146. PD target attainment

In which Jame waxes lyrical about pharmacodynamic target attainment and its role in breakpoint setting and dosing of antibiotics, and how you can apply it in clinical practice. 

Take a look at the prep notes for this one, a picture says a thousand words!

Transcript

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Jame 0:18

callum, that's a nice cup of tea that you've got there.

Callum 0:20

Yes. It's from a very famous

Jame 0:24

Uhhuh. And what brand is that? Callum.

Callum 0:26

It's PD tips.

Jame 0:27

PG tips or PD tips.

Callum 0:29

PD tips.

Jame 0:30

Ah, and what a coincidence that is Callum. 'cause what are we discussing today?

Callum 0:35

We're talking about Farmer coco diet. Pharmacodynamic Target.

Jame 0:41

Yes. I'm gonna give you some PD tips on PD targeting with your antibiotics. So is this part of our ongoing, evolving how to choose an antibiotics series or is this part of the new pharmacodynamics mini cies that I'm getting around to preparing any decade now.

Callum 0:57

Yes.

Jame 0:59

Brilliant. Okay, good. We will figure that out on the back end. What do you know about this?

Callum 1:02

I feel like I started off and I heard about PKPD. I remember a Professor came give us a talk when I was a junior registrar, and my mind was kind of blown by how complex it seemed.

Jame 1:14

Yeah.

Callum 1:14

often when you learn about something completely new I think my journey was really initially just trying to be like, what's pharmacokinetics and what's pharmacodynamics? We quite often lump these two topics together. James has taken us through already with a series before on pharmacokinetics. Resulting in the one PK table to rule them all. Which I certainly found useful. So that's pharmacokinetics, which is like how the drug moves through the body. pharmacodynamics is

Jame 1:44

pK is what the body does to the drug. And PD is what the drug does to the body.

Callum 1:50

a good way of explaining it.

Jame 1:51

Yeah, but that doesn't work for antibiotics. 'cause with antimicrobials you've got two targets, one of whom you're trying to keep alive, the patient and the other of whom you want to kill. The bacteria or the virus or the fungi. So what the drug does to the body doesn't work because unlike, say, an ace inhibitor or an opiate, it's not working in your body. It's working on the, in the cell of the bacteria. That's your on target effect is bacterial death. So we'll just talk about it as if we're just talking about antibacterial antimicrobials hence forth called antibiotics for now. So the what the drug does to the body that doesn't work. So let's just talk about the PD targeting is what you're wanting it to do. What we're gonna talk about today is the different PD indices that we use for each antibiotic to try and maximize its effectiveness. And that depends on how it's killing the the bacteria that we're talking about,

Callum 2:48

So PK is what your body does to your drug and PD in the context of antimicrobials is what the drug does to the bug.

Jame 2:57

Okay, and there are three that we're gonna talk about today. Am I just gonna talk at you?

Callum 3:01

I'll, yeah. And then I'll ask questions 'cause you're the

Jame 3:04

Fine.

Callum 3:04

of wisdom in this way and I am the pat one.

Jame 3:07

Ha. Was ever, thus Callum. So we've got three PD indices that we talk about. We've got time over MIC, which I bet most people are familiar with 'cause you learn about it in medical school, kind of. You've got a UC over MIC and you've got Cmax over MIC. But actually the way that I've laid this out, I'm going to talk about time over mic, Cmax over mic, and then a UC over mix.

Callum 3:28

But Jane, what is a Mick? And we're not talking about McCree. And what is a clinical breakpoint and, ah.

Jame 3:36

and what to do when there are no break points. I'm happy to report, cam, that we have already covered this in our

Callum 3:41

antimicrobial susceptibility testing miniseries, which are episodes number,

Jame 3:46

1 0 1 and 1 0 2.

Callum 3:48

and also 92, which is where you talked about what resistance is anyway, which is Most useful one to listen to before this one.

Jame 3:54

Yes, exactly. So let's talk about our. PD targeting Cal. I want you to imagine a concentration time curve. So you are measuring the drug in a. A particular tissue. Let's just use plasma for now. And you've got concentration on the Y axis and you've got time in hours or minutes or whatever on the X axis. And if you infuse a drug, It could be vancomycin, could be penicillin, doesn't matter what it is. Initially you will get peak. And you'll get a peak up to a certain maximal concentration. And if you give something iv, that will happen over about five to 10 minutes because it takes time for the drug to disseminate throughout all of the five liters of plasma that you've got. If you take it orally, it will be between 30 to 60 minutes, something like that. But you will get a plasma peak level there and then. Your body will start to metabolize that drug or it will start to be eliminated in urine. And so then you've got this steadily declining concentration as you measure it steadily over time. And then eventually it will be eliminated completely from the body unless you give another dose. So we're just talking about one a one off dose here. And that gives you this triangular shaped concentration time curve. And we've got a little picture in the prep notes, pointing out the different PD parameters that we've got. That plasma peak is Cmax and usually that is expressed as a multiple of your MIC of your organism. So if your MIC of your organism is set at one to make the math simple and your Cmax is five, then your Cmax is a function of MIC is five. If your MIC is two and your Cmax is 10,

Callum 5:38

your Cmax MIC ratio is also five.

Jame 5:40

Yeah, and then you've got the amount of time that your plasma level is spending above the MIC. So here you don't care how high the Cmax gets, and you don't really care about the the a UC which is the next thing that we're about to talk about. You just care how long the plasma level stays above the MIC of the organism. That's time over MIC and it's usually expressed as a percentage of the dosing end flow that you've got.

Callum 6:06

Yeah. And that graphic that you've got there makes it really simple Because basically you've got your concentration on the Y axis time on the X axis, and then you've drawn the MIC at along the Y axis is a straight line, and then all you have to do is measure, where the drug concentration crosses over, that as it goes up, and then crosses over as it goes down, and then that actually makes it very simple to understand.

Jame 6:30

Yeah, actually I haven't drawn this. I nicked this from a document that I've linked to in the notes as well. And then you've got the third feature, which is a UC over MIC. So if you look at that concentration time curve, and you look at the proportion of the curve, which is above the MIC dotted line that you've got, and you shade in that top bit, that's the EUC.

Callum 6:53

Does.

Jame 6:54

Area under the curve. Yeah. So area under the curve is the sheed area, if you like. That's above the the MIC and we'll come onto that definition in a sec.

Callum 7:04

It's at the top of the Smurf hat.

Jame 7:07

Yeah. It's the top of the smurf at, are we doing smurf analogs here?

Callum 7:12

I think, I don't really know any Smurf analogs, but we

Jame 7:14

Fine. So let's go back to time over m so time over MIC. This is also known as time dependent killing, and this is where your only goal is to keep the concentration over the MIC and that is beta-lactams. So beta-lactams are time dependent killing famously, and that's the reason that most people are taught about them in medical school is because beta-lactams are best lactams. If you're going to teach anybody about any PD parameter, you're gonna teach about it for the beta-lactams. And so it's all the beta lactams. It's your, penicillins, cephalosporins, carbapenems, and Astrium. And next you've got Cmax expressed as a function of MIC. And this is what Aminoglycosides do. This is why you can dose them once daily because you're going to get the maximal bacterial kill in a once daily dosing, but you will eliminate that toxicity phase from sustained exposure to aminoglycoside that happens if in the kidneys. An a UC over MIC is basically. Everything else. And that's both time and concentration dependent killing. So you will get more kill if you increase the Cmax and you will get more kill if you increase the time over MIC. So it's exposure dependent of the drug, but you can give more drug and you can give less drug but more frequently and it doesn't really matter. Okay? And that's not true of the other two and just so you know, Callum I went through Ucast has rationale documents for their dosing, and I went through all the published dosing documents. This is not e every drug that's available in the uk, some of them don't have dosing documents. But I said for each of the drugs at what the pd parameter is. So again, for all betal Liams, it's time over MIC for Metronidazole, it's Cmax over MIC. But actually for the aminoglycosides, they've started dosing according to EUC over MIC. And this is the first little asterisk here, which is that. almost all other drugs are their time kill kinetics are now being calculated by a UC over MIC in vitro and animal models including the aminoglycosides. So when they're extrapolating from that data, they're using a UC over MIC, but historically. Cmax as a function of MIC was what we used. And that sort of explains the once a day dosing. So I've put them in this column here

Callum 9:42

Why

Jame 9:42

and then you'll see.

Callum 9:43

changed?

Jame 9:44

Sorry.

Callum 9:44

Why do you think that's changed?

Jame 9:46

It's changed because actually if you have, I mean all of this is a bit of a fudge and some of these drugs that are now in the a UC over MIC column were once. Thought to be time dependent, killing like erythromycin. For example was initially calculated if it was time over MIC as the PD parameter. So basically for all drugs, including for beta-lactams, you could use a uc over MIC because although everything has gone into this column, actually there's a bit of a spectrum and some is. More towards the time dependent killing end of things. And some is more towards the concentration dependent killing end of things, and most stuff is in the middle. So it depends on how, if you get additional kill once you go over the MIC. So for beta-lactams, once you're between two and four times over the MIC, you've maxed out the amount of kill that you're going to get. There's no point going any higher. You're just gonna increase toxicity. So it's because beta aams are so good at killing stuff upfront that they're time dependent killing, because then the only question that you've got is like, how much time are you gonna be able to spend above the MIC? Whereas other drugs don't really work that way. You can increase the concentration and get more kill. You can increase the time and get more kill. And Amin glycosides are towards the increase, the concentration end of the scale. But you can still use a UC if you want to.

Callum 11:14

And what's really interesting is that this is basically done for plasma, isn't it?

Jame 11:18

I'm talking here about at the Target site. But actually for a lot of the stuff, it was calculated based on plasma,

Callum 11:23

so

Jame 11:24

Levels.

Callum 11:24

of our data. But then also, and want to do this at point, some point about a PD meaning series. If you're looking at things like a bone or joint infection or a CNS infection, this all slightly changes because you know how the drug gets there depends on those pharmacokinetic properties that James talked about. Certain body sites are protected by barriers or membranes and other things,

Jame 11:46

yeah.

Callum 11:46

I guess the more I learn about PK and pd, it just adds layers of complexity and I'm like, oh, so we're tackling this as a bite-sized bit of that big puzzle,

Jame 11:57

Yeah,

Callum 11:58

and that's how you learn things.

Jame 11:59

Yeah, I think it's good to take it out and talk about it as a little bite-sized bit, although we are 50 minutes in and only halfway down the prep notes. So let me move on. Are you ready for another bite-sized complexity call?

Callum 12:10

Okay,

Jame 12:11

Let's talk about Monte Carlo simulation.

Callum 12:13

Yes, monte Carlo, so it's administrative area of Monaco

Jame 12:18

So Monte Carlo simulation was originally developed in, in betting casinos to see about probabilities of winning and losing across multiple games. And this has been extrapolated into statistics and is now its own statistical thing. And Ucast have used it to calculate for certain mics of an organism. What is the likelihood that you're going to be able to attain your your PD targeting? So let's take the example of Piperacillin. So they've got different ways of doing this. Sometimes it's bug specific and sometimes it's not. It depends on how old the document is that you're looking at. Because some of these were written in 2010 and some of those were updated like this year, but for Piperacillin, for example, they've got a table here, which I think illustrates the point nicely. You've got the MIC. On the in the first column there, and it goes from two or less than two to 64, pretty high. MICI think you Greg Cal certainly for being able to obtain that in plasma. And then you've got here the target attainment time over MIC in a percentage, and they've got likelihoods of attainment at 20, 30, 40, 50, and 60%. And so the listener knows usually for intra batch rallies and. Strep and stuff like that. You usually want sort of 30 to 45% of your time over MIC, something like that. So you don't need to be over the MIC 100% of the time 'cause that would lead to pretty bad toxicity. So you usually do about aiming for about 40% and it varies per organism, but let's just look at the 40% column and then. The chances of attaining that with a cent dosage of piperacillin for less than two is a hundred percent. For four, for eight, it's 99.4%. Not bad. For 16, it's 74.3%. So now you're starting to get, say actually you're probably not gonna be able to to attain that in a quarter of patients. That's probably worth thinking about. For an MIC of 32, it's 2.4%, and for an MIC of 64 0, so that's. How they're trying to calculate. So you would set the break point there at an MIC of about eight probably. 'cause 99.4% is okay. Do you see what I mean? And then below that, I've got the same.

Callum 14:45

the percentage the likelihood as expressed as a percentage that you will have time over the minimum inhibitory concentration of 40% of the time.

Jame 14:59

Yeah. 40% time over MIC for a given, MIC of the organism?

Callum 15:04

So you've got say if a MIC of four and your target is 40% of your time over MIC, you've got a hundred percent chance of achieving that

Jame 15:15

Yes.

Callum 15:15

Carlo simulation

Jame 15:16

With that dosage.

Callum 15:18

Yeah, with that

Jame 15:18

Yeah. And usually it's based on like neutropenic thigh models and animal models and stuff. It's not based on clinical data. So you then need to go and get a bit of clinical data.

Callum 15:27

Yeah.

Jame 15:28

But that's ucas problem, not us. We're talking about PD parameters. That's.

Callum 15:31

said sets a break point, but the break point will be set based on getting a distribution of MSC different organisms, figuring out your epithelial cutoff value, then doing the drug simulation to the pharmacokinetic

Jame 15:42

Yeah. So this all comes after and then it then has to be backed up by clinical data too.

Callum 15:47

So it's three levels to it, isn't it?

Jame 15:49

Yeah. And then below this, I've got an example for a more modern way that they're displaying this for ciprofloxacin. And maybe this is worth chatting about. I was gonna gloss over at Cal, but will I

Callum 15:59

it. Because I think this is a common

Jame 16:00

fine. So here we've got on the. On the X axis, the mics of the organism. And this actually the, you can see these little sort of green bars, and that's the wild type distribution of the. Susceptible. And then the resistant population is on the right most. So the this is for Ciproflox is in the organism of staph aureus. The cipro dose is 500 milligrams bd on the left hand side and seven 50 BD on the right hand side. And you've got the resistant population. MIC is more than four but for the wild type population, it tops out at about 0.5 or one or something like that. So you might think about setting the break point, roundabout roundabout there, and then. The Y axis is both the relative frequency of the MIC distributions. That's the green boxes that we were just talking about, but you'll see that there's some red lines there. And those red lines are pd chances of PD target attainment for those mics with that dosage. And there's three red lines. And if you look at the bars, you'll see that one of them is for bacteria stasis. So inhibited growth. One is for one log kill, so tenfold reduc one log 10 kill and that's a tenfold reduction. And the other is two log kill, which is a 100 fold reduction when exposed to the drug. And you'll see that for the bacteria stasis the line stays at 100% target attainment until you get to an MIC of about. Point five and then it starts to drop. And by the time you get to one it's you don't have any chance of target attainment. And then for one log hill, it starts to drop. Once you get to 0.25, I think that is, and for two log hill, it starts to drop. One, two, you're at 0.12. Which is the next bit down. But before that you got basically 100% target attainment, even for too long kill at 0.06 and 0.12. Do you see what I mean?

Callum 18:09

Yes.

Jame 18:10

Yes.

Callum 18:10

I think To

Jame 18:11

this is much easier. Yeah, this is much easier to look at. Yeah.

Callum 18:14

with the note. The link to it is in the episode description. I

Jame 18:17

Yeah.

Callum 18:18

Just trying to puzzle what you're saying there. They're trying to display quite a lot of complex data on a graph. They're trying to show you in one breath the MIC distributions of the organism, and then compare that to, if you are using this dose of the drug, how often are you attaining your PD target,

Jame 18:36

a OC over MIC. Yeah, but I mean this is actually why they moved to seven 50 BD for treatment sta forus. 'cause if you look at the graph on the right that's the dose with seven 50 BD dosing in healthy subjects and you can see that there you are getting, two log hill until you get to an MIC of about 0.25, 0.5, and then a one log kill is maintained until you're at an MIC of 0.5, which is like all of the wild type distribution. So that's why they're they've moved to that. It's a PK argument.

Callum 19:08

discussion we had before about the myth of, bactericidal or bacterio static as a drug. Saying that drug is bacterio static, that drug is bactericidal. as we're seeing here, as you increase the concentration of the drug, you will kill the bacteria more quickly. So it's like such a. Like pointless statement to say some things, so

Jame 19:28

Yeah.

Callum 19:28

like, this specific concentration in this setting, I know we talked about the ratios of MIC and NBC and all these sort of things and how that defines it. But

Jame 19:37

I guess most,

Callum 19:38

you

Jame 19:38

as you said right at the beginning,

Callum 19:40

for

Jame 19:40

for most antibiotics.

Callum 19:42

if you get a higher concentration of the drug at the site where the infection is, you're gonna kill it better

Jame 19:47

Yeah.

Callum 19:47

in a very simple way. and so that's what's important.

Jame 19:52

Yeah. Let's talk now about what to do with this information. Like why am I chewing your ear off about this? Why is it important? It's important because when you are trying to maximize the effect of these antibiotics, you can play with the dosing, and you do this all the time. Cal with an endocarditis, you will move the ben pen dosing from four times a day to six times a day. Why are you doing that? You could just double the dose, couldn't you? Maybe you could and maybe you couldn't. Right? So let's talk now about what to do with this information, how to practically apply it. Let's talk about time over MIC, which again is basically just beta-lactams. These days. Your PD target is normally within the realm of 30 to 70%, something like that. And for some bugs it is higher than others. So for pseudomonas, I've got an example in here which I screen grabbed from the ucast document from Meropenum. But if you want a one log. 10 kill for pseudomonas, you need to get a time over of between 35 to 55%. So call it 45%. For intra that's the same, but for staph reus it's 15 to 40. So maybe call it like 25 to 30%, something like that. So that's, it's different for different organisms, but base basically more time over MIC is more kill. Now. That means if you want to improve your time over MIC, there's a few things that you can do. One is that you can increase the dose, and two is that you can increase the duration, and then there's a third one, which is prolong the infusion, increasing the dose. Let's say that you've got an endocarditis patient. You've got 'em on Ben Pen, and you, know, this as well as I do Callum people that are young, pee out penicillin constantly. It's really difficult to maintain their time over MIC. If you ever monitor their beta-lactam level levels, which we don't do locally, you'll. Note that the half-life is quite short. So I usually say that the half-life of penicillin is about an hour. Actually, it's about 0.8 to 1.2. So actually it can be as little as, in particularly in young people, it can be as little as 45 minutes, but let's call it an hour because it makes the sums easier. If I go from 1.2 grams four times a day to 2.4 grams four times a day, I have doubled the amount of penicillin that person is getting. But because the half-life is one hour, I have only increased the time over MIC by one hour because it's only gone up by one half life at most, actually, because I've doubled the dose, but he's still just going to pee it out.

Callum 22:22

are four hours a day. Yeah.

Jame 22:24

Yes, that's right.

Callum 22:24

Yeah.

Jame 22:25

Whereas the other thing that I could do is I could decrease the time between infusions. So in endocarditis we do this quite a lot, we will move penicillin or amoxicillin from four times a day to six times a day. So they will get it at four hourly intervals. This is a real pain in the neck. For the nurses. It really disturbs the sleep of the patient. So why would you bother to do this? You would do it because in moving from six hours between infusions to four hours between infusions, you have dropped two half lives. And so you have optimized the time over MIC that way more than if you simply doubled the dose because doubling the dose gives you one additional half-life. If your half-life is an hour. So you might also increase the dose. You might also want to do that. So you might bump it up to 1.8 or 2.4, whatever. It depends on how sick the patient is and how concerned you are. But by reducing the interval between infusions, you are improving the time over MIC much more than you could by increasing the dose. And there's the third thing that you could do, which is a prolonged infusion. This was the subject of the bling three trial and associated meta analysis, which caused quite a stir when it was published last year or the year before, I think. And break points have done a really big tear down episode on it, so go and listen to that if you want the details. But essentially, if you are going to push a antibiotic into somebody like Benzo, penicillin, or Meropenem, for example, you can put it in over half an hour or you can put it in over three hours. And that's what the current recommendation is for serious infections with Meropenem. That's what ucast expects you to do if you're giving the two gram high dose, particularly in intensive care patients. And what that does is it delays the time to Cmax because if you shove it in instantly, your body instantly starts to pee it out and metabolize it. Whereas if you put in slowly, that time to Cmax is delayed, your body has less chance to metabolize it and pee it out. You get this prolonging of time over MIC. Every trial that's ever been done, Callum has technically been negative, but there have been interesting signals and when you meta analyze them all together, the signal for improved mortality becomes positive. So people kind of think this works, but they kind of think it probably works in intensive care people and it's not worth doing it in anyone else? Wait, just think about your.

Callum 24:52

patient that's got an infection. Like we, we talk to

Jame 24:55

Cool.

Callum 24:56

the importance of keeping mobile and, the holistic approach to their effects. You're balancing that potential microbiological treatment improvement with the other impacts on being tied up to a line all the time. Although you can get things like, continuous infusion pump that is set up for the patient and they're out of the hospital with it for things like Piptaz.

Jame 25:16

Yeah. And penicillin and flu CLOs for that matter. Yeah, I think that ela, American fers are maybe a little underused, mostly on grounds of cost, but the advantage of them is that they kind of do this automatically. And when we start Piptaz, certainly down in Naro soiling for me south, we would. Start Piptaz 13.5 grams a day. So that's four and a half grams, three times a day equivalent, but just in, in one polyus and I think there's good data out there to say that Pharmacokinetically, that's probably giving you the same time over MIC. As 4.5 grams four times a day. So if we were treating pseudomonas infection as an outpatient with elastomeric peptides, we wouldn't bump up to 18 grams in the infusers. I mean, our ones didn't do it, but other infusers can contain that much. But we would just give the 13.5 grams and assume that continuous infusion is maximizing time over MIC in a way that we didn't need to worry about it.

Callum 26:14

So it does open up some interesting things about, patients on extremes for weight. Recently had a very underweight patient and talking about the dosing of their piptaz and wanted to give it more frequently 'cause I think we were treating pseudomonas and what we ended up doing was dropping down the dose because they were on 4.5 grams, eight hourly. So you drop down the dose to. So half of that, so 2.25

Jame 26:37

Yeah.

Callum 26:38

but gave it more frequently and in conjunction with the pharmacist and award, we felt that was actually gonna give us better target attainment. But one of the commonest problems I see with this is that, we can talk in a lot of detail about the science behind administering antibiotics, but it really relies on who's prescribing the drug inpatients and who's administering it, whether that be the patient or the nurse, and. So you see like a Piptaz four, four times a day, so six hourly, prescribed at 8:00 AM 12:00 PM 6:00 PM 10:00 PM because obviously, I don't wanna be woken up overnight for my antibiotics, but I'd also like my infection to get better. And then you're waiting from like 10:00 PM to 8:00 AM the, you're not gonna get any time over MIC in the middle of the night. And I guess it's saying that if we're gonna give a dosing record, this is why I personally have moved away from giving antimicrobials and saying four times a day. Three times a day, because that opens it to interpretation. I give an hourly dosing, so I always say give it four hourly, give it six hourly. I feel like that's cementing that it is really important. although I guess you could probably go off and study does it absolutely matter? You probably have more time over IC in the day, less overnight. Personally, I think it probably does matter, but I'm not sure anybody's ever looked at that in detail.

Jame 27:59

I don't think they've looked it in that granular detail. I would say that if you're going to give it at 6 12, 6 12, that is six hours to get a decent amount of sleep. So actually I think if it matters that much to give it that kind of dosing interval does allow them to get a bit of a snooze. And certainly in UK hospitals, a lot of people are already up at 6:00 AM anyway, 'cause wards are inherently noisy places. Yeah. Let's talk about Cmax over MIC. Here the PD target is expressed as a ratio to the MIC. So if your MIC let's call it one again and you get a peak plasma level of 10, then your Cmax, MIC ratio is 10. Usually the SR breakpoint for intact is, is two for for Gentamycin and tobramycin as well. I think and so what you would want there, if you wanted a. Cmax to over MIC ratio of eight to 10 would be a peak plasma level of between 16 and 20. And luck would have a Callum, five to seven milligrams per kilogram of gentamycin and tobramycin just so happens to hit that peak plasma level, which is why when pseudomonas. MIC was Sr. Breakpoint was raised to eight. Genta no longer was available to us as an option because if you're getting a peak p level of 20, that's a Cmax to MIC ratio of 2.5, which is not considered to be good enough for bacterial kill. Although I would maintain that in the urine, it's still a viable option.

Callum 29:27

Yeah, because it'll concentrate into your new tract. what your CM Maxs MIC ratio needs to be for it to be effective?

Jame 29:35

Our old white guy about 50 or 60 years ago did in a lab, and it's been grandfathered into modern break points, I think. But yeah, when you look at it in vitro, I mean now ucast are looking at a UC over MIC as I said. But when we're thinking about the Cmax over MIC, that, eight to 10 is from, decades ago. The pharmacodynamic studies that were set then, and so that's what we're attaining for. But actually I think your kill is kind of maxed out at that level, and any more might bring a bit more kill, but actually the toxicity would be enough that you couldn't take it. And toxicity with aminoglycosides is a big, significant issue.

Callum 30:14

Yeah.

Jame 30:14

But it does mean that if you're, when your MIC goes up, you can't attain this Cmax over MIC target anymore, and then the drug is no longer considered acceptable. But there's an advantage in it too, which is mean that you can dose it once a day safe in the knowledge that, that the once a day dosing, just giving Nolan the big winner will. Achieve the same amount of kill as if you had dosed it at three separate intervals. So the old dosing was like one to 1.5 milligrams per kilogram, eight hour. So if you had a hundred kilogram meal, just to make the sums easier, you'd be giving 100 to 150 milligrams, but you would, give it three times a day and that wouldn't be worse in terms of bugs killed. Which is a common misconception that the concentration dependent killing means that if you give it once a day, then you get more than if you had given it a three separate intervals. That's not the case. That's not what the Hartford people showed when they published their once a day dosing regimen. They showed equal efficacy, but what they showed was fewer side effects, less nephrotoxicity, and that's because the kidneys then have this gentamicin free period. And so the amount of kill is the same and probably because Amy Glycosides have a good post antibiotic effect. So once you go underneath MIC, the bugs don't grow for a little while. 'cause their cellular machinery is still a bit stunned from being exposed to the antibiotic. That then means that you can dose once daily and get fewer side effects and the same outcome.

Callum 31:44

I say witchcraft.

Jame 31:46

Yeah, and let's finish off by talking about EUC over MIC. And this one is, remember every other antibiotic? But we are going to talk about Vancomycin 'cause that's the one that probably people have particularly in America might be more familiar with because they have moved in several places over to EUC over MIC dosing as opposed to trough levels, which is what we are doing mostly in the uk. I don't know of anybody who's doing a UC over MIC dosing 'cause the calculations are tricky, although there are calculators that can do it for you. So remember a UC over MIC is like the shaded bit over the MIC, so you can do whatever you like, really. You can increase the dosing frequency or you can increase the amount of drug you're giving at every dose and you will get more bacterial kill. So for Vancomycin, they are targeting and. A UC over MIC ratio of 400 to 600. And this is different from U cast's, preclinical targeting when they were maybe suggesting something like 240 as their FAUC over MIC. But that's because the target of 400 to 600 was associated with better clinical outcomes. And so the calculators all suggest that as a targeting. Let me explain that a little bit.

Callum 33:01

Yeah.

Jame 33:01

because there's a difference between a UC over MC and FAUC over MIC. So FAUC over MC is fraction of a UC over MICI think. But let's say your average Vancomycin plasma level over 24 hours is 20. So it starts off at, like 80 or a hundred and it finishes at 10 less, or 10 or something like that. But the average over that 24 hour period is 20. Your EUC 24 would be 20. Times 24, so that would be 480 milligrams times hour divided by liter. So

Callum 33:37

Because you take

Jame 33:38

average.

Callum 33:39

you're looking at the area under the curve on the graph, and that's obviously a complex shape. So

Jame 33:43

Yeah.

Callum 33:44

that you get the

Jame 33:45

Average time,

Callum 33:46

gives you essentially a rectangular shape,

Jame 33:47

yeah.

Callum 33:48

basically just times the bottom half

Jame 33:51

Times by your unit interval of time. Yeah. So usually a day. And so if you are bacteria, MIC is one. But your average was was 20, so you had 480 milligrams times hour divided by liter, and your MIC was one. Then your EUC over MC would be 480, right? Because it was that divided by one. If it was two, it would be 240. It was four, it would be 120, and so on.

Callum 34:17

the units for, because I always find the units easy in maths to help me understand what's going on. So the units for the MIC is milligrams per liter 'cause it's a concentration. And then your units for the area under the curve, because you've done it by hours, it's milligrams. per liter.

Jame 34:34

Yeah,

Callum 34:35

Yeah.

Jame 34:36

which I, it took me a couple of,

Callum 34:37

hour.

Jame 34:38

yeah, it took me a couple of read throughs to get this, if anybody wants a bit more detail. Actually I've linked to the ucast rationale documents, but also there's oh, I'll put it in here. There's like a Ucast paper where they say, this is how we're calculating all this stuff. And they talk about a UC over MIC and it's worth a read. It's about five or six pages. So what can you do to improve the FAUC over MIC? You can either increase the dose or reduce the dosing interval. As I've said, you can, if your dose is one gram twice a day, you can move to 1.5 grams twice a day or one gram three times a day. And it doesn't really make much difference. You can get a similar outcome. So that's moving from two to three grams a day. But it just depends on how you give it. Do you see what I mean? Most calculators will do this. You're set and do this, and I've actually linked to the clin calc vancomycin calculator. It was in the EUC over MIC calculator and they've actually got the PD calculations in the back. If you click on one of the tabs, it says, this is how we're doing it. It's inordinately complex. I don't understand it. And I don't pretend to, and I don't use a UC over MIC calculations for Vancomycin. We thought about it and it made our brains hurt. So we never introduced it in any of the hospitals that I've worked in. And to be honest with you, Kam, I haven't used Vancomycin in quite a while. I'm using other stuff for treatment of, MRSA and intraocular infections. But if you want to do it, this is how to do it. And if you want an explanation of what's going on underneath the hood, so to speak, then that's a reasonable calculator to go and look at.

Callum 36:04

I guess it. Is it shown to improve outcomes to use this method of dosing rather than just our standard trough dosing that we

Jame 36:13

So the last time I loot it had been proven to be less toxic and I think people think that it is associated with better outcomes. I people throw that about and I'm never too sure how evidence-based it is. It's certainly not evidence-based enough that where the UK has thought it mandatory to introduce it. But whether or not that's because of declining Vancomycin usage overall, I don't know.

Callum 36:38

if people want to write in with their thoughts on the evidence for that, then we'd be all ears.

Jame 36:43

If I could put in a request, if anybody on Breakpoint is listening, a dosing consult episode on Vancomycin would be just tickety boo. Thank you very much. And you could explain all this to me like I'm five years old and then I would be most grateful and that Callum.

Callum 36:59

to me. Like just, just working it through my head. This the fraction of a UC over MIC because I was thinking about like our patients in intensive care unit where we give a vancomycin infusion now, usually when we're giving like a. A trough based dosing calculation infusion. We aim for a trough of either 10 to 15 milligrams per liter or 15 to 20 milligrams per liter based on the indication with the higher dosing band for severe infections. But when someone's on a continuous infusion in ICU, you expect that they'll have a steady state of the drug. essentially the whatever drug level you take at that point will be the average. Which is what we're calculating anyway. And in that we aim for 2025. And you just said that if we're trying to calculate our a UC over MIC sort of ratio then we're aiming for the sort of average plasma concentration of 20 to give us 480 on that ratio. And

Jame 37:54

Yeah. Or.

Callum 37:55

for.

Jame 37:55

Or 400 to 600. I mean, I have to say that

Callum 37:58

it's the

Jame 37:58

the same as

Callum 37:59

is

Jame 37:59

as

Callum 38:00

doing in some ways.

Jame 38:01

Kind of, but unlike the EUC over MIC, that peak plasma ratio of 15 to 20, I think that was associated with better outcomes for Sta Aureus in one study that was highly flawed. Brad s Spellberg has a whole mini rant on this one. One of many, as I'm sure you're aware, but the he says that we should probably be using 10 to 15. For everything. And the reason that we keep experiencing vancomycin toxicity is because we're overdosing it in everybody. So it's not as simple as all that let's say Cal,

Callum 38:29

So maybe

Jame 38:29

but yeah.

Callum 38:30

for moving to a UC over MSC dosing there.

Jame 38:32

I think the reason that in America it's much easier to do is because usually pharmacists are doing it. So they've got like much more I, not antimicrobial pharmacists, but PharmDs ev everywhere and they are probably handling all the vancomycin dosing. So the doctors saying we should start some vancomycin, and then that's the extent of their involvement.

Callum 38:51

Whereas there are often people that are maybe not so familiar with it and, we just don't have the same quantity of pharmacy input available. It's just a much more limited re resource, isn't it?

Jame 39:03

Yeah.

Callum 39:03

Particularly specialists, infection pharmacists.

Jame 39:06

Yeah. But anyway, that callem is that. So a quick tour through PD targeting. This is probably all that you need to know before you CCT, and some would argue maybe a little bit more than you need to know.

Callum 39:20

Thanks, Jim.

Jame 39:21

No problem, man.