58. Mythbusting Cidal vs Static with Microbe Mail

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

Chapters

• 0:00 Bactericidal vs. Bacterostatic Antibiotics
• 14:17 Myths About Antibiotics Debunked
• 26:57 Comparing Static and Saddle Antibiotics
• 37:30 Debunking Antibiotic Myths

Transcript

58. Mythbusting Static vs Cidal with Microbe Mail

Vindana: [00:00:00] Under 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 cidal 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 microbe mail, what better thing to do today than idiot proof the myth of CIDL being better than static. Speaking of idiots, Jayme, Callum, how are you doing today? 

Jame: Yeah, I'm doing great. Thanks very much, Vin. Well done for working idiots into the introduction.

Callum: Yeah, , that was smooth. It's almost like you're sensible and plan what you're going to say rather [00:01:00] than just making it up on the spot like we often do. 

Vindana: I'm not as good as you with making it up on the spot. I'm not sure 

Jame: good at making it up on the spot is how I would describe what we do. I agree.

Good is doing a lot of heavy lifting in these sentences here. How are you doing, Vin? Good. 

Vindana: Yeah. Good. Good. Dark. It's a winter solstice. So yeah, that's a head heads up , for the listeners of when we actually recorded this episode. , but otherwise, 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?

Callum: Thanks, Finn. So, we're from the IDIOTS podcast, and that stands for Infectious Diseases Insights of Two Specialists, although sometimes the two switches to three 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 looking at sort of infection for the perspective of clinicians or [00:02:00] 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.

Jame: That's right. And long may it continue. 

Vindana: Long may it continue. Absolutely. Just a couple of reminders. Remember to sign up for updates on the MicrobeMail website. You can follow MicrobeMail and the Idiots podcast on social media. Rate both shows on your pod player of choice. Remember to share with colleagues, friends, and students.

And have I missed anything else, Jay, Callum? 

Jame: I don't think so. We're not organized enough to have a newsletter. We've got nothing to point people towards except the podcast itself. Give us a go. Of the two podcasts out there, Micromail and the Idiots podcast are probably the two most similar.

So if you enjoy Micromail, you probably enjoy Idiots and vice versa. [00:03:00] So give us a try. , it's not like there's a limit on the number you can subscribe to. 

Vindana: Yeah, give us a try and give us a rating. Okay, great. So I think we're ready to get into this episode. So, Jayme, I think first question would be, what do each of these terms mean?

What is bactericidal and bacterostatic? 

Jame: Glad you asked. Vin, you already know this, so let me explain this to Callum.

Imagine a perfect daycare facility. Plate cap 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 [00:04:00] 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 sec. And there is another concentration, which is above the MIC, which we sometimes also refer to, which is the Minimum Bacteticidal Concentration. Concentration. And that is the concentration which generates a 3 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've determined the MBC minimum bactericidal concentration for [00:05:00] reasons that we probably don't need to get into unless you feel like getting into them. It's difficult to look for the MBC all the time in the lab.

So for for technical reasons, we usually go to the MIC, and when you have antibiotic susceptibility testing, either machines or you're putting antibiotic discs on a plate, the MIC is what , you're looking for, and we've mapped the zones of inhibition and things like that , to the MICs.

And so what's the definition of bactericidal and bactericidal? If your NBC divided by your MIC is less than four. Then it's bactericidal and if it's greater than four, 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 one.

Okay. So if the MBC is five, then that would be a bacteriostatic antibiotic.[00:06:00] 

Mbc was 3. 99999, then it would be determined to be bacteriocidal. Do 

Callum: you get it? Yeah, so you take that Mbc, you divide it by the MiC, and if that's less than 4, then it's bacteriocidal. 

Jame: Yes. So it has to be Less than four 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 NBC, then that would be your bacterial cytoantibiotic and bacteriostatic.

So, you know, that's simple. Those are the definitions. And, do you have any questions, Callum? 

Callum: Yeah, I guess for me, , I always think of CIDL as it kills, inverted commas, and STAT as it sort of inhibits growth, but it's not killing the organism, but I guess we'll get on to whether that actually matters or not.

Vindana: And why the magic number four? 

Jame: Well, that's is a very interesting question because there are loads of holes that we can poke in this. [00:07:00] 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, but they no, 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. Why are we looking at visible growth? You know, 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 NBC, why is it a thousand fold reduction?

So, if I have 1000 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 NBC, but I've killed almost everything , on the 

Vindana: plate. 

Jame: Is that not good enough? Like why? 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 eight and we would be, , wanting a 512 fold , reduction [00:08:00] or a 1024 fold reduction. And it's for the ratio, which I guess is what you asked me originally. Yeah. . I just thought, just 

Callum: saying here like, James is just going off, he's taking off, he's flying.

Here we go. You can 

Vindana: see this chopping, excites James . 

Jame: James be unleashed. I don't know why four. Why isn't it five? Why isn't it ten? Why isn't it two? Do you know why isn't it just two times over the MIC? Like, these numbers seem to have been picked completely at random. 

Vindana: Random. 

Jame: 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 sidle against another. So say macrolides, for example, are bacteria sidle against streptococci, like group A strep and strep pneumoniae, 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 [00:09:00] antibiotic of them all, famously bacteriostatic. Okay. Is cytal against strep Coi. Mm-Hmm. , but not intra coi. The closest relative to streptococci or staphylococci, the thing that you're usually using it against in serious infections and chloramphenicol is also bacteria static or purports to be bacterias static, but is bacteria.

Strypneumo, which is why it was a good choice for pneumonia in the first place. So the bug drug combinations don't work, and even if you do get a bactericidal antibiotic that is working against, , that particular bug, , let's say, beta latans and, and Staph aureus, they might not be Bacterial, 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 beta lactans interfere with that, so you will get a kill. But if they're in the stationary phase, then the bacteria kill is going to be much less. And if they're, , this is, we're [00:10:00] getting onto the kind of role that protected sites play, , if they're in biofilm, then the whole issue is that they tend not to be doing a lot of growing 

silence: there.

Jame: So as well as having difficulty penetrating into the biofilm, the, once the betal atom gets there, it doesn't have any PBP activity to neutralize. And so they're not going to be killing the bugs, even though it's a bactericidal antibiotic, even though it's a bactericidal bug drug combination. 

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. 

Callum: We know that, I don't, 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, what was the, where did this come from?

Do you, do you know Vin? I don't really know what the sort of, Who first wrote about this? I don't actually 

Vindana: know either. But James on a roll, so I think he probably 

Jame: knows. [00:11:00] 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 yore.

They just, somebody just tried it and it worked. And so it just got made into Into current practice, and then, you know, today's current practice is tomorrow's dogma, regardless of the evidence, based behind it. And so then , we've ended up in the situation where, I'll tell you why I'm so angry.

I, I told you this before the podcast started, but for the loyal, loyal listeners from the Idiot's Podcast , and the micro mail mob, , or , whatever your collective name for your fan base is. I spent ages on this one. I was a medical student and an early years junior doctor.

I had pretty little mind maps with everything color coded and I had a big green box for if it was a bactericidal antibiotic and was therefore trustworthy, and then a little red box if it was a bacteriostatic antibiotic and therefore presumably not [00:12:00] worth using. , the prescription, that it was written on, and that's how I thought about them.

I thought about them as a bunch of good antibiotics that worked and a bunch of bad 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, , the, , I'm working to some notes here, and these notes are case based discussion that I did, like, just, like, four years ago, five years ago.

And the thing that I did was I recommended, Keflex in a step down for a, , A UTI or doxycycline, which is normally bacteriostatic, 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 bacteriostatic. And I now know that to be complete crap.

Theme song: Sure. 

Jame: But. That, that's , the world that I grew up in and, you know, until relatively recently I was, I was practicing that way and I just think [00:13:00] that this is an example of the kind of things that happen when you accept dogma, , unquestioningly, is that you, you kind of end up making decisions which are bad for the patient, which is why I'm so fanatical about people not practicing that way, , these days.

Callum: All you need to do to get James to go off on one is, , is to tell him that he's wrong. So anyway, what was question 

Jame: two? 

Vindana: 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, 

Jame: not because they're, , not because they've done something wrong and they didn't do any proper learning. It's because you told them, yeah, I've got another job where [00:14:00] I'm a clinical lead, clinical pharmacology lead for a medical school.

Part of that, I have to review questions that pertain to clinical pharmacology and because they know I'm an infectious disease too, I was asked to review a bunch of the infectious disease like teaching materials and Static versus CIDR was in there and was stated in pretty plain terms that static antibiotics are crap and they're bacteria so I know that's the real good stuff.

That's the stuff that you really want to give to the patients and I ripped it out. And that was written not 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, you know, give IVs, , because they're the best, the golden hour, all these things, which there's more and more evidence , for there not being very, either not much evidence of benefit or no benefit at 

Theme song: all.

Jame: And if you misimply it, it's, there's, you know, potential for, for harm. I don't know how you feel about this Vinay. I kind of feel that [00:15:00] infectious disease is just coming into its evidence based medicine era. 

Vindana: Absolutely. It's lagging behind many other specialties and , it's only just waking up, I think.

Jame: Yeah, it's good that it's happening now, but the pace of change is quite slow. It's very slow, yeah. It's quite frustrating. 

Vindana: 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 cidal and which are traditionally grouped as static.

Jame: Callum, do you want to take that? Because otherwise I'm just mouthing off. 

Callum: So as James said earlier on, I guess it's worth, as we just said, things aren't always black and white. And the same goes for bactericidal versus bacteriostatic. So I think the classes that we would commonly think of being bactericidal would include your beta lactams, penicillin type antibiotics.

Classically, , your aminoglycosides. Although we've recovered amino Glycoside episodes, they've got [00:16:00] multiple mechanisms of effect. , glycopeptides like van, they're things like rifampicin, , strepto, Gramin, so PRIs, mycin, quinolones, like Cipro, and, , lipopeptides like daptomycin. And then things that would be commonly thought of as bacteria static in most circumstances would be things like sulfonamides.

tetracyclines, chloramphenicol, macrolides like , zephromycin or oxazolidinones like linizolid. I think that's the main classes in my head. And I think it's interesting to think back to, at the beginning of when we were using antibiotics and we had penicillin or sulfonamides. And I think that sort of static, sidle debate came in there.

Jame: Penicillin was discovered first, I think, technically, but sulfonamides were used properly first . 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.

Callum: [00:17:00] And then sulfonamides , fell out of use because everyone was like, O beta lactams are best for lactams, which I think is true, , part of the issue there might be to do with the, perceived cytostatic 

Jame: to be. Yeah, and yet, , trimethoprim and sulfamethoxazole are both bacteriostatic in their effect, but because they're double hitting the same pathway, cotrimoxazole, the drug, is profoundly bacteriocidal.

Theme song: Yeah. 

Jame: So it also depends on what your drug components are. The only double drug that we use these days is that's hitting the same pathway is to cotrimoxazole. So the other stuff like comoxglav and piperacin, 

Theme song: tizobatam, 

Jame: the belatum is never protecting the belatum but has no functional effect.

On the bug itself with one notable exception of cell baam, with ampicillin. All this is covered in the basis of lactamase inhibitors. One of our recent podcast episodes, which I'll give you a link to, thank you very much. , but, , basically , the , double hit drugs, it's really just oxil that, [00:18:00] that remains ulfa methol that only currently used sulfur.

Sulfonamide, antibiotic. 

Vindana: I think that's a pretty good introduction to the topic. So are you ready to bust a couple of myths? 

Jame: I'd love to. Yeah, let's do it. Okay. I'm ready. 

Vindana: First one is bacteriostatic agents slow or inhibit the growth of bacteria, but do not kill them. We've touched on that already.

So that's when we can keep brief. 

Jame: Yeah, Calum, do you want to take this or 

Callum: will I just pile on? , 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? , I guess all this stuff is in vitro data. 

silence: And 

Callum: what really matters is the in vivo, the, , clinical data.

I suspect 

Jame: that may be the next question that we're about to be asked so yeah, like the, but as an in vitro phenomenon, I Yes, if you hit the MBC and don't [00:19:00] go a single micromolar per liter over it, then you will, you will inhibit, but you will not kill. But the reality is that when we are thinking about antibiotics and dosing, you're getting over, your goal is not to hit the MIC and then go no further.

It's to get over the MIC. And as a reminder for the listeners, you've got. Time dependent killing, which is things like beta-lactams, and, , macrolides. And then you've got concentration dependent killing. , that's , things like aminoglycosides, gentamycin, Ana's favorite antibiotic and mine too.

And then stuff like daptomycin. And then you've got stuff that's like , a sort of a mix between the two. And , we talk about a UC, , as in the proportion of the a UC , that's over. over the MIC on a time concentration curve, but that's determined by the peak that you get up to and the half life of the drug.

So when you think about those parameters, , then you get, can get an idea of how to dose the drug and the [00:20:00] dosing's all been determined and UCAST and CLSI set the breakpoints with one eye , 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 cidal, 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 bacteriostatic or bacteriocidal antibiotic probably doesn't make a lot of difference. 

Vindana: Yeah. So that brings us then to myth number two, which is bacteriocidal antibiotics always actively kill bacteria, which I suppose is what you've just been saying anyway.

Jame: Yeah, , they will always try to kill, but they may be stopped because, say, the organism has a,, something, a resistance mechanism, which means that they've got a [00:21:00] 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 you're, , Time over make is like 60%, so say for Pseudomonas, usually you have a higher time over, , time over MIC.

If your MIC is 2 instead of 1, you might not be able to hit 

Theme song: that. You might 

Jame: 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 bacteriocidal antibiotic, but it may not be effective. You may have to go and use a different bacteriocidal antibiotic 

silence: or, 

Jame: sorry, you may have to use a different antibiotic altogether in order to be able to hit that.

And that might depend on whether it's static or sidal. It might depend on the PK of that antibiotic and whether or not you can achieve it at the target tissue. 

Theme song: Right. 

Jame: But the sidality or staticity of it is almost, is almost unimportant. 

Theme song: Yeah. 

Vindana: . [00:22:00] So myth number three is that the evidence we have for sidal agents being superior is based on high quality evidence.

Callum, 

Jame: you better say something because otherwise I'm just going to talk all. 

Callum: Yeah, so essentially, no. So I think this is something that has been dogma, and because it's been dogma, it hasn't been challenged. And more recently, there's been trials that look at the, whether the bacteriocidal or bacteriostatic is superior.

, and essentially. When they've looked at it from different indications, so there's a really great review article by Brad Spellberg, the, , the very famous, , writer and author of the short, the website shorter is better. they've essentially found no difference. And in fact, , some circumstances, the supposedly static agent is superior.

 I think it just highlights that, 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. It's, there wasn't really [00:23:00] evidence to say it was better, it was all theory, is my understanding.

And then we've come up with quite good, strong, blinded studies to say, actually, there's no difference. And yet still, , these studies, so looking back, a lot of the studies were published in 2005. , like for example, take a cyclone versus vancomycin for skin soft tissue infection of take a cyclone being your sort of static and vancomycin being your supposed cycle.

And there was no significant difference. Or if you look at lanezolid versus vancomycin in that same setting, then. , La Neslade actually came out superior in some of the trials. 

Theme song: Yeah. 

Callum: , but it's still really hard to walk it back. And I think Jayme and I have talked about this before, where we say, , people like confirmation bias, isn't it?

You're looking for stuff that supports your prehead belief. 

Vindana: Yeah. There 

Callum: isn't anything to support acidal being better than static. 

Vindana: That's true. And there is 

Callum: stuff to say it doesn't matter. 

Vindana: That's very true. So we'll make sure that we put the link for the Brad Spellberg systematic [00:24:00] review in the show notes.

Thanks. So I thought it would 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, CIDL is superior for pneumonia. 

Callum: Yeah, so in 2018, , there may have been more evidence published since, but essentially there was 19 trials that they found that compared bacteria static to CIDL agents.

They looked at, Leneslade was, , in terms of the, which, , static. Drugs they looked at for pneumonia. So they looked at like a nesolid, tigacycline , zeframycin, so 

Theme song: microlyde, 

Callum: 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 CIDL versus static, 

silence: like 

Callum: we could have [00:25:00] simplifying it quite a lot to say CIDL versus static as a big picture, especially now that we know that, , CIDL, and static doesn't really matter.

So, 

Theme song: you 

Callum: know, I think there's going to be some static agents, which, , like lodesolid, for example, which has a really effective activity. And we can see that in the clinical trials. And there's some side agents that you might not use for pneumonia. So like that to my son, for example, , it just doesn't work. So, , just saying like we need to use a static or a side of drug , doesn't work. 

Vindana: Yeah. It's oversimplified. Absolutely. Yeah. And then what about sidle being superior for skin and soft tissue infections?

Callum: Yeah, I think that's the one for me that is the most, compelling. , this is the most straightforward one. , because, , pneumonia is a bit complicated in my head, because there's quite a range of organisms that can cause it, and it's community acquired, hospital acquired. There's a large range of things that are studied.

I think skin soft tissue, It's a bit more straightforward, because essentially you're looking at, it's probably going to be a Staphylococcus aureus or a [00:26:00] strep, basically a hemolytic strep. And then your agent is going to be, , ideally some sort of beta lactam or a glycopeptide or, , linozolid or something else.

And it's a bit more narrow in its focus. And again, they found, No difference. So when they looked at , Tegacycline was no difference. Lonezolid versus Vancomycin, there was no difference, or Lonezolid was slightly superior. You look to things like, Doxycyrtosis Coltrim, no difference. Lonezolid versus Vank, again, no difference.

What I find interesting there is that , the studies that they've collected are all looking at non beta lactam antibiotics. 

Theme song: Yeah. 

Callum: , and I think if we also look at beta lactam versus non beta lactam antibiotics, you usually find that the beta lactam antibiotic is superior. 

Vindana: That's true. 

Callum: So, which is interesting because you'd be like, , that might lead you to think beta lactams are cidal and they're better if you compare them to vancomycin.

That's cidal as well, but it's worse. So again, , it's not about whether it's static or cytal, it's the [00:27:00] specific antibiotic for the specific bug and that specific patient 

Vindana: or the specific group potentially. 

Callum: Yeah. Yeah. 

Vindana: And then what about intra abdominal infections? Cytal, is cytal better for intra abdominal infections?

Callum: Yeah, so again, a couple of studies in this area, mainly looking at, , Tegacycline, , versus, we looked at Tegacycline versus Imipenems or Carbapenem, and didn't find any significant difference in a couple of studies. Tegacycline versus Keftrax and Metronidazole, which are pretty commonly used. Yeah.

combo, no significant difference. And, , erythrocycline, which is another sort of, , tetracycline type antibiotic against ertopenem and no significant difference. Again, it's , it's not obviously comparing it to, I think, what I would certainly use as standard care for an intra abdominal infection.

, but I still think it puts It's like paid to the argument that it needs to be CIDL, and also, I , on a side note, a lot of these studies are static versus CIDL looking at tigacycline, and I think, , there's clearly some issues initially with [00:28:00] 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. , maybe that's something that we need to, to deep dive into more. 

Vindana: And it's based on those initial dosing studies, as you say., should we look at specific pathogens such as Salmonella typhi? I think hyphoid fever has been studied quite a bit in the space of cidal and static.

So is a cidal agent superior for Salmonella typhi? 

Callum: I don't think it'd be any surprise by now that no, it's not any, any better. Know, looking at typhoid, the commonly used drugs , are kefalosporins, macrolides, , and chloramphenicol is something that is used particularly when there's quite resistant, quite a lot of resistance.

, and essentially a couple of studies. So looking at macrolides as a formicin versus as a sort of a static agent in , this context, which is interesting again, because the other one we said that macrolides [00:29:00] were. bactericidal. 

Vindana: Yeah. In the 

Callum: context of typhoid, they're bacteriostatic. 

Vindana: Correct. 

Callum: It gets more and more complicated, doesn't it?

Essentially comparing that against various keflasporins or quinolone, there was no difference. Comparing chloramphenicol , so bacteriostatic against, , keftraxone or quinolones, again, no significant difference. So in the studies that we have. That there was any difference and then you can try and pick holes in that in terms of , why else wasn't the right agent to use?

But yeah, , we're not talking about specific agents. We're talking about the general static recicidal myth. 

Vindana: Exactly.

So we've got two more clinical syndromes to charge through. , is CIDL superior for endocarditis? That's a big one. 

Callum: We're getting more and more evidence now about oral therapy and infective endocarditis and moving away from the need to have, a solely beta lactam therapy.

And it's, for example, in the PORT trial. Quite a few of the oral agents that are used are things like, Nezlet, so [00:30:00] bacteriostatic. , and in their paper, they mentioned, and we were talking about this earlier on, I hadn't noticed this. They mentioned it, and then they think that the potential route for the whole bacteriostatic versus side of the bait, , may have come from an older case series in the 50s in Finland, where they were treating patients with bacterial endocarditis.

And that study in the 50s found that bacteriostatic agents, including things like tetracyclines and, , Magcolides, which in this setting were bacteriostatic, resulted with poor outcomes. , and that potentially led to the belief that these bacteriostatic agents were generally inferior for infective endocarditis.

And. So that has led to this fear and there's some theory behind that, that, , okay, , maybe the heart valves are 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 cytos.

, but I think. , as we talked about there, like the whole cut off the team back to your [00:31:00] side on static, , kill or not kill. It's just not, it's just arbitrary just made up. Back to your state, static antibiotics do kill bacteria. And probably the reason why that trial found a difference was that things like tetracyclines and macrolides.

Don't stick in your blood, so , they diffusion to tissue very well. And so the pharmacokinetics of them is potentially why they were inferior rather than any sort of static side or debate. And if you look at things like linezolid, which is bacteriostatic 

Theme song: when 

Callum: it's used for bacteria endocritis, it has good outcomes.

So, , yeah, and actually probably linezolid is better than vancomycin. 

Vindana: Absolutely. And I fully agree with you and, and probably from the 1950s, I doubt the dosing was adequate as well, you know, in those initial couple of decades. It was very low doses of the antimicrobials in general that were given. So I'm sure it comes back to that as well.

As you said, , the PKPD. And then our last infection that we'll touch on [00:32:00] is whether CIDL is superior for osteomyelitis. 

Callum: Yeah, again, here, I think the answer is no, this isn't, again, included 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, static agents, , something things like tetracyclines, like doxycycline, , linezolid, .

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, , there was just as good as, , in sometimes the cidal agents that were used on the other side.

 This is again, something that we can myth bust and say, it doesn't matter. Like you need to make sure that you're. Ideally, getting sampling and, , putting the drug against the bug that's sensitive and it's going to get there an adequate dosing and all the same, , pharmacokinetic considerations, but you don't need it to be CIDL.

Vindana: Absolutely. And then we're on the home run, Helen, because we're on the last myth to bust. So CIDL and static is the most [00:33:00] important aspect. or parameter which will determine clinical outcome in a patient. 

Callum: And I think if you've been listening at all through the discussion here, I think maybe we can all say this together, those that are listening at home and us now, and I think that , like most, least important, in fact of no importance.

Of no importance. I don't actually understand why we still talk about it. 

Vindana: Yeah. 

Callum: Obviously we're doing a podcast episode on it because people still talk about it. 

Vindana: Yeah, but absolutely. 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. 

Callum: Yeah. I guess, can I throw a question back? 

Vindana: Yeah. 

Callum: Rather than saying, , is Sati versus [00:34:00] Seidel is the most important consideration. I guess my, the question that comes into my head, and maybe there is, but I don't think there , Is there any circumstance, any infection, any bacteria, , any clinical entity where we care about something being bacteriostatic recital?

Is that ever important? 

Vindana: Sure, that's a really good question, actually. I wonder, do you think maybe a prosthetic joint infection, potentially? , I think the question is, do we have enough evidence for every single case? Invasive infection yet, or is the door still open on it? 

Callum: And , that's the other question, is it like , when something is so established as dogma, you're almost like, oh, , you only studied it in this specific indication, you didn't study it in my patient population, you didn't study it in my country, you didn't study this drug, and you have to walk it back and say, , Yeah, but the thing that you've based the dogma on initially wasn't good evidence, 

Theme song: you 

Callum: know, was like all the wrong reasons. So why are you still [00:35:00] holding on to it? 

At all. But you know, change people's minds is difficult and we are quite skeptical, I think, in science, with good reason. James, do you think, , is there any reason for someone to? to try and remember this at all, or listen, or even care which class of antibiotic is static versus cytosol.

Jame: Well, I think, , there is one sort of circumstance in which I think people are twitchy about not using bactericidal antibiotics, and that's when, and it's possibly based on a sort of super dogma above the dogma of cytosol versus 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 a 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 made one, , one mouse neutrophilic and another mouse neutrophilic and tried to estimate how much [00:36:00] kill was the responsibility of the immune system and how much the antibiotic.

And, , How much that would extrapolate to humans, I have no idea. But , 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 patient's undergoing chemotherapy, or they've had their, , immune system depleted in some other manner.

If you've, , so much of the bacterial response, The initial, , early response is pathogen associated molecular pattern or PAMP recognition on, your neutrophils and your monocytes and macrophages, your, the, , cannon fodder immune cells and the terminator immune cells. That's how I think of them in my head.

, 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 bacteriostatic? And until [00:37:00] 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 used.

 I will look it up and we can drop it in the show notes thing. , but essentially proving non inferiority, not superiority or anything, but non inferiority. Just non 

Theme song: inferiority. 

Jame: In that case, and I think one of the agents was And whether or not that's just a linezolid effect because it's such a good antibiotic for gram positives, , or not, I don't know.

, it's kind of interesting that this, even that last sort of pillar of, , Of sidality being important, maybe in the process of being knocked down. It's not knocked down so much that I wouldn't want to use a beta lactam in all of my neutropenic sepsis patients. , but, it's, people are looking into it , as we speak.

Vindana: All right. Great. So we're coming to the end [00:38:00] of this episode and it's time for our spotlight feature. You guys ready to play a game? 

Jame: Okay. Go for it. 

Vindana: 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 until one of you gets stumped, and the last one standing is the winner. Who wants to go first? 

Jame: Callum, your name starts with a C, so I 

Callum: guess Deb's on going first. Okay. And does it have to be drug names or brand names?

Vindana: Drug names. 

Jame: Okay. No brand names on micromail. Nope. Uh, Colmotsaclav. [00:39:00] Clarithromycin. Ciprofloxacin. Clindamycin. Keftraxone. Kefalexin. Kefalexin. 

Callum: Kef for 

Jame: roxine. Kef denir. Kef a peme. 

Theme song: Kef 

Jame: a chlora. Kepha lexin, 

Callum: kepha, 

Jame: kepha myxin. Kepha myxin's not one, and if, that means I win, right? Kepha myxin's an antibiotic, isn't 

silence: it?

We 

Jame: use it in the lab to test things. Kepha myxin, I think you mean. Oh yeah. And kepha myxin is the drug class, that would also be wrong. 

Callum: Maybe, if kepha's foreign, I think you just say kepha merolub, and drug? 

Jame: So, in any random collection of numbers, yeah, I mean, Kefamixin should be one. Whoever's listening from drug companies, you should make Kefamixin.

It's a great name. They've gone off the Kefs lately. I think they're, , they go to Keftariline and they were like, good enough, that's got MRSA cover. We're [00:40:00] leaving this drug class forever. Maybe Kefiderico actually. Oh God, Calum, we weren't even close to being finished. Kultra, Moxisol? Oh yeah. 

Vindana: 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. Coliston! 

Callum: We didn't say Coliston. 

Vindana: You didn't say Coliston. Vindana's favorite as well. Kiftasadim. The new 

Callum: PLBLIs. 

Vindana: PLBLIs. There's a whole bunch. Oh, there's 

Callum: so many. It was just the time pressure.

It was the time. 

Vindana: Yeah. Oh, 

Callum: yeah. Well, you had to put 

Vindana: the time pressure. Otherwise you would have gone on Facebook. Oh, 

Jame: yeah, yeah. It happens to us all, Callum. 

Vindana: It does. Anyway, I think that was a great episode. Thank you both for joining me and. Yeah, any last short words? 

Jame: No, that's, that's fine. Apologies to anybody who doesn't like to hear like an angry Scottish man just absolutely go off on, on his pet subject for 10 minutes at a time.

Um, but yeah, thanks very much for [00:41:00] having us, Vin. 

Vindana: That's great. Thanks very 

Callum: much. Yeah. I think we should sidle versus static to the sidelines. 

Vindana: Yeah. To the 

Callum: sidelines. 

Vindana: Or maybe the static lines. Great. Thank you so much for joining me once again. And that's it for me, Vin, your Microbe Messenger and 

Jame: Jame and Callum.

Vindana: We'll see you again soon. 

Jame: You're local, you're idiots. 

Vindana: We'll see you again soon with more Potato Slam.