#130 – Dosing Consult: Amoxicillin

Meet Our Experts: Amoxicillin Dosing in Pediatrics Hello faithful listeners. Welcome to Breakpoints, the Society of Infectious Diseases Pharmacist podcast. I'm Ryan Minster, professor of pharmacy practice at Saint Louis College of Pharmacy at UHSP. And this week we're getting a little bit younger or at least our topic is. We have a pediatric focused episode for you this week and we're going to be discussing amoxicillin dosing with our two esteemed guests. We are delighted to have with us doctors Christine Lockowitz and Ted Morton. I'm also going to call this our Central Time Zone pod because it's a very much a rarity for all three of us to be in the same time zone, but we are today. We're going to start by introducing Dr. Lockowitz. Doctor Christine Lockowitz is a pediatric infectious diseases and antimicrobial stewardship clinical pharmacist at Saint Louis Children's Hospital, where she also serves as the pharmacy Director of the Antimicrobial Stewardship Program and residency program Director for the PGY 2 Infectious Diseases residency. Some of her clinical interests and ongoing scholarly work focus on dose optimization of antimicrobials in children, impact of antimicrobial use and resultant gut dysbiosis on outcomes in patients undergoing allogenic hematopoietic cell transplantation, and implementation of diagnostic stewardship principles. Welcome, Christy. Speaker 2 Hi, Ryan. Hi, Ted. Glad to be here. So honored really and excited to be here and super excited for our topic today. Well. Speaker 1 We are very glad to have you. We are also excited to have Doctor Ted Morton join us. Doctor Morton is a clinical pharmacy specialist and the PGY 2 Infectious Diseases Pharmacy residency program director at Saint Jude Children's Research Hospital in Memphis, TN. He is also professor of clinical pharmacy and translational science at the University of Tennessee Health Science Center. He has over 30 years experience practicing and teaching infectious diseases pharmacotherapy in a wide range of patient populations and settings. Over his career, he has helped lead nationally recognized pharmacy residency and antimicrobial stewardship programs and has been a proud member of SIDP since 1997. Great to have you, Ted. Speaker 3 Thanks, Ryan. Great to be here. Great to be partnered up with Christy. This is going to be a lot of fun, so let's get to it. Speaker 1 Perfect. Well, I've already told you guys. I know I'm going to learn a lot today, certainly. And before we go any further, we want to make sure that you know that today's episode is available for BCIDP credit. Go to the Education Center on the SIDP website and learn how to claim your BCIDP credit for listening today. From Ampicillin to Amoxicillin: PK Overview Now before we get started, I'm going to give a very brief history of amoxicillin and then I'm going to get out of the way and let our experts talk. Ampicillin is where the story of amoxicillin really begins. It was the first semi synthetic broad spectrum penicillin, improving upon the gram positive and gram negative activity of penicillin. Ampicillin differed from penicillin by attaching an amino group onto the penicillin molecule. It was discovered by scientists at Beecham Research Laboratories in 1958 and first released onto the market in the UK in 1961. Amoxicillin was developed in part because of the poor oral absorption of ampicillin. A single hydroxyl group was added to the benzene ring of ampicillin and significantly improved its oral absorption. Amoxicillin was approved for medical use in the US in 1974. We all know amoxicillin is used to treat a wide variety of infections and it remains the most prescribed antibiotic either for talking about it in alone or in combination with clavulanate in the United States. Now with all of that out of the way, let's get down into the amoxicillin weeds. Christy, I was hoping that you could start us off and give us an overview of the pharmacokinetics of amoxicillin. Speaker 2 Absolutely. And that was great background. Thank you. So we'll start with absorption, wrap it in most children with or without food. Bioavailability interestingly comes with a range anywhere from about 75 to 95% with a large range reported in all various PK studies and actually appears to have some interpatient variability likely impacting that. It also may be saturable, meaning more frequent dosing may be more beneficial in just a continuously increasing the dose to achieve target attainment which will come into play a little bit later. And then we don't need distribution readily distributes into most body tissues. And then with the metabolism and half life, it is quick. So the half life is about one hour in adults and it can be a little bit longer in newborns, particularly those that are premature up to about 3 hours. But in general in our most of our children in an adult population that's about an hour. We will get to this later, but it's half life, however, may be extended in the middle ear canal and maybe it drives some of our dosing strategies which we'll talk about. Protein binding is about 20% and then finally jumping to excretion about 60% unchanged in the urine. And then as we Segway to Pharmago dynamics next, I'll quickly mention its mechanism, which is to inhibit bacterial cell wall synthesis by binding to penicillin binding proteins or PBPS. So as such, PBP mutations can lead to reduced binding affinity of amoxicillin and that sometimes can be overcome by increasing the amoxicillin dose, which will be a recurring theme today during the discussion. Understanding Amoxicillin's PD and Resistance Evolution Great. Thank you so much. Ted, do you have anything you'd like to add to the PK of amoxicillin? Speaker 3 Well, just a comment, what a what a difference in amino acid substitution and benzene ring can make in terms of clinical utility because you described as our first broad spectrum antibiotic and it's it's remarkable that it has maintained so much clinical utility. But just to get a little more specific about the mechanisms of action and mechanism of resistance, it's critical to go over not just because I love pharmacology, I love microbiology and PK, but as Christie's alluded to are the evolution of dosing of amoxicillin really reflects the evolution of resistance in the most common pathogens in several critical disease states that we see in the pediatric population. Critical in not so that they may be life threatening, but rather very, very common acutitis media community acquired pneumonia, arguably pharyngitis and then a bunch of other stuff mechanism of action yes, specifically binds to penicillin binding proteins, but we know not all PB PS are created equal. There's Organism antibiotic specificity in the case of the major pathogens. We just I just mentioned it's worth going into streptococcus pneumonia a little bit deeper. It has a number of penicillin binding proteins that it can express and it's alterations in this penicillin binding proteins that confer I'll I'll use the air quote tolerance. We'll call it an increase MIC to penicillin and by extrapolation amoxicillin. And So what we've seen is penicillin binding protein 2B, when that mutation occurs, when you get that penicillin binding protein, what you get is an incremental increase in MIC and that can be overcome by using higher doses and hence higher concentrations of whichever beta lactam you're looking at using penicillin, amoxicillin or not. We're not going to talk about subtraction, but for subtraction for meningitis, you just push the dose if you're trying to be able to increase your time above MIC. However, there is APPP 2X and that's the one that if the mutation occurs will be true resistance. But when we'll we'll talk about the epidemiology of resistance, we'll call it like 65% of pneumococcus in the United States are fully susceptible at the incredibly low break point of less than equal to 0.06. Then you've got depending on which you look at and, and Christie's going to go in into even more detail about the critical importance of knowing your local susceptibility, but you've got 17% or so that have a higher MIC, but still one that can be clinically treated with higher doses of in this case, amoxicillin. And then lastly, depending on where you are and depending on which specific breakpoints you're using, you know whether it's greater than or equal to two for resistance or non susceptibility, that might be 10% of isolates. So for pneumococcus, it's alterations dependent on binding protein, but it's the, it's the details about the, the ones being somewhat tolerant and, and being able to overcome that with high dose amoxicillin versus true resistance, which is actually quite rare depending on where you are in the, in the country where again, the usual threshold that's turned out there about 10%. I think it's important to also remember there is a, a trial that was a mouse model of pneumonia that showed that high dose amoxicillin would work even against some of those antibiotic resistance strains. Now that's not the end of the story because that's not the only bug that we treat in kids. Another major pathogen that I mentioned is Haemophilus influenzae. And Haemophilus influenzae, it's resistance to amoxicillin is through beta lactamase production specifically mostly a penicillinase. However, you know, we know there are hundreds of different beta lactamases, but about 1/3 rough average of Haemophilus influenzae will be a beta lactamase producer and therefore resistant to amoxicillin by itself. That's where clavulanate and that magical combination of amoxicillin clavulanate comes into play because of the beta lactamase inhibition conferring susceptibility against essentially all Haemophilus. And Valente is something like more excel cataralis also seen in kids. About 100% of those are producers of beta lactamases. And then lastly, Staph aureus, you know, I think we'd be remiss not to talk about that. So MSSA by definition, 90 plus percent of them produce penicillinases. So moxillin is not going to work. Not reliable. However, the additional clavulanate will confer activity of a Mox clav against MSS AM RSA we know resistant to all the beta lactams except for ones that are designed to work on PPP. 2A. So those are the mechanisms of action, mechanisms of resistance. Pharmacodynamically though, it's not. All bugs and not drug combinations are created equal for those working in the gram negative space. And I've worked with immunocompromised kids time MIC above MIC exposure dependent killing. That's that's where we're going with our beta lactams against, you know, gram negative gram positives, but the, but the thresholds are different gram negative rods immunocompromised hosts at least 100% free drug above MIC. Some folks use for for immunocompetent kiddos and for pneumococcus and specifically and in vitro models, the sweet spot in terms of time of MIC for mortality was at about 40 to 50% time above MIC. That's not that long above MIC. Christie mentioned plasma concentrations, half life, about an hour, 61.3 minutes in adults. Yeah, but we can round that to an hour. Just quick sketching that out in a, you know, an AR dosing interval, it's going to be gone by, we'll call it five half lives or says that's five hours. So you're, you're already in AQ 8 hour interval above the MIC for was over 50%, which is where the idea that we'll talk about later on that longer intervals might be OK if we might use a little bit of a higher dose. So again, the key things pharmacodynamically, First off, what bugs are we trying to treat and then what do we know about them? And at least for pneumococcus, which is the most common pathogen in the disease states that I've the upper respiratory tract infections I've mentioned. And then that 40 to 50 is really probably going to be our our goal. And then for then we're going to start thinking about how we're going to dose it. Long winded answer, but hopefully that's a good background and and I'm going to turn it back over to y'all. The Nuance of Strep Pneumo Resistance & Local MICs That was perfect. We really appreciate the mechanistic background to for not only the drug mechanism of action, but mechanism of resistance because that's going to set the table for much more of what we're going to talk about. And you've given already a clue into what the big thing here is high dose versus standard dose. Christy, do you have any amoxicillin pharmacodynamic pearls you'd like to add? Speaker 2 I totally echo everything Ted said, and I love how he described how the mic distribution appears in our hosts and in our patients. I will say just to take a step back, I think it's really interesting to look at the history of strep pneumo resistance. And if we recall back right after the introduction of PCB 7, that's when a lot of the strep pneumo resistance occur. We had a lot more penicillin resistant strep pneumo and then after some of our additional pneumococcal vaccines, we have seen those rates decline and now around anywhere from 5 to 10% or truly penicillin resistant. But then when you look at the MIC like Ted was alluding to, we have to understand what, what MIC do you then start to require what dose to achieve target attainment and what is your target attainment? To Ted's point, if you're immunocompromised and certainly for severe infections, maybe you want closer to 100% time over MIC, whereas most of our patients in the community who may just have a viral infection, who are getting amoxicillin, certainly 50% time over MIC is OK for those patients. So I think that it's important to know your local epidemiology, but also to know the distribution, the MIC distribution and how it's changed over time. And it's actually quite similar between children and adults, which is one thing I was interested in when coming to this podcast, seeing why do we treat children sometimes so different than adults. But interestingly, the MIC distribution over the past several years is pretty similar across the whole entire spectrum of age. And as Ted mentioned, about 10% have an MIC of two with the plurality really having an MIC even point O1 fiber less. So I think those are just all additional context as we dive into some of these fun questions. Speaker 1 Great. Thank you so much. The Pediatric Amoxicillin Dosing Debate Well, we've already alluded to it. One of the major controversies here or something we're going to spend I think the most of our time talking about is the dosing of amoxicillin in the pediatric population, most notably high dose versus standard dose. And I think what we're going to be talking about here, and you guys can correct me if you are working with another number, but we're probably thinking about 40 to 45 milligrams per kilo per day as our standard dose for pediatric patients and 80 to 90 milligrams per kilo per day as high dose, at least as we see it referenced in most guidelines or tertiary references that people use. I thought we could probably break this up into two components. They're definitely going to crossover, but we can talk about the individual dose of amoxicillin and then talk about the frequency TID versus BID dosing. So let's start with dosages. And Ted, do you believe higher doses should be used in the pediatric population? And if so, when or for what types of infections are they going to be most beneficial? Speaker 3 Yes, I do however the devil's in the details that they say. I do want to take a quick, quick step back and and talk about epidemiology and different disease states because that's necessary to then talk about when do you really need or when is it justified to use higher doses recognizing higher doses will come with more side effects. She's point about the evolution of susceptible of reduced susceptibility in pneumococcus in adults and kids. This is really interesting to me because back in the 90s, yes, I was practicing then we actually saw that in adults. It was I did a poster at ACAC. If you guys remember that meeting in Toronto about the increase in pneumococcal tolerance so to speak. And when I transitioned from adult medicine to Peed 7 years ago, eight years ago, it was remarkable to me how much the susceptibility had actually improved. And I and, and again, through the collateral effects on the different pneumococcal serovars. I mean, just just a huge benefit of vaccines beyond preventing disease was actually shifting A susceptibility profile. So as if we need any more reason to love vaccines, but there. But there you go. The epidemiology that Christy was talking about, which that's informed by at a national level as a century database. And it's, it's a super, super cool, readily available database where you can go in and plug in geographic regions, ages, different infections to then be able to see what the susceptibilities look like overall. But as I say about politics, you know, they say all politics is local. Well, antibiotic treatment guidelines are local. They are informed nationally, but they're adapted locally based on your bugs and your susceptibilities. So, you know, if you're thinking about trying to make decisions about which dose you're going to treat in your patients, reach out to your micro lab, go to your antibiogram, get the details about pneumococcus and these other bugs in your practice setting. Because Christine, now we're sharing back and forth our local sub abilities and like, there are differences and you know, she's a five mile drive up the Mississippi River from us, but there are differences there. Those are worth trying to figure out to go into the local the epidemiology it it varies by the anatomic site, it varies by the age, it varies by underlying patient characteristics. For example in pneumonia and children less than five years old if they have pneumonia, we rarely see atypical pathogens like like mycoplasma. The major pathogens we see are First off viruses. 2/3 of all pneumonia are caused by viruses and we know how well amoxicillin works for viruses. It don't. Only a third of those are going to be bacterial in origin and of those pneumococcus and non typeable hemophilus influenza are going to be the most common. Again, not most cases pneumonia. So in can be acquired pneumonia because these are patients being admitted that even though we know epidemiologically maybe 2/3 of them are viral, we'll still end up using high dose amoxicillin. Although in the Kappa trial, which was out of the UK very large like 1600 kids basically looking at standard versus high dose, short versus long course, all those groups did fine. Although it was a clinical diagnosis of pneumonia, it wasn't radiologically proven pneumonia. So you could say again, it was a lot of those kids probably would have gotten better on their own, but in general for pneumonia and especially if they're hospitalized, you would want to use a higher dose to cover a major pathogens like pneumococcus. I will say also there's an opportunity for diagnostic stewardships with RVPS. The the respiratory viral panels that are now readily available if, if they're not particularly sick, if they have an RVP positive for virus. I think even for us, for kids with like even sickle cell disease, if they're well and have a have a virus on their panel, we might give them 48 hours amoxicillin, we would use high dose, but then we would stop. So shorter duration being possible there. Acutitis media, yeah, six months to two years, yeah, we'd want to go ahead and and treat and, and again because pneumococcus is one of the major pathogens there. The more standard practice, at least for kids, we'd see in the emergency department, which would be a sicker cohort than the general community we'd probably be using. High dose amoxicillin there, but also in well kids, the approach of watchful waiting and a preemptive script that can be filled if they aren't getting better is another stewardship opportunity. But I would say for, you know, those are probably your two disease states of common community infections where pneumococcus is likely high dose based on those MIC distribution should be considered. And then you've got a lot of 1 offs like you know any sort of step down therapy, which we'll probably talk about later for an invasive infection that would probably be using high dose, but that's because of different pathogens and also difficult to penetrate sites. So in summary, can be acquired pneumonia, especially if they're in the emergency department or about to be discharged otitis media, particularly if you've got close to or over that 10% not penicillin on susceptible that that's probably where your sweet spot is for using higher doses of amoxicillin. Speaker 1 Yeah. Christy, what are your thoughts on this? Speaker 2 Yeah, I think this is first of all, this wouldn't be such a debate if we already knew the answer. So I think that there is a lot of nuance and some room for different thoughts depending on the patient or the clinical scenario. And I think one thing that will, I will probably say multiple times throughout this podcast is it's all about your willingness to be wrong. We all use some kind of risk ratification equation or calculus in our head, right to decide what that what that willingness is. So I think that in these patients who are outpatient who have pneumonia, acquired pneumonia, certainly uncomplicated otitis media, maybe I'm willing to take that 10 to 20% chance that I'm not dosing it as optimally as I could be knowing that one, most of them are probably viral to a lot of these including bacterial acute otitis media actually have been shown to resolve on their own even in the setting of watchful waiting. So I think that's where the willingness to be wrong and you know, choosing different things can be OK. The other thing I find interesting if when we talk about CAP and I I agree with Ted that I'm especially in hospitalized CAP, we're almost always using high dose Amox to say, you know, I'm not willing to be wrong that 10 to 20% of the time. That being said, I do find it interesting if you look at the adult community acquired pneumonia guidelines, for example, they're isolates again, have a similar distribution for strep pneumo MI CS, but they recommend amoxicillin 1g TID, which mimics are high dosing just in a three thrice daily regimen. But then they also in the same token recommend a Mox Clav standard dose, whether that's 875 BID or 500 TID. So it's just, it's just, I find it kind of interesting how all over the map the clinical data is, which certainly feeds into these clinical guidelines, but it just shows how nuanced it can be and how I think these actually are more patient specific decisions than than meets the eye. Speaker 1 I also wanted to ask you guys here, while we're still talking about dosing, do you have a maximum dose in mind that you would give to patients that you were still using high dose or I guess mostly to do with high dose, is there a maximum dose that you would use? We can start with Christie on this one. Speaker 2 I think that most of us would probably fall within a range. But in Ted, I'm curious your thoughts. But I think about 4G per day and then a Max single dose, usually a gram. You can maybe convince me to go higher in certain situations, but usually a gram TID or there's as we've seen in some other trials like POET, they used 1g QID. So I think that would probably be my Max. Speaker 3 Yeah, it's interesting to to contrast is Christie started to do like adult doses during pediatric doses because you know, and adults still throw 875 at of people that weigh 100 kilos and like, Oh yeah, that's fine. Whereas in peas we may actually end up going, going higher. I mean, if you actually look at Augmentin up there for greater than 40 kilos, they actually recommend like a 2G of amoxicillin dose per dose for a total of 4 grams a day. I think the the the 4 grams a day is, is a, is sort of an evidence free ceiling, but that's where most people stop. And then I think we're going to talk about this later on. But regardless of what your, your, your ceiling is, then you get in these practical considerations about how does it come and can I actually get to that specific dose? And I think we have to have some kindness on ourselves that there still needs to be at least a 10 to 20% wiggle room because this is not, you know, as much as you like to practice precision medicine, we're still going to end up rounding in some cases to get to something that's pragmatic, especially if we're looking at whole tablets and that kind of thing. But yeah, that's that's a usual, usual threshold of the four gram a day. Optimizing Amoxicillin Frequency: BID or TID? Now we've had a good discussion about the dosage, individual dosages and when we might use the higher dose there. Wanted to talk a little bit about frequency now, BID versus TID. Christie, does it matter to you? And does that answer depend upon the Organism, the type of infection, and even whether or not you're using higher dose as a component of the individual dosage? Speaker 2 Yeah. This is to preface again, I think that if you pulled a lot of pediatric ID pharmacists, you might get a slightly different answer. And again, we need more clinical data in the space with strong methodology. But yeah, I think that it does matter and it depends on the patient's scenario in the clinical syndrome. And both PKE and clinical use data are either mixed or lacking in my opinion, which is why, again, this continues to be a controversy. And then we also know that what is demonstrated in vitro, which we've talked a lot about based on PK models doesn't always translate in vivo. And I think if you, again, just to reiterate that if you think about all the misuse of amoxicillin for viral infections, plus all those mild infections that can resolve on their own, you're looking at a pretty high number needed to treat with high dose Amox to, to show a benefit or to prevent a negative outcome. And I think that matters, especially as we get into certain formulations that are either tricky to find or, you know, may be cost prohibitive. So I often reserve it this the high dosing for cases where I'm less willing to be wrong. So in my practice, if we think about BID for his T Tris daily dosing or thrice daily dosing, the way I think about it is one, if I know I'm going to use standard dose. So either because I know I have a super low strep pneumo MIC, which you would only know if you had a culture or if you had a syndrome that you were treating where strep pneuma were not implicated. So let's say for whatever reason you have skin and soft tissue infection, for example, I tend to stick to BID dosing knowing that I'm using standard dose as at 45 mix per K per day. And data would show that target attainment appears to be adequate in those situations. And just pull in an example Group A strep pharyngitis for example, target attainment is achieved with 50 mix per K per day even given once daily. So we know that target attainment is effective for an Organism such as that. So I'm not going to go out on my way to use high dose for those situations. Now if using high dose, I think that for me personally is at least when the question of twice a day, three times a day comes into play more. And I think there's two kind of situations that present themselves. And Ted alluded to 1, and that's severe infections where strep pneumo out of the is out of the equation, but you're using it for severe infections to optimize your PKPD target or maybe you're shooting for a higher PKPD target. So that's for example, step down bacteremia, osteomyelitis, which I think we'll get to later on. But again, that is not specific to using this quote UN quote high dose to overcome PvP mutations seen in strep pneumo. However, the situation that I think we want to focus on for this question is those strep pneumo infections of any kind where you want to ensure adequate target attainment for those higher MI CS. So you've already decided I'm not willing to be wrong. I want to make sure I'm covering for those MI CS of two or maybe even a little bit lower. So in that case, I think about infections in two different ways. One's otitis media, which you've already alluded to. I think we've proven based on some minimal PK and clinical use data that the high dose given twice daily is adequate, again likely due to the extended half life in the inner ear. But then the question is can we extrapolate that to other HE&T infections or other upper lower respiratory tract infections? And I don't think we've answered that as a community. And I don't think the clinical data are super strong in that realm to help answer that. There are minimal PK data that would suggest the ELF penetration of a Mox is actually lower than serum levels. But then on the flip side, there's also PK data that exists that demonstrate higher target attainment in the plural space compared to the serum. So I don't know what to do with that information, but I think that we need more data and that's why again this continues to be a controversy. I think that that's the situation though where I am thinking about going into a three times a day scenario where I'm getting to those situations where I have a more severe infection. Maybe it's a complicated ammonia, maybe it's just anyone hospitalized with pneumonia where I don't want to be wrong that 10% of the time that maybe I have an MIC of two and that's where I'm seeking that three times a day amoxicillin dosing. Now that gets even more tricky when we start talking about Augmentin or Amox class, but I will hold when in case we get to in case we get there. Speaker 3 I'll just throw all my, you know, patient counseling hat here just to say, you know, that the other factor that comes into consideration is can then will they take it that, you know, with, with that additional dose that that might be the, you know, the straw that breaks the camel's back when you've got a mom that's breastfeeding, got other kids in the house they're trying to take care of. It may be worth that quick reality check of is that extra dose, especially if it's like, say, step down therapy after hospitalization or extenuating circumstances that, you know, that we used to joke, Oh yeah, we'll prescribe it three times a day and hopefully they'll take it twice a day. But that, that would just be one more other factor to the great analysis that that Christy had. She mentioned the, the community and, and, and literature. This topic is very timely because First off, a huge shout out to the pediatric ID community, the physicians, and the pharmacist in general. A wonderful group of individuals, incredibly collaborative. And there's a pediatric ID listserv out of Wash U that people post questions, they get responses, you know, people, you know. That's a sounding board. This exact question about amoxicillin dosing got put out there within the past couple of years and there were literally like 8 or 9 different responses and some of them were for people who are like primary authors on the quintessential review of commute acquired pneumonia saying I read this article, here are my thoughts. Here's how I do this other. And, and there there was a range and you know, some, not everybody practiced the same, but it was, it was great to hear that we're not alone and struggling without it. Dispensing High Doses & Managing Side Effects How to make, you know, take, take all this PKPD knowledge and apply it at the bedside in the clinic to our patients. So anybody interested in in being part of the Pete's ID community, I would, I would definitely give a plug for joining that that let's serve also on that was shared dosing tables from a couple institutions and policies around amoxicillin Augmentin. Some of them were 7 pages long with multiple charts. We, we went through this ourselves like trying to distill down the available formulations into, into something that made sense for our, for our patient population involved Excel spreadsheets at, at different dosing weights with the milligram per kilogram of amoxicillin and clavulanate with like green, yellow, red, whether or not we were exceeding certain thresholds to try to figure out which doses we're going to going to carry. And there's at least usually one or two posters at every ID meeting about how do we dose Amox or Amox Clav. So very, very, very timely. And just to say, you know that we're not going to settle this during this one podcast, one of the. Speaker 1 Things pharmacists do the best in the interest of ultimate and optimal patient care, I think is making things really complicated sometimes and we have to guard against that and that's why forms like this are really important. Well, we've already alluded to it or you have already alluded to it already, but definitely another issue surrounding higher doses, How do we practically do it, meaning that we are limited by size or concentration of a particular product. I wanted to start with Christy here and see how you recommend practically dispensing these higher doses and is it better to use the suspension or is being a little bit more liberal rounding doses with tablets or other formulations? OK? Yeah, great. Speaker 2 Question, I think, again, I think this gets more complicated when we go to Amox class, but I think for Amox it can be a little bit more simpler. I'm always rounding with my team and asking the patient and their family members what what is easiest for you? Do you want suspension or not? So I think first we have to ensure what is the formulation the patient prefers and therefore let's start there. I rarely just give a dose without knowing that because it could change, of course. So knowing that, I think suspension is easier, right? If you prefer suspension, especially our kids that aren't swallowing whole tablets or whole capsules, certainly that's easier. You can do your big per K and get a good dose. I will say I do try to do the math to make sure that the milliliter dose based on the product you're using is measurable with the suspension that family gets. That being said, if we pivot to some of the interval or the whole tablet form formulations, I think that's where we have to have some wiggle room. And thankfully, amoxicillin, similar to our other beta lactams have a pretty wide therapeutic index where, you know, we'll talk about safety I'm sure, but it's relatively safe. And I think there's this wiggle room. We often say as long as you can round up or down to about 10% of the dose, that's great. I may even give some more wiggle room. I think Ted mentioned up to 20% earlier. I think that's fine, especially for these patients where they have some wiggle room to be wrong in my opinion, right. With these uncomplicated respiratory infections, I'm willing to round to a tablet size that is the closest to whatever I feel they need, whether that's a standard dose or high dose. And usually that's not cost prohibitive when we use high dosing for amoxicillin, whether it's suspension or hold tabs. So I, I'm pretty, you know, liberal with my rounding when it comes to this, knowing that there's some wiggle room to be wrong. Speaker 1 Ted, how about you? What is your practice in prescribing these doses Exactly like Christy said. Speaker 3 Yeah, that the liquid's the way to go for most patients, allows you to get reasonably close. Just yeah, remember your syringe sizes. Don't, don't, don't try to make it too, too complicated. The amoxicillin tablets themselves are kind of big. They're scored. You can cut them in half, but please don't try to do 3/4 or 1/4 of a tablet. It's just it, you know, that's not, that's not fair to anybody. You're not that. That's just not not worth it. Trying to be practical, practical and pragmatic about it, we'll start. Speaker 1 With Ted on this one, if we do use the higher doses of amoxicillin, how well tolerated have you found them to be? What are the major adverse reactions that we should be looking out for in children that do get prescribed these higher doses? Gastrointestinal. Speaker 3 That's it. So yeah, yeah that as we alluded to the, the, the overall safety margin there just fantastic for amoxicillin dose spend adverse effects, you know, even though it's very well absorbed, certainly better than than ampicillin. Then the higher dose you give Christy mentioned might be a little bit saturable. That just means we're getting down and potentially causing dysbiosis. Other amoxicillin adverse effects are going to be, you know, the immunologic stuff is not going to be particularly dose dependent converting standard dose to high dose. If you're giving it to somebody with Epstein Barr virus, it doesn't you know, standard or high dose will still give you a mononucleosis like rash. You're taking that chance no matter, no matter how you're dosing it, Christine. Speaker 1 Your experience? What adverse reactions have you seen with higher dose? Very. Speaker 2 Few and I echo everything Ted said. It's so well tolerated. I love the call out or the shout out about rashes developing while on amoxicillin when they actually have a virus. Just another plug for antimicrobial stewardship and also diagnostic stewardship. And that's a real problem, right? We you know, we see these kids get labeled that go to adulthood and we that's a whole different podcast that we could talk about. But I I very little if we're on high dose, maybe for prolonged periods of time, just like any other beta lactam, thinking about your cytopenias and some ASALT elevation, but I just rarely see it. Amoxicillin's Role in MSSA and Bacteremia I would like to. Speaker 1 Talk for just a few moments about Staphylococcus aureus, particularly the MSSA variety. I'm curious, Christie, are you comfortable using amoxicillin to treat an MSSA infection in pediatric patient? Oh, that's a good question. Speaker 2 So being that it's methicillin susceptible staph aureus, I assume we're also talking about PSSA. It's like penicillin susceptible staph aureus, which at my institution we actually don't get penicillin results. But if you are an institution that does get penicillin susceptibility results to your staph aureus, I certainly think this is something to consider. We don't routinely do it since we don't routinely see it, but I certainly think it's safe. Target attainment is certainly doable with amoxicillin. And we have other clinical data, particularly out of Europe that for PSSA infections that penicillin, amoxicillin are certainly adequate. And again, it just goes back to what's your dose, what's your target attainment depending on the source of infection. But you don't have to worry about the PBP alterations, right, because that's not the mechanism of resistance. It's a beta lactamase production that in these cases aren't present. So in theory for mild infections you can get away with standard dosing and more severe infections. We think about higher dosing, but again, not because it's strep pneumo in overcoming PvP mutations, but just to achieve a higher PKP target attainment. I I think the last. Speaker 3 Susceptibility I've seen for penicillin susceptibility for staff virus might be 5%. However, classically in the literature if you have a penicillin staphyrus that you can use penicillin to treat that. That's the old school staff that Alexander Fleming used penicillin for forever until we got MSSA. If you had had to choose between amoxicillin and penicillin, I think my my preference would be for penicillin because it's more narrow spectrum. However, pharmacokinetically, amoxicillin might might be a little bit more forgiving and that you can probably dose it less frequently because it's got a slightly longer half life than penicillin would be. And then you know, if you had a mixed infection with MSSA and say anaerobes or a bite wound where you're worried about iconel or something else like that, then you know, using amoxicillin clavulanate, that additional clavulanate for non severe non invasive skin, soft tissue infection. We're recovering from MSSA and something else you need to clavulanate for makes makes good sense. Next thing I wanted to touch. Speaker 1 On are bacteremias at least just a little bit, Christy, would you be or are you comfortable using amoxicillin to treat bacteremias in pediatric patients, especially with the knowledge of in the US anyway, this is only APO medication. And if so, how does that change or which kind of camp would that put you in with your dosing? Yeah, this. Speaker 2 Is a great question. I will say I think this is an ever evolving question as we use this drug more for these indications. But I do think there are times where we can certainly use oral amoxicillin at a dose optimized for step down bacteremia or osteomyelitis associated with transient bacteremia, severe infections such as that. And I will just put a plug in at this before I made my way to pediatric ID. But if you look back before a lot of the pneumococcal vaccines, a Colt strep pneumobactermia is actually really well documented and it's described and it's really associated with a low percent chance of developing persistent bacteria, meningitis or other focal infectious complications even if left untreated. So these patients had a fever, but they were overall well appearing and had an occult bactermia. So without treatment, the majority of those patients actually saw a clinical resolution of that fever. Post vaccine, we don't see this as much, which is great. But if we learn from the past, I think we can take that and apply it to some of the situations we see now. So for transient bacteremia, with that in mind, I think we can certainly use amoxicillin. So of course sometimes we see this transiently with the pneumonia, sometimes with osteomyelitis, although that is much more rare. Then the question is what dose? Like you asked from my review, the dosing of amoxicillin that's used for invasive, whether it's endovascular or other severe infections is all over the place. So take that with a grain of salt. There are some adult data that is published for Group A strep bacteremia, different target attainment than some of our other organisms where dosages of Amox 1G, TID are used. There's also publications of Amox, CLAV 875 BID, some more standard dosing. And then if you look at something like the POET trial, they used Septon for endocrititis. They used a gram four times a day in combination with rifampin or fucidic acid and that was specifically for PSSA or Enterococcus, not strep pneumo or not. Some of our other organisms we think about. So it's all over the place. I will say in my practice for strep pneumobacteria I am comfortable using amoxicillin Septon therapy assuming you know human dynamically stable blood cultures are clear they're getting ready to go. I do tend to do high dose just to optimize our PK over PD profile. Not again, not because I need PvP saturation necessarily, and I'm less willing to gamble that I'm doing something wrong here. So I will opt choose to do three times a day high dose, usually 30 mix per K per dose TID rounding accordingly, anywhere between 80 to 100 mix per K per day. And that includes up to MI CS of two. And I've done that numerous times with anecdotal success. And strep numo is that's what, strep numo or without strep numo. So I'll in there and see what Ted thinks. I absolutely agree. Speaker 3 I'd probably carve out some of the patients that I see just because we've got a very large population of children with sickle cell disease and they're asplenic or if they got neculizumab, they don't have a normal immune system specifically the immunity that helps is protective against pneumococcus. I'd be, I'd be more inclined to you'll bring them in and give them a dose of traction once a day or something like that, you know, come up with, you know, something, something else like that. You mentioned Enterococcus. I think an Enterococco bacteria from a urinary source would make perfect sense for giving Amoxon since it's really eliminated, be able to concentrate there, probably clear it out pretty easily. As long as there isn't like a stent or some other other source that's, that's there because this point there a lot of folks that you, you know, you can let them go home on oral Mox and and should be able to do just fine. Is Therapeutic Drug Monitoring Needed for Amoxicillin? Now let's talk. Speaker 1 About a topic that some people run to and some people run away from therapeutic drug monitoring. I wanted to see what you both thought about therapeutic drug monitoring for amoxicillin in pediatric patients. Is this something that you have ever done that there's a specific patient population you would consider it in? Just what are your thoughts on the potential role for TDM and amoxicillin impedes? Christy, we can start with you here. TDM for. Speaker 2 All beta lactams, especially in the pediatric population continues to be a pro con debate honestly. And I and what to do with those is another thing. I think you know my my personal opinion, I've never done amoxicillin TDM and I think that once you're starting to get to an oral amoxicillin regimen, you've you're kind of out of the window where I would be interested in TDM. So presumably you're not still critically ill or on ECMO or any of these other have any of these other PK factors where I'd be more interested in performing TDM. Once you're getting into amoxicillin, it's either a severe infection that you've improved, you maybe have source control, you're going to step down there and you're going home. I don't think that I care about it as much in that situation unless I continue to see recurred essence of symptoms or what have you, but I think that would be rare. And then on the flip side, for these mild to moderate otitis media, uncomplicated community acquired pneumonia, I think that again, I've hopefully already alluded to the fact that the number needed to treat with amoxicillin alone is high, much less to then perform TDM on those. I think it's probably not the best use of our resources. I'm sure a case will pop up tomorrow. What that convinces me that I want to do TDM on amoxicillin, but that just has not occurred yet. I'm curious if Ted is done in his practice though, with his population, the paradigm. Speaker 3 Of who do you do beta lactam TDM in would be with basically multi drug resistant organisms with high Mics in a patient population that's expected to have variable pharmacokinetics. So at least for us, we've we've start to get start to get into the lactam TDM, but we've been targeting Miropenem in our ICU patients or on continuous renal replacement or hemodynamically unstable where they just got a bunch of fluid boluses. So their volume distribution is going to be altered. So as this is an emerging field, especially in Pediatrics, that's really probably where we prioritize since NA children just publish a fantastic overview of of their cephene model infused precision dosing strategy. But again, that would be Vascepa pine with Amina penicillins. I think that, you know, maybe intercoccal endocarditis or something where it's a high risk infection with a difficult treat pathogen. Yeah, that would be with ampicillin. But yeah, I get by the time they're ready to go on amoxicillin, hopefully that that variability or the MIC has already been addressed and you got a good clinical response. So the benefits of TDM are even less clear in that in that setting all. Navigating Amoxicillin-Clavulanate Dosing Complexities Right. For my final question for you both before we get to have a little bit of fun, I wanted to divert a little bit from amoxicillin alone and talk about amoxicillin and clavulanate. I remember learning way back in pharmacy school that this product was more irritating to the GI tract because of the clavulanic acid component. This also makes it more difficult to give higher doses of amoxicillin because at least for adults, you really don't want to go over that 125 milligram per dose of the Clavulani. So Ted, do you think this is true? And if So, what is the strategy that you may use for prescribing or recommending higher dose amoxicillin clavulanate impedes well? Speaker 3 Yes, it is true that clavulanate will mess you up all your patients up. So what you were taught correctly and the and my first line of defense against gastrointestinal toxicity from amoxicillin clavulanate is to always ask myself, do I really need the clavulanate? Because there are so many times that people think Augmentin's better, but what they really just need is amoxicillin. They don't need the beta lactamase inhibitor. And so being very thoughtful about is it worth that extra coverage for this patient for this indication before giving him something that will have increases of GI toxicity. The second thing is it's dose dependent. And so they're they're formulations of amoxil and clavulanate that have been developed specifically with proportionally more amoxicillin than clavulanate so that you can avoid that cap of 6.4 milligram per kilogram per day of clavulanate, which you can hit that very, very quickly with your traditional Amoxil and clavulanate doses. And, and when we went through our formulary and did that chart that I described of the weights and the, you know, amoxicillin then clavulanate and red, yellow, green, we ended up with for the purposes of, of treating our patients basically just two suspensions and two tablets. We were able to distill that down. Yet I mentioned before the Pizza ID listserv, there was another one, another chain about Augmentin dosing and that's where you had many, many charts where they were just trying to figure out based on weight in kilograms what the what the right dose was to not exceed those thresholds when you need to use the clavulant 8, if you can get, and I know there's sometimes trouble getting the the higher dose Amoxil formulations, if you can get that, use that. And also, depending on your electronic medical record, try to hardwire that dosing into the EMR to help make it easier to not exceed the clavulanate dosing maximum because that that can just sneak in there and you don't even realize you've ever dosed the kid and it just, it just happens. Those would be my words of advice, but love to hear what Christy has to say. Speaker 1 Having also. Speaker 2 Started in adult infectious diseases and transitioning to pediatric infectious diseases. I never knew amoxicillin clavulanate would be so complicated and it really is. So I think that the formulations that Ted was alluding to and I absolutely echo everything he said, I think it's really interesting how these formulations came to be. It's actually quite genius. If you think about the XR tabs and the ES suspension, those are the two kind of high dose formulations, if you will. I mean, when we say high dose in this context, we mean high dose for strep pneumo. So we just want high dose Amox. We don't also want to double the clavulanate component because as you both mentioned, your patient will not be very happy with you because of the GI effects that it may have. So for example, if you're using the high dose formulations but dosing standard dose, then you're getting too little Clav. If you're using the standard dose formulations and doing high dose, you're getting double the Clav. So there really has to be a sweet spot. And when you're using that high dose for strep pneumo target attainment, you really need to use one of those high dose formulations to make sure that you're getting the right dosing of both the Mox and Clavulani. And it is super confusing. And like Ted said, highly suggest setting up an order panel or order set of some kind. We actually got broken down into indication base. So we kind of highlight here's the ones where strep pneumo is implicated. So whether that's otitis media, media acquiring pneumonia, etcetera. And we only present those high dose formulations to them. And then when you have things like dental Abscess, when you probably should just be using a Mox, but sometimes we make our way to a Mox Clab, dental abscesses or skin infections, we then have here's the dose and here's a standard dose formulations that should be used. And it still continues to be a place of medication error. So it's something that we have a lot of work to do to improve upon. That's kind of my thoughts about how to think about it. And I wish I could show a chart that Ted is talking about because I almost have to look at it every time just to understand, OK, here's what we're doing. And I highly recommend having a chart of some kind in your pharmacy as well. Speaker 1 I'll just amplify what Chrissy? Speaker 3 Said about hardwiring safe and appropriate dosing into your electronic medical record as much as possible. However, it will be a painful process. We, we just updated our, in the process of updating our acutatitis media order set and you've got three or four really smart pharmacists, including an informaticist having multiple meetings to talk through line by line, all the doses, all the decisions in order to try to get it as as good as we can, knowing that it may not be perfect. But like with the amoxicillin clavulanate, we just realized if they're less than 40 kilos, we just go straight to the suspension because there's no real practically good way to do the tablets splitting or whatever to get the right dose. And kids, it was just simpler to have a, a rule 40 kilos less. They only see the suspension and it it just makes things safer for everybody. Such an important. Speaker 1 Point to to really consider whether or not you need the clavulanic component at all. We fight that even in adults where if someone has an enerococcal UTI, they automatically will prescribe Augmentin instead of amoxicillin. And then you can go back and hopefully they haven't had the medication dispensed already and say probably you just need the amoxicillin. A problem everywhere. Nerding Out: Our Top Pediatric Antibiotic Picks Well, great. I want to thank you both so much for sharing your insights about amoxicillin dosing. Now it's time for us to have a little bit of fun. It's time for our I Feel Nerdy segment. This 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 segment, I want to know what is your favorite antibiotic to use in pediatric patients? And I'll put a qualifier on what I mean by favorite here. You can use this antibiotic to treat a wide variety of infections. It works well and it's well tolerated. So let's start with Christy. OK? I love this so. Speaker 2 I'm gonna have to go with doxycycline for a few reasons and I'm sure that's been used before. I personally, from the pediatric lens, find it fascinating that there's this huge dogma surrounding its use in children less than 8. The T staining thing has been debunked numerous times. We can certainly with safe, we can safely use doxycycline in this age group. And then also it's sneaky broad spectrum. I think we often forget how broad it is. It covers tons of anaerobes and also aerobes and then also has some unique coverage. So for example, like Ehrlichia, which we see a good bit of in Saint Louis. So we get plenty of use and it's done so safely. It can be used for a variety of infections including step down therapy for severe infections assuming you don't have bacteremia. And then lastly, although some people might argue with me on this, I do believe it's relatively safe and well tolerated with a couple exceptions that can easily be educated on. Speaker 1 Ted, what's your favorite antibiotic? I'll tell. Speaker 3 You, but I have to tell a story of myself. Going back to what Christie said, it is safe and well tolerated. However, the worst pharmacist in the world forgot to warn their wife about photosensitivity. It would taking doxycycline and it was actually taking it from malaria prophylaxis in an area where that would where that was safe to do. But it also involved a trip to the beach that the rest of the rest of the trip had a horrible sunburn. So photosensitivity with doxy is real. Don't be me. Tell the you know your friends and family to wear sunscreen. Be careful out there. One of the things to educate. Speaker 2 On though, yeah, yeah. Speaker 3 So mine's trim sulfa and I and I want to explain that a little bit on the safety profile. Actually, I find it's, it's adverse event profile absolutely fascinating. Drug interaction profile fascinating. I did adult internal medicine for 25 years. And so the interaction with warfarin, you know, we would see that at least a couple times a year. But why? OK, I'm an OG like I, I practiced back in the late 80s, early 90s and in adult internal medicine and we had all these gay men coming in with pneumonia and they had Pneumocystis disease state we'd never seen before. And my preceptor was, you know, it's like, OK, here's what we're going to do. We, we've just learned about this, this therapy that can be life saving for Pneumocystis and it's trimethoprim sulfamethoxazole, but it's going to be a really high scary dose. And I'm like, wow, that's great. You know, and we, we literally use that regimen for 1520 years when we had so much Pneumocystis. But I remember the preceptor telling me, yeah, we, we know how to dose this because of work that was done in in patients with leukemia. I'm like, oh, interesting. OK, didn't think about them getting, getting pneumococcus. I'm sorry, Pneumocystis. Fast forward 25 years, I come to Saint Jude and I'm walking in and there is a portrait of Walter Hughes, who is an ID physician, founder of the Pediatric Infectious Disease Society. He was a scientist at Saint Jude. He figured out back in the 1970s in kids with leukemia who were dying from pneumocystis that instead of using 4 pentamidine, which is a wicked drug, use it once or twice, hate it. We could dose trim sulfa and he figured out what dose, and it was basically the highest dose they could tolerate. But it was work that was done at where I'm now back in the 70s in kids with leukemia who had pneumocystis that informed how he dosed trim sulfa for Pneumocystis throughout the AIDS epidemic. And, and so that was absolutely life saving. But informed by children now we still use trim sulfa for prophylaxis to pneumocystis in kids with cancer, solid tumors as well as leukemias. About half the kids we have in the hospital right now are on trim sulfaprophy for pneumocystis or toxin. But that's not all it does. Back in the 2000s, we started to see outbreaks in adults, but then also Pediatrics of staph aureus, methicillin resistant staph Rs, the USA 300 strain causing all of these horrible focal necrotic abscesses that we all thought were spider bites. Nope, they weren't spider bites. This was MRSA. And suddenly here's trim sulfa that was effective against virtually all the, all the isolates. Could we use doxycycline? Yes, we could have. But we also had trim sulfa as another oral antibiotic with very good bioavailability. And then I guess the last bug that trim sulfa in adults and Pete's is, is fascinating to me with stenotrophomonas and the, the burn unit, trauma unit I used to work at, they'd get outbreaks of steno every once in a while. Here we've got a lot of kids with cancer. They've got central lines in place so we can give chemotherapy, but kids in lines can sometimes just, things can get a little messy. And a couple times a year we'll have someone with steno bacteremia. And we're sitting there trying to figure out, is it 5 makes for KQ three times a day, You know, what's the right dose? We think, we know. We used to think we could use as monotherapy. Now the guidance is to use it in combination. OK. But it's a drug that has been with me throughout my professional journey. It's filled all these critical roles both in adults, but also impedes the dosing's quirky. It goes anywhere from just UTI prophylaxis all the way up to super high doses that are probably gonna crystallize in your urine. And like I mentioned, drug interactions and side effects that are just pharmacologically fascinating. So that's my choice and why that's a. Speaker 1 Great story. It's hard to beat the oldies but goodies, right? Like Doxycycline Bactrim, there still are gold standards to compare newer antimicrobials to whatever we're studying. Can't get better than the originals. Thank You for Listening to Breakpoints Well, wonderful. And with that, I want to thank you for listening to Breakpoints, the SIDP podcast. A huge thank you to our guest today for sharing their time and insights with us. For Christine Lockowitz and Ted Morton, I'm Ryan Minster, and we'll catch you next time on Breakpoints. And PS don't forget to go to the Education Center on the SIDP website and claim your BC IDP credit for listening. The viewpoints and opinions expressed here are our own and do not necessarily reflect that of the institutions that employ us. Breakpoints was created by Julianne Justo, Aaron Mccurry, and Jason Pogue. This episode was produced by Megan Clat and Lacey Warden. It was edited by Nicole Sunshine and peer reviewed by Ashley Selby and Drew Dickinson. The executive producer at Breakpoints is Lisa Dumco, and our theme song was recorded by SIDP member Steve Smoke. You can subscribe to Breakpoints on Apple Podcasts, Spotify, or wherever you get your podcasts. If you'd like to support us further, please consider writing a review on your favorite podcast platform and sharing this episode with a friend. Thank you, dear Listener, for your ongoing support of our podcast and helping SIDP achieve our vision of safe and effective antimicrobials for now and the future.