#88 – Dosing Consult: Can we BID farewell to Q8H Metronidazole?

Speaker 1 Hello wonderful listeners and welcome to Break Points, the Society of Infectious Diseases Pharmacist podcast. My name is Jeanette Bouchard and I am a liaison clinical pharmacist with the Duke Antimicrobial Stewardship Outreach Network or DAISON. This is our next episode in the series. We like to call dosing consult. We've had a few other of these, including dosing regarding Lenasolid ceftriaxone, as well as dosing in children and adults with obesity. And so this is our next in our series to start out. How many times have you've been asked, do I have to give FLAGYL 500 milligrams, Q 8 hours, Can we get away with Q 12 hour dosing? I would say that I haven't been aggressively asked about this question in my practice, but it is coming up more often. One thing I have been asked recently is wouldn't it save costs and be more convenient for the patient and the healthcare providers? And so we're going to get into that a little bit today as well as review some of the data and the consensus on dosing in this specific dosing consult. Today we've got two experts to help us navigate this question. First, I'd like to welcome Doctor Nicholas Turney, who is an infectious diseases clinical pharmacist at Munson Healthcare in Traverse City, MI. He is a fellow SIDP member and helped fundraise for numerous SIDP educational efforts in the past, including this podcast. So if you like it, he's one of our many folks working tirelessly behind the scenes to make it happen. He's wicked smart and I look forward to hearing his thoughts on this topic. Nick, thanks for joining us. Speaker 2 Thank you Jeanette for those kind words. And it's really been an absolute pleasure working with the Break Points team over the last few years and being a small part of the success that this podcast has experienced. And I'm really ecstatic to complete the trifecta of listener, behind the scenes fundraiser and now a guest on the Break Points podcast. So thank you for giving me this opportunity. Speaker 1 Yeah, I don't think we have very many people who have hit that trifecta. So I was thinking that maybe we should hand out some sort of badge with like the trifecta symbol on it as part of our break points merch that we're going to do in the future. Next we have doctor Suneesh Shah, who is an infectious diseases pharmacist at the University of Pittsburgh Medical Center. His research interests include gram negative resistance, endocarditis and infections in patients who inject drugs. Interestingly enough, I met him at last ID week and so one of those happenstances where we both have a mutual friend in common, Doctor Ryan Shields, and we ended up hanging out at ID Week. So I'm very excited to have him here on the pod and get his expertise there. He also fun fact, loves playing chess, skateboarding and has a cat he is very fond of. So thanks for joining us today. Speaker 3 Thanks so much for having me. It's a It's an honor to get to be here. Speaker 1 All right. I have a patient question to angle us into this discussion. So we've received a dosing consult for metronidazole, 500 milligrams by mouth every 12 hours. A physician colleague heard that the half life of this agent is long enough to warrant this more convenient dosing regimen compared to the more commonly used every eight hour dosing against systemic anaerobic bacterial infections for patients in the hospital setting. She wonders, is this true? First, let me ask you, Nick, can you give us a brief review of Metronidazole pharmacokinetics? Speaker 2 All right, let's dive into some adme. So absorption, distribution, metabolism and elimination, it certainly brings me back to second year pharmacy school. We'll start with absorption. So metronidazole is nearly completely absorbed in its oral form. I'd argue that this is one of metronidazole superpowers. The bioavailability is over 90% which has been consistently found in several PK studies over the last few decades. And it's this high bioavailability of metronidazole that gives us more confidence in extrapolating the IV administration outcomes data which there are plenty to oral administration and it allows especially in the hospital setting to implement IV to PO conversions for patients with functional GI tracts and that are taking other oral medications. Now let's dive into the distribution. So metronidazole has significant distribution into many body fluids and and tissues including the bile Seminole fluid bone, liver and liver abscesses, lung and vaginal secretions. And also importantly it does cross the blood, brain barrier and CSF concentrations can reach those that are in the plasma. So the exceptions of this though of this vast distribution would be metronidazole is penetration into adipose tissue, the placenta which come in less than 20% of the serum concentration. Next, let's talk about the metabolism. So this is usually where a lot of people tend to tune out in the program, but hear me out here, this is actually quite interesting. So metronidazole is metabolized by the liver into 5 metabolites and one of those metabolites called the hydroxy metabolite is of its particular clinical significance because this hydroxy metabolite has antimicrobial activity that approaches 30 to 65% that of metronidazole. So more on this in in a little bit here, but I wanted to give the the listeners an idea that metronidazole is not just metronidazole that it's metabolites are also significant. Speaker 1 Metabolism is a very important part for us pharmacists. I feel like it goes mostly ignored by most others, but I feel like we really nerd out about metabolism. Speaker 2 Most definitely. And if you're going to nerd out about metabolism, let's learn nerd out about elimination too. So let's round this out. And as far as elimination of metronidazole, around 20% of the total drug is excreted unchanged in the urine and six to 15% is excreted in the feces. The elimination half life, this is probably the most interesting piece of this in regards to this conversation. The elimination half life ranges between 6:00 and 10:00 hours and in most studies reporting this half life is in the 8 hour range. And So what about the active hydroxy metabolite? I doubt this was in your PKPD exam in pharmacy school or Med school, but let's talk about it. The half life of this less active metabolite is about 11 to 13 hours. So not only is the parent molecule and not only does the parent molecule have an 8 hour half life, but it's active metabolite has almost a 12 hour half life as well. And this makes the argument and one of the main drivers for a BID dosing versus TID dosing. And lastly, let's just briefly touch on pharmacodynamics. How can we talk about PK without PD? Metronidazole appears to have an extremely rapid rate of killing against susceptible anaerobes and like aminoglycosides and fluoroquinolones, metronidazole appears to exhibit a concentration dependent killing. So you might be asking yourself why do we give metronidazole more frequently when it has exhibited concentration dependent killing? And I think that's a great question. And just looking briefly at Metronidazole's product labeling, of the 18 indications listed in there, seven of those are for ABID frequency, whereas 11 are listed as ATID or QID frequency. So there is controversy here, and I hope that today's podcast can shed some light on that. Speaker 1 I love how you called. It's absorption, It's superpower. So we do love a good bioavailable drug, especially in the inpatient realm where we can have protocols and policies where we just automatically switch that without any sort of physician consent. So I really love that. And then pharmacodynamics, something I've never really thought about beyond potentially beta lactams, maybe fluorquinolones. So really honing in on those pharmacodynamics of metronidazole I think are important because again not things that you learn in pharmacy school, things that we learn after the fact. Speaker 2 And probably not a talk you'll see at ID Week either. Speaker 1 No, although I think metronidazole kind of has a mystery mechanism of action, So might be an interesting thing to deep dive into. All right. So Sunish, what indications do you typically see metronidazole used in the hospital versus the community setting? Speaker 3 Mostly on the inpatient side. We'll see it often furniture abdominal infections in combination with Cephalosporin, so things like septriaxone or cepipine, so small bowel obstructions, perforations and it's usually in the empiric setting. Although I think at my program we do a pretty good job trying to follow recommendations from the stop at trial and usually won't continue antibiotics longer than four days if the source is controlled. A good amount of cholangitis too is again same thing in combination with septriaxone or cepipime, but even there there's been more data coming out questioning if it's needed if the anaerobic coverage is needed. Like there was one earlier this year from Simeonova and colleagues and Jack AMR where they did a propensity match study and didn't really find a benefit towards adding anaerobic coverage and biliary tract infections. All things considered it was a real world study. So with their microbiology it was things like E coli and Klebs Yellow that were covered and few patients actually had an anaerobic Organism recovered otherwise deeper diabetic foot infections it's common to use again in combination with Cephalosporin based regimens. I'll sometimes see it with, you know if we have patients with penicillin allergies and they aspirate, I'll see some people do things like ceftriaxone plus metronidazole. But I'll I'll usually ask my colleagues to discontinue the metronidazole there just because ceftriaxone has pretty good oral anaerobic coverage. So things like PEPTO streptococcus by anella, it's going to be able to cover without the metronidazole. Speaking of that, I try to think of the pathogen itself, and metronidazole isn't universal in all of its anaerobic bacteria, but similarly, some of the other agents aren't either. So one that I'll think of as a good example is Agrithela lenta, where I think metronidazole does really well and probably better than most of the other agents such as piptazo. So in the empiric setting, right, a lot of patients might be on piptazo plus or minus vancomycin, but when then cultures come back and you see something like eggertela lenta. It's worth noting that the Mics to this Organism run a little bit higher and there's also a study by Garte and Torres in CID where they had patients with bacteremia due to this Organism and the piptazo actually failed compared to regimens such as metronidazole. But I think the bigger concept with all this is with this Organism. We knew that MICS tended to run higher with piptazo and I I think it may hint towards a role for testing anaerobic bacteria more routinely that there might be some benefit there. But in another example I could say that I also see it in combination with things like ampicillin sole, bactam or peptazo. And I think while most of us are taught that that's duplicative, I do wonder right. If you look at the CLSI cumulative antibiogram, non susceptibility rates run between 4 to 13% for bacteroid ease with peptazo. So you know, I wonder if I'm doing the right thing, thereby always pulling off the metronidazole, although I I still do it. Speaker 1 Yeah, I mean metronidazole is really a powerhouse anaerobic, antibacterial. Like when you take a look back and just think about how reliable it is against all of these anaerobes and how throughout history it's been pretty reliable the entire time. It's hard sometimes to argue that dual anaerobic coverage right with the Piptasos. So I do think in a lot of instances the anaerobe is not necessarily the Organism that you're targeting in terms of what's causing clinical disease. And so that's probably why in a lot of these clinical studies we see that the addition of metronidazole isn't necessarily needed and leading to better clinical outcomes for community types of disease states that we can use this for. Bacterial vaginosis is a really good example, PID trichomoniasis, so things like that in the community is where we see a lot of our metronidazole and then we pretty much see it in almost all patients on antibiotics, especially if they have one of those cephalosporins on board. You'd be hard pressed to find a patient with Cephalosporin on board and not metronidazole. So all right, going into kind of the nitty gritty of why we have this dosing consult, have either of you ever utilized this dosing strategy of every 12 hours? And Nick, we'll start with you. Speaker 2 So on the inpatient side, in my practice which is a a community teaching hospital, we have stuck really to the standard 500 milligrams every eight hour dosing approach. We had maybe one or two patients in the outpatient setting where less dosing was more advantageous and I work with our infectious disease physicians to move to a 750 milligram twice daily dose for those patients. But by and large, we're sticking to the product labeling in many instances on the inpatient side. Speaker 1 I would say I also probably am in the same boat as Nick in my previous institution and then throughout most of my sights at Daison. It's pretty much every eight hour approach right now. I do know I believe some of the major institutions in North Carolina are pushing for twice daily dosing and there's a reason why we have Sunish on the pod today. So if you could give us a little bit of background as to your history with this dosing. Speaker 3 Yeah. So when I was at P4I rotated at the Hospital University of Pennsylvania and they were using 500 milligrams twice daily and you know it didn't match my school notes or Lexi comp or any of the references I was using at the time. So I asked my preceptor, they gave me the response of go look it up and that's really I think the first time I became familiar with the pharmacokinetics and started to I guess just right from the start get used to doing it as 500 Q 12. And then from there, when I got more interested in, Idi ended up doing a P GY2 in the fields. The physician at our stewardship program, it was Jeff Till Pal. He actually rotated at HOP and then but had been doing antibiotic stewardship over at Yale New Haven, where I had trained for my P2I2. And for the past few decades, probably for most of his career, he'd also been dosing it at 500 Q 12. So I really never thought of it that much to go back to Q8 until I ventured out of the health system. So I got a job, my current site over at UPMC Presbyterian and I dosed at Q12 and it started to raise some eyebrows. But you know from there we ended up doing, we ended up talking about it quite a bit extensively. We ended up doing an MUE on it and really found no difference and I guess a little bit more of that data to come. But yeah, like I said, I was first introduced to the concept from some of the folks at Penn, and I'm told Paul Edelstein was the first person to start dosing at 500 Q 12 over there. Speaker 1 So we have the, the hallmark provider who is using SQ 12. So that's pretty cool. I definitely think that's very interesting that you've been doing this since you were a student. Go look it up as one of my favorite terms as like a preceptor now, but literally one of the worst things I could ever be told as a student because that most likely meant I could have done better before I got there. So that's awesome that you've taken this all the way to your practice currently as a big pharmacist. So you kind of dipped a little bit into this with where you started with Q12 dosing back at hub. And So what evidence is there behind this approach? Can you provide a little bit more backing what you brought to your current institution to really push this movement forward? Speaker 3 I think the the backing towards it is just the data to support 500Q8 or Q12I. I mean there's some data to support Q12. I I think it's one of those things where most people are just comfortable dosing it 500 Q 8 and that maybe is why there may be some support to continue to do so. But overall, I'm not aware of anything to really suggest that there is going to be more killing or better killing in that way. I think Nick did a really nice job highlighting the PK and re emphasizing that there is an active hydroxy metabolite that has 11.6 hours and 65% of the activity of the parent compound. But I mean with that I I start to scrutinize maybe the disadvantages towards continuing QA dosing. So it's one more pill to take throughout the day. QA can be a tough regimen, especially if the patient's struggling with compliance, and we hinted at this earlier. But if they're on something oral also in the outpatient setting, say they're on like Sephiroxine, Flagyl, I think 1 less dose administration might go a long way. Or if you're also given something, Q12 with the metronidazole could be helpful. There's drug interactions with it, which I still don't think we fully understand. So things like warfarin maybe affect the INR less, but also all the other things that we're aware of, gastrointestinal intolerance, encephalopathy, peripheral neuropathy. Historically, there was a meta analysis out there that says that once you get to the magic 42G, that's when you're most at risk. But there's been more recent data to say that that might not be the case when it might actually just happen with whatever dose. But nonetheless, maybe the sparing that extra 500 milligrams a day might have its advantages. But in terms of actual clinical data that's out there, like I said, it's, it's thin but it's accumulating I think. So I mean some of this data goes all the way back to 1980. And 9, there's a study in Journal of Antimicrobial Chemotherapy where they had 48 surgery patients. They check levels of metronidazole through levels and found that the through concentrations were 6.7. And that runs several times the mic of obligate anaerobes such as Bacteroides, which is really where it's most often used, especially when you're given in combination with under antibiotics otherwise from a clinical standpoint like an efficacy standpoint. The first people I was aware of that was Solon colleagues from Novant Health in North Carolina. They had published a study of 200 patients comparing metronidazole at 500 Q 12 versus Q8 and they found no difference in clinical cure mortality. I think I this paper again it's one of the first to really look at this from a clinical standpoint. But a major limitation here was that they didn't really have any micro data. And thinking back to real world outcomes or real world scenarios we talked about earlier, it's like how often is the anaerobe actually causing disease. Not to mention some of these were like they weren't really, it wasn't really clear like what the full indication was if you really needed antibiotics for some of these disease states. So also that came to mind too. Back in 2021 our team when I was at Yale, New Haven, we had published our experience. It was actually one of those few papers where I submitted it and it was like slam dunk like no, no reviewer comments, nothing like that. And I I really wasn't used to that like first try. But anyway with all that I I think there was a lot of excitement with it and I was not expecting it. But either way, it's what we did was we published it in the journal and a row, but we took all of our patients who were back to Remic. Jake Murwidi from the Yale New Haven micro Lab was able to just pull only obligate anaerobic bacteria. Myself, Kathleen Adams, Dana McManus and Jeff Sopow, we all worked on it to look at 500 Q 8 versus Q12 regimens and we again found no difference. It was a small study. Most of these were Bacteroides patients, but there were only 85 S with that. Then going forward I use that data. When I tried to get everyone on board at UPMC and they wanted more data and rightfully so, it was only 85 patients. So we ended up adding in more patients and we have 11 different hospitals throughout UPMC. And so far it's 208 patients or 208 patients that we took to ID week in 2022. But we're still going on it. And when we did our interim analysis at 208 patients, we did not find a benefit towards going queue 8 hours on clinical cure or mortality. So I'm hopeful on 2024 we can have this finalized though. Speaker 1 That's awesome. We definitely need more data out there as someone who creates documents for PNT in order to post things through. The more clinical data like you said, the better. So 85 patients can sometimes cut it, but the more we have the better and not really applaud you guys efforts up at UPMC to put this out there as well as Novant for putting it out there a couple of years ago. I love the throwback to 1989. I love me a good good early article. Seventies 80s, love those. Nick, do you have anything to add? Speaker 2 I just want to comment that the study design is is brilliant because you pick patients with an actual anaerobic infection. Like you mentioned we use metronidazole so frequently empirically and I don't know what percentage of patients it is but I'm assuming very high that are of those patients on metronidazole that really don't have a clinical anaerobic infection. So I really appreciate that you you selected those those patients that that would clearly benefit from an anti anaerobic antibiotic. Speaker 3 Thanks. Yeah. And it's, it's hard too because it's like there's no real right way I think to ever do any study. Like the more I think about it too, it's like a lot of these patients got ceftriaxone in combination. And then when you look to some studies report that ceftriaxone is active against 30% of Bacteroides species. I I think it's probably better with just Bacteroides though as opposed to some of the other obligate anaerobes where I think ceftriaxone might even be a little bit more active. But yeah, appreciate that. Thanks. Speaker 1 So I wanted to have Nick maybe touch on a little bit of this. How do we get this going in our healthcare system? What does it look like to start this up as a pharmacist? Because it it's really cool going through this data, but it's how we're going to implement and what the steps are to make that possible that are the most important, I think, to a lot of pharmacists and a lot of our listeners here in order to implement this at our own institutions. Speaker 2 So I think it's fair to say we're probably unlikely to see a randomized controlled trial in this space in the near future. So I think reviewing the the limited clinical data that's out there and if you're compelled by that, I think the next steps would be a standard plan do study act cycle. It's likely the stewardship program that's going to be leading this to get by in regarding this dosing change which is quite significant. I mean metronidazole comes in certainly in the top 8, seven or eight antibiotics administered in the hospital. So this isn't just a simple modification. You need to define I would say the patient population that would receive twice daily metronidazole. So I'm thinking excluding C diff patients, so severe fulminant C diff excluding potentially CNS infections potentially. So I think there are some exclusions to that and you have to work on carve outs with that. I think discussing with key stakeholders is extremely important. I want to I want to give a shout out to my wife who is a physician assistant in the general surgery department. So we have many dinner conversations surrounding antibiotic use and and Metronet is all comes up. Great dinner. Speaker 1 Conversations. Speaker 2 Yeah, exactly. Talk about. Speaker 1 Metronet is solid. Speaker 2 Dinner. And so the question of like well you know piptazo that I only have to click one box for that but subtracts on metronet is all I have to click two boxes. So I'm working working on implementing stewardship activities not only at work but but discussing with key stakeholders ID, hospitalists, intensivists, GI obviously in our in our general surgery in pharmacy departments and providing robust education around that. Why so including memos to these groups? But you know, I think the bring doughnuts with with a smile is also important that I think that really helps bridge the gap of a common peace. Speaker 1 And crumble cookie bait. Speaker 2 Yes, also a memo to community pharmacies too, I mean we we can't forget about them. You know I think if they are are routinely seeing three time a day prescriptions in your area that quick memo is is worth it because then they're calling less they trying to verify orders and in that and just determining the scope. So is this inpatient, is it outpatient as well selecting a go live date, switching all those orders and the EMR and all those guidelines that you have. And then I think last but not least is performing that post intervention analysis starting out with an MUE and then potentially moving that into a pre post study that gets published and everyone can benefit from. So, wow, look at that. We just laid out exactly what everyone is going to start doing and in fiscal year 24, right? Speaker 1 Yeah, and definitely working with IT is going to be a big that's that was our big hold up at my last institution when I was going through this process of potentially changing over is had those those darn physician favourites, how do you get rid of them 'cause that's like always the big IT thing, right. You can change all the order sets you want, but if they have it saved as a favorite already, then I don't know what you can do about it. But some things that I've personally come up with is changing metronidazole at a ERX level or like the baseline drug level to only prompt to give twice a day dosing. And it should potentially help any of those aspects depending on what kind of system you have, It can change the if you change the baseline drug, it'll change in the favorite itself. And so that's a potential idea there. I don't know if any of you guys have ideas. I think that's one of the biggest things we've ever run into is, OK, we can tell them to do twice a day dosing, but if they're just going to pull from their favorites and use three times a day, then I don't know how we're going to stop that. Speaker 3 Yeah. No, I mean, that's exactly what we did at both sites. So one of the hospitals I was at like right out of residency was Lawrence Memorial, which is a part of the Yale New Haven system. But they weren't routinely dosing it Q 12 hours. So actually once. But The thing is like most people weren't really thinking about it that much and they were comfortable with Q12. So actually just defaulting it to Q12 ended up increasing order usage for Q12 and the same thing. Well, at UPMC we use power chart, so when you type in metronidazole, it gives you 2 doses and originally the every eight hour 1 would pop up first, but we switched it so that the every 12 hour one would pop up first. And from there our usage for every 12 hours went up much higher. Speaker 1 Love that stewardship nudge right there. Shout out to nudges. I did have a question. Is there any sort of cost savings that you have potentially calculated out of this? I know it's such a cheap drug so might not be like the highest on the list, but could be another potential driver to make people OK with the decision despite the limited clinical data. Speaker 3 Yeah, unfortunately, like you said, it's it's not the most expensive drug fortunately, but unfortunately. So yeah, when it came time for us to pitch our cost savings idea, but I felt like mine barely counted, it was like less than a few $1000. But still, I mean it goes a long way, right? It's less nursing administration time, less pharmacy technician time delivering. So I think those things are harder to calculate. Speaker 1 But just as important. Speaker 3 Right. Speaker 1 Nurses don't want to be hanging bags three times a day, especially when they could be hanging in at the same time as other drugs. Speaker 3 Or giving it oral. Speaker 1 Or giving it oral, yeah, those oral protocols will really come into play there. So I think we've touched on a lot of the main points to help our initial dosing consult be more confident in their decision to to dose every 12 hours instead of every eight hours. We've touched on PKPD which we always love touching on in these dosing consults as well as some of the benefits that we can have in the health system and how we can push this through and make it an initiative of priority saving nursing time as well as technician time and any sort of metallic taste that the patients may feel after each dose reducing that is definitely also worthwhile. And so the time has come. Breakpoints faithfuls for our I feel Nerdy. I feel Nerdy is meant to be a safe place and closing segment for our panelists to nerd out over their favorite ID topics, quirks, and fun facts. For today's I feel nerdy. There will be two options to pick from. So the first is What is your favorite fun, fact or counseling point for metronidazole? Or what is your favorite time? Metronidazole has been added to an already absurd antimicrobial regimen. Speaker 2 I'll start up. I'm going to navigate around the disulfuram like reaction on this one and I'm I'm going to go with the hydroxy metabolite. I think this was something I was unaware of, but Metronidazole's long acting and half active hydroxy metabolite I think is the unsung hero here and would allow us to maybe more comfortably move into a twice daily dosing regimen. Speaker 1 Thanks. I also feel like that is an unsung hero of this specific pod, as well as all of our dosing worries in the future. Speaker 3 Yeah, I guess a favorite time it's been added. I don't know if it's a favorite time, but I always get a mini aneurysm when somebody will be on Piptazo and I try to deescalate to Sephiroxim and Flagyl and then they forget to DC the Peptazone, they'll be on Peptazone. So if you're Oxy men, Flagyl so. Speaker 1 The Truth, Trifecta, all of the oral and the IV. Well, thank you both for joining me today and thank you to our loyal audience for listening to Break Points, the Society of Infectious Diseases Pharmacist Podcast. I have been your host Jeanette Bouchard and our featured speakers have been Doctors Nick Turney and Sunish Shah. Breakpoints was created by Julie Angusto, Aaron McCreary, and Jason Pogue. This episode was produced by Doctors Julian Hayes and myself, Jeanette Bouchard, and it was edited by Rachel Britt and peer reviewed by David Butler and Jenna Januska. Our production team includes Veronica Savante and Justin Moore. The executive producer of Breakpoints is Kate Decier. Our theme song was recorded by SIDP member Steve Smoke. You can subscribe to breakpoints on Apple Podcasts, Stitcher, or wherever you get your podcasts. Thanks for listening and helping SATP achieve our vision of safe and effective antimicrobials for now and the future.