ID:IOTS - Infectious Disease Insight Of Two Specialists
Join Callum and Jame, two infectious diseases doctors, as they discuss everything you need to know to diagnose and treat infections. Aimed at doctors and clinical staff working in the UK.
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ID:IOTS - Infectious Disease Insight Of Two Specialists
91. The ID:IOTS Guide to Tetracyclines 2: Tigecycline, Eravacycline, Omadacycline
They're new, they're weird, and we don't use them very much (or at all), but that won't stop your favourite ID:IOTS sounding off on these novel tetracyclines!
In this episode we discuss: An overview of the 3 drugs, including spectrum & penetrance; pharmacokinetics; EUCAST breakpoints; resistance mechanisms; and the recommendations for use in the IDSA DTR Gram Negative guidelines 2024.
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fine. Callum, I just wanted to cyclone back to what we were talking about before.
callum_1_10-15-2024_222017:Oh Yeah?
jame_1_10-15-2024_222018:Yeah? A couple of episodes, we said that the next episode after we talked about, you know, the Idiot's Guide to Tetracyclones was definitely going to be about the new tetracycline ones, Ticocyclone, Aravacyclone, do you remember how we instantly recorded a bunch of different episodes that weren't absolutely anything to do with those?
callum_1_10-15-2024_222017:Well I think what, happened was that there was a terrible pun there, but um, it's been cut.
jame_1_10-15-2024_222018:Fine. So Callum, what are we going to talk about today?
callum_1_10-15-2024_222017:Um,
jame_1_10-15-2024_222018:I didn't write the premnos.
callum_1_10-15-2024_222017:just get that in. I'll cut that as
jame_1_10-15-2024_222018:Ha ha! ha
callum_1_10-15-2024_222017:I, I think the first thing is a slight disclaimer, which is in a recent episode, James abandoned me, dear listeners, and recorded solo, without my knowledge. In secret hermit like way. was not invited to and then he said that I'd abandoned him. So, just to set the record straight, here in front of all of you, I have not abandoned you. James has abandoned me. But we have reunited, in a sort of circle of mutual,
jame_1_10-15-2024_222018:An uneasy alliance. You know, Like the first half of a buddy cop movie. You know what I mean? One of us is a stickler for the rules and the other one's chaotic neutral. That's a little deep cut there. Okay then. What
callum_1_10-15-2024_222017:Well, we're going to be talking about the new tetracyclines, new kids on the block. These antibiotics, one of which, we have in the UK.
jame_1_10-15-2024_222018:Uh, new. One of them got its license in 2005, so, like, we're not talking about a spring chicken here, but yes, they are considered the new ones, not least because the one that was, like, discovered in the 70s or something yeah.
callum_1_10-15-2024_222017:I guess we're going to just go through them in order. Tegacycline, Aravacycline, and Amandacycline.
jame_1_10-15-2024_222018:I in sort of you know, phase 3 trial order, if not outright approval order.
callum_1_10-15-2024_222017:Yeah, for each one, we'll just go through, we'll talk a bit about the class in general, and then we're going to, for each one, the mechanism, action, spectrum, root. dose, adverse drug reactions, and then a little bit about the pharmacodynamics and pharmacokinetics.
jame_1_10-15-2024_222018:Yeah, okay. Fine. Why don't we start with Ticker Cycling then?
callum_1_10-15-2024_222017:Well, tigacycline's a tetracycline, and it's a, glycycline derivative of minocycline. which I talked about before, which isn't really that widely used. So James, what is a glycycline?
jame_1_10-15-2024_222018:I'm glad you asked Callum. Well, uh, glycyclines were first synthesized in the early 1990s by making modifications to the tetracyclines. By adding a bulky N, N dimethylglycolamido side chain to Position nine of minocycline, the compound became less susceptible to tetracycline resistance mediated by acquired FLX pumps and or ribosomal protection. Further development of this initial work led to the creation of tetracycline, the first glyco cyclone available for clinical use citation needed. End quote. Uh, I mean, uh, I just knew all that off the top of my head.
callum_1_10-15-2024_222017:Yeah, just accessing the archives. so like the tetracyclines protein synthesis inhibitor and it binds to the 30S ribosomal subunit, which is, something that basically all bacteria share. And we'll come on to that, in terms of its wide spectrum of action.
jame_1_10-15-2024_222018:and all tetracyclines do, and the aminoglycides for that matter, but, what's the binding sort of affinity compared to like tetracyclines?
callum_1_10-15-2024_222017:yeah. So well, as Jamie mentioned there, it's modified and it has much higher affinity than the tetracyclines for this 30S subunit, five times more. And essentially by binding there, it blocks the interaction of aminoacyl tRNA with ribosomal A site. So basically blocks the ribosome from doing its function, so you just don't get protein synthesis. You've written here that it's back to your static. Do we care about
jame_1_10-15-2024_222018:well, I put it in there because it is bacteriostatic, but I would argue that I don't care about that we've made our position on Static Versus Cidal clear on
callum_1_10-15-2024_222017:episode 58.
jame_1_10-15-2024_222018:Yeah, but, the other interesting thing about, Tegacycline is it also seems to bind the 70S ribosomal subunit five times more than minocycline and 100 times more than tetracycline.
callum_1_10-15-2024_222017:Hmm. Hmm.
jame_1_10-15-2024_222018:So let's talk about the spectrum now.
callum_1_10-15-2024_222017:Yeah, so it's got broad activity against both gram positive and negative and anaerobes and atypicals. So it covers things like methicillin sensitive staph aureus, MRSA, entrococci, streptococci. It'll cover most of your introbacterioles and the gram negatives. Acinetobacter, Stenotrophomonas, supposedly. Anirobes, and atypical organisms, so your Clamidofla, your Legionella, it's almost too good to be true. And it also covers Listeria, so, you know, this one stop shop drug. It doesn't cover three things. What three things doesn't it cover and how do you remember them, James?
jame_1_10-15-2024_222018:well, it's almost easier to think about what. Ticocycline doesn't cover. So it doesn't cover the three Ps, Pseudomonas, Proteus, and Providentia. So those two fairly obvious sort of gaps. Proteus is more of a urinary organism and actually you wouldn't really use Ticocycline because it's not really excreted urinarily anyway. but UCAS has also actually stated inadequate activity. based on, post hoc analysis of a couple of randomized control trials against Morganella species, but also Klebsiella, which if you think about the gram negative cover that you would want is a pretty big hole. So it does cover Klebsiella, but there have been reports of sort of failure. the details are at the bottom of the UCAS position document on, Tigacyclines. They recommend not using TIGI for that unless there's no other alternative. And in terms of how you would give it, I'll just run through this. So it's IV only, there's no oral, option. And usually there, there are two regimens. There's a 100 milligram load followed by 50 milligrams 12 hourly. And there's a higher dose, which is a 200 milligram load followed by 100 milligram 12 hourly. And that's the regimen that people will tend to use these days.
callum_1_10-15-2024_222017:I think, the issue there, is that the lower dose in quotation mark, the dosing that was initially. Licensed is in the BNF and actually that's the standard dosing in a lot of the guidelines. So it is, I think it's been quite hard to convince people to move to the higher dosing because it's not really. What is licensed
jame_1_10-15-2024_222018:Fair enough, but the IDSA DTR Gram Negative Guidance, which is updated yearly, they specifically recommend the higher dose regimen. And the BMF kind of has its hands tied a little bit here, because they can only recommend the approved licensing dosage, and so if it's approved at the low dose, they can really only put that. But you're not a slavish BNF follower, you're an ID physician, or a microbiologist, or pharmacist, or interested third party. You can prescribe whatever you like. And so I would argue that if you're dealing with a difficult to treat gram negative infection in particular, and you feel the need to use ticacycline, you are within your rights to use the higher dose, because that's what I think what the most robust evidence base is used on.
callum_1_10-15-2024_222017:come on to that. You don't need to convince me of that. I just find it interesting that there is that IDSA guidance, but with the way that it was introduced initially, take a cyclin, the lower dosing has become established in all the sort of main places that people go to their guidance for dosing. And so when you're coming along and saying, we should really use a hundred milligrams twice daily, people are like, that's not what it says here.
jame_1_10-15-2024_222018:Yeah, true enough. And normally I don't say, go against the BNF, but here I am and here I'm using the IDSA guidance, which I think is probably the best gram negative guidance in the world as a reason to
callum_1_10-15-2024_222017:There's lots of things that BNF gets wrong, lots of things.
jame_1_10-15-2024_222018:In terms of side effects though, Cal, the main ones, and this is going to be a recurring theme, is GI disturbance. And what do I mean by that? I mean, nausea and vomiting, and diarrhea. As well, these are very common, in all three of what we're about to discuss, but, to give you an example, about 20 percent of people given to the cyclone will experience nausea and vomiting. So that's quite a lot, and in some reports, it's as high as 30 percent and sometimes this can be changed by extending the infusion time. as well, so it's a dose dependent effect, so you can get around it by increasing the length of time that the infusion goes in over. And then other things, pancreatitis and hepatitis, phlebitis at the infusion site, and then coagulopathy. These are less commonly observed, let's see.
callum_1_10-15-2024_222017:yeah.
jame_1_10-15-2024_222018:What about its, PD parameters, Cal?
callum_1_10-15-2024_222017:Yeah, for pharmacodynamics, the target It's the proportion of the AUC the curve, of the MIC, the minimum inhibitory concentration.
jame_1_10-15-2024_222018:Hmm,
callum_1_10-15-2024_222017:relative to serum, four hours after that 100 milligram dose, there's 38 times concentration into the gallbladder, 8. 6 times into the lungs, 2. 1 in the colon. Bone is 4. fluid is 0. 58. It doesn't cross the blood brain barrier, and it has poor plasma levels. So you can see initially, you know, it's, hepatic clearance, it's getting into the biliary tree, great for there. The fact that it's going so much into the biliary tree, into the gut, might explain why it's got so much GI side effects.
jame_1_10-15-2024_222018:maybe, yeah.
callum_1_10-15-2024_222017:yeah. it's concentrated onto bone, but not joint fluid, so it's worth being aware of. And, it's not getting into the brain, so it's not really useful there.
jame_1_10-15-2024_222018:And it has a bit of a post antibiotic effect as well, Calum, doesn't it?
callum_1_10-15-2024_222017:Yeah, so the, growth is inhibited for things like Staph aureus, reported to be about 4 hours, and E. coli, about 2 hours, growth inhibited. Why is that? Is it just they're sort of stunned into
jame_1_10-15-2024_222018:Why does anything have a post antibiotic effect? But I mean, I would argue that if you shut down all protein synthesis, that might stop something from growing.
callum_1_10-15-2024_222017:Yeah.
jame_1_10-15-2024_222018:Yeah, anything else to say on tickle cycling, Calum? Because I think it's got, for something that's very broad spectrum and can be effective, it's got quite a bad reputation, even though it's gone head to head against a bunch of different, antibiotic alternatives and has been, in the high dose, very robust in those trials. Mm
callum_1_10-15-2024_222017:I think the issue is that the initial studies all looked at the 50 milligrams twice daily. And, there was some signals in randomized controlled trials that suggested that there was a higher, mortality rate. Yep. in the Tegacycline arms. now the comparator drugs, so there's, in the show notes, there's a paper that, is a meta analysis and systematic review, CHI, TAL, 2011. And, they go through all the papers and it was quite an interesting read just to get an understanding. It's from 2011, so it's, before The more recent papers were looking at the higher dosing, and obviously the IDSA guidelines have got a really great literature review on the most recent paper, but looking back at 2011, of the randomized controlled trials when looked at by, the FDA in their approval showed a higher level of mortality. Kaya Tell's paper said that they couldn't get all the data because some of it was unpublished data looking at hospital acquired infection. But it ended up with this warning, essentially, that there might be excess mortality to the cyclone. And that sort of thing sticks, when you get a warning saying there might be excess mortality. So people tend to avoid using agents that might lead to that. The comparators are quite interesting. So, for, Intra abdominal infection, it was usually compared to either Imipenem and Cytostatin., Or the other option was Keftrax and Metronidazole. And you think, take a second, it's got this broad spectrum activity, but You know, would you really trust it for anaerobes? And, I think one of the problems with it is that because it works against everything, the trials looking at its use of looked at everything. So hospital chiromony, acute bacteria, skin cell tissue infection, and job domino infection. And, there's, very heterogeneous groups. And so maybe the answer is that we're seeing as UCAS are saying that, actually it's not. It isn't going to treat everything, some organisms it's less effective against. Like maybe it was just the patients selected in those RCTs weren't the right ones. And certainly, although there was that warning, when you look at the meta analysis, actually it's got comparable outcomes, mortality rate, clinical cure rates. I guess I think a takeaway from that was that this isn't your first line go to agent. For any of these clinical conditions, but actually it's a really useful thing to have in your back pocket when, for whatever reasons, potentially resistance or, other considerations, renal impairment, for example, allergy, you know, it's something that you've got there like, for pneumonia, actually, I was really thinking about it, but the thing that covers the typical, one size fits all sort of drug. So yeah, I think as a back up, reserve antibiotic, it's definitely got a place.
jame_1_10-15-2024_222018:And I think that's being reflected in the IDSA DTR gram negative guidance as well. And with new breakpoints coming through, at least for UCAST as well, it's, you IDSA Can it increase a little bit? But it's a reserve antibiotic. It's always going to be used in those cases where for whatever reason, doxycycline and minocycline aren't appropriate. And, maybe it's used in combination, but it is useful for some stuff. And it is recommended in the IDSA guidance for some things as we'll talk about shortly. Will we chat about Aravacycline?
callum_1_10-15-2024_222017:Yeah, I, now completely out of my knowledge on ticacycline. I have some experience using, as we mentioned before, meroliniantibiotics, ravacycline, madacycline, which is not available
jame_1_10-15-2024_222018:yeah, and
callum_1_10-15-2024_222017:we can still talk about the facts, I
jame_1_10-15-2024_222018:yeah, we don't have easy access to these things in the UK, but they are maybe coming, maybe not a matter.
callum_1_10-15-2024_222017:What?
jame_1_10-15-2024_222018:sort of depends on what approach the MHRA take to local. regulation now that we don't have oversight from the EMA now that we've left the EU, but let's talk about Arabicycle at least. It is part of a new subclass of tetracyclines called the aminomythylcyclines. And what's happening there? Well, there's the core tetracycline sort of four ring scaffold and with two unique modifications in the tetracycline D ring. Which is, oddly enough, the left most ring, because it goes A is right most and then B, C, and then D is left. At position C7 there's the addition of a fluorine atom, and at C9 there's an addition of a pyrolidinoacetamol group. Which I'm sure you're more than familiar with, Callum, so I won't bother you with the details. it's, Another 30S subunit reversible binder, same as most of the tetracyclines are. And it does about 10 times more tight binding compared to tetracycline. Its PD parameter is AUC its spectrum is very similar to TIGGY. So I've, for these two, I've said, how is it different from TIGGYcycline? Well, it also covers Proteus and Klebsiella, as far as we can tell. And it's increased activity compared to ticocycline is that it will be more two to four times more active against GPCs and two to eight times more active against gram negative bacilli. It is currently available IV only, but actually in earlier In its life cycle, they did try oral formulations. So you'll see some trials would mention it being given orally, but it's only 28 percent bioavailable calum. So it's really an IV only formulation. I'll talk about the studies that were part of his licensing shortly. The dose that is typically kilogram twice daily. And the main side effects are nausea and vomiting, and raised pancreatic enzymes, so lipase and amylase, whatever you're using in your local practice. And the way that Goddard's marketing authorization was mostly based on the IGNITE, program, There's the IGNITE 1 trial, which is for complicated intra abdominal infection, IRAVA versus ertepenem, and the IGNITE 4 trial, which is IRAVA versus meropenem, and no difference in clinical outcomes for complicated intra abdominal infection for these two. So that's pretty good, isn't it Callum?
callum_1_10-15-2024_222017:Yeah,
jame_1_10-15-2024_222018:you're pretty impressed, aren't you?
callum_1_10-15-2024_222017:Mm
jame_1_10-15-2024_222018:Yeah, you're going to be giving a rev a cycle into everybody, with complicated abdominal affection, aren't you?
callum_1_10-15-2024_222017:No, because it's, it's a reserve
jame_1_10-15-2024_222018:And it's super expensive. Yeah, okay, fine. That was a little bit of a trap, but I know what you're wondering, Callum.
callum_1_10-15-2024_222017:What about other clinical indications?
jame_1_10-15-2024_222018:you're not wondering that.
callum_1_10-15-2024_222017:Okay, um, what am I
jame_1_10-15-2024_222018:You're wondering what about Ignite 2 and Ignite 3.
callum_1_10-15-2024_222017:oh yeah, that's, that makes sense, yeah.
jame_1_10-15-2024_222018:You're wondering about what about ignite 2
callum_1_10-15-2024_222017:what about IGNITE 2, james?
jame_1_10-15-2024_222018:you! Thank you, Callum.
callum_1_10-15-2024_222017:What about it?
jame_1_10-15-2024_222018:Well, Ignite 2, these were both for complicated UTI. And Ignite 2 was a Ravis Cyclone. IV and then oral switch versus levofloxacin, IV and then oral switch. You could argue that wasn't necessary, levofloxacin is highly bioavailable, but never mind. And then IGNITE3 was a ravicicin versus ertapenem. And I can only tell you what is wrong. Uh, another review paper, which I think I've linked to in the prep notes, said about these because they, as far as I can tell, they've been presented at a conference. I forget which one, but not published. I couldn't find Ignite 2 for all the tea in China. Calum, so if you, if anybody can find them, please do send me on a copy. But the, review paper says, and I quote, Both trials could not demonstrate efficacy for Rorava cyclin compared with Erdapendium or Levofloxacin. End quote. Now the first trial, the IGNITE 2 trial, is Arava Seichen IV upfront within an oral switch and because of the low bioavailability, you could argue probably there was treatment failure because of that. Arava versus Erta, the IGNITE 3 trial, I think that was all IV and wasn't, superior. If I'm wrong, please do email and correct me, idiotspodcasting at gmail. com, but yeah, for this reason, I presume that Aravacycline is maybe not so good for the urinary tract. And when we come on to the PK, we'll, you know, find out exactly why.
callum_1_10-15-2024_222017:Hmm,
jame_1_10-15-2024_222018:Callum, take us through Omadacycline,
callum_1_10-15-2024_222017:So, um, I'm at a cyclone, so this is a, aminomythylcyclines, as we heard about for a rathocycline. it again reversibly binds to the 30S subunit, and its binding affinity is meant to be two times higher than tetracycline, so similar to minocycline. So maybe not quite as, as bindy as a rathocycline. PD target's the same, as you'd expect. AUC to MIC. The spectrum compared to tigacycline. So gram positive is about the same gram negative. Essentially the same except for the three Ps that we mentioned earlier on, which was You can remember, listener.
jame_1_10-15-2024_222018:and Proteus.
callum_1_10-15-2024_222017:Well, I was asking the listener, James.
jame_1_10-15-2024_222018:Oh, right. I'm sorry. I didn't realize it was a phone in your answer podcast these days.
callum_1_10-15-2024_222017:I definitely remember. I wasn't asking because I forgot.
jame_1_10-15-2024_222018:Where's the thought, Callum?
callum_1_10-15-2024_222017:and same as anaerobes atypical. So it's, it's the same as tigacyclone. So why, why do we care about this? It's root drum roll, please. so IV or oral! Wow! So, oral, you can dose it 300mg twice a day for 24 hours, and then 300mg once a day. slightly strange, or IV 200 milligrams once a day or 100 milligram twice a day for 24 hours and then 100 milligrams once a day. I really dislike doing that because I'm not trying prescribing having to do one dose of something and then
jame_1_10-15-2024_222018:Doing another one.
callum_1_10-15-2024_222017:and it's just more complicated. Although actually that's probably an issue with the prescriber and they should just set it up so it does the first dose of higher but that's tangent.
jame_1_10-15-2024_222018:yeah.
callum_1_10-15-2024_222017:So yeah, so there's an oral option. Great. Adverse drug reactions, like the other ones, GI, so nausea and vomiting. Is there any other adverse drug? The other ones had hepatitis or
jame_1_10-15-2024_222018:That's the main one. I couldn't find much more, actually. Not least because there's no, it's not in the BNF, there's no SPC. I'm just going on trial, data, but yeah.
callum_1_10-15-2024_222017:fair enough. And then, so there's probably more ADRs, but we just don't know about them. And studies, so for skin soft tissue infection, there was two trials, OASIS 1 and OASIS 2, we're getting the Oasis reunion soon. So Oasis one was Ivy and Madacyclone, versus Ivy Lenezilud. And Oasis 2 was Oral Madacyclone versus Oral
jame_1_10-15-2024_222018:Calum, did you mention at the beginning that these were for skin soft tissue infection? Did I miss
callum_1_10-15-2024_222017:I said, I did say you did miss that? you should pay more
jame_1_10-15-2024_222018:Sorry pal.
callum_1_10-15-2024_222017:You're not a loyal listener because you don't listen.
jame_1_10-15-2024_222018:I'm a disloyal listener.
callum_1_10-15-2024_222017:You're just, or you're a loyal
jame_1_10-15-2024_222018:a loyal idiot. Anyway, was there a difference in outcomes?
callum_1_10-15-2024_222017:But why did they give Ivy Lineslid? There was no difference in outcomes, but the main question to me is why would you ever give Ivy Lineslid? So
jame_1_10-15-2024_222018:Like maybe dose equivalency. because if you know that Omadacycline IV to oral, know, the oral, you give them 300 IV, you give them 100. Why? It's about 33 percent bioavailable. That's why. So they are there, the doses are equivalent. And so maybe they were just trying to confirm that you could use oral
callum_1_10-15-2024_222017:it's pretty good that it was, non equivalent, um, when the viability was that low. But I would caveat that with, I think Brad Spellberg was having a rant on Twitter or was it an article where he was talking about,
jame_1_10-15-2024_222018:Imagine that Callum. Brad spellberg having a rant? Harris,
callum_1_10-15-2024_222017:About the way in which the trial approvals go through for skin soft tissue infection or acute bacterial skin soft tissue infection. Like if you're doing it by the FDA standards, like the out, the outcomes that you need to meet are, It's not hard to demonstrate efficacy, is it?
jame_1_10-15-2024_222018:No, and yet also I think a big problem with trials is that they ask for like microbiological test of cure. I'm thinking about urine in particular, where they're like, you need to re culture the urine and make sure that the urine is cleared, and I'm sitting there thinking I couldn't give any less of a crap about whether or not their urine is clear if you paid me. But it because it's in, ESCMID and the EMA's, testing standards, you just have to do it. Speaking of which, Callum, do you want to take us through oPTIC?
callum_1_10-15-2024_222017:Yeah. So this is in the community acquired pneumonia where optic trials where they looked at IV amidocycline versus IV moxifloxacin. And there was no difference in outcomes. There was some more diarrhea in the moxifloxacin group, but there was numerically higher deaths in the madocycline group. So it was eight versus four, so low numbers. And for this reason, the,
jame_1_10-15-2024_222018:and just so you know, just so you know, Cam, that's 2 percent versus 1 percent of the, each arm of the trial. So it's, it's really
callum_1_10-15-2024_222017:very much possible within random number. And for, and for this reason, And the EMA, the European Medicines Agency, asked for a second run of the mill control trial, which Paratech, the company that was, you know, pushing forward a motorcycle declined to do so and withdrew their EMA license application. So we talked to where all the new antibiotics going before, and I think this is a good example of where, our company was just like, yeah, just, we're not doing that. And now we don't have it. So.
jame_1_10-15-2024_222018:no, we don't. And I wonder if we ever will. I mean, maybe when it comes off patent, but yeah, there are issues associated with that.
callum_1_10-15-2024_222017:I guess the fact of having an oral option is quite appealing, but I just not, at 34, buy availability is, so low, is it actually, I guess they've done the dosing for that, haven't they?
jame_1_10-15-2024_222018:the macrolides is quite low. But you wouldn't call them a useless drug because they've got low bioavailability, because stuff that spreads into the intracellular compartment quite well is quite useful for some stuff. It's fine. I wouldn't recommend any of what we've just discussed for plasma bound infection. You know, I'm not going to be using ticlocycline for endocarditis anytime soon, but there's plenty of other infections for which they would be useful and where in fact penetrants into the intracellular compartment would be, functional for you as an ID clinician, to be able to use. So the next little bit, we've, got a little table, about the pharmacokinetics of the three drugs that we've just mentioned. The. I'm not going to go through this in detail. It's in the prep notes. The prep notes are linked in the show notes. You can have a quick look. You can steal the image and use it for yourself. No problem. All of these drugs are very lipophilic and they've got very high volumes of distribution because they're leaving the plasma very quickly and they don't undergo a huge amount of metabolism. Before they are excreted and they are excreted predominantly in, in the liver, in bile. a small amount gets into the, into the urinary tract, particularly, Arabicycline and Imidacycline. But I'm not sure how much you would read into that. And that's about all I'll say about the, about the PK of these drugs. And you can look the rest up yourself. Have any breakpoints?
callum_1_10-15-2024_222017:so yeah, UCAST 2024 breakpoints. We have breakpoints for tiggycycline and avraphycycline for some organisms, which is great. So, tiggy, they've got breakpoints for Staphylococci, Bt hemolytic strep, enterococci, E. coli, and citrobacter. And avraphycycline. Very similar, Staphylococci, Viridan strep, but not mutually hemolytic, Endrococci and E. coli, but not Citrobacter. And then for, the missing strep in either of them is IE and sufficient evidence. So, basically they're saying when it's IE, it probably does work. We need to go to the, where there's no breakpoints table and interpret it a bit more, which I won't go into the complexities of that because that is a whole
jame_1_10-15-2024_222018:yeah. But just to summarize that summary, for tigacycline, there's no breakpoint for viridan strep, and for arabicycline there's no breakpoint for the beta hemolytic strep, or citrobacter coseri, and for every organism that hasn't been mentioned in the past one minute, there is no breakpoint. so, although it's got this, they've got these huge wide spectra, there's no, distinct, breakpoint from UCAS at least available for it.
callum_1_10-15-2024_222017:you can go away and test it, and you can use an MSE and use an interpretation. It's just not as simple as sensitive for a resistant is. You're going to need to put more interpretation, so. But I imagine more great points will come as we get more data.
jame_1_10-15-2024_222018:Callum, what about resistance mechanisms to these drugs?
callum_1_10-15-2024_222017:Yeah, well in the Idiot's Guide to Tetracyclones, before we went through the resistance mechanisms, um, James did a good summary of that. And I essentially, for all three of these drugs, we're looking at four main mechanisms of resistance. So efflux pumps, ribosomal protection protein, drug degradation, and that's really only in
jame_1_10-15-2024_222018:Yeah, so that's the tetracycline destructases.
callum_1_10-15-2024_222017:I remember them. They sounded like a transformer or something. And then rRNA mutation. So Jane, which of these have been reported for which of these
jame_1_10-15-2024_222018:Well, I mean, the whole thing about these drugs is that they are resistant to the first two, efflux pumps and ribosomal protection proteins, which are the, lion's share of tetracycline resistance. So their whole raison d'etre is that they're not susceptible to a bunch of these things that we've mentioned in the, previous episode. But there are some reports of resistance. So for in intracocci, ticocycline can be excreted through, an MFS pump. And we've mentioned all the efflux pump subtypes before. and, in gram negatives, there are RND efflux pumps, which I have Listed here in the prep notes, but I don't think the loyal listener needs to know about them in detail. And then for Aravacycline, there are some reports of MDR, efflux pumps. So they'll be excreting a bunch of different drugs. And one of which is Aravacycline. and then again, for imidacycline, there's little to none reported resistance due to efflux pumps. there are some resistant organisms for all of these three drugs, but the precise mechanism is difficult to determine. And then for ribosomal protection, there's been, reports of ticky resistance associated with TETM in intracocci, and some sporadic reports with the other two. For drug degradation, I actually couldn't find any specific, destructases that work on these three. And for ribosomal rotation, again, it's been reported for Arava or Nomada cyclin, and maybe Ticacycline as well. I couldn't find anything definitive there. But the resistance mechanisms are scanty, although, you know, because of the concerns about it being, leaving the plasma and not penetrating the CNS, there's You know, reasons for failure, not associated with the resistance that you have to think about.
callum_1_10-15-2024_222017:Yeah, even if it's not a resistant organism, you still need to get the drug there for it to work, don't you? Sufficient concentrations.
jame_1_10-15-2024_222018:Which leads me to the last section Callum, which is What does the IDSA recommend using these drugs for? Let's take it one at a time, why don't you talk about TIGI.
callum_1_10-15-2024_222017:Do you want to take it drug by drug or resistance
jame_1_10-15-2024_222018:I just specifically said you take TIGAcycline and then we'll
callum_1_10-15-2024_222017:Oh, okay, that makes sense. Let's do it drug by drug.
jame_1_10-15-2024_222018:Thanks. Oh, great. Thank you, Callum. What a brilliant idea. I wish I thought of that.
callum_1_10-15-2024_222017:Haha. Tiggy Cyclone. I wonder if there's a different way to pronounce it? Like, Tiger
jame_1_10-15-2024_222018:Oh, we'll find out when we have our guest in a few weeks time. That's a little, that's a little tidbit for later.
callum_1_10-15-2024_222017:Let's go through it in order. So, ESBLs. So ticacycline IDSA say you can use unless it's a bloodstream infection or UTI for carbapenem resistant enterobacterioles, uh, you can use it, unless it's a bloodstream infection or UTI, for crabs or acinetobacter, you can use it in combination and then for centrifumonas, it says. Not in UTIs. You can use it unless it's a UTI.
jame_1_10-15-2024_222018:Yeah. So I mean the none of these have reliable urinary penetrance, you know As opposed to some of the other chenter cyclins where you actually get pretty good levels So yeah, I wouldn't use any of these for UTI frankly Let me take So for ESBL and CRE you can use unless bloodstream infection or UTI. For CRAB they recommend use if no other option available, that's because of limited data. And then for STENO it says also can use unless UTI present. and so for hematocycline, again, because of the low plasma levels, they recommend that you avoid, for bloodstream infections.
callum_1_10-15-2024_222017:Can you use it in other indications or they just say don't
jame_1_10-15-2024_222018:Yeah, they say you can use them, but they also mentioned the limited data available compared to the other two. Yeah and then they recommend avoiding the use of a bad acyclin again because of limited data in CRE, CRAB, and Stenotrophomonas. And they finish by saying that Tiggy or Cylin, can be considered as alternative options for intraabdominal infections, skin soft tissue infection, osteomyelitis and respiratory, infections. And that Callum, is that, so, I mean, what do you think about these drugs? I think both of us, our use of these drugs has been fairly limited.
callum_1_10-15-2024_222017:Yeah, I've, yeah, we've used tigacycline, or recommended it in quite a few situations where I've been really stuck, I think it has a place and often with antibiotics it's more, it's useful having more options, and obviously there's this concern, I think. With the newer literature, if we just used a higher dose all the time, we might see quite a lot of those concerns fall away, but it's not that tolerable, and it's really just got a bad launch, and now I don't think we're going to get to a stage where people are comfortable using this, even if it is the best thing to be used.
jame_1_10-15-2024_222018:I think 20 to 30 percent of your people, your patients puking their guts out. Like that is a significant side effect.
callum_1_10-15-2024_222017:What is that? Because it's like you're saying 20 to 30 percent people have a, cause when they grade at ADRs and drug trials, they look at. seriousness.
jame_1_10-15-2024_222018:Yeah, I guess you would say that nausea and vomiting isn't very serious, and fine, it is not bleeding to death, but to advocate for the patient for a second, it is possible to ignore pain, it is possible to ignore a bunch of different symptoms, but nausea and vomiting is really difficult too.
callum_1_10-15-2024_222017:but I guess how does that compare to other drugs? Cause when we talk about things like high dose oral mox, like the tolerability of that is quite poor in terms of nausea.
jame_1_10-15-2024_222018:Yeah, that's what's been reported, Cal, but I don't know about you. I use high dose amox a lot, and I don't encounter the GI side effects that have been mentioned that I think you're alluding to. so the, side effect profile in meta analyses of, amox high dose has been equivalent to erythromycin. Maybe this is just because I don't use a lot of erythromycin, I don't really encounter a lot of GI side effects with amoxicillin, not that I know, and I'm certainly using it as one of my main drugs when I'm seeing people from day to day. I don't know, you can't tell a lot from your own clinical experience, can you? That's what the trials and the studies are for. But yeah, it's certainly not my experience.
callum_1_10-15-2024_222017:Yeah. Well, one other thing actually to mention just randomly this popped into my head is that we had a clinical case where someone had severe C diff and for some reason they couldn't have a rectal tube for, vancomycin enemas. And for some reason they, there was some other reason they couldn't have an NG or something that was very complicated. And they were really sick and the surgeons phoned us saying like, you know, we really want to avoid taking this person to
jame_1_10-15-2024_222018:Oh, God. Yeah, yeah,
callum_1_10-15-2024_222017:Because they're very frail, et cetera, et cetera. And I found something in the guidance about tick cycling can be used for C.
jame_1_10-15-2024_222018:it does. I haven't put that in the primaries, but you're absolutely right. Yeah. So it targets, C def and, has less of an effect on it's like it's enemies than you might think. And so it has been used as like Hail Mary for, recalcitrant, let's say a C. diff infection. Yeah. And I didn't see any data with Arava or Ramada on that. But, yeah, take a cyclin. You can use it and it does seem to be, Sort of seed of stable, let's say, in a
callum_1_10-15-2024_222017:It was, I can't remember which guideline it was in, but it was like hidden away in the like fourth line bit and you're like, it was one of those situations where you're like, I think it was in the middle of the night and I was like reading around trying to find something to offer, To help. I don't know if they actually really did anything, who knows, but,
jame_1_10-15-2024_222018:Well, I mean, you can only try your best caliber,
callum_1_10-15-2024_222017:yeah, and I think this is where take a cyclone is, isn't it? It's not your first line is probably not your second line. and the other drugs as well, but, useful to have,
jame_1_10-15-2024_222018:but the, but there is a role is there not for third line stuff. Do
callum_1_10-15-2024_222017:Yeah, we need a third line.
jame_1_10-15-2024_222018:Would love everybody to just be able to use the,, your access antibiotics, but there's a reason for watch and reserve, to be, to be there as for when all that stuff fails and you need to keep on going. And then, an antibiotic like Tegacycline, Arava, Omada, it being just basically for use by IV physicians and microbiologists doesn't necessarily mean that it's got a bit less value. Like we need stuff in our back pocket because we are called to the weird stuff, the stuff that is difficult to handle. And there, I think, Tiggy and Arava Nomada, would be useful to have. I just wish we had a bit more access to them for these patients,
callum_1_10-15-2024_222017:well we'll end there. I'm glad we could follow up the previous Idiot's Guide to Tetracycling immediately with this episode.
jame_1_10-15-2024_222018:Yes, absolutely. Nobody have a look at any of the, of the actual release dates.
