Bản chép lời đầy đủ của 146. PD target attainment

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WEBVTT 00:00:18.489 --> 00:00:20.500 callum, that's a nice cup of tea that you've got there. 00:00:20.500 --> 00:00:21.070 Yes. 00:00:21.070 --> 00:00:23.649 It's from a very famous 00:00:24.946 --> 00:00:25.096 Uhhuh. 00:00:25.317 --> 00:00:26.241 And what brand is that? 00:00:26.241 --> 00:00:26.601 Callum. 00:00:26.601 --> 00:00:27.981 It's PD tips. 00:00:27.981 --> 00:00:29.601 PG tips or PD tips. 00:00:29.631 --> 00:00:30.411 PD tips. 00:00:30.652 --> 00:00:32.332 Ah, and what a coincidence that is Callum. 00:00:32.332 --> 00:00:33.652 'cause what are we discussing today? 00:00:35.001 --> 00:00:36.712 We're talking about Farmer coco diet. 00:00:37.881 --> 00:00:40.101 Pharmacodynamic Target. 00:00:41.451 --> 00:00:41.781 Yes. 00:00:41.781 --> 00:00:45.731 I'm gonna give you some PD tips on PD targeting with your antibiotics. 00:00:46.121 --> 00:00:56.621 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. 00:00:57.161 --> 00:00:57.822 Yes. 00:00:59.081 --> 00:00:59.531 Brilliant. 00:00:59.652 --> 00:01:00.161 Okay, good. 00:01:00.161 --> 00:01:01.841 We will figure that out on the back end. 00:01:01.841 --> 00:01:02.652 What do you know about this? 00:01:02.981 --> 00:01:06.341 I feel like I started off and I heard about PKPD. 00:01:06.402 --> 00:01:13.852 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. 00:01:14.402 --> 00:01:14.691 Yeah. 00:01:14.932 --> 00:01:23.512 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? 00:01:24.281 --> 00:01:26.471 We quite often lump these two topics together. 00:01:27.431 --> 00:01:32.031 James has taken us through already with a series before on pharmacokinetics. 00:01:32.341 --> 00:01:35.821 Resulting in the one PK table to rule them all. 00:01:36.161 --> 00:01:37.781 Which I certainly found useful. 00:01:37.841 --> 00:01:41.381 So that's pharmacokinetics, which is like how the drug moves through the body. 00:01:41.411 --> 00:01:43.661 pharmacodynamics is 00:01:44.681 --> 00:01:47.296 pK is what the body does to the drug. 00:01:47.296 --> 00:01:50.387 And PD is what the drug does to the body. 00:01:50.411 --> 00:01:51.281 a good way of explaining it. 00:01:51.496 --> 00:01:53.496 Yeah, but that doesn't work for antibiotics. 00:01:53.556 --> 00:02:02.292 '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. 00:02:03.036 --> 00:02:05.887 The bacteria or the virus or the fungi. 00:02:06.576 --> 00:02:14.097 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. 00:02:14.097 --> 00:02:16.527 It's working on the, in the cell of the bacteria. 00:02:16.616 --> 00:02:19.606 That's your on target effect is bacterial death. 00:02:19.877 --> 00:02:25.977 So we'll just talk about it as if we're just talking about antibacterial antimicrobials hence forth called antibiotics for now. 00:02:26.813 --> 00:02:29.783 So the what the drug does to the body that doesn't work. 00:02:29.943 --> 00:02:33.953 So let's just talk about the PD targeting is what you're wanting it to do. 00:02:34.343 --> 00:02:44.033 What we're gonna talk about today is the different PD indices that we use for each antibiotic to try and maximize its effectiveness. 00:02:44.063 --> 00:02:47.968 And that depends on how it's killing the the bacteria that we're talking about, 00:02:48.748 --> 00:02:56.987 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. 00:02:57.038 --> 00:02:59.677 Okay, and there are three that we're gonna talk about today. 00:02:59.768 --> 00:03:00.938 Am I just gonna talk at you? 00:03:01.718 --> 00:03:02.438 I'll, yeah. 00:03:02.438 --> 00:03:04.538 And then I'll ask questions'cause you're the 00:03:04.538 --> 00:03:04.808 Fine. 00:03:04.838 --> 00:03:07.013 of wisdom in this way and I am the pat one. 00:03:07.647 --> 00:03:07.867 Ha. 00:03:08.742 --> 00:03:09.763 Was ever, thus Callum. 00:03:09.813 --> 00:03:12.033 So we've got three PD indices that we talk about. 00:03:12.033 --> 00:03:17.193 We've got time over MIC, which I bet most people are familiar with'cause you learn about it in medical school, kind of. 00:03:17.823 --> 00:03:21.843 You've got a UC over MIC and you've got Cmax over MIC. 00:03:21.992 --> 00:03:28.503 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. 00:03:28.552 --> 00:03:30.983 But Jane, what is a Mick? 00:03:31.073 --> 00:03:32.783 And we're not talking about McCree. 00:03:33.033 --> 00:03:36.153 And what is a clinical breakpoint and, ah. 00:03:36.768 --> 00:03:38.328 and what to do when there are no break points. 00:03:38.328 --> 00:03:41.598 I'm happy to report, cam, that we have already covered this in our 00:03:41.897 --> 00:03:46.758 antimicrobial susceptibility testing miniseries, which are episodes number, 00:03:46.758 --> 00:03:48.272 1 0 1 and 1 0 2. 00:03:48.707 --> 00:03:54.362 and also 92, which is where you talked about what resistance is anyway, which is Most useful one to listen to before this one. 00:03:54.737 --> 00:03:55.758 Yes, exactly. 00:03:55.808 --> 00:03:57.098 So let's talk about our. 00:03:58.478 --> 00:03:59.688 PD targeting Cal. 00:03:59.688 --> 00:04:02.138 I want you to imagine a concentration time curve. 00:04:02.768 --> 00:04:05.498 So you are measuring the drug in a. 00:04:06.218 --> 00:04:08.108 A particular tissue. 00:04:08.198 --> 00:04:10.258 Let's just use plasma for now. 00:04:10.858 --> 00:04:16.588 And you've got concentration on the Y axis and you've got time in hours or minutes

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or whatever on the X axis. 00:04:16.978 --> 00:04:21.778 And if you infuse a drug, It could be vancomycin, could be penicillin, doesn't matter what it is. 00:04:22.168 --> 00:04:23.492 Initially you will get peak. 00:04:23.987 --> 00:04:26.757 And you'll get a peak up to a certain maximal concentration. 00:04:26.757 --> 00:04:35.487 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. 00:04:36.418 --> 00:04:40.497 If you take it orally, it will be between 30 to 60 minutes, something like that. 00:04:40.497 --> 00:04:44.877 But you will get a plasma peak level there and then. 00:04:45.208 --> 00:04:49.768 Your body will start to metabolize that drug or it will start to be eliminated in urine. 00:04:49.948 --> 00:04:55.658 And so then you've got this steadily declining concentration as you measure it steadily over time. 00:04:55.658 --> 00:05:00.588 And then eventually it will be eliminated completely from the body unless you give another dose. 00:05:00.588 --> 00:05:02.747 So we're just talking about one a one off dose here. 00:05:03.557 --> 00:05:07.752 And that gives you this triangular shaped concentration time curve. 00:05:09.143 --> 00:05:15.153 And we've got a little picture in the prep notes, pointing out the different PD parameters that we've got. 00:05:15.632 --> 00:05:23.583 That plasma peak is Cmax and usually that is expressed as a multiple of your MIC of your organism. 00:05:23.793 --> 00:05:33.882 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. 00:05:34.182 --> 00:05:38.173 If your MIC is two and your Cmax is 10, 00:05:38.413 --> 00:05:40.393 your Cmax MIC ratio is also five. 00:05:40.453 --> 00:05:47.853 Yeah, and then you've got the amount of time that your plasma level is spending above the MIC. 00:05:48.033 --> 00:05:55.843 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. 00:05:56.833 --> 00:06:00.913 You just care how long the plasma level stays above the MIC of the organism. 00:06:00.913 --> 00:06:05.823 That's time over MIC and it's usually expressed as a percentage of the dosing end flow that you've got. 00:06:06.163 --> 00:06:06.463 Yeah. 00:06:06.882 --> 00:06:30.158 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. 00:06:30.538 --> 00:06:32.148 Yeah, actually I haven't drawn this. 00:06:32.148 --> 00:06:35.028 I nicked this from a document that I've linked to in the notes as well. 00:06:35.968 --> 00:06:40.858 And then you've got the third feature, which is a UC over MIC. 00:06:40.858 --> 00:06:52.557 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. 00:06:53.293 --> 00:06:53.442 Does. 00:06:54.127 --> 00:06:55.028 Area under the curve. 00:06:56.198 --> 00:06:56.497 Yeah. 00:06:56.768 --> 00:06:59.978 So area under the curve is the sheed area, if you like. 00:06:59.978 --> 00:07:04.458 That's above the the MIC and we'll come onto that definition in a sec. 00:07:04.507 --> 00:07:05.843 It's at the top of the Smurf hat. 00:07:07.583 --> 00:07:07.942 Yeah. 00:07:07.942 --> 00:07:11.362 It's the top of the smurf at, are we doing smurf analogs here? 00:07:12.492 --> 00:07:14.653 I think, I don't really know any Smurf analogs, but we 00:07:14.698 --> 00:07:14.997 Fine. 00:07:16.028 --> 00:07:19.078 So let's go back to time over m so time over MIC. 00:07:19.138 --> 00:07:28.703 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. 00:07:28.763 --> 00:07:38.393 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. 00:07:38.423 --> 00:07:43.823 If you're going to teach anybody about any PD parameter, you're gonna teach about it for the beta-lactams. 00:07:44.543 --> 00:07:45.893 And so it's all the beta lactams. 00:07:45.893 --> 00:07:49.427 It's your, penicillins, cephalosporins, carbapenems, and Astrium. 00:07:50.328 --> 00:07:55.247 And next you've got Cmax expressed as a function of MIC. 00:07:55.698 --> 00:07:57.557 And this is what Aminoglycosides do. 00:07:58.018 --> 00:08:12.168 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. 00:08:13.578 --> 00:08:16.698 An a UC over MIC is basically. 00:08:17.117 --> 00:08:17.958 Everything else. 00:08:18.437 --> 00:08:21.557 And that's both time and concentration dependent killing. 00:08:21.858 --> 00:08:29.987 So you will get more kill if you increase the Cmax and you will get more kill if you increase the time over MIC. 00:08:29.987 --> 00:08:39.587 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. 00:08:39.947 --> 00:08:40.247 Okay? 00:08:40.247 --> 00:08:51.061 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. 00:08:51.811 --> 00:08:56.490 This is not e every drug that's available in the

uk, some of them don't have dosing documents. 00:08:56.890 --> 00:09:02.211 But I said for each of the drugs at what the pd parameter is. 00:09:02.211 --> 00:09:08.520 So again, for all betal Liams, it's time over MIC for Metronidazole, it's Cmax over MIC. 00:09:08.760 --> 00:09:12.961 But actually for the aminoglycosides, they've started dosing according to EUC over MIC. 00:09:12.961 --> 00:09:16.081 And this is the first little asterisk here, which is that. 00:09:16.081 --> 00:09:28.431 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. 00:09:28.431 --> 00:09:33.561 So when they're extrapolating from that data, they're using a UC over MIC, but historically. 00:09:34.536 --> 00:09:37.916 Cmax as a function of MIC was what we used. 00:09:38.446 --> 00:09:40.515 And that sort of explains the once a day dosing. 00:09:40.515 --> 00:09:41.806 So I've put them in this column here 00:09:42.240 --> 00:09:42.390 Why 00:09:42.436 --> 00:09:43.156 and then you'll see. 00:09:43.230 --> 00:09:43.770 changed? 00:09:44.115 --> 00:09:44.416 Sorry. 00:09:44.821 --> 00:09:45.556 Why do you think that's changed? 00:09:46.406 --> 00:09:57.385 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. 00:09:58.255 --> 00:10:00.656 Thought to be time dependent, killing like erythromycin. 00:10:00.846 --> 00:10:06.525 For example was initially calculated if it was time over MIC as the PD parameter. 00:10:06.525 --> 00:10:19.645 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. 00:10:20.140 --> 00:10:22.541 More towards the time dependent killing end of things. 00:10:22.721 --> 00:10:26.980 And some is more towards the concentration dependent killing end of things, and most stuff is in the middle. 00:10:28.301 --> 00:10:33.711 So it depends on how, if you get additional kill once you go over the MIC. 00:10:34.071 --> 00:10:40.971 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. 00:10:41.120 --> 00:10:42.561 There's no point going any higher. 00:10:42.561 --> 00:10:43.791 You're just gonna increase toxicity. 00:10:45.081 --> 00:10:56.691 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? 00:10:58.010 --> 00:11:00.471 Whereas other drugs don't really work that way. 00:11:00.471 --> 00:11:03.471 You can increase the concentration and get more kill. 00:11:03.471 --> 00:11:05.270 You can increase the time and get more kill. 00:11:06.531 --> 00:11:10.821 And Amin glycosides are towards the increase, the concentration end of the scale. 00:11:11.000 --> 00:11:12.735 But you can still use a UC if you want to. 00:11:14.885 --> 00:11:18.255 And what's really interesting is that this is basically done for plasma, isn't it? 00:11:18.255 --> 00:11:20.446 I'm talking here about at the Target site. 00:11:20.816 --> 00:11:23.696 But actually for a lot of the stuff, it was calculated based on plasma, 00:11:23.921 --> 00:11:24.071 so 00:11:24.125 --> 00:11:24.546 Levels. 00:11:24.650 --> 00:11:25.161 of our data. 00:11:25.161 --> 00:11:29.000 But then also, and want to do this at point, some point about a PD meaning series. 00:11:29.000 --> 00:11:41.326 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. 00:11:41.375 --> 00:11:45.975 Certain body sites are protected by barriers or membranes and other things, 00:11:46.025 --> 00:11:46.316 yeah. 00:11:46.456 --> 00:11:57.411 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, 00:11:57.786 --> 00:11:58.235 Yeah, 00:11:58.281 --> 00:11:59.421 and that's how you learn things. 00:11:59.421 --> 00:12:06.911 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. 00:12:06.911 --> 00:12:07.781 So let me move on. 00:12:07.811 --> 00:12:10.120 Are you ready for another bite-sized complexity call? 00:12:10.211 --> 00:12:10.600 Okay, 00:12:11.471 --> 00:12:13.245 Let's talk about Monte Carlo simulation. 00:12:13.245 --> 00:12:17.005 Yes, monte Carlo, so it's administrative area of Monaco 00:12:18.056 --> 00:12:27.686 So Monte Carlo simulation was originally developed in, in betting casinos to see about probabilities of winning and losing across multiple games. 00:12:27.686 --> 00:12:33.096 And this has been extrapolated into statistics and is now its own statistical thing. 00:12:33.096 --> 00:12:37.605 And Ucast have used it to calculate for certain mics of an organism. 00:12:38.206 --> 00:12:45.546 What is the likelihood that you're going to be able to attain your your PD targeting? 00:12:46.025 --> 00:12:48.786 So let's take the example of Piperacillin. 00:12:48.885 --> 00:12:51.105 So they've got different ways of doing this. 00:12:51.105 --> 00:12:53.115 Sometimes it's bug specific and sometimes it's not. 00:12:53.115 --> 00:12:56.186 It depends on how old the document is that you're looking at. 00:12:56.235 --> 00:13:05.495 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. 00:13:06.036 --> 00:13:08.145 You've got the MIC. 00:13:08.926 --> 00:13:14.916 On the in the first column there, and it goes from

two or less than two to 64, pretty high. 00:13:14.916 --> 00:13:19.306 MICI think you Greg Cal certainly for being able to obtain that in plasma. 00:13:19.786 --> 00:13:30.645 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%. 00:13:30.645 --> 00:13:35.385 And so the listener knows usually for intra batch rallies and. 00:13:35.770 --> 00:13:37.860 Strep and stuff like that. 00:13:38.311 --> 00:13:45.360 You usually want sort of 30 to 45% of your time over MIC, something like that. 00:13:45.691 --> 00:13:51.331 So you don't need to be over the MIC 100% of the time'cause that would lead to pretty bad toxicity. 00:13:51.811 --> 00:14:00.745 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. 00:14:01.541 --> 00:14:11.260 The chances of attaining that with a cent dosage of piperacillin for less than two is a hundred percent. 00:14:12.130 --> 00:14:15.341 For four, for eight, it's 99.4%. 00:14:15.581 --> 00:14:16.120 Not bad. 00:14:16.691 --> 00:14:19.571 For 16, it's 74.3%. 00:14:19.571 --> 00:14:25.431 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. 00:14:25.431 --> 00:14:26.691 That's probably worth thinking about. 00:14:27.230 --> 00:14:33.711 For an MIC of 32, it's 2.4%, and for an MIC of 64 0, so that's. 00:14:34.865 --> 00:14:36.515 How they're trying to calculate. 00:14:36.936 --> 00:14:41.806 So you would set the break point there at an MIC of about eight probably. 00:14:41.806 --> 00:14:43.546 'cause 99.4% is okay. 00:14:43.546 --> 00:14:44.115 Do you see what I mean? 00:14:44.115 --> 00:14:45.436 And then below that, I've got the same. 00:14:45.615 --> 00:14:58.500 the percentage the likelihood as expressed as a percentage that you will have time over the minimum inhibitory concentration of 40% of the time. 00:14:59.071 --> 00:14:59.341 Yeah. 00:14:59.341 --> 00:15:03.480 40% time over MIC for a given, MIC of the organism? 00:15:04.291 --> 00:15:15.000 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 00:15:15.390 --> 00:15:15.870 Yes. 00:15:15.990 --> 00:15:16.890 Carlo simulation 00:15:16.975 --> 00:15:18.025 With that dosage. 00:15:18.041 --> 00:15:18.551 Yeah, with that 00:15:18.775 --> 00:15:19.166 Yeah. 00:15:19.166 --> 00:15:23.605 And usually it's based on like neutropenic thigh models and animal models and stuff. 00:15:23.605 --> 00:15:25.166 It's not based on clinical data. 00:15:25.166 --> 00:15:27.536 So you then need to go and get a bit of clinical data. 00:15:27.911 --> 00:15:28.181 Yeah. 00:15:28.225 --> 00:15:29.666 But that's ucas problem, not us. 00:15:29.666 --> 00:15:31.076 We're talking about PD parameters. 00:15:31.135 --> 00:15:31.286 That's. 00:15:31.301 --> 00:15:42.721 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 00:15:42.975 --> 00:15:43.216 Yeah. 00:15:43.216 --> 00:15:47.395 So this all comes after and then it then has to be backed up by clinical data too. 00:15:47.605 --> 00:15:49.196 So it's three levels to it, isn't it? 00:15:49.466 --> 00:15:49.735 Yeah. 00:15:50.216 --> 00:15:55.515 And then below this, I've got an example for a more modern way that they're displaying this for ciprofloxacin. 00:15:55.966 --> 00:15:57.255 And maybe this is worth chatting about. 00:15:57.255 --> 00:15:59.086 I was gonna gloss over at Cal, but will I 00:15:59.176 --> 00:15:59.296 it. 00:15:59.296 --> 00:16:00.495 Because I think this is a common 00:16:00.975 --> 00:16:01.245 fine. 00:16:02.086 --> 00:16:04.096 So here we've got on the. 00:16:05.036 --> 00:16:08.515 On the X axis, the mics of the organism. 00:16:08.796 --> 00:16:15.895 And this actually the, you can see these little sort of green bars, and that's the wild type distribution of the. 00:16:16.375 --> 00:16:17.546 Susceptible. 00:16:17.816 --> 00:16:20.966 And then the resistant population is on the right most. 00:16:20.966 --> 00:16:25.076 So the this is for Ciproflox is in the organism of staph aureus. 00:16:25.076 --> 00:16:30.725 The cipro dose is 500 milligrams bd on the left hand side and seven 50 BD on the right hand side. 00:16:31.446 --> 00:16:34.596 And you've got the resistant population. 00:16:35.171 --> 00:16:41.900 MIC is more than four but for the wild type population, it tops out at about 0.5 or one or something like that. 00:16:41.990 --> 00:16:48.100 So you might think about setting the break point, roundabout roundabout there, and then. 00:16:49.566 --> 00:16:54.426 The Y axis is both the relative frequency of the MIC distributions. 00:16:54.426 --> 00:16:59.196 That's the green boxes that we were just talking about, but you'll see that there's some red lines there. 00:16:59.196 --> 00:17:06.066 And those red lines are pd chances of PD target attainment for those mics with that dosage. 00:17:06.275 --> 00:17:08.735 And there's three red lines. 00:17:08.735 --> 00:17:13.485 And if you look at the bars, you'll see that one of them is for bacteria stasis. 00:17:13.546 --> 00:17:14.955 So inhibited growth. 00:17:15.695 --> 00:17:22.365 One is for one log kill, so tenfold reduc one log 10 kill and that's a tenfold reduction. 00:17:22.365 --> 00:17:28.216 And the other is two log kill, which is a 100 fold reduction when exposed to the drug. 00:17:28.216 --> 00:17:39.175 And you'll see that for the bacteria stasis the line stays at 100% target attainment until you get to an MIC of about. 00:17:39.621 --> 00:17:41.841 Point five and then it starts to drop. 00:17:41.841 --> 00:17:46.471 And by the time you get to one it's you don't have any chance of target attainment. 00:17:46.951 --> 00:17:50.711 And then

for one log hill, it starts to drop. 00:17:50.711 --> 00:17:55.480 Once you get to 0.25, I think that is, and for two log hill, it starts to drop. 00:17:55.480 --> 00:17:57.010 One, two, you're at 0.12. 00:17:57.691 --> 00:17:58.830 Which is the next bit down. 00:17:59.111 --> 00:18:06.171 But before that you got basically 100% target attainment, even for too long kill at 0.06 and 0.12. 00:18:06.351 --> 00:18:07.010 Do you see what I mean? 00:18:09.881 --> 00:18:10.101 Yes. 00:18:10.135 --> 00:18:10.355 Yes. 00:18:10.875 --> 00:18:11.401 I think To 00:18:11.526 --> 00:18:12.635 this is much easier. 00:18:12.635 --> 00:18:14.556 Yeah, this is much easier to look at. 00:18:14.556 --> 00:18:14.615 Yeah. 00:18:14.871 --> 00:18:15.320 with the note. 00:18:15.320 --> 00:18:17.480 The link to it is in the episode description. 00:18:17.691 --> 00:18:17.810 I 00:18:17.841 --> 00:18:18.131 Yeah. 00:18:18.451 --> 00:18:20.520 Just trying to puzzle what you're saying there. 00:18:20.520 --> 00:18:23.560 They're trying to display quite a lot of complex data on a graph. 00:18:23.861 --> 00:18:36.310 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, 00:18:36.520 --> 00:18:37.570 a OC over MIC. 00:18:37.570 --> 00:18:43.091 Yeah, but I mean this is actually why they moved to seven 50 BD for treatment sta forus. 00:18:43.121 --> 00:19:03.671 '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. 00:19:04.466 --> 00:19:06.875 So that's why they're they've moved to that. 00:19:06.925 --> 00:19:08.036 It's a PK argument. 00:19:08.036 --> 00:19:13.855 discussion we had before about the myth of, bactericidal or bacterio static as a drug. 00:19:14.046 --> 00:19:17.165 Saying that drug is bacterio static, that drug is bactericidal. 00:19:18.786 --> 00:19:23.566 as we're seeing here, as you increase the concentration of the drug, you will kill the bacteria more quickly. 00:19:24.435 --> 00:19:25.246 So it's like such a. 00:19:26.221 --> 00:19:28.230 Like pointless statement to say some things, so 00:19:28.421 --> 00:19:28.711 Yeah. 00:19:28.770 --> 00:19:36.770 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. 00:19:36.770 --> 00:19:36.980 But 00:19:37.611 --> 00:19:38.391 I guess most, 00:19:38.540 --> 00:19:38.631 you 00:19:38.750 --> 00:19:39.586 as you said right at the beginning, 00:19:40.490 --> 00:19:40.701 for 00:19:40.806 --> 00:19:42.145 for most antibiotics. 00:19:42.320 --> 00:19:46.820 if you get a higher concentration of the drug at the site where the infection is, you're gonna kill it better 00:19:47.145 --> 00:19:47.435 Yeah. 00:19:47.931 --> 00:19:49.101 in a very simple way. 00:19:50.780 --> 00:19:51.716 and so that's what's important. 00:19:52.405 --> 00:19:52.625 Yeah. 00:19:53.145 --> 00:19:55.786 Let's talk now about what to do with this information. 00:19:55.786 --> 00:19:57.976 Like why am I chewing your ear off about this? 00:19:57.976 --> 00:19:58.486 Why is it important? 00:19:59.580 --> 00:20:07.861 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. 00:20:07.861 --> 00:20:14.431 Cal with an endocarditis, you will move the ben pen dosing from four times a day to six times a day. 00:20:14.611 --> 00:20:15.480 Why are you doing that? 00:20:15.480 --> 00:20:16.921 You could just double the dose, couldn't you? 00:20:17.020 --> 00:20:18.401 Maybe you could and maybe you couldn't. 00:20:18.461 --> 00:20:18.701 Right? 00:20:19.330 --> 00:20:24.050 So let's talk now about what to do with this information, how to practically apply it. 00:20:24.351 --> 00:20:28.121 Let's talk about time over MIC, which again is basically just beta-lactams. 00:20:28.401 --> 00:20:28.941 These days. 00:20:29.391 --> 00:20:35.121 Your PD target is normally within the realm of 30 to 70%, something like that. 00:20:35.181 --> 00:20:39.871 And for some bugs it is higher than others. 00:20:39.871 --> 00:20:45.601 So for pseudomonas, I've got an example in here which I screen grabbed from the ucast document from Meropenum. 00:20:45.931 --> 00:20:46.766 But if you want a one log. 00:20:47.405 --> 00:20:54.066 10 kill for pseudomonas, you need to get a time over of between 35 to 55%. 00:20:54.066 --> 00:20:55.355 So call it 45%. 00:20:56.016 --> 00:21:01.175 For intra that's the same, but for staph reus it's 15 to 40. 00:21:01.175 --> 00:21:04.546 So maybe call it like 25 to 30%, something like that. 00:21:04.846 --> 00:21:10.286 So that's, it's different for different organisms, but base basically more time over MIC is more kill. 00:21:11.635 --> 00:21:11.905 Now. 00:21:12.705 --> 00:21:17.645 That means if you want to improve your time over MIC, there's a few things that you can do. 00:21:18.336 --> 00:21:25.955 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. 00:21:25.986 --> 00:21:27.816 Let's say that you've got an endocarditis patient. 00:21:27.816 --> 00:21:36.118 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. 00:21:36.449 --> 00:21:39.209 It's really difficult to maintain their time over MIC. 00:21:39.239 --> 00:21:43.568 If you ever monitor their beta-lactam level levels, which we don't do locally, you'll. 00:21:43.942 --> 00:21:45.982 Note that the half-life is quite short. 00:21:45.982 --> 00:21:49.952 So I usually say

that the half-life of penicillin is about an hour. 00:21:50.432 --> 00:21:52.502 Actually, it's about 0.8 to 1.2. 00:21:52.502 --> 00:22:00.762 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. 00:22:01.123 --> 00:22:09.553 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. 00:22:09.853 --> 00:22:22.512 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. 00:22:22.918 --> 00:22:23.698 are four hours a day. 00:22:23.788 --> 00:22:23.847 Yeah. 00:22:24.103 --> 00:22:24.853 Yes, that's right. 00:22:24.958 --> 00:22:25.168 Yeah. 00:22:25.673 --> 00:22:28.823 Whereas the other thing that I could do is I could decrease the time between infusions. 00:22:28.823 --> 00:22:36.623 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. 00:22:37.073 --> 00:22:39.472 So they will get it at four hourly intervals. 00:22:39.472 --> 00:22:41.303 This is a real pain in the neck. 00:22:41.353 --> 00:22:42.103 For the nurses. 00:22:42.133 --> 00:22:44.413 It really disturbs the sleep of the patient. 00:22:44.543 --> 00:22:46.442 So why would you bother to do this? 00:22:46.563 --> 00:22:54.282 You would do it because in moving from six hours between infusions to four hours between infusions, you have dropped two half lives. 00:22:54.793 --> 00:23:02.502 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. 00:23:02.502 --> 00:23:03.387 If your half-life is an hour. 00:23:05.143 --> 00:23:07.123 So you might also increase the dose. 00:23:07.123 --> 00:23:08.353 You might also want to do that. 00:23:08.353 --> 00:23:11.442 So you might bump it up to 1.8 or 2.4, whatever. 00:23:11.442 --> 00:23:14.532 It depends on how sick the patient is and how concerned you are. 00:23:14.682 --> 00:23:25.012 But by reducing the interval between infusions, you are improving the time over MIC much more than you could by increasing the dose. 00:23:25.566 --> 00:23:30.365 And there's the third thing that you could do, which is a prolonged infusion. 00:23:30.365 --> 00:23:38.966 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. 00:23:39.236 --> 00:23:44.875 And break points have done a really big tear down episode on it, so go and listen to that if you want the details. 00:23:44.875 --> 00:23:56.935 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. 00:23:57.550 --> 00:24:01.661 And that's what the current recommendation is for serious infections with Meropenem. 00:24:01.661 --> 00:24:07.570 That's what ucast expects you to do if you're giving the two gram high dose, particularly in intensive care patients. 00:24:08.441 --> 00:24:18.671 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. 00:24:18.730 --> 00:24:25.721 Whereas if you put in slowly, that time to Cmax is delayed, your body has less chance to metabolize it and pee it out. 00:24:26.711 --> 00:24:29.330 You get this prolonging of time over MIC. 00:24:30.260 --> 00:24:42.530 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. 00:24:42.830 --> 00:24:51.080 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? 00:24:51.320 --> 00:24:52.266 Wait, just think about your. 00:24:52.506 --> 00:24:54.036 patient that's got an infection. 00:24:54.086 --> 00:24:55.796 Like we, we talk to 00:24:55.905 --> 00:24:56.195 Cool. 00:24:56.246 --> 00:25:00.155 the importance of keeping mobile and, the holistic approach to their effects. 00:25:00.155 --> 00:25:08.405 You're balancing that potential microbiological treatment improvement with the other impacts on being tied up to a line all the time. 00:25:08.466 --> 00:25:16.556 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. 00:25:16.605 --> 00:25:16.895 Yeah. 00:25:17.091 --> 00:25:19.294 And penicillin and flu CLOs for that matter. 00:25:19.344 --> 00:25:28.584 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. 00:25:28.584 --> 00:25:35.084 And when we start Piptaz, certainly down in Naro soiling for me south, we would. 00:25:35.489 --> 00:25:38.969 Start Piptaz 13.5 grams a day. 00:25:38.969 --> 00:25:49.824 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. 00:25:50.213 --> 00:25:53.124 As 4.5 grams four times a day. 00:25:53.334 --> 00:26:00.473 So if we were treating pseudomonas infection as an outpatient with elastomeric peptides, we wouldn't bump up to 18 grams in the infusers. 00:26:00.624 --> 00:26:05.144 I mean, our ones didn't do it, but other infusers can contain that much. 00:26:05.384 --> 00:26:13.814 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. 00:26:14.294 --> 00:26:18.104 So it does open up some interesting things about, patients on extremes for weight. 00:26:18.104 --> 00:26:32.594 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. 00:26:32.864 --> 00:26:34.723 So you drop down the dose to. 00:26:35.144 --> 00:26:37.634 So half of that, so 2.25 00:26:37.858 --> 00:26:38.149 Yeah. 00:26:38.413 --> 00:26:46.183 but gave it more frequently and in conjunction with the pharmacist and award, we felt that was actually gonna give us better target attainment. 00:26:46.903 --> 00:27:03.304 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. 00:27:03.378 --> 00:27:20.278 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. 00:27:20.308 --> 00:27:26.118 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. 00:27:27.213 --> 00:27:34.864 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. 00:27:34.864 --> 00:27:37.713 Three times a day, because that opens it to interpretation. 00:27:37.953 --> 00:27:41.854 I give an hourly dosing, so I always say give it four hourly, give it six hourly. 00:27:41.903 --> 00:27:45.973 I feel like that's cementing that it is really important. 00:27:47.653 --> 00:27:51.134 although I guess you could probably go off and study does it absolutely matter? 00:27:51.804 --> 00:27:55.253 You probably have more time over IC in the day, less overnight. 00:27:55.554 --> 00:27:58.854 Personally, I think it probably does matter, but I'm not sure anybody's ever looked at that in detail. 00:27:59.844 --> 00:28:02.663 I don't think they've looked it in that granular detail. 00:28:03.144 --> 00:28:09.074 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. 00:28:09.763 --> 00:28:15.614 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. 00:28:15.614 --> 00:28:22.814 And certainly in UK hospitals, a lot of people are already up at 6:00 AM anyway,'cause wards are inherently noisy places. 00:28:22.923 --> 00:28:23.253 Yeah. 00:28:23.524 --> 00:28:25.903 Let's talk about Cmax over MIC. 00:28:26.473 --> 00:28:30.104 Here the PD target is expressed as a

ratio to the MIC. 00:28:30.104 --> 00:28:38.203 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. 00:28:39.074 --> 00:28:45.472 Usually the SR breakpoint for intact is, is two for for Gentamycin and tobramycin as well. 00:28:45.502 --> 00:28:48.567 I think and so what you would want there, if you wanted a. 00:28:49.627 --> 00:28:54.948 Cmax to over MIC ratio of eight to 10 would be a peak plasma level of between 16 and 20. 00:28:55.278 --> 00:29:06.817 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. 00:29:07.998 --> 00:29:09.137 MIC was Sr. 00:29:09.137 --> 00:29:10.907 Breakpoint was raised to eight. 00:29:11.238 --> 00:29:24.607 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. 00:29:24.607 --> 00:29:27.218 Although I would maintain that in the urine, it's still a viable option. 00:29:27.428 --> 00:29:29.498 Yeah, because it'll concentrate into your new tract. 00:29:30.998 --> 00:29:34.966 what your CM Maxs MIC ratio needs to be for it to be effective? 00:29:35.685 --> 00:29:42.786 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. 00:29:43.536 --> 00:29:49.326 But yeah, when you look at it in vitro, I mean now ucast are looking at a UC over MIC as I said. 00:29:49.716 --> 00:29:54.286 But when we're thinking about the Cmax over MIC, that, eight to 10 is from, decades ago. 00:29:54.355 --> 00:30:00.276 The pharmacodynamic studies that were set then, and so that's what we're attaining for. 00:30:00.395 --> 00:30:10.556 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. 00:30:10.915 --> 00:30:14.246 And toxicity with aminoglycosides is a big, significant issue. 00:30:14.296 --> 00:30:14.586 Yeah. 00:30:14.625 --> 00:30:24.355 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. 00:30:24.355 --> 00:30:34.246 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. 00:30:34.756 --> 00:30:39.976 Achieve the same amount of kill as if you had dosed it at three separate intervals. 00:30:39.976 --> 00:30:44.236 So the old dosing was like one to 1.5 milligrams per kilogram, eight hour. 00:30:45.375 --> 00:31:00.236 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.

00:31:00.790 --> 00:31:10.030 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. 00:31:10.030 --> 00:31:10.871 That's not the case. 00:31:10.901 --> 00:31:17.280 That's not what the Hartford people showed when they published their once a day dosing regimen. 00:31:17.280 --> 00:31:26.790 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. 00:31:26.790 --> 00:31:32.280 And so the amount of kill is the same and probably because Amy Glycosides have a good post antibiotic effect. 00:31:32.280 --> 00:31:35.401 So once you go underneath MIC, the bugs don't grow for a little while. 00:31:35.401 --> 00:31:39.471 'cause their cellular machinery is still a bit stunned from being exposed to the antibiotic. 00:31:40.080 --> 00:31:44.391 That then means that you can dose once daily and get fewer side effects and the same outcome. 00:31:44.891 --> 00:31:45.851 I say witchcraft. 00:31:46.221 --> 00:31:51.326 Yeah, and let's finish off by talking about EUC over MIC. 00:31:51.532 --> 00:31:54.833 And this one is, remember every other antibiotic? 00:31:54.883 --> 00:32:09.923 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. 00:32:09.952 --> 00:32:17.252 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. 00:32:17.655 --> 00:32:25.336 So remember a UC over MIC is like the shaded bit over the MIC, so you can do whatever you like, really. 00:32:25.336 --> 00:32:32.486 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. 00:32:33.026 --> 00:32:36.891 So for Vancomycin, they are targeting and. 00:32:36.891 --> 00:32:39.655 A UC over MIC ratio of 400 to 600. 00:32:39.776 --> 00:32:50.096 And this is different from U cast's, preclinical targeting when they were maybe suggesting something like 240 as their FAUC over MIC. 00:32:50.336 --> 00:32:55.865 But that's because the target of 400 to 600 was associated with better clinical outcomes. 00:32:56.105 --> 00:32:59.175 And so the calculators all suggest that as a targeting. 00:32:59.175 --> 00:33:00.796 Let me explain that a little bit. 00:33:01.236 --> 00:33:01.526 Yeah. 00:33:01.621 --> 00:33:05.161 because there's a difference between a UC over MC and FAUC over MIC. 00:33:05.161 --> 00:33:09.885 So FAUC over MC is fraction of a UC over MICI think. 00:33:10.605 --> 00:33:16.036 But let's say your average Vancomycin plasma level over 24 hours is 20. 00:33:16.665 --> 00:33:22.086 So it starts off at, like 80 or a hundred and it finishes at 10 less, or 10 or something like that. 00:33:22.776 --> 00:33:26.496 But the average over that 24 hour period is 20. 00:33:27.096 --> 00:33:30.756 Your EUC 24 would be 20. 00:33:31.266 --> 00:33:37.026 Times 24, so that would be 480 milligrams times hour divided by liter. 00:33:37.026 --> 00:33:37.086 So 00:33:37.820 --> 00:33:38.211 Because you take 00:33:38.260 --> 00:33:38.750 average. 00:33:39.080 --> 00:33:43.441 you're looking at the area under the curve on the graph, and that's obviously a complex shape. 00:33:43.441 --> 00:33:43.740 So 00:33:43.786 --> 00:33:44.266 Yeah. 00:33:44.580 --> 00:33:45.060 that you get the 00:33:45.121 --> 00:33:46.050 Average time, 00:33:46.050 --> 00:33:47.760 gives you essentially a rectangular shape, 00:33:47.931 --> 00:33:48.221 yeah. 00:33:48.391 --> 00:33:51.111 basically just times the bottom half 00:33:51.216 --> 00:33:52.836 Times by your unit interval of time. 00:33:52.836 --> 00:33:53.046 Yeah. 00:33:53.046 --> 00:33:53.855 So usually a day. 00:33:54.455 --> 00:33:57.246 And so if you are bacteria, MIC is one. 00:33:58.296 --> 00:34:07.746 But your average was was 20, so you had 480 milligrams times hour divided by liter, and your MIC was one. 00:34:07.895 --> 00:34:11.016 Then your EUC over MC would be 480, right? 00:34:11.016 --> 00:34:12.516 Because it was that divided by one. 00:34:12.516 --> 00:34:14.405 If it was two, it would be 240. 00:34:14.405 --> 00:34:16.955 It was four, it would be 120, and so on. 00:34:17.181 --> 00:34:20.940 the units for, because I always find the units easy in maths to help me understand what's going on. 00:34:20.940 --> 00:34:24.810 So the units for the MIC is milligrams per liter'cause it's a concentration. 00:34:25.770 --> 00:34:32.340 And then your units for the area under the curve, because you've done it by hours, it's milligrams. 00:34:33.765 --> 00:34:34.305 per liter. 00:34:34.770 --> 00:34:35.130 Yeah, 00:34:35.655 --> 00:34:35.955 Yeah. 00:34:36.000 --> 00:34:37.350 which I, it took me a couple of, 00:34:37.485 --> 00:34:37.875 hour. 00:34:38.340 --> 00:34:41.940 yeah, it took me a couple of read throughs to get this, if anybody wants a bit more detail. 00:34:42.580 --> 00:34:47.770 Actually I've linked to the ucast rationale documents, but also there's oh, I'll put it in here. 00:34:47.770 --> 00:34:51.550 There's like a Ucast paper where they say, this is how we're calculating all this stuff. 00:34:51.550 --> 00:34:54.010 And they talk about a UC over MIC and it's worth a read. 00:34:54.100 --> 00:34:55.450 It's about five or six pages. 00:34:55.884 --> 00:34:59.304 So what can you do to improve the FAUC over MIC? 00:34:59.304 --> 00:35:01.734 You can either increase the dose or reduce the dosing interval. 00:35:01.734 --> 00:35:09.444 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. 00:35:09.444 -->

00:35:11.034 And it doesn't really make much difference. 00:35:11.334 --> 00:35:12.474 You can get a similar outcome. 00:35:12.474 --> 00:35:14.394 So that's moving from two to three grams a day. 00:35:14.394 --> 00:35:15.834 But it just depends on how you give it. 00:35:15.834 --> 00:35:16.459 Do you see what I mean? 00:35:16.459 --> 00:35:17.899 Most calculators will do this. 00:35:17.899 --> 00:35:22.799 You're set and do this, and I've actually linked to the clin calc vancomycin calculator. 00:35:22.799 --> 00:35:28.699 It was in the EUC over MIC calculator and they've actually got the PD calculations in the back. 00:35:28.699 --> 00:35:31.309 If you click on one of the tabs, it says, this is how we're doing it. 00:35:32.059 --> 00:35:34.189 It's inordinately complex. 00:35:34.250 --> 00:35:35.449 I don't understand it. 00:35:36.004 --> 00:35:40.474 And I don't pretend to, and I don't use a UC over MIC calculations for Vancomycin. 00:35:40.474 --> 00:35:42.964 We thought about it and it made our brains hurt. 00:35:42.964 --> 00:35:45.754 So we never introduced it in any of the hospitals that I've worked in. 00:35:46.684 --> 00:35:50.194 And to be honest with you, Kam, I haven't used Vancomycin in quite a while. 00:35:50.294 --> 00:35:55.689 I'm using other stuff for treatment of, MRSA and intraocular infections. 00:35:56.169 --> 00:35:58.509 But if you want to do it, this is how to do it. 00:35:58.509 --> 00:36:04.979 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. 00:36:04.979 --> 00:36:05.429 I guess it. 00:36:05.429 --> 00:36:13.779 Is it shown to improve outcomes to use this method of dosing rather than just our standard trough dosing that we 00:36:13.794 --> 00:36:22.644 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. 00:36:22.644 --> 00:36:28.634 I people throw that about and I'm never too sure how evidence-based it is. 00:36:28.694 --> 00:36:33.375 It's certainly not evidence-based enough that where the UK has thought it mandatory to introduce it. 00:36:33.834 --> 00:36:38.139 But whether or not that's because of declining Vancomycin usage overall, I don't know. 00:36:38.694 --> 00:36:43.404 if people want to write in with their thoughts on the evidence for that, then we'd be all ears. 00:36:43.514 --> 00:36:50.824 If I could put in a request, if anybody on Breakpoint is listening, a dosing consult episode on Vancomycin would be just tickety boo. 00:36:50.824 --> 00:36:51.544 Thank you very much. 00:36:51.544 --> 00:36:59.674 And you could explain all this to me like I'm five years old and then I would be most grateful and that Callum. 00:36:59.679 --> 00:37:00.069 to me. 00:37:00.099 --> 00:37:02.459 Like just, just working it through my head. 00:37:02.459 --> 00:37:12.964 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. 00:37:13.589 --> 00:37:15.919 A trough based dosing calculation infusion. 00:37:15.919 --> 00:37:24.759 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. 00:37:25.119 --> 00:37:29.589 But when someone's on a continuous infusion in ICU, you expect that they'll have a steady state of the drug. 00:37:30.309 --> 00:37:35.529 essentially the whatever drug level you take at that point will be the average. 00:37:36.129 --> 00:37:37.419 Which is what we're calculating anyway. 00:37:37.449 --> 00:37:39.609 And in that we aim for 2025. 00:37:40.000 --> 00:37:53.979 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. 00:37:54.039 --> 00:37:54.219 And 00:37:54.294 --> 00:37:54.625 Yeah. 00:37:54.625 --> 00:37:54.984 Or. 00:37:55.239 --> 00:37:55.509 for. 00:37:55.704 --> 00:37:57.174 Or 400 to 600. 00:37:57.174 --> 00:37:58.404 I mean, I have to say that 00:37:58.419 --> 00:37:58.599 it's the 00:37:58.809 --> 00:37:59.469 the same as 00:37:59.519 --> 00:37:59.729 is 00:37:59.750 --> 00:37:59.969 as 00:38:00.000 --> 00:38:01.169 doing in some ways. 00:38:01.519 --> 00:38:11.294 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. 00:38:11.294 --> 00:38:14.844 Brad s Spellberg has a whole mini rant on this one. 00:38:14.875 --> 00:38:19.074 One of many, as I'm sure you're aware, but the he says that we should probably be using 10 to 15. 00:38:19.584 --> 00:38:20.184 For everything. 00:38:20.184 --> 00:38:25.194 And the reason that we keep experiencing vancomycin toxicity is because we're overdosing it in everybody. 00:38:25.704 --> 00:38:28.934 So it's not as simple as all that let's say Cal, 00:38:29.234 --> 00:38:29.594 So maybe 00:38:29.654 --> 00:38:29.954 but yeah. 00:38:30.134 --> 00:38:32.139 for moving to a UC over MSC dosing there. 00:38:32.759 --> 00:38:37.919 I think the reason that in America it's much easier to do is because usually pharmacists are doing it. 00:38:37.949 --> 00:38:46.509 So they've got like much more I, not antimicrobial pharmacists, but PharmDs ev everywhere and they are probably handling all the vancomycin dosing. 00:38:46.509 --> 00:38:51.319 So the doctors saying we should start some vancomycin, and then that's the extent of their involvement. 00:38:51.564 --> 00:39:00.924 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. 00:39:00.924 --> 00:39:03.084 It's just a much more limited re resource, isn't it? 00:39:03.469 --> 00:39:03.679 Yeah. 00:39:03.774 --> 00:39:05.809 Particularly specialists, infection pharmacists. 00:39:06.649 --> 00:39:06.979 Yeah. 00:39:07.489 --> 00:39:09.049 But anyway, that callem is that. 00:39:09.139 --> 00:39:11.899 So a quick tour through PD targeting. 00:39:11.929 --> 00:39:18.134 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. 00:39:20.255 --> 00:39:20.705 Thanks, Jim. 00:39:21.335 --> 00:39:21.846 No problem, man.

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