Gentamicin over a best-a-lactam?!  Listen in as Jame & Callum from the ID:IOTS podcast extoll the virtues of aminoglycosides in empiric therapy…and teach Sara some Scottish slang

Episodes | Consult Notes | Subscribe | Twitter | Merch | febrilepodcast@gmail.com

Hello everyone.

Welcome to Febrile, a cultured podcast with all things infectious disease.

I'm Sara Dong, your host and an adult and pediatric ID fellow.

We are back with another Febrile Digest.

I know it has been a while, but these are bonus episodes in between our cases about various topics or questions in ID.

I am always on the hunt for different resources to share with people.

And I found a new podcast, but it's not actually a new podcast.

It's just new to me.

um, so I invited some new friends from the ID:IOTS podcast, but, uh, rather than introducing you as an idiot, I would much prefer if you guys would tell everyone a little bit about yourself.

Uh, thanks, Sara.

Uh, hi everybody.

Uh, we are from the ID:IOTS podcast that stands for Infectious Disease - Insight of Two Specialists.

I'm Jame, and that's Callum, Cal, how you doing?

Good.

Uh, I was saying before we started recording that I thought it would be strange because I'm usually the editor and it's such a, such a joy actually to be thinking that I'm not gonna be listening back to myself and having to edit out all the I, well, I don't actually have to edit myself at all because everything I say is, is just straight away correct and right.

so difficult.

Well, can you guys tell everyone, maybe just like a quick snippet about like, why you started the podcast and what you guys cover.

Sure.

So, um, we, Jame and I were training together in Scotland in Infectious Diseases, and we were both sitting a, um, infectious diseases exam that we have to sit for.

Well, for Jame, it was his exit exam training.

And for me it was part one of a two parter.

And we were revising for that.

And we, I guess we thought that there was a, a gap in the market for another resource to help people revise for the exam.

So that's really where it came.

Um, that's the combined infection certificate examination.

I never quite remember what it stands for.

Mm.

Uh, so Jame, at this point, well, I'll let Jame say, but I, I, I'm still in training.

I've got two more years left of infectious diseases and um, medical microbiology, uh, training before becoming a consultant or attending.

Although at the moment I'm doing a medical education fellowship.

Ah, so that's me.

Yeah, and I'm, uh, I, I finished training, so I, um, I've come down to, to England and I'm doing a, uh, post CCT clinical fellowship, uh, in infectious disease, uh, in Naedosh Royal Infirmary [South], which is the fictionalized hospital that me and Callum, uh, working, uh, and Cal remains in Naedosh Royal Infirmary [North], which we anonymized several weeks into the podcast and stated several times before we did that, we worked in Lothian.

And just to be absolutely clear, Callum has not moved since we started the podcast, but nevertheless, we have completely anonymized, um, where we work.

So Naedosh Royal Infirmary North is an undisclosed location in Scotland.

I see, well, one, I wanted to introduce everyone to you guys.

And then two, we get to talk about whatever we really want in these digest episodes.

And we thought that talking about how gentamicin is used in different settings would be really interesting, um, which in the States is, is really just not that much, but you guys have a lot more experience with Gentamicin

Let, let me start by asking you a question.

Um, Sara how much gentamicin or any aminoglycoside do you use in your practice?

Be it pediatric or be it adult.

In general.

It's I mean, it's not a lot.

I, I would say most of the time it comes up, it's gonna be some kind of combination therapy.

You know, in the empiric setting, it might be that we're already giving some kind of cephalosporin and, you know, you're worried because of either the patient's history or they're really sick, critically ill.

And so you think you might be dealing with a serious Gram negative infection.

And so you give a second agent, meaning the aminoglycoside, in hopes that your bug is susceptible to at least one of them.

And then we'll sort of peel it off as quickly as we can.

Mm.

You know, it's in, in pediatrics, it's not uncommon for neonates to get the ampicillin gentamicin combo, but some of it is often historical or just protocol based.

And so I think a lot of us see perhaps OB GYN infections that are based on older guidelines that recommend combos of amp[icillin], gent[amicin], and clinda[mycin]..

Typically, if we're consulted, we'll come on and say, oh, there's not really any reason we can't use an alternative and we'll transition them.

There are of course cases where we might use it for directed therapy when you have a known resistant organism.

But I think monotherapy in most settings in the States is relatively rare.

and outside of that, it's usually synergistic settings, like for endocarditis, but really even in that setting, I feel like we're moving away from that if we have some sort of alternative that we can use.

Yeah.

I feel the same, particularly with enterococcal endocarditis.

Yeah.

People have moved away from AEG, so amoxicillin plus gentamicin and towards AC amoxicillin ceftriaxone for toxicity concerns and that's that's happening even in, in Scotland where, um, me and Callum were working and Callum still works where people are very comfortable with aminoglycoside use.

Um, because it's used as our, in our empirical, uh, therapy, and that's kind of why we wanted to, uh, to talk about it today.

So this is a bit of a, sort of an intellectual sort of like why you would want to use this more and how you could use it and why you may be moving towards using it more in the future.

As we encounter more problems with like kind of antimicrobial resistance.

Callum, do you want to kind of go through the sort of structure background bit?

Or do you want me to take that?

I, I can take something cause I feel like otherwise there's gonna be another, uh, Jame McCrae show

Jame's rants nonstop.

Also.

I feel like I might just like simplify it a little bit because, uh, Jame uh, not only trained infectious diseases, but also in clinical pharmacology.

And so I don't think there's anything that you like more in life than.

Uh, explaining the, the, the, the minutiae of, uh,

He's drawing molecular structures in the wall.

this is all scurrilous accusations, which I'm not going to deny . Um, but,

um, so aminoglycosides are, uh, so most people likely know, but they're amines, that's a protein part.

And then glycosides, that's the sugar part of the molecule.

They're very polarized.

So they, they have a, a charge.

And that means that they usually stay where you, the, the space that you place them into.

So whether that's topical, so thinking about like ear drops or something,

uh, and if you're giving it intravenously or, uh, in the urinary tract, Um, they've been around for quite a long time.

So streptomycin neomycin discovered in 1943 and is for TB treatment.

Uh, although we're still getting more.

So the newer one is plazomicin 2018.

Callum.

Why do some of them, uh, end with an -my, -mycin and some end with an -mi, -micin.

Well, I'm glad you asked uh, so the ones that end with an -my are in the Streptomyces group, whereas the ones that end of -micin they're in the micromonospora group.

And they-, they're what you can isolate them from, uh, the different aminoglycosides

so generally speaking, the older ones are in the Y group, but that doesn't always bear out

yeah, yeah, yeah.

Um, and you can also structure them.

You can group them by a chemical structure as well, is the other way of doing it?

Yeah.

I think that's the better way of doing that, actually.

Yeah, it makes more sense.

Doesn't it?

So, uh, you've got your streptomycin group, so that's streptomycin or the neomycin group, which is neomycin, which is generally only used topical I believe, cuz of toxicity reasons.

Uh, yes.

Um, and, uh, paromomycin, which, um, I don't think actually recognized was an aminoglycoside until right now, but we use it for GI clearance of Giardia to, um, get rid of the cysts.

I forget the term

it's for intraluminal clearance of the Giardia

That's right, its the intraluminal clearance.

Yeah.

Um, and then finally got the kanamycin group, which has got gentamicin, tobramycin, amikacin, and plazomicin, which is, I think, you know, we use gentamicin in Scotland mostly, but other centers will use different ones usually based on local epidemiology of resistance.

Yeah, well, quite a lot of the time actually, it's due to what got the license first.

So, um, uh, gentamycin and tobramycin and in Eastern Europe, it would be streptomycin, are very commonly used.

Um, some centers would suggest that tobramycin cuz it's got better Pseudomonal cover should be the drug of choice.

And really in terms of toxicity, they're both kind of about the same.

Um, and so you've got that better Pseudomonal cover without kind of a noticeable increase in side effects and certainly EUCAST would, uh, agree, which will come onto in a sec.

If you're gonna use an aminoglycoside, Sara, would you,

Yeah.

What do you use in the US?

Um, people will use gent or tobra for those sort of like, um, Uh, empiric settings and then, you know, amikacin when we're treating TB NTM type stuff.

Mm.

Yeah.

So there's a mixture.

Most places have, I feel like they'll have all of them available or maybe they'll only stock one or the other, but,

um, yeah.

And is it hospital specific?

So if you go to a different hospital, would you have a different one or is it sort of by, by, by kind of area or like would all of Boston use the same one or is it not like that?

I feel like most places could have access to both, but there may be places that they like tend to use one more than the other.

Mm-hmm

. . Yeah.

So, um, I suppose the, the kanamycin group is the one that's got the antibiotics that we use for, uh, for kind of serious um, infection.

Uh, Callum how do they work?

How do they work?

So they irreversibly bind to the 30 S subunit of the rRNA complex, and that leads to misreading of RNA codons.

And that leads to impaired protein synthesis.

So they're in this sort of, if you, you know, bacteriostatic category from that,

if you care about that anyway

We don't really.

Yeah.

I feel like it's something that you learn and read in textbooks and then people talk about, oh, well, you know, you can't use that on its own.

Cause it's, bacteriostatic, but I don't know if it's ever really born out in the data to say, you know, and I think I'm sure I saw a paper recently, which was comparing bacteriostatic and bactericidal agents.

And they're just like, you know what.

Who cares.

Like the clinical importance as being important.

So why do we keep teaching it?

And if by recently, Callum

static, like why, why are we perpetuating?

Isn't it

if, uh, by recently Callum you mean three years ago in a journal club presented by me then yes.

You have recently, uh, uh, watched a paper being presented and yes, you're right.

The static versus cidal thing, I think it's actually pretty well known in the ID community now is absolute nonsense.

And the fact they there's plenty of antibiotics like linezolid is a bacteriostatic, um, uh, antibiotic and has gone head to head with fluclox for treatment of Staph aureus infection, and is the only thing that's ever been, non-inferior, to the best of my knowledge, uh, compared to anti staphylococcal penicillins, be it fluclox or cloxacillin or, or diclox.

So I mean that just kinda on its own sort of puts the whole idea of static and cidal to bed, but they do have another, a second mechanism of action, don't they Callum, a bactericidal

because it's cationic.

So we talked about having a charge.

So, uh, it's cationic, uh, charge, which means that it binds the anionic cell membrane components and the, the sort of charge effect.

It reduces the membrane integrity, which leads to cell lysis.

And that part is thought to be bactericidal

mm-hmm and that's, um, kind of hard for the cell to deal with because the gentamicin is usually actively transported into the cell.

I forget exactly the, the mechanism.

Uh, I know that streptococci don't have it, and that's why streptococci aren't covered by, uh, uh, by aminoglycosides, uh, in general.

Um, Uh, and it's something that can be lost, like pseudomonas likes to lose it.

And that's how it requires resistance.

That's the main mechanism, um, that, and aminoglycoside modifying enzymes.

When it comes to sort of spectrum of action, gent and tobra have very similar, uh, spectrums of action.

So in fact that that most of them will cover staphylococci and they'll cover Gram negative organisms.

And they'll cover Pseudomonas except streptomycin doesn't cover pseudomonas so much.

Uh, another reason that, that you might not want to use it as your kind of baseline, um, gram negative cover.

Um, but it does cover TB as does amikacin.

Tobramycin has, as we've said before, has better anti pseudomonal cover.

And so some people like the Canadians for example, would suggest that if you're covering, if you're trying to treat pseudomonal infection, you should just use tobra, um, all the time we can.

So why are we talking about this historical drug?

Everybody knows it's got terrible kidney, uh, toxicity, and it can make you go deaf and it can make you have vestibular symptoms as well.

We've got other things that cover gram negatives.

We've got pip-taz, we've got coamox.

We've got, um, you know, cephalosporins.

Why would you bother using gentamicin at all?

So

I presume this is where you tell us.

Yeah.

Well, I'm just trying to figure out what to talk about first.

Um, so about, uh, here's a quick history, uh, lesson, Sara.

Up, until about maybe 10 or 15 years ago, Scotland and the rest of the UK were using cephalosporins as their, as their, um, sort of gram negative cover for empirical treatment of infection.

And historically sort of up until the eighties, when cephalosporins became widely available, people would usually use something like amoxicillin or ampicillin plus gentamicin to cover stuff.

If they had an infection and they didn't know what they were covering.

And then because cephalosporins are, you know, cheaper, some of them are once a day.

Like ceftriaxone, uh, is once a day.

Um, and, uh, that's less nursing time.

You know, people just kind of moved over to that and cephalosporins and things like amoxicillin-clavulanate were used as the kind of basic cover.

Uh, I've mentioned before on our podcast, like when I was starting training as a, as a F1 in 2006.

So like the first year, uh, of, of being an intern, uh, the joke was that if you came in under the surgeons, you got ceftriaxone metronidazole.

And if you came in under the medics, you got coamoxclav and clarithromycin, uh, to treat chests and basically just treat everything.

And it was kind of true.

And then in 2008 or in the two years for 2007 to 2008, there was a C diff outbreak in a small hospital in Scotland called Vale of Levin.

Uh, it was in the two years of the outbreak, there were 143 cases of C difficile and uh, 34 of them died.

That is a 24% mortality.

And Sara, just for reference, this is a 92 bed hospital, so barely bigger than a community hospital or a cottage hospital in the west of Scotland, sort of, kind of west of Glasgow.

So these are absolutely massive numbers.

Like a big proportion of people were getting C diff if they went to the Vale and then, uh, some of them were dying and there was a huge inquiry, uh, and.

There was lots of reasons for failing.

The building was kind of falling to bits as some, quite a lot of hospitals in, in the UK are.

There were no wash hand basins in some wards.

There was lots of understaffing.

All the doctors were basically juniors.

There was hardly any consulting cover.

And one thing that also came out was that the prescribing was absolutely terrible.

People were basically going on ceftriaxone at the drop of a hat and people thought that that was one of the, one of the main contributors, because if you've got a drug environment where Cdiff can flourish, because everybody's on ceftriaxone or coamoxiclav, if you have an outbreak strain, because there are outbreak and non-outbreak strains of C diff, and it gets into your hospital, it's just going to spread like wildfire

and, uh, then you know, a bunch of people are gonna die and that's exactly what happened.

It was, you know, it was profoundly embarrassing for the, for the government.

And then people said that basically this is, this should never happen again.

So starting in 2008 in Glasgow and Lanakshire, and then spreading throughout the rest of the country over the next six years, we moved from

using cephalosporins and coamoxiclav and ciprofloxacin and other quinolones and what's the other four Cs?

Clindamycin.

We took them out of our empirical, uh, treatments for everything basically, except where they were absolutely essential.

Like ceftriaxone for meningitis or clindamycin for necrotizing fascitis.

And we replaced it with our current, uh, sort of regimen.

So just give people an idea of what it is.

Say, Sara, you wanted to cover somebody for kind of broad spectrum infection.

So you didn't know what you were wanting to cover and you wanted to cover Gram positives, gram negatives, maybe Pseudomonas, maybe not.

It doesn't matter.

And anaerobes, what would your choices be?

What would you use in your, in your hospital?

Yeah, I mean, most of the time it's gonna be something like ceftriaxone or cefepime plus or minus anaerobic coverage if they need it plus, or minus MRSA coverage if they need it.

Mm.

And so for MRSA, what would you use?

I mean, usually vanc

Vancomycin.

Yeah.

Okay.

Fine.

I mean, if the, I, I would say in the adult hospital.

There certainly is more clindamycin use in pediatrics, but, um, that's probably usually the combo they'll get placed on in the emergency department.

Yes.

Yes.

Um, and that's, and, and that's even true of where I work, uh, uh, at the moment down here, because this, what Scotland has done.

Um, it's not spread throughout the UK.

It hit the border and then like nothing happened.

Um, and that was kind of a bit of a shock to find out.

So say you, uh, came in and you had sepsis of unknown source and you were in Glasgow, Edinburgh and, or what have you, um, we would give you.

Amoxicillin to cover streptococci and some enterococci but mostly it's the streps that matter.

Gentamicin for some Staph aureus cover.

It's not as good as anti staphylococcal penicillin, but it'll do, and gram negatives and pseudomonas.

And metronidazole is anaerobic cover.

If we thought there was like a GI thing going on, or if there was a possibility.

And so if you think of somebody coming in with say, Chest infection.

Um, the amoxicillin is good for that.

Gentamicin what's it contributing?

Probably not all that much.

if it's skin and soft tissue, I have to say we'd probably just give them flucloxacillin and we wouldn't give them anything else.

But this is for people where they've got sepsis and you don't know where it's coming from, so you have to cover urine, chest and GI.

And then if you're thinking about urine chest and GI sources, amoxicillin, gentamicin, and metronidazole is appropriate polymicrobial cover.

It's appropriate urine cover.

Um, and.

It's uh, okay for the chest.

I mean, it's not very, uh, good.

If you were really concerned, you might want to consider adding a macrolide or changing the amoxicillin to coamoxiclav but certainly that's kind of reasonably broad cover.

And the, the reason that we started using it is that it's a low risk for C diff.

So metronidazole and gentamycin are, you know, low, not zero risk, but very low risk for C difficile.

And amoxicillin is only kind of mild to moderate, really.

Whereas just giving everybody coamoxiclav or just giving everybody ceftriaxone plus or minus metronidazole, um, is quite Cdiff-ogenic

so if you have that in your empirical guidance, you run the risk of having another outbreak.

And at the time that it was implemented in Scotland, that was just completely unacceptable.

I was gonna say that there, because I guess we talk about individual antibiotics and say, this is low risk or this is high risk

And, you know, you can find there's like a meta-analysis that's is it meta-analysis or is a systematic review where they do a forest plot of all the, an different antibiotics.

And I find that quite useful to go back and review because the qu-, the like level of evidence and the quality of the evidence to make these inferences about the C diff risk and different antibiotics, I don't think is very good.

But the clinical data for, for this is good in terms of, you know, well, you were talking about the, the history there.

2008 comes around and you can see a marked drop in C diff rates with the change to the gentamicin backbone.

Yeah.

So, so what happened, uh, then Callum, what were the effects of, uh, changing over to this, uh, this kind of low risk?

Yeah.

So, um, You know, after it's changed over, I think one, there was a lot of people that spent a lot more time prescribing as gentamicin is more complicated to prescribe.

Mm it is.

And I, something that popped in my head there was actually is, is the fact that there's a slightly higher barrier to giving antibiotics.

It's slightly more difficult.

Does that make people actually.

That balance of , you know, if, if it's slightly more difficult to do something you're less likely to do it and you don't give antibiotics just because it's easy to give, you have to like, actually think, do I really want to go and do a gentamicin chart?

I mean, that's an aside and I don't know about the answers to that, but what we do know is that there was a lot lower C diff risks.

So you can see there's like graphs, where they look at the, the rates over time and map it to the health board.

And when they change and, you know, very sizable drop in C diff rates.

Um, other thing that we noted was lower, lower MRSA rates.

Mm.

Um, there may be other reasons for that ongoing in terms of that time period, but, you know, prior to 2010, there was quite a big problem of MRSA in Scotland.

And that's really, MRSA I would say is now very rare, uh, to encounter as a clinical phenomenon, uh, unless the patients had a lot of healthcare

contact.

Yeah, that that is, um, a bit odd.

And I don't really know that I've got like a hard explanation for that, but certainly that's something that we saw when we looked at the data.

Um, and then the other things, as you see that there, the mortality rate from gram negative sepsis dropped, um, there wasn't any difference in ICU admission, length of stay or need for renal replacement therapy, which was a sort of proxy for, um, uh, nephro toxicity.

Uh, we also haven't really seen an increase in aminoglycoside resistance.

So although.

The vast, you know, 30% of hospitalized patients end up with an infection and of those in, uh, in Scotland, most of those patients will be treated of aminoglycoside.

We haven't seen a rise really in aminoglycoside resistance, and we've got really good data for this, which is really.

You know, surprising, I guess.

Uh, and the other thing we've seen is a drop in coamoxiclav, ceftriaxone resistance.

We don't really map like most labs in Scotland don't look at the mechanism of resistance or test for, so you can infer but, you know, ESBL and ampC uh, rates have of dropped as well.

So, which does mean that when you have to use those antimicrobials, then you're less stuck, you know, I guess.

In my head part of it is, is it actually because of which antibiotic we're using or is it because, and there's so many other things that have happened, but there's a real big focus on antimicrobial stewardship and saying to people thinking hard about, do you actually need to start antimicrobials?

And that is in the.

But then, you know, I guess my clinical experience is that we still use loads and loads of antibiotics, and most people end up getting some antibiotics during their admission.

So, well, yeah, we do, but I mean, the antibiotics that people are using are narrow spectrum and and sort of low risk.

And so if there's less of a need for stewardship, if they're reaching for the Amox and the gentamicin as opposed to if they're reaching for the ceftriaxone or meropenem, do you know what I mean?

Like, if you're trying, if we're trying to preserve beta-lactams cuz beta-lactams are best-a-lactams and.

They're the thing that everybody uses, then that's gonna be really difficult because, you know, resistance you're, you're gonna create a hospital environment in which third generation cephalosporin resistance and coamoxiclav resistance is like the first on the priority list of the bugs.

And if you're a hospital, uh, bug and you're trying to live in the environment like a Serratia, you're living in some of these GI tract, like your top priority will be to acquire resistance to third generation cephalosporins.

If that's the only thing that you see all the time.

Um, so yeah, I mean, there, there are other reasons for thinking that the, uh, switching to, uh, to gentamicin is a, is a good idea.

The bit that was surprising, that was, is that we've not really seen an increase in resistance.

And the only thing that I can think of as a, as a kind of a reason is.

It's hospital only.

You can't really get it in the community.

We certainly in Embra, at Lothian I mean, wherever Naedosh Royal infirmary north happens to be, um, never really used it in OPAT in an OPAT setting

um, unless we absolutely had to.

And even then some of the times you would be given amikacin for, for kind of resistance issues.

And I guess the, the fact that you can't give it, and I guess that's true of ceftriaxone too, but certainly coamoxiclav you can get in the community and it can be prescribed, you know, in a range of infection scenarios, and, and that can sort of increase your, your, uh, kind of risk of resistance developing.

So.

Why, why is, you know, we're, we're extolling the virtues of moving to, uh, aminoglycoside base backbone for your treatment.

And, you know, I think you've left the bubble, um, Jame and, and moved somewhere where they're not using it.

And I know that we've had many conversations offline.

About about this and your, your thoughts on it.

So why, you know, is, is this a failure of, of us to, to, you know, evangelize the use of aminoglycosides and go around with, you know, branding, you know, what what's happened?

That means that nobody else is doing that because you know, my experience in training is, is really just been in Scotland.

So I haven't practiced elsewhere.

And, uh, I, I can't really imagine a world where I wouldn't be using it.

I guess that's that happens a lot of the time for silo of practice.

Isn't it?

Well, imagine my shock Callum when I, uh, left, uh, Scotland for pastures new and found that everybody was getting coamoxiclav with one hand and ceftriaxone with the other.

Um, but I, I, I dunno what to tell you.

I, I mean, I certainly, I there's lots of reasons not to use aminoglycoside, um, you know, giving ceftriaxone is easier.

You know, it's, it's one dose a day and you've covered Gram pos and Gram neg in a, in a variety of different situations.

And you know, the metronidazole, you can just give orally, you don't even need to, uh, give it as an injection.

Injection unless the oral route is compromised.

Um, whereas if you're given, say amoxicillin-gentamicin-metronidazole, uh, amox-gent-met for, uh, sepsis unknown source or intrabdominal sepsis, the amox it can be IV or oral, but it's three times a day, no matter which it is say it's IV it's three times a day.

The gent is one time a day.

That's four.

And then there's the metronidazole two.

So there's more nursing time involved with administering.

Particularly if the amoxicillin is IV, but then also there's calculation time as well.

And this is the thing gentamycin has to be dosed according to the patient's weight and their renal function.

And you need to do kind of trough levels to make sure that they, um, have a sort of a gent free period in the, um, uh, that means that junior doctors have to do the.

Our pharmacists, depending on where you do it in the UK, it's junior doctors, would've to make the calculation initiate the prescription.

And that introduces the possibility for error.

Um, and, uh, the.

Scottish antimicrobial prescribing group, who are the people that draw forward with this kind of like, um, this policy realized that in advance and developed a calculator that basically every trust uses that are in one form or another to automatically do.

It's an Excel spreadsheet.

You open up, you put in the patient sort of age, height, sex,

weight and creatinine and it spits out value and it says, give this idiot and they print it out and they give it, um, and then it even tells you when to do the troughs.

It has a little chart so that you can, you can sort of look at it, um, and figure out when you're going to do the blood level.

It's goes in the patient's notes, the nurses all are trained on how to use it.

Every new junior doctor in Scotland has taught how to use it mandatorily as part of their induction training.

So it's completely uncontroversial and you need all of that in the background in order to prescribe aminoglycosides safely and.

That's, uh, certainly not the case in other parts of the UK and all of that kind of backbone,

if you don't have that, aminoglycosides become really dangerous.

Uh, all of a sudden, uh, if you're giving more than one dose, uh, of it, if you're giving just a stat, it's really hard to kind of screw up some of these kidneys.

But if you are giving three days or five days, or even god forbid seven.

Um, that really has kind of a follow on effect.

The, the toxicity is more to do with the duration of therapy and, and lack of time free from gentamicin so, you know, you it's really, I don't think you can really cause harm, generally speaking, by a one off dose of gen and sometimes, you know, you would give it empirically before you even had the renal function.

You know, you went to get antibiotic in quickly and then it comes back.

The creatinine was actually 800 and they had a massive AKI.

Whoops.

But you know, generally speaking, if they've got sepsis, then this is what I had this conversation quite a lot, if even if someone's got renal impairment, but they've got a severe infection, then the most important thing to do is to sort that infection and the renal function will

if, if it is related to the sepsis improved.

So, um, even then I'm not, I'm not too concerned, but as you say, it's the, it's the duration and the time.

So most of our policy is related to around.

Okay, well, let's start with gent and then, you know, either after two or three days, they'll be ready for an IV to oral switch and we'll use something else, um, or they're not getting better and they'll be a discussion with an infection specialist.

In which case, you know, we can review that, um, You know, sometimes that discussion is let's keep going for gent out to five days.

You know, that's the best agent at this point.

And we'll just be really careful about asking about symptoms of toxicity and measuring the renal function and levels, or sometimes it's, you know, let's switch to piperacillin-tazobactam or something.

Is that usually are ID consultants involved in all?

Is, is this happening in like the primary teams, like without ID input?

No, this is like, there's also an ID person involved to yeah.

Think through that.

Right?

Our, our setup is, is most of these calls will come.

So we've got, you know, clinical microbiology or medical microbiology however you put it, uh, which are, um, usually accessible by, by phone.

And so I'd say the vast majority of less complex infection consults happen through that channel and each, you know, microbiologist will have an input to a department with a, with a link.

Um, and so, you know, the timeframe of getting advice will be, you know, we've got really great guidelines, which people use for anything routine.

So, you know, they shouldn't call us.

And if someone called me with a question that was in the guideline, I'd be like, go and look at the guideline.

Uh, N no, if it gets to like 3 day, I mean, like I said, they'll phone micro is what it's always written the notes.

And I think we're quite lucky as a specialty in that, that there's a real.

We we've got our thumb in all the pies and everyone phones us.

And, uh, you know, you're really tuned into the hospital and you get a lot of calls.

Um, but I think that's really great because there's a sort of trust.

It means there's a slight de-skilling of everybody else.

I'd saying that I dunno how it works in, in America.

Uh, and in infectious diseases really are the people that come in and, you know, we have a lot of time and will do consult in person.

So most of the consult work for infection is done by telephone and nobody won't go and see the patient.

It's more just about like talking through.

Yeah.

Okay.

And then, then if it's more complicated, then we'll, we'll get someone to go.

Uh, I saw a tweet, uh, today, which was, uh, ID docs, uh, seven new consults on the Sunday.

This is too much.

The teams are killing us, but also ID docs.

Our study clearly proves that ID consultation, approves patient morbidity, mortality, fertility, stamina at a credit score, the weather, blah, blah, blah.

so political teams just can't win or lose.

Can they, like, we want them to call us, but we also don't want em to call us.

Cause we're too busy.

I always try and keep that frame in my head when I'm like really busy, uh, on call and someone's phoning.

And they ask me a question that in my head I'm like, oh, like, it didn't really need to phone me, but like, I'm like, well, at the end of the day, you know, I want the best outcome for that patient.

And so they called you because they, they need help and thats sort of the bottom line

I really enjoy like having that, that role of someone that is there to, to help.

And you, you sometimes end up with calls and you, you get the sense you like, you're just calling me cuz you knew you wanted someone and we're very available to help.

And it might not actually be the antibiotics is the bit that you're advising on it.

Some something unrelated.

Like actually maybe you need to, you know, maybe this patient's dying or you know that that's the sort of role that you play, but that's a real privilege to get to.

I mean gone way off topic.

Sorry.

that's alright.

Well, I mean the, the 72 hour review is baked in to the empirical guidelines.

So if you're still on, you know, gent at 72 hours, you have to call and that, that even goes for something like, like necrotizing, fascitis, um, gentamicin is involved there as well in their, in the sort of local protocol.

You would still call and check.

And that, that provides a good point on which to deescalate, um, and, and do an antimicrobial switch.

And then at that point, you can, you can, you know, think about using piptaz or coamox or ceftriaxone on, or, you know, whatever, uh, is considered appropriate.

A bit about dosing side effects, cuz people might not realize this.

So the, the main two side effects are nephrotoxicity and ototoxicity.

Nephrotoxicity is dose dependent and ototoxicity is duration dependent but dose independent.

So it doesn't matter how much of it you're giving, it doesn't accumulate like that.

But what's happening is that every, you know, the, the length of time that the patient's on, uh, gent the, some of it is getting into the hair cells

in the, in the, in the vestibular apparatus and they're not getting out.

So once they're in, they can't go.

And then the hair cells get killed, uh, by the, by the local, um, increase in gentamicin levels.

And so that is usually seen if therapy extends beyond seven days.

And there are few case reports where if you're given a second ototoxic agent, like furosemide is the main, uh, or furosemide is the main, uh, culprit there.

Uh, and quite a lot of people in the UK are on furosemide it's the main loop diuretic.

Um, Uh, used in heart failure.

Um, you can get ototoxicity sooner.

That's, that's kind of a reason to maybe kinda, if you can pause the furosemide until they're finished, uh, their gentamicin of course, or use something else, obviously.

Um, and the nephrotoxicity.

There was a lot of concern when we moved over to this, that we were gonna have like this massive increase in dialysis rates and people's kidneys were gonna get completely screwed with these, these courses.

But because we've kept the courses short, when you look at the sort of before and after they're introduced by trust the rates of AKI one.

According to KDIGO, uh, categorizations, that's kind of creatinine of, um, creatinine loss of about maybe 20 to 40%.

I think, um, those rates increase, but rates of AKI, 2, 3, 4 and need for dialysis stay the same.

And if you look at people like six months down the line after they've had a course of gentamicin and when they're out of hospital, their creatinine is returned to whatever their baseline rate was.

So there's no kind of permanent loss of renal function.

So if you're just using short little tiny courses, like what we are doing, there's no problem.

Really.

You just need to watch their creatinine in.

um, in the moment.

And, and for that reason, our monitoring is pretty tight.

Like if you are on gentamicin and you have a gen level and a used knees, uh, uh, or, you know, renal function checked every day, uh, without exception there's no, uh, wait a couple of days and then give it a check and then see what's happening.

Like none of that, you have to take it and it must be plotted.

And if you don't, it.

Know, reported on as a, as a failure of care.

And the nurses all know this as well.

And so the nurses will all kinda make sure that it's done as well, kind of a belt and braces, uh, approach clinic, uh, clinical and nursing staff as well.

But this is gonna be increasingly hard to sell outside of Scotland.

Um, because of something that EUCAST have done.

So, do you know who EUCAST are?

Sara?

I do.

Yeah, I do.

Um, so for the loyal listener and, uh, uh, febrilologist listening,

I still have not found a name.

You have not find a collective name for febrile.

Well, I'm putting febrilologist as a, as, as a possibility, um, the EUCAST are the EU version of C LSI and they set the, uh, the break points, um, for what is susceptible and what is resistant.

And, uh, C LSI have got some break points for, uh, for aminoglycosides, which I think are pretty sensible.

Um, and so they are so for Enterobacterales and Pseudomonas, there's, there's no difference.

If it's less than equal 4, susceptible.

If it's greater than 16, it's resistant.

And if it's eight, then it's in considered intermediates.

And probably, and, and I dunno how you feel about this here.

I'd probably avoid it if I possibly could.

And to try and use an alternative when intermediate.

EUCAST changed their interpretation of aminoglycosides breakpoints.

And so now for Enterobacterales, if it's less than a equal to two, so it's quite a lot lower than, um, C LSI, that's sensitive.

If greater than two is resistant.

And for Pseudomonas, those break points apply only to tobramycin.

And there are separate ones for amikacin as well.

They've got, they've got three points for that too.

Um, but not to gentamicin so we talked about how gentamicin's got, um, uh, is, is not so good for a.

Um, pseudomonas compared to a tobramycin and EUCAST certainly agree.

And that's because of research, they've done about kind of ECOFFs.

And at this point I will hand over to Callum, who is normally the microbiologist of the two of us in the ID:IOTS podcast to remind me what the hell an ECOFF is and and why it applies, uh, here.

Callum.

Yeah.

I don't know if this has been talked about before, but.

in febrile, but, um, so I think CSLI call it, uh, ECV and EUCAST they call ECOFF, but it's epidemiological cutoff values and

ECOFF sounds a bit fun.

More fun, huh?

Yeah.

Yeah.

E ECOFFs quite cool.

Sounding nice.

ECV is quite hard to

say.

Yeah.

Sounds like a brand of espresso, but I mean, that's very European.

Like your

now to go to coffee shop, just get.

Email coffee um, it's measures of the drugs MI C distribution that separate the bacterial populations into that is, which are fought to be the wild population without any new resistance mechanisms and those with an acquired or mutational resistance.

And so.

You're basically looking at the whole range of what isolates are found, and they do this by gathering samples from all over Europe and then testing them essentially.

And the idea is that the ECOFF gives you a rougher idea of, of where you should set your break because you know, breakpoints are, are, are made up.

And really you're just balancing the risk of calling something sensitive when it's resistant or calling something resistant when it's sensitive.

And there's a huge field, which I don't know a huge amount about, but of, you know, setting those values.

And that is hugely important to get it right, because if you get it wrong, then you, you might, you know, Uh, mistreat someone.

Uh, so it's a really hard question, but I think, I don't know, in this situation, um, it's quite hard to say.

What do you put your faith in?

Do you put it in ECOFFs?

Do you put it in, uh, in, uh, vitro data and the lab side?

Although it makes sense scientifically, but then, you know, clinically we have this wealth of experience and it's being used very well.

And obviously it's not like you can just say, well, we want you gentamicin and no problem, you know, there's huge risks to getting rid of that as a treatment.

So I, I think in this situation, it's not, not been the right decision.

Yeah.

I mean, yeah.

In resistant to these definitely.

So like what the ECOFF for tobramycin is two,

and so that corresponds with sensitivity and the ECOFF for gent is eight.

Is that right?

Yeah.

So the ECOFF for, uh, for Pseudomonas, yeah.

Uh, for gent is eight, uh, compared to two for tobra or 16 for amikacin.

Okay.

Uh, which, you know, we, we, we knew that already.

We, it kinda makes sense.

Less resistant, but now they're saying can use gent for Pseudomonas at all.

Yeah.

And I mean, I, I, I, I certainly know in my local hospital, uh, Naedosh south, we still report gentamycin.

Um, we report all three, so we report gentamycin, tobramycin, amikacin.

Um, but we use gentamycin or amikacin, basically.

We don't really use tobra.

Um, uh, and.

Um, but yeah, like for, for, you know, kind of in the wake of this.

Because this, that, that position statement, the ECUAST, um, gave that came out in 2019, 5 years after the last trust, which was Lothian by the way, adopted these kind of narrow spectrum guidances.

And we'd been using gentamicin, you know, um, in, uh, Scotland as the gram negative backbone, including pseudomonas cover for five years, by that point, the whole country and bits of the country from 2008 to, to 2014.

And.

We'd basically not had a problem, uh, with, uh, with outcomes, uh, dropping with pseudomonas and we, then the Scottish antimicrobial prescribing then had to kind of think, well, what are we going to do?

Like, are we going to, uh, Move everything over to tobramycin.

Are we going to do, you know, something else that was felt to be logistically quite difficult.

And, um, so they put out a position paper, um, which we can link to, uh, in the show notes, that's freely available online, basically saying we note what EUCAST have said.

Um, and we're going to ignore it because we've got a nation of 5 million people, uh, being covered with, uh, aminoglycosides for, you know, five to.

10 years, uh, at this point.

And we've had no problem, uh, with it, as long as you use the dosages that are commonly used these days.

And that brings me to something that I want to point out.

So EUCAST have did a pretty big literature review of, um, gentamicin before they decided to kinda recommend against it.

And if you look at that literature and you look at the dosages that are used, they're all really titchy doses given multiple times a day.

What is titchy mean?

I, I knew you were gonna ask that.

Not first thing I, I Google it look at, but no, I want you, I think it'll be better if you tell me

what

no problem, Sara titchy means wee

what does wee mean, Jame

oh, we means toaty

what does toaty mean?

toaty means titchy.

Oh, no.

Um, so if you look, so if you look at the doses that are being used, they're all little, um, and they're, we they're, you know, some of them, maybe some of them add up to five milligrams per kilogram per day, but they'll be given three over, over three doses.

So it'll be 1.6, six milligrams per kilogram, per dose.

And quite a lot of them are even less than that.

And this is kinda all relating back to how aminoglycosides were given before the Hartford nomogram.

So the Hartford hospital, which is in, Hmm, Connecticut, I think I want to say they at, at some point in the nineties, they were like, well, gentamycin is

expresses concentration dependent, killing what really matters is how high above the MIC you get.

So why are we giving it three times a day?

Why not give it once a day?

They've got this concentration dependent killing, which is good.

They've got a post antibiotic effect which means even when you drift below the MICC, the bugs are too stunned to start growing again.

And so you will still have kind of a beneficial effect even though, uh, the level is, is, is below the, I see in the blood and, you'll get less nephro toxicity because the kidneys to have a gentamicin free period.

It's gentamicin accumulating renal tissue.

And it also accumulates in the urine, obviously, which is why it's so good for UTIs and pyelonephritis.

But if your kidneys have a period of the day, even if it's just like two or three hours where the gent level is quite low, you get less nephrotoxicity compared to giving it three times a day.

Even if it's the same total daily dosage.

And so the Hartford nomogram came out, it become fairly quickly adopted in the US and then that spread over to the UK and the EU.

And so that's now what we give.

So we now give gentamicin in this kind of optimized way, but when EUCAST were looking at how good it was and what the outcomes were, they were looking at all the old data from the sixties, seventies, and eighties, when we weren't giving it optimally.

And so they looked at all that and they said, uh, this is, um, You know, this is not very good.

And we don't think that you're gonna get good levels.

Uh, and even if you did, um, uh, even if you did, we, we, uh, think that that ECOFF is too high for pseudomonas.

And so we're not gonna recommend, uh, using it.

And that ignores all of the real world hard outcome data that, uh, could have been, uh, obtained from Scotland at the time.

And I know that that's not like a double blind multicenter, pragmatic, randomized control trial.

It's not the Recovery trial we're talking about here, but quantity has a quality all of its own as Diane Carlin would say.

And if you've got a nation of 5 million people relying on gentamycin for their empirical Pseudomonas cover.

And you see no increase in mortality that is worth taking notice of.

So do

you have a t-shirt that has gentamycin rules on it?

you guys need merch for idiots?

All gentamicin.

This

I did.

We did have a, I was thinking at what point would Callum suggest that we get merch

well, now, you know what your first item

will.

If whoever makes gentamicin is listening, then, you know, get in touch.

. Well,

I suppose the last thing I'll, uh, I'll point out is that if you are going to use, um, there, there, there's another reason to consider moving over to, to gentamicin as your gram negative backboard that's for stewardship considerations.

And in you, your audience will probably have heard of the Access Watch and Reserve, the WHO classification of antibiotics.

And, they, that was kind of brought out, and I think 2016, the idea is that most of the antibiotics used should be Access antibiotics.

And then the Watch ones are for kind of moderately resistant disease to kind of get you rid of a bind and Reserve is kinda last resort stuff.

And that's kind of what you think about like carbapenems and kind of aztreonam on one end and amoxicillin and, and trimethoprim on the other.

And NHS England took Access Watch and Reserve classifications moved a few bits around to kind of like support UK practice and then, uh, put it out and said, trusts have to have 60% of their antibiotics be access by, you know, this such and such a date.

And they keep on sort of shifting the goalposts as kind of people keep on hitting target.

So it was 55 and then it's kinda moved up and.

You know, the we've, we've got our show notes, like a, a slide that I picked of the, uh, of the Access Watch & Reserve.

So I'm not gonna read them all out, but if you look at the Access ones, um, Sara and Callum, um, you have a look at those.

And the, the, the listeners should know that the access thing are things like penicillins, um, co-trim, doxy, oral fosfomycin but not IV, um, gentamicin, metronidazole uh, and look and try and concoct an empirical antibiotic regimen that was only Access.

So you're not allowed to use cephalosporins.

You're not allowed to use chloramphenicol.

You can't use Quinones and you can't use coamoxiclav or piptaz.

What would you give if you wanted to try and sort of cover everything?

So like, to my mind, there's only really two options you can use cotrim plus metronidazole, or you can give amox-gent-met.

Those are the only kinda options that I can see that we give you decent grams to cover good gram negative cover, and, you know, for add cover, it's really just, just metronidazole

isn't it.

Everything else is sort of like, I would use it for urine tract infection, you know, or say penicillin.

I would use it for if I knew it was targeting streptococci, only streptococci I'd use doxy for a chest infection, but basically everything else is, is too narrow spectrum.

So if you are creating.

List of sorry, creating an empirical antibiotic treatment list.

And you want to try and use as much access antibiotics as you can, because you're trying to hit this, this target.

That's really the only game in town or you put everyone in cotrim-met, which cause is perfectly a reasonable take home conclusion from this, uh, this as well.

Co-trim is

trimethoprim-sulfa?

Trim-sulfa yes, that's right.

Sorry, Bactrim um, uh, sometimes known as, or, uh, Septra yeah.

Exception in the UK.

I think

that's a across the pond.

Well, I, I slowly am like picking up which ones things are, but

I, you yes on otherwise just be saying it in your term.

Cause it's your podcast.

So we should, should be telling us what words are

meant to be using.

Do you know what that's absolutely true, actually.

Yeah.

So, um, you

can splice, you could edit like over every time you can like record a snippet of us saying.

augmentin and then everything it says just goes augmentin no, I mean, I think

it's good for people to know the different names for things.

I hope everyone enjoyed your pitch for gentamicin and maybe they can, on Twitter where they can find idiots podcast and, and me, and they can let us know what they're using and what they think.

But I would love to have, you know, one last plug about where people can find you guys and find ID:IOTS podcast.

Um, and of course, any other closing thoughts you.

Yeah, so they can find us at @IDIOTS_pod on Twitter, uh, idiotspodcasting@gmail.com and, uh, IT:IOTS that's ID colon.

I OTs because I didn't realize how much that would screw up the search algorithm.

Um, if you plug that into your podcast, pair of twice in our faces will pop up and you can subscribe it to your leisure.

Yeah, thanks very much for having us on Sara this is like, yeah.

Thanks for, thanks for having us.

And, uh, this is like podcasting with ID podcast royalty here.

I feel like I'm having tea with a queen.

I don't know about . Well, we're hoping that.

I, I really want you guys to come back and for us to keep talking about, we can make it a series and call it like across the pond or something, but just like talking about in daily practice, the things that we're doing similarly or, or

differently.

Yeah.

Yeah.

The differences.

Yeah.

I mean, this was a weird one, cuz it's different practice in different bits of the UK, let alone across in the us.

But then, um, you know, the way that we do things, uh, differently in the UK, us, that's definitely rich ground.

Um, we'll have plenty more.

Yeah.

So yeah.

Uh, thanks for having us

on.

Thanks.

All right.

Thanks to Jame and Callum for joining Febrile today.

Everyone, please check out the ID:IOTS podcast for more and send us topics that we can chat about in future combo episodes.

Don't forget to check out the website, febrilepodcast.com to find the Consult Notes, our library of ID infographics, and a link to our merch store.

Thanks for listening.