like that, which can happen. Also, moving on to our next rapid fire question, this actually comes from a fellow breakpoints host, so shout out to her for this really great question that I thought was really intriguing about renal dose adjustment for a Mox Clav. So we kind of alluded to the fact that a Mox Clav is highly renaly excreted or has really good renal excretion. And so her question was related to should we dose suggest or is this a situation in where you can hopefully get some additional exposure by not dose adjusting a Mox Clav in our patient. So what are your guys' thoughts on that? I have no response to this question, Megan, because all residents could be fine. I mean, if you look to what FDA and even EMA recommends, they recommend to reduce dose in patient below 30 minutes. So if you have to follow the rules, we have to reduce the dose. However, the normal evidence is that reducing the dose at 500 milligram every 20 hours expose patient to lower FDA. And so this dose could could also concern after an MIC of aid, which is the breakpoint for entering back the round as and so probably I don't have my response. What I follow is that it does a reduction to confess. So generally, I use for patient between 30 and 60, let's say 60 minutes a minute, I did used to 500 every eight. And for those below 30 minutes, I did used to 250 every eight hours. But I mean, there is no sign. Yeah, I don't know, because I don't know what to give. Does it make sense of these on paper or in discussion that you are sort of using the natural reduction in clearance to read all impairment to boost your exposures by not having to give bigger doses and, you know, or the tummy, but you're just getting better exposure. But what is the exposure? You know, at what cranial clearance does it calibrate? There's no noograms that shows you if this is the cranial clearance or 24 hour urine, this is what you're equivalent exposure. So we don't know. I mean, in theory, is it help exposure? Yes. But if you just completely ignore it and you're giving them one gram, Q6 and you're like, I need to maximize the exposure, then you're obviously going to risk safety and liability issues in that sense. And so the only, yeah, non-rocket science thing that I could say, because I agree with Pierre, is that, you know, you would calibrate your read all those adjustments based on your base dose, right? Don't just, you know, look at some drug information research, the pack is insert and just use exactly that. You should calibrate based on what your, quote unquote, normal dose would be in it and someone without read all impairment. And then if you're, once again, I feel like there's such a selection bias of why we try to get away with using a mock clav for enter back. like, "Oh, you know, we'll just give him 875 BID. He looks so good. He's going home. He's so, like, there's a selection bias there, right? - Absolutely. - Yeah. Absolutely. The people you try to get away with it is people that are doing so well and have responded so well to whatever is actually doing the leg work. And so once you start running it to, can I calibrate the dose increase the exposure? It's probably not a situation you should be repurposing a MoxLab in the first place. And so I would just keep in mind the populations we're sort of talking about. And then where we feel like, "Oh, well, I've gotten away with that." Because that's a very different population most likely in my mind. Yeah, absolutely. We love the idea in theory, but maybe not the best in practice. Because it is at least a whole slew of questions. Are you getting the necessary exposure that you want? And if you're using those modified doses that we've discussed to kind of bump up that exposure and then accounting for the renal dose adjustment, you're kind of playing in a very interesting field, which maybe we shouldn't be exploring at that point. So that was really fascinating. And that also kind of segues nicely into talking about therapeutic drug monitoring of a MoxLab. So fear, this is directed specifically to you. Do you know what's been done in the space of TDM for a MoxLab and clinical scenarios that you've seen personally or that you would support TDM for a MoxLab? Yeah. This is another forth topic question for which the response is not unique. I mean, now as you know, for beta-lactin TDM is compelling in many clinical scenarios. Light for instance, critical invasion patient with services patient with pathophysiological condition that out of drug clearance from pediatrics to well-derived patient. If you're asking specifically of the DM of a MoxLab, when first of all, I have to say that experiences here is very, very limited. And simply because a MoxLab is not used for severe infections and a MoxLab doesn't carry particularly important concern in terms of toxicity. Due to higher-mathene exposure, like for instance, the fatigue of septalidemic, and which TDM is also used to control this type of high-expologians. I found very few studies about TDM of a MoxLab. One of the most recent, while it was published as theory in the Crabinagians chemotherapy, which was a monocentric experience of TDM of a Moxis in and for a drug-occapander cognitis, where they created the patient with IV-emoxic clang. And the final method of the study was that, "Throt TDM, you can use very, very small dose of a MoxLab." And I had to confirm this finding when I told you before that for inter-coccal infection we use ampicinine. And we do TDM of ampicinine here, routinely. And for inter-coccal infection, the dose is, well, grams daily, start their dose. With TDM of ampicinine, we use doses as low as one gram daily. Simply because the Macy are so skewed to the neck, so, so small that you don't need so high-expologian. So high, it is likely that for a Moxis in could be the same, could be essentially the same. TDM could need to reduce dosing of amoxicinine. At the same time, I'm less sure about the role of TDM of the Moxic clang. It could ever roll, turn around in the future. The net result is that it reveals the dose of amoxicinine, like with ampicinine. But if you ask me, if you would first implement the in-euro-in-euro setting in your hospital, TDM of amoxicinine type of sake, probably there are a lot of drugs that re-retired TDM, or is this like an isolate, I mean, or an antibiotic rather than a moxic clang to be honest. Yeah, that makes sense. I mean, we all want the information. So I'm still going to ask you about it. Hopefully, one day we actually have that information because that would be so interesting, because if I've learned one thing from this conversation is that we need more data on how to dose a moxic clang in modern day for enter-a-bacterialis and try to answer this question because I think we did a good job covering all the nuances and all of the kind of holes in the data. And the end kind of summary statement here is that if you can push the dose, consider it. But at the end of the day, some of these organisms that were using a moxic clang just allowed to try to cover, it just might not be a good drug for that combination, particularly if it is a serious infection, but potentially with step down, but that all has to be in the consideration of the whole patient, tolerability, source control, all of those things that we need to consider, wonderful. It's been so much fun, you guys. And now for the breakpoints, Faithful, it's time for I feel nerdy. I feel nerdy is meant to be a safe space and closing segment for our panelists to nerd out over their favorite ID topics, quirks and fun facts. For today's I feel nerdy, I'd love to hear either a fun fact about a moxic clavs since we all love a good, I feel nerdy fun fact that we can take to our other pharmacists chat about or physicians to make us feel smart or a patient case where you used non-standard, a moxic clav dosing. What was the situation? What dose did you end up using? And what was the outcome for the patient? Who wants to take a stab at it first? I'll start maybe. Actually, it's funny. It was inspired by one of the articles you wrote recently, Megan on TB. So tuberculosis is like an area of research and practice that I really care about, and especially in this sort of day and age where it's still killing millions of folks and we don't have it under control. I think we tend to forget about it. And the link to a moxic clav is that we can use a moxic clav in a funny combination or first stewardship folks, probably a painful combination of a carburetendum plus clavilani. And so actually it's a recommended option for drug-resistant TB after you've exhausted all the first line options. But it's interesting to see Miropendum plus a moxic clav as a sort of bridging regimen for a media patient hospitalized with drug-resistant TB. Yeah, you're like, what does that do in there? That shouldn't be there. It's probably a spooking pharmacist when it comes to their acute to see those two given together. But I thought it's really interesting of another repurposed use to actually find some good use, especially in the hospitalized setting when you're waiting for certain medications that you can't get access to right away. And it might be better tolerated than in a meninglite side. So it's an interesting use, something that you probably don't see a lot. But for drug-resistant TB, I think it's quite fascinating to see that. And yeah, Megan, that was a nice article that Benchdebetside that you wrote in terms of summarizing those new guidelines. So I thought it was quite sitting for this episode. Oh, thanks so much. That's really nice beer. What do you think? Yeah, I make a fan of that, which is. It was not a really fan of that. That happened to me directly to me with a moxic clav. That happened to my fund. She was under a hemodialysis, and she was admitted to hospital three years ago for this interagigiana. But the treatment for shigana is watching away. But after a week of watching waiting, she continued to be here. And if Lorkin and I also couldn't be administered because she had a previous sip of moxic saline, the use of the night is. And so if you're not discussing, it could be. It could not be prescribed. And guess what I did? It prescribed a moxic clav, which is not a test lab. So a moxic clav in the blink of the night with a moxic one dose for moxic clav. And she got admitted to the better. So this is why. And I am also glad to say that the next autumn, she received her second hidden transplantation. So this. And. So a moxic clav, it can solve even complex clinical cases, like patient hemodialysis that depend upon infection and for which funeral, you know, it's good enough to use. You have to go with reduced dose. So a moxic clav say the situation, I could say. That's great. I'm glad she's doing better. And again, I love that we're ending with kind of the high notes of a moxic clav. And that it really does a lot of good work, doesn't it? And so thank goodness we have a moxic clav in our. our antibiotic arsenal. Well, that was been a really amazing discussion. I want to once again thank our amazing expert panelists. And thank you to our little audience for listening to breakpoints, the Society of Infectious Diseases Pharmacist podcast. I have been your host, Megan Klatte, and again, our featured speakers have been doctors, Pierre, Georgia, Kojuti, and Navanith Narionan. Breakpoints was created by Julian Gesto, Aaron McCreary, and Jason Pogue. This episode was produced by myself in Lacey Warden. It was edited by Mary Vance and peer reviewed by Irene Ahiscoly and Drew Dickinson. It was transcribed by Ed Kaczynski and Jenny Thomas. The executive producer of Breakpoints is Lisa Dumbco. Our theme song was recorded by SIEP member Steve Smoke. And you can subscribe to Breakpoints on Apple Podcasts, Spotify, and wherever you get your podcasts. Thanks for listening and helping SIEP achieve our vision of safe and effective antimicrobials for now in the future. [MUSIC]