Jame and Callum were delighted to be invited as guests to the podcast Microbe Mail by host Vindana (Vin) Chibabhai. Check out the Microbe Mail podcast:
https://microbemail.captivate.fm/ @microbemail
We discuss how bactericidal and bacteriostatic are defined, what the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) are and why this isn't as simple as it first seems. We then discuss specific clinical situations and where bactercidal vs static have been compared.
Links/papers mentioned in this episode:
The basics of beta lactamases
Wald-Dickler N, Holtom P, Spellberg B. Busting the Myth of ‘Static vs Cidal’: A Systemic Literature Review. Clin Infect Dis. 2018 17;66(9):1470–4.
Use of bacteriostatic agents in Neutropenic fever:
The RCT referred to in the abstract is here:
Jaksic B, Martinelli G, Oteyza JP, Hartman CS, Leonard LB, Tack KJ. Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with Cancer. Clinical Infectious Diseases. 2006 Mar 1;42(5):597–607
Questions, comments, suggestions to idiotspodcasting@gmail.com or on X/Threads @IDiots_pod
Prep notes for completed episodes can be found here (Not all episodes have prep notes).
If you are enjoying the podcast please leave a review on your preferred podcast app!
Feel like giving back? Donations of caffeine gratefully received!
https://www.buymeacoffee.com/idiotspod
Jame and Callum were delighted to be invited as guests to the podcast Microbe Mail by host Vindana (Vin) Chibabhai. Check out the Microbe Mail podcast:
https://microbemail.captivate.fm/ @microbemail
We discuss how bactericidal and bacteriostatic are defined, what the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) are and why this isn't as simple as it first seems. We then discuss specific clinical situations and where bactercidal vs static have been compared.
Links/papers mentioned in this episode:
The basics of beta lactamases
Wald-Dickler N, Holtom P, Spellberg B. Busting the Myth of ‘Static vs Cidal’: A Systemic Literature Review. Clin Infect Dis. 2018 17;66(9):1470–4.
Use of bacteriostatic agents in Neutropenic fever:
The RCT referred to in the abstract is here:
Jaksic B, Martinelli G, Oteyza JP, Hartman CS, Leonard LB, Tack KJ. Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with Cancer. Clinical Infectious Diseases. 2006 Mar 1;42(5):597–607
Questions, comments, suggestions to idiotspodcasting@gmail.com or on X/Threads @IDiots_pod
Prep notes for completed episodes can be found here (Not all episodes have prep notes).
If you are enjoying the podcast please leave a review on your preferred podcast app!
Feel like giving back? Donations of caffeine gratefully received!
https://www.buymeacoffee.com/idiotspod
Well, what you're about to hear is an episode of the Micro Mail podcast. Kalman and I were lucky enough to be invited on by a Vindana Sheepavai, the host, and a microbiology professor from South Africa. If you like what you hear, please consider subscribing to the Micro Mail podcast. Hope you enjoy the show.
Speaker 2:And the very strict laboratory conditions, the distinction between bactericidal and bacterostatic antibiotics seems clear-cut and straightforward. In a clinical situation, however, these lines are pretty blurry. More recently, the idea that sidle is better than static as a general rule has been considered a myth, and since it's been absolutely ages since we've busted any myths on Micro Mail, what better thing to do today than idiot-proof the myth of sidle being better than static? Speaking of idiots, james Talem, how are you doing today?
Speaker 1:Yeah, I'm doing great. Thanks very much, Ben. Well done for walking idiots into the introduction.
Speaker 3:Yeah, that was smooth. It's almost like you're sensible and plan what you're going to say, rather than just making it up on the spot like we often do.
Speaker 2:I'm not as good as you with making it up on the spot.
Speaker 3:I'm not sure good at making it up on the spot is how I would describe what we do.
Speaker 1:I agree, good is doing a lot of heavy lifting in these sentences here. How are you doing, ben?
Speaker 2:Yeah, good, good Dark, it's winter solstice, so yeah that's a heads up for the listeners of when we actually recorded this episode, but otherwise, well, will you tell us about the Idiots podcast and a little bit about yourselves, for those listeners who didn't catch our previous episode together?
Speaker 1:Talem, you take this.
Speaker 3:Thanks, ben. So we're from the Idiots podcast and that stands for infectious diseases insights of two specialists, although sometimes the two pushes to free or tetrad or any other number beginning with T, so there's a set number of people that can be on. And what are we? So we're a podcast book looking at sort of infection for the perspective of clinicians or laboratory workers or anybody's interested. We're based in the UK and our sort of reason for starting was to provide content for people sitting their sort of membership exams for infection medicine and we've been going for almost two years now.
Speaker 1:That's right. A long may continue.
Speaker 2:Long may continue, absolutely. Just a couple of reminders. Remember to sign up for updates on the Microbail website. You can follow Microbail and the Idiots podcast on social media. Great, both shows on your pod player of choice. Remember to share with colleagues, friends and students. And have I missed anything else, jay?
Speaker 1:I don't think so. We're not organized enough to have a newsletter. So no, we've got nothing to point people towards except the podcast itself. Give us a go of the two podcasts out there. Microbail and the Idiots podcast are probably two more similar. So if you enjoy Microbail, you'll probably enjoy Idiots, and vice versa. So give us a try. It's not like there's a limit on the number you can subscribe to.
Speaker 2:Yeah, give us a try and give us a rating. Okay, great. So I think we're ready to get into this episode. So, jay, I think first question would be what do each of these terms mean? What is bactericidal and bacterostatic?
Speaker 1:Glad you asked, vin. You already know this. So let me explain this to Callum Callum.
Speaker 1:Imagine a perfect day card plate on which you have a colony of bugs and you have an antibiotic and you want to know what the antibiotic is doing to that colony. So you maybe set up a bunch of plates and you've got. You know for a fact that you've got 1000 colony forming units or bacterial cells however you want to think about it on that plate and then you add a certain amount of antibiotic and you come back and you check that plate at 24 hours. If you had exactly 1000 bugs on that plate, then you would have determined what the MIC is. So the minimum inhibitory concentration, or MIC, is the concentration that inhibits visible growth at 24 hours. So you know, visible, but I'm just using this bugs analogy for you'll see why in a little bit.
Speaker 1:But I'll say and there is a another concentration which is above the MIC, which we sometimes also refer to, which is the minimum bactedocidal concentration, and that is the concentration which generates a three log 10 reduction of bacterial density, again at 24 hours. So you've got your 1000 bugs on the agar plate and you come back and you have one or less than one bug on that plate. You think to yourselves aha, I have determined the NBC minimum bactedocidal concentration for reasons that we probably don't need to get into, unless you feel like getting into them. It's kind of difficult to look for the NBC all the time in the lab. So for technical reasons, we usually go to the MIC and when you have antibiotic susceptibility testing either machines or you're putting antibiotic this on a plate the MIC is what you're you're kind of looking for. We've mapped zones of inhibition and things like that to the, to the MICs.
Speaker 3:And so what's the?
Speaker 1:definition of bactedocidal. Bactedocidal, yeah, just some. If your MBC divided by your MIC is less than 4, then, it's bacteriocidal, and if it's greater than 4, then it's bacteriostatic. So, callum, once again I'm going to make this very simple for you. I'm going to tell you about a bug drug combination and the MIC for this bug drug combination is 1. So if the MBC is 5, then that would be a bacteriostatic antibiotic, and if the MBC was 3.99999, then it would be determined to be bacteriocidal. Do you get it?
Speaker 3:Yeah, so you take that MBC divided by the MIC, and if that's less than 4, then it's back to your side.
Speaker 2:Yep.
Speaker 1:Yes, so it has to be less than 4 times, as in they've got to be closer to each other. So once you get above the MIC, you only need to get a little bit higher and then you hit the MBC. Then that would be your bacteriocidal antibiotic and bacteriostatic. So you know, that's simple. Those are the definitions, and do you have any questions? Callum.
Speaker 3:Yeah, I guess for me I always think of sidal as it kills inverted commas and stat is as it sort of inhibits growth, but it's not killing the organism. But I guess we'll get onto whether that actually matters or not.
Speaker 2:And why the magic number 4?
Speaker 1:That is a very interesting question because there are loads of holes that we can poke in this. So let's start at the very, very beginning. Why 24 hours? The bugs don't know that it's 24 hours and they don't work. I'll say that they don't work to a diurnal rhythm, same as they don't work to the number of days in the week, for how many doses of antibiotic will kill them. So the 24 hours thing is a little bit odd For the MIC.
Speaker 1:Why are we looking at visible growth, Visible growth on the plate, according to a human eye that's full of potential errors, not only to do with the human's eyesight, but to do with how the bug is actually growing on the plate. When it comes to the MBC, why is it a thousand fold reduction? So if I have 1,000 bugs and I apply a certain concentration and I come back the following day and I have two cells on the plate instead of one cell, I've not achieved the MBC, but I've killed almost everything on the plate. Is that not good enough? Why is it a thousand fold? It's because we like working in base 10, but if we didn't use our thumbs like the Mayans did, we'd be working in base 8 and we would be wanting a 512 fold reduction or a 1,024 fold reduction, and it's for the ratio, which I guess is what you asked me originally.
Speaker 3:Just saying here, like James is just going off.
Speaker 2:He's taking all the apart. You can see this topic excites James.
Speaker 3:James beyond leached.
Speaker 1:I don't know why. Four, why isn't it five? Why isn't it 10? Why isn't it two? Do you know? Why isn't it just two times over the MIC?
Speaker 1:Like these numbers seem to have been picked completely at random. And then the ultimate kicker is even if you get that, we talk about bug drug combinations for targeting antibiotics and the bugs don't play by the rules. So the antibiotic in question could be static against something but sidal against another. So see, macro lights, for example, are bacteriocidal against streptocci, like group A, streptenium, ammonia, the kind of things that you would even want it to be active against, but they're bacteriostatic against almost everything else. Linazolid, our favorite bacteriostatic antibiotic of all, famously bacteriostatic, is bacteriocidal against streptocci, but no entrecocci, the closest relative to streptocci, or staphylococci, the thing that you're usually using against in serious infections. And chloramphenicol is also bacteriostatic, or purports to be bacteriostatic, but is bacteriostatic streptenium, which is why it was a good choice for pneumonia in the first place. So the bug drug combinations don't work.
Speaker 1:And even if you do get a bacteriocidal antibiotic that is working against that particular bug, let's say Betel-Athans and Staphonius they might not be bacteriocidal, dependent on where they are and what they're doing. So if they're in the exponential growth phase, then they're trying to create more cell wall and Betel-Athans interfere with that, so you will get a kill. But if they're in the stationary phase, then the bacteriocidal kill is going to be much less. And if they're, you know this is we're getting onto the kind of role that protected sites play. But you know, if they're in biofilm, then the whole issue is that they tend not to be doing a lot of growing there. So as well as having the difficulty penetrating into the biofilm, the once the Betel-Athans gets there it doesn't have any PPP activity to neutralize and so they're not going to be killing the bugs, even though it's a bacteriocidal antibiotic, even though it's a bacteriocidal bug drug combination. So microbiologically there's so many holes to poke in this that I'm surprised it got any traction in the first place. But got traction it did.
Speaker 3:Do you know what I've not read into the like old papers that you go back to like the 60s or 50s and you know the heyday of microbiology or even earlier? Do we know like? What was the? Where did this come from? Do you know Vin? I don't really know what this sort of who first spoke about this?
Speaker 2:But James on a roll, so I think he probably knows.
Speaker 1:No, I looked into this. I tried my hardest to figure out where all these different parameters came from and it's a bit like breakpoints from the days of your they just somebody just tried it and it worked, and so it just got made into into current practice.
Speaker 1:And then you know today's current practice is tomorrow's dogma, regardless of the evidence base behind it. And so then we've we've sort of ended up in the situation where I tell you why I'm so angry. I told you this before the podcast started. But for the loyal, for loyal listeners from the Idiots podcast and the and the and the micro mail mob or whatever you, whatever your collective name of your fan base is, I spent ages on this.
Speaker 1:When I was a medical student and an early years junior doctor, I had pretty little mind maps with with everything color coded, and I had a had a big green box for if it was a bacteriocidal antibiotic and was therefore trustworthy, and then a little red box if it was a material, static antibiotic and therefore presumably not worth the prescription that it was written on.
Speaker 1:And that's how I thought about them. I thought about a bunch of good antibiotics that weren't in the budget ban, antibiotics that didn't, and it was just built on this paper tower of lies and I wasted so much time and did so much what I now think of as kind of bad antibiotic stewardship. So, like the, the. You know I'm working to some notes here and these notes are a case based discussion that I did like just like four years ago, five years ago, and the thing that I did was I I I recommend Keflx and a step down for a, a UTI, or or doxocycline, which is normally bacteria static, and was told in no uncertain terms that these were completely wrong and the reason for them being wrong was because they were. They were bacteria static, and I now know that to be complete crap.
Speaker 2:Sure.
Speaker 1:But that that's the the world that I grew up in and, you know, until relatively recently I was I was practicing that way, and I just think that this is an example of the kind of things that happen when you accept dogma unquestioningly is that you kind of end up making decisions which are kind of bad for the patient, which is why I'm kind of so fanatical about people not practicing that way these days.
Speaker 3:I'll introduce you to get James to go off, and one is is to tell him that he's wrong.
Speaker 1:What was requested to?
Speaker 2:Fortunately we're not there yet, but yeah, I think that's the problem with teaching medical students things in black and white boxes is that it's oversimplified and in fact, you end up creating medical practitioners who prescribe inappropriately just because it's been oversimplified.
Speaker 1:But not because they've done something wrong and they didn't do any proper learning.
Speaker 2:It's because you told them.
Speaker 1:Yeah, I've got another job where I'm a clinical pharmacology lead for a medical school and part of that I have to review questions that pertain to clinical pharmacology. And because they know I'm infectious disease too, I was asked to review a bunch of the infectious disease like teaching materials, and static versus cytoside was in there and was stated in pretty plain terms like static antibiotics are kind of crap in the bacteria.
Speaker 3:So I know that's the real good stuff.
Speaker 1:That's the stuff that you really want to give to the patient and I ripped it out and that was written no very long ago, like three or four years ago, tops, and there was stuff on penicillin allergy there that was from yesteryear. There was everything that you could think of IVs, you know, because they're the best, the golden hour, all these things which there's more and more evidence for for there not being very, you know, either not much evidence of benefit or no benefit at all, and if you misimply it, there's, you know, potential for for harm. I don't know how you feel about this Vin. I kind of feel that infectious disease is just coming into its evidence based medicine. Yeah, absolutely.
Speaker 2:It's lagging behind many other specialties and it's it's only just waking up. I think.
Speaker 1:Yeah, yeah, it's good that it's happening now, but, like I the, the pace of change is quite slow, it's very slow.
Speaker 2:Yeah, it's quite frustrating, yeah, okay, and then, before we head into the myths, it's probably a good idea for us to talk about which groups are traditionally grouped as sidle and which are traditionally grouped as static Callum, do you?
Speaker 1:want to take that, because otherwise I'm just mowing off.
Speaker 3:So, as James said earlier on, I guess it's worth we we, as we just said, things aren't always black and white, and the same goes for a bacterial side versus back to your static.
Speaker 3:So I think the classes that we would commonly think of being back to your side would include your beta-lactam, you know, penicillin type antibiotics, classically. Your aminoglycosides Although we've recovered aminoglycoside episodes, they've got sort of multiple mechanisms of effect Glycopeptides like vanc there are things like rifampicin, streptogrammins, so pristinomycin, quinolones like Cyphero and lipopeptides like datamysin, and then things that would be commonly thought of as back to your static and most circumstances would be things like sulfonamides, tetracycline, chloramphenicol, macrolides like zephromycin or oxazilidinones like lanizolid. I think that's the main classes in my head and I think it's interesting to think back to, you know, at the beginning of when we were using antibiotics and we had, you know, penicillin or sulfonamides, and I think that sort of static, sidled debate came in there and it's perhaps, you know, sulfonamides were discovered before penicillin and were used slightly and then kind of fell out of favor and you know Well, penicillin was discovered first, I think technically, but sulfonamides were used properly first in Camar.
Speaker 1:Penicillin was really only used in anger once the Americans had figured out how to mass produce it. But they figured out how to mass produce sulfonamides first.
Speaker 3:And sulfonamides sort of fell out of use because everyone was like, oh, beta-lactam are best for lactam, which I think is true. But you know, part of the issue there might be to do with the, you know, perceived sidal static debate. Yeah, yeah.
Speaker 1:And yet you know, trimethyprim and sulfonamethylopso are both bacteria static in their effect Because they're double hitting the same pathway Cotramoxazole the drug is profoundly bactericidal, so it also sort of depends on what your drug components are. The only double drug that we use these days is that's hitting the same pathway, is Cotramoxazole. So the other stuff like comox, clavin, perperasantazole, bactam, the b-latamase it's protecting the b-latamase but has no functional effect on the bug itself, with one notable exception of cell-bactam with hampsilin. All of this is covered in the basics of b-latamase inhibitors, one of our recent podcast episodes, which I'll give you a link to in the end. Thank you very much, but you know, basically the double hit drugs, it's really just Cotramoxazole that remains and sulfanethropso is the only currently used sulfonamide antibiotic.
Speaker 2:I think that's a pretty good introduction to the topic. So are you ready to bust a couple of myths?
Speaker 1:I'd love to. Let's do it.
Speaker 2:Okay, I'm ready. So first one is bacteriostatic agents slow or inhibit the growth of bacteria but do not kill them. We've kind of touched on that already, so that's when we can keep sort of brief.
Speaker 1:Yeah, callan, do you want to take this, or will I just pile on?
Speaker 3:I guess I would just say that it's not true. But I'm not sure I can just say that, can I? And I guess the other question is does it matter? You know, I guess all the stuff is in vitro data and what really matches is the in vivo, the, you know, clinical data.
Speaker 1:Yeah, I suspect that may be the next question that we're about to be asked. So yeah, like the, but as an in vitro phenomenon. Yes, if you hit the NBC and don't go a single micromolar per liter over it, then you will. You will inhibit, but you will. You will not kill them. But the reality is that when we're thinking about antibiotics and dosing, you're getting over.
Speaker 1:Your goal is not to hit the MIC and then go no further, it's to get over the MIC.
Speaker 1:And as a reminder for the, for the listeners, you've got time dependent killing, which is things like beta lactamors and macrolides, and then you've got concentration dependent killing, that's that's things like amnibolicides, gentamicin, vindanis favorite antibiotic and mine too and then stuff like datamison.
Speaker 1:And then you've got stuff that's like a sort of a mix between the two. And there we talk about AUC, as in the proportion of the AUC, that's, that's over, over the MIC, on a time concentration curve, in fact that's determined by the peak that you get up to and the half life of the of the drug. So when you think about those parameters then then you kind of get can get an idea of how to dose the drug and the dosing is all being sort of determined and UCAS and CLSI sort of set the breakpoints with one eye on the on the PK of these antimicrobials. So when you're looking at a sensitive or resistant organism, regardless of whether the antibiotic is static or sidal, you're going to be getting over the MIC. So you're going to be getting more than just inhibition. You're going to be getting some kill. And as long as you have an intact immune system, you'll probably you know whether or not you're using a bacteria static or bacterial sidal antibiotic probably doesn't make a lot of difference.
Speaker 2:So that brings us then to myth number two, which is bactericidal antibiotics always actively killed bacteria, which I suppose is kind of what you've just been saying.
Speaker 1:Anyway, yeah, well, I mean, they will always try to kill, but they may be stomped because, say, the organism has a you know something, a resistance mechanism which means that they've got a higher MIC than normal. And then it will be say, you've got something that has time-dependent killing and you've got, instead of an MIC of one, you have an MIC of two that might inhibit the. If your target PK targets that, your time over MIC is like 60%. So say, for pseudomonas usually you have a higher time over time over MIC. If your MIC is two instead of one, you might not be able to hit that. You might be able to get 40 or 50% and then you might still be able to cure the infection, but you might not. You are still using bactericidal antibiotic but it may not be effective. You may have to go and use a different bactericidal antibiotic or, you know sorry you may have to use a different antibiotic altogether in order to be able to hit that. And that might not be dependent on whether it's static or cydel. It might depend on the PK of that antibiotic and whether or not you can achieve it at the target tissue. But the sidality or statisticity of it is can it almost, is almost unimportant.
Speaker 1:Here's an example from the last episode we recorded, you and me, callum, you know doxycycline is not normally considered to be a anti-seudomonal antibiotic, and with good reason. So the wild type pseudomonasas in MIC is about 150. But you can't achieve that in plasma, not without killing the patient. So doxycycline 200 milligrams will give you a peak concentration of about four, but it's about 60% extruded in the urine, which means that you will get a urine peak concentration of about 300. And doxycycline has a half-life of 16 hours, so you only hit 150, if you hit that peak of 300, you'll only hit that 150, so you only start going below the MIC 16 hours or two thirds of the day after you dose.
Speaker 1:So there have been reports of pseudomonas UTIs being cured with doxycycline. Now that's difficult to roll out, you know immediately, because UCAS and CLSI don't set breakpoints. So it's really difficult to use that information, but as a sort of a hail, mainly because, as a reminder, pseudomonas only has one oral agent and it's the quinolones that can be used. So once they are out and the quinolone resistance in pseudomonas is very common in the UK and probably in South Africa too you're then stuck admitting the patient or if you've got an opact that can give them an anti-seudomonal antibiotic. You can try that. But maybe you can use doxycycline as a bridge, even though it's about antideosynolantibiotic and even though it's not normally considered to be anti-seudomonic.
Speaker 2:Yeah, so I think we need more work on pseudomonas, especially because there aren't oral options and, as you say, we need to be moving away from admitting patients, exposing them to hospital pathogens. Having to have a line in looking at these Definitely wasn't.
Speaker 1:Yeah, hospitals are dangerous places and expensive if you don't have. You know, thinking about the US. If you are in a commercial healthcare space, not a state-run healthcare space, then all that cost can really mount up.
Speaker 2:It's a massive cost. So myth number three is that the evidence we have for cydel agents being superior is based on high quality evidence.
Speaker 1:Callum, you better say something, because otherwise I'm just gonna talk all.
Speaker 3:Yeah, so essentially no. So I think this is something that's been dogma and because it's been dogma it hasn't been challenged. And more recently there's been trials that look at the you know whether the bacteria or cyrobrate's yourostatic is superior and essentially, when they've looked at it from different indications. So there's a really great review article by Brand Spellberg, the very famous writer and author of the website Shorter is Better. They've essentially found no difference and in fact, some circumstances the supposedly static agent is superior. So you know, it's quite difficult to. I think it just highlights that.
Speaker 3:You know, there wasn't like a lot of dogma, it wasn't like someone thought, oh, here's really good evidence to support this and then we're coming along with evidence and challenging that there wasn't really evidence to say it was better, it was all theory is my understanding. And then we've come up with, you know, quite good, strong, you know blinded studies to say actually there's no difference and yet still you know these studies. So, looking back, a lot of the studies were published in like 2005. So looking at you know, like, for example, ticacyclin versus Vancomycin risk and soft tissue infection, if Ticacyclin being your sort of static and Vancomycin being your supposed saddle and there was no significant difference. Or if you look at Laneslid versus Vancomycin in that same setting, then you know Laneslid actually came out superior in some of the trials, yeah, but it's still really hard to walk it back. And you know, I think Jamie and I have talked about this before where we say you know people, it's sort of like confirmation bias, isn't it? You're looking for stuff that supports your pre-heard belief.
Speaker 1:Yeah.
Speaker 3:And I think to support the saddle being better than static.
Speaker 2:That's true.
Speaker 3:And there is stuff to say. It doesn't matter.
Speaker 2:Yeah, that's very true. So we'll make sure that we put the link for the Brad Spellberg systematic review in the show notes. So I thought it'll be a good idea for us to go through the different clinical syndromes and what evidence we have for the various syndromes. Okay, so myth number four saddle is superior for pneumonia.
Speaker 3:Yeah, so in 2018, there may have been more evidence published since, but essentially there was 19 trials that they found that, compared back to your static to saddle agents they looked at sort of Laneslid was you know, in terms of the which static drugs they looked at for pneumonia.
Speaker 3:So they looked at Laneslid, ticacycline, zephyromycin, so macrolide, doxycycline, chloramphenicol and clindamycin were some of the trials that were done, and the comparison agents was a mix of things, and I think this is a key bit actually in my head is that I think it's more important like which drug versus which drug rather than saddle versus static, like we could have simplifying it quite a lot to say saddle versus static as a big picture, especially now that we know that saddle and static doesn't really matter. So, you know, I think there's going to be some static agents which, like Laneslid, for example, which has a really effective activity, and we can see that in the clinical trials and it also depends on, you know, what's going to get into. There's some static drugs that you might not use, for that's a little bit around. So there's some side of the agency you might not use for pneumonia, sort of like that to my son, for example. You know, just doesn't work. Yeah, so you know, just saying like we need to use a static or a saddle drug doesn't work.
Speaker 2:Yeah, as always, simplifying, absolutely yeah. And then what about saddle being superior for skin and soft tissue infections?
Speaker 3:Yeah, I think this is the one for me that is the most compelling right. This is the most straightforward one Because, you know, pneumonia is a bit complicated in my head because there's quite a range of organisms that can cause it and since the community acquired, hospital acquired, there's a large range of things that are studied. I think skin soft tissue is a bit more straightforward because essentially, looking at it's probably going to be a staphococcus aureus or a strep, it's a hemolytic strep, and then your agent is going to be, you know, ideally some sort of beta-lactam or glycopeptide, or you know lonezolid or something else, and it's sort of a bit more narrow in its focus and again, they found no difference. So when they looked at, like tigacycline versus vancomycin, there was no difference. When they looked at lonezolid versus vancomycin, there was no difference, or lonezolid was slightly superior, you know the things like doxyxerces, cotrim no difference. Lonezolid versus vancomycin again no difference. What I find interesting there is that, like the studies that they've collected are all looking at non-betalactam antibiotics.
Speaker 2:And.
Speaker 3:I think if we also look at betalactam versus non-betalactam antibiotics, you usually find that the betalactam antibiotic is superior. That's true. So, which is interesting, because you'd be like, well, you know, that might lead you to think of betalactam or sidal, and they're better. If you compare them to vancomycin, that's sidal as well, but it's worse. So, again, you know, it's not about whether it's static or sidal, it's the specific antibiotic for the specific bug and that specific patient.
Speaker 2:Well, the specific group potentially.
Speaker 3:Yeah, yeah.
Speaker 2:And then what about intra-abdominal infections? Is sidal better for intra-abdominal infections?
Speaker 3:Yeah. So again a couple of studies in this area, mainly looking at tigacycline versus the legit, tigacycline versus imopenems or carbapenem, and didn't find any significant difference. In a couple of studies, tigacycline versus keftraxin and metronidazole, which are pretty commonly used combo no significant difference. And oraphycycline, which is another sort of tetracycline type antibiotic, against artipenem, and no significant difference. Again, it's like you know, it's not obviously comparing it to, I think, what I would certainly use the standard care for an intra-abdominal infection. Yeah, but I still think it puts slight pay to the argument that it needs to be sidal and also, I guess, on a sidal, a lot of these studies are static versus sidal. Looking at tigacycline, and I think you know there's clearly some issues initially with how that was dosed in clinical trials, meaning that people have got this maybe that's a whole myth in itself is that tigacycline isn't effective for severe infection. You know, maybe that's something that we need to deep dive into more.
Speaker 2:Yeah, and it's based on those initial dosing studies. As you say, should we look at specific pathogens such as salmonella typhi? I think high food fever has been studied quite a bit in the space of sidal and static. So is a sidal agent superior for salmonella typhi?
Speaker 3:I don't think it'll be any surprise by now that, no, it's not any better. So you know, looking at typhoid, the commonly used drugs, I guess are Kevilsporen, macrolides, and chloramphenicol is something that is used particularly when there's quite a lot of resistance. And essentially a couple studies. So looking at macrolides as a fromycin versus as a sort of static agent in this context which is interesting again because the other one we said that macrolides were bactericidal. In the context of typhoid they're bactericidal. So you know, it's just. It's more complicated, isn't it?
Speaker 3:Essentially comparing that against various Kevilsporen or quinolone, there was no difference. Comparing chloramphenicol, so biturial static, against keftraxone or quinolones, again no significant difference. So in these studies that we have there wasn't any difference. And you can try and pick holes in that in terms of like, well, that's wasn't the right agent to use. But you know we're not talking about specific agents, we're talking about general static versus cydel myth.
Speaker 2:Exactly, and I suppose, if you look at it from an antimicrobial stewardship perspective, you'd want to avoid a quinolone for a single pathogen because it's quite broad spectrum and is associated with quite a lot of collateral damage. So if you could go with something like isithromycin with a narrow spectrum of activity, you know that's a win.
Speaker 3:Yeah, definitely and I guess like barrage resistance, you know, and Cipro resistance is pretty high in typhoid and a lot of parts of the world as well.
Speaker 2:Exactly.
Speaker 3:You know, it's that sort of stewardship from that perspective as well.
Speaker 2:Yeah, so we've got two more clinical syndromes to charge through. Is cydel superior for endocarditis? That's a big one.
Speaker 3:I think obviously you know we're getting more and more evidence now about oral therapy and effective endocritis and moving away from the need to have, you know, a solely betalatum therapy and it's, for example, in the poet trial.
Speaker 3:Quite a few of the oral agents that are used are things like von Eslitz. So bacterial static, and in their paper they mentioned and we were talking about this earlier on, I hadn't noticed this, mentioned that and then they think that the potential route for the whole bacterial static versus cydel debate may have come from an older case series in the 50s in Finland where they were treating patients with bacterial endocritis, and that study in the 50s found that bacterial static agents, including things like tetracyclins and macrolides, which in the setting were back to your static resulted with poor outcomes and that potentially led to the belief that these bacterial static agents were generally inferior for infective endocritis. And so that has led to this fear. And there's some theory behind that that you know, okay. Well, maybe the heart valves or the sort of area where there's immune suppression, because there's not as much access to immune cells, therefore the immune system won't do the killing. Therefore it's more important to have bacterial cydles.
Speaker 3:But I think you know, as we talked about there, like the whole cutoff between bacterial cydel and static, you know, kill or not kill is just not. You know, it's just arbitrary, just made up. So you know, back to your state. Static antibiotics do kill bacteria and probably the reason why that trial found a difference was that things like tetracyclins and macrolides don't stick in your blood, so they diffusion the tissue very well and so the pharmaconetics of them is potentially why they were inferior rather than any sort of static cydel debate.
Speaker 3:And if you look at things like Linnesolid, which is back to your static when it's used for batch into bacteria and the caritas, that has good outcomes, so yeah, and actually probably Linnesolid is better than vancomycin, which is a you know something that actually we are lost around this. It kind of amazes me that we still use vancomycin as our sort of first line. You know, go to ground. Positive cover in patients are penicillin allergic and like I'm going to be like jumping up and down like hello Linnesolid, you know it's quite safe, side effects are overglown, it's probably superior.
Speaker 2:Yeah, absolutely, and I fully agree with you. And probably from the 1950s. I doubt the dosing was adequate as well. You know in those initial couple of decades very low doses of the antimicrobals in general that were given, so I'm sure it comes back to that as well. As you said, you know the PKPD. And then our last infection that we'll touch on is whether sidle is superior for osteomyelitis.
Speaker 3:So yeah, again here, I think the answer is no. This isn't again clinton in the sort of paper that we're looking at as one of the things in the supplementary table. But if you look at different sort of static agents, some thing, you know, things like tetracycline, like doxycycline, linnesolid.
Speaker 2:The Tramoxazole yeah.
Speaker 3:Yeah. So these are very commonly used drugs that we use for osteomyelitis and in things like the Aviva trial, where they looked at oral agents based on sensitivity patterns, there was no. You know, there was just as good as in, sometimes, the sidal agents that were used on other sides. So you know, I think that this is again something that we can myth bust and say doesn't matter, like you need to make sure that you're ideally getting sampling and you know putting the drug against the bog, that sensitive and it's going to get there, inadequate dosing and all the same, you know pharmaconetic considerations but that you don't need it to be sidal.
Speaker 2:Absolutely. And then we're on the homerun, helen, because we're on the last myth to bust. So sidal and static is the most important aspect or parameter which will determine clinical outcome in a patient.
Speaker 3:And I think, if you've been listening at all through the discussion here, I think maybe we can only say this together those are listening at home and us now. I think that it's like most, like the least important, in fact of no importance. I don't actually understand why we still talk about it.
Speaker 2:Yeah.
Speaker 3:Obviously we're doing a podcast episode. Right, because people still talk about it. Yeah, but absolutely.
Speaker 2:It's, it's yeah, it shouldn't even be a discussion. There's so many other more important parameters around that, and I suppose that's the point with infections is that there's no single aspect and there's no single parameter which is ultimate or most important, and that it's a combination of patient related, pathogen related and antimicrobial related factors combined.
Speaker 3:Yeah, do you. I guess can I throw a question back.
Speaker 2:Yeah.
Speaker 3:You know rather than saying you know, is bat to your back, to your study? Versus side is the most important consideration. I guess my question comes into my head, and maybe there is. I don't think there is. Is there any circumstance, any infection, any bacteria, you know any clinical entity where we care about something being back to your static or side? Is that ever important?
Speaker 2:Sure, that's a really good question. Actually, I wonder, I think, maybe a prosthetic joint infection potentially? I mean, I think the question is, do we have enough evidence for every single invasive infection yet, or is it also open on?
Speaker 3:that and that's. That's a little quick, is it like when, when something is so established as dogma, you're, you're almost like oh well, you know, you only studied it in this specific indication agent? Study in my case and population. You didn't study this drug and you have to walk it back and say like, yeah, but the thing that you've based the dogma on initially was just you know was like all the wrong reasons, yeah. So why are you still holding on to it?
Speaker 2:That's true.
Speaker 3:That's true At all. But you know, change people's minds is difficult and we are quite skeptical, I think, in science, for good reason, james, do you think? Is there any? Is there any reason for for someone to to try and remember this at all, or listen, or even care which class of antibiotics, static versus side?
Speaker 1:Well, I think, I think well there is there's one sort of circumstance in which I think people are twitchy about not using that to the side of antibiotics. And that's when and it's possibly based on an, on a sort of super dogma, above the dogma of side over static, which is if you don't have a functioning immune system, so if you don't have white blood cells that are doing all the killing, then, and it's sort of a bit of a toss up. And I did try and find this data I couldn't really find it other than some sort of mouse models of E coli pneumonia, where they they made one, you know, one mouse neutrophilic and another mouse neutrophilic and tried to sort of estimate how much Kale was the responsibility of the immune system and how much the antibiotic.
Speaker 2:Yeah.
Speaker 1:And you know how much that would extrapolate to humans.
Speaker 2:Yeah.
Speaker 1:And that's my idea. But the the sort of conclusion was that the immune system plays a pretty important role and I forget the actual numbers. What if you remove it? So the patients undergoing chemotherapy or they've had their you know immune system depleted in some other manner, and if you've, you know so much of the bacterial response. The initial early response is pathogen, associated molecular pattern or PAMP recognition on you know your neutrophils and your monocytes and macrophages, your you know, the can and fodder immune cells and the terminator immune cells. That's what I think of them in my head. If you, if you take them out of the equation and everything else is coming on later on, once the infection is more established, is the benefit of bactericidal antibiotics better than than bacteria static? And until recently I would have said that the jury's out. But there is. There has been a recent publication of use of bacteria static antibiotics in neutropenic sepsis and I can't remember the exact agents. Use Callum, do you remember it? I will look it up and we can drop it in the show notes.
Speaker 1:But essentially proving non inferiority, not superiority, but non inferiority in that case, and I think one of the agents was Linaisland, with whether or not that's just a Linaisla defect because it's such a good antibiotic for grand positives or not, I don't know, but you know it's. It's kind of interesting that this, even that last sort of pillar of of sidalicy being important, maybe in the process of being knocked down, is not knocked down so much that I wouldn't want to use a bit of that time and all of my neutropenic sepsis patients.
Speaker 1:But you know it's people are looking into it, sort of as, as we speak, Okay, All right, great.
Speaker 2:So we're coming to the end of this episode and it's time for our spotlight feature. You guys ready to play a game?
Speaker 1:Okay, go for it.
Speaker 2:Okay, so this game is about the number of antibiotics you can name that start with the letter C. We could go on for a very long time, I'm sure you can imagine. But the rules are that you're playing against each other and you're only allowed to name one at a time and there's a three second countdown before the next person's got to answer. Okay, and you keep going. One of you gets stumped and the last one standing is the winner. Who wants to go first?
Speaker 1:Callum, your name starts with the C, so it is. I'm going to dibs on going first.
Speaker 3:Okay, and it's after being drug names or brand names.
Speaker 2:Drag names.
Speaker 1:Okay, no brand names on micro mail.
Speaker 3:Okay.
Speaker 1:Come on.
Speaker 3:So Clav.
Speaker 1:Arethromycin Cypher foxeson. Clinton the mice Kev. Traktor Kev. Elexin Kev. Pharoxine Kev.
Speaker 3:Dinear Kev Pim.
Speaker 1:Kev Chloro.
Speaker 3:Kev Elex Kev, m Kev Mixin.
Speaker 1:Kev Mixin's not one, and that means I win Right.
Speaker 3:Kev Mixin's an antibiotic. He's a lamp testing thing. Kev Pharoxine.
Speaker 1:I think you mean oh yeah.
Speaker 3:Kev. Pharoxine is the drug class.
Speaker 1:That would also be wrong.
Speaker 3:Kev Pharoxin's Sporins. I think you just said Kev, pharoxine, kev.
Speaker 1:Pharoxine is any random collection of numbers.
Speaker 3:Yeah, kev Mixin should be one Whoever's listening from drug companies. You should make Kev Mixin. That's a great name.
Speaker 1:They've gone off the kefs lately. I think they, you know they got to Kev Tarlene and they were like good enough, that's got MRC cover, we're leaving this drug class forever. Maybe Kev Fadera call actually, oh God Kal, we weren't even close to being finished. Kouta mox is all, oh yeah.
Speaker 2:I have a yeah, I have a very, very long list. I thought, okay, I'm going to have to keep up with the two of you. So, yeah, I had my list going waiting for you.
Speaker 3:Holliston, we didn't say Holliston, you didn't say Holliston. Holliston.
Speaker 1:Vindana's favorite as well.
Speaker 2:Kev Tazadeem LLBLI's there's a whole bunch.
Speaker 3:Oh, there's so much. It was just the time pressure, it was the time.
Speaker 2:Yeah, oh yeah, you had to put the time pressure, otherwise you would have gone on paper.
Speaker 1:Yeah, it happens to us all, Kalin.
Speaker 2:Anyway, I think that was a great episode. Thank you both for joining me and, yeah, any last short words.
Speaker 1:No, that's fine. Apologies to anybody who doesn't like to hear like an angry Scottish man just absolutely go off on his pet subject for 10 minutes at a time. But yeah, thanks very much for having us, vin.
Speaker 3:It's great. Thanks very much. Yeah, I think we should put sidle versus satec to the sidelines.
Speaker 2:Yeah. To the sidelines, or maybe the static lines. Great, thank you so much for joining me once again, and that's it from me, vin, your micro messenger, and.
Speaker 1:James and Kalin. We'll see you again soon your local, your ideas.
Speaker 2:We'll see you again soon with more potato smell.