75. PK: Blethering about Bioavailability

It's the Pharmacokinetics episode you never knew you wanted! Callum didn't know either, but never mind that let's talk about how antibiotics are absorbed, and how we can use that to improve our use of them in clinical practice.

Want ammunition for that oral switch? Got someone who's doubting oral antibiotics' effectiveness? Then this is the episode for you! Check out our prep notes (including for this episode) here. 

Transcript

Callum: 0:18

Jame how you doing?

Jame: 0:21

I, I'm fine. Callum, I've my clothes are feeling a little bit scratchy. I had to use the non-biological washing powder this evening'cause there was no bio available. And that reminds me, Callum, that,

Callum: 0:35

I'm not sure where that was going.

Jame: 0:37

that reminds me. Callum what are we talking about today?

Callum: 0:40

We're we're not talking about anything. We're blathering about bioavailability.

Jame: 0:46

Oh, that's right, Callum. It's a pharmacokinetics mini series. It's finally here by chance to shine.

Callum: 0:54

Yeah, they, what they said when he set off on his training journey, they said, how do pharmacology, that's a weird CCT. Little do they know that all of James training was just for this moment in the sun where he gets to wax lyrical about PK pharmacokinetics and nobody can stop him.

Jame: 1:13

Well,

Callum: 1:14

you loyal listener by stopping listening.

Jame: 1:16

well, I mean, or you could edit all of it out, but it would be a real short episode after that.

Callum: 1:20

yeah, Yeah.

Jame: 1:21

I, well, so why are we doing this? Cal. I Think that when it comes to infectious disease, the pharmacokinetics and the pharmacodynamics of the antibiotic are more important to understand than other drugs, drug classes. And now, why do I say that? Callum the P key of Most drugs has been worked out, in the forties, fifties, and sixties. It's been well known for decades. fOr example, furosemide, it's 50% bioavailable. People have known that for ages, and so that means that people dose it accordingly. And then when you move from oral to iv, you get a sort of a doubling of its effect. That's, that would be part of the justification for moving from or to double. But really, there's a lot of drugs where the regimens have been set because they're known bioavailability, absorption, distribution and sort of half-life and elimination as is well known. So you know that you can just dose lisinopril once a day. But there are some other drugs that you might have to dose two or three times a day. But antibiotics are not like other drug classes because they stop working sometimes. If you don't dose them right, if you underdose them, and some of them are excessively toxic as well, here I'm just talking about, effectiveness and leveraging your knowledge about the PK of antibiotics can make you a better infectious disease doctor. So that's why I wanted to just dive into the pharmacokinetics of antibiotics and tell people what I think they need to know for for that reason. So I think we're gonna do this in two stages. First is that we're gonna talk about bioavailability in general and how the drugs get into the body, and then we're gonna talk about some sort of fun facts about antibiotics absorption. Question from the audience.

Callum: 3:28

sO we did an episode recently, which was choosing an antimicrobial,

Jame: 3:35

Yeah.

Callum: 3:35

what it was called.

Jame: 3:36

that sort of inspired me to do this,

Callum: 3:38

well, Yeah. and I think that was a very basic overview or maybe it was, I dunno. I, it was a high-level discussion about choosing an antibiotic, and I think I was reflecting on that afterwards and I was like if you got more complicated and divided it up, the way that you can think about choosing your antibiotic is there's host factors. So that would be Your, is the oral root available, what allergies and tolerances the patient have,

Jame: 4:05

Renal failure, obesity, pregnancy.

Callum: 4:08

Yeah. Yeah. exactly. So things that are specific to that person their preferences as well, obviously. Then there's bug factors. Do they have the organism yes or no? If you do, then, do you have the sensitivity data? What are those, what expected phenotypes might you see? And there's a whole load of discussion that can go on there about, specifics of bacteria, like the UCAS expected phenotypes document, for example. And then there's drug factors. And I think the drug factors is probably the most complicated bit, like obviously under the bug bit is also very complicated, although when you're working clinically, the complicated lab stuff, hopefully your lab has done that, right? And you've got the results. So you can just say, okay, I can trust that the lab's got that there. It's not quite as simple as that. And I think maybe we'll come back to that. But I'm really interested in some of the stuff that I. James got to say about that, those drug factors. So when you're choosing an antibiotic, and that's probably the thing that's most important outta the three of them, maybe I wouldn't say that. Take that back out.

Jame: 5:08

yeah. No, take that back because it's the susceptibility is the most important

Callum: 5:11

well, I actually think the patient's preferences are the most important. James

Jame: 5:17

You're such a, you're so woke, Callum. So anyway, let's talk about bioavailability. So let's start with a quick definition, which I think most people will know. So bioavailability is the relative amount of a drug that will reach the systemic circulation if given orally compared to if it was given IV at the same dosage. Historically, here's how you do this. You get a bunch of medical students usually, and you will give them a pill and you will measure the concentration in plasma over, at lots of different time periods. And then you will do the same thing with the same dosage. Only this time you will inject it and you will get two different concentration time curves and you will measure the a UC area under curve of each. And then you will compare the oral one to the IV one. Usually they won't be exactly the same. anD say only four fifths of the oral dose gets into the into the plasma, then you will have an 80% bioavailable drug. And so the in order for the drug to get into the plasma, it has to be ingested transited to the GI tract, absorbed in almost definitely the small intestine and then undergo first-pass metabolism with CYP ISO enzymes. That happens mostly in the liver, but also in the small intestine on mucosa.

Callum: 6:37

Oh, I didn't know that.

Jame: 6:39

Yeah. And so the bioavailability, it's used to determine the ideal route to get the therapeutic concentration.'cause of course, after it's absorbed, it has to go to the target site and kill the bug and the amount of drug that needs to be given in order to achieve this. And so, Give me an example of a drug that's not very bioavailable. I would tell you gentamycin, it's not really absorbed from the GI tract, it's too polar. And you wouldn't give it orally. You would give it iv. So I'm gonna take you through each stage bit by bit Callum and give you a little bit of what you need to know. Now, this is, I think, more than you need to know. Now that you've passed the part two, of course you need never learn anything ever again. BuT this I'm telling you more than you need to know so that you can remember bits of it that might be interesting or come up in pop quizzes. Okay,

Callum: 7:32

What sort of pub quizzes are you going to, but okay. I'm looking forward to the day this comes up in a pub quiz.

Jame: 7:37

fantastic. so In terms of oral absorption in the GI tract, once it gets a drug gets ingested, not much of it will be absorbed from the stomach. It's too, it's got this thick mucus layer that stops the stomach acid from, killing the stomach epithelial cells. And that also prevents significant drug absorption. It's also not got much of a surface area. It's about a meter squared, whereas the. Small intestine. It's tailor made for, absorbing stuff.'cause that's its job. It absorbs food. And so it's got a surface area of about 30 to 35 meters squared. And that's because it's got the pky circularity, which those folds, which increase the surface area. And epithelia VII and micro vii. And they're increasing the surface area almost a hundred fold compared to if they weren't there. And so it, it also has a longish transit time, so it's about four to six hours. And the whole small intestine is about six to seven meters long. And so all that gives it plenty of time to absorb lots of stuff and sort of peristalsis is happening to, to bring the food contents, but also the drug in regular contact with the intestinal wall to allow absorption to happen. And the other interesting thing is that the unlike the stomach, which is quite acidic the small intestine is weekly acidic and because of the PK of most drugs, that means, that makes them exist in, in both an ionized non-AI state. And there's different absorption methods which will pick up either of those drugs in either of those states.

Callum: 9:16

And just expand on that slightly. The pH or the relative acidity of a environment changes how much of a drug is ionized or has a charged and non ionized, and that'll be different between like different drugs. That'll be a drug to drug specific thing.

Jame: 9:33

Yes, it will. So I've actually got a little note on this that I've in, in the prep notes that I've included as a, like a dropdown note. But basically drugs are usually weak acids or weak basis. And so their rate of uptake, certainly passive uptakes is determined by their ionized versus an ionized state. So if you're an acidic drug, then you can release an H plus ion and you will go, then you will adopt a negative charge. So you'll be a negatively charged acidic drug plus H plus. And if you're a basic drug, then you can accept an H plus and you will go from, being basic to be a basic drug which has a H plus attached to it. And this is called a protonated base, right?'cause it's got a proton. It's got an extra proton.'cause an H plus ion is just a proton. And the PK of our. Molecule is the from taking acids for a second. The PK of an acid is the pH at which the acid will exist in a 50% ionized and 50% un ionized form

Callum: 10:43

What's a PKA? Sorry, just what does that

Jame: 10:46

PK of the acid.

Callum: 10:47

But what does PKA stand for?

Jame: 10:49

It is the pH at which it's 50 50. Ionized.

Callum: 10:53

Oh, I see. So it's not, doesn't stand

Jame: 10:55

PKB is the same for basis.

Callum: 10:57

Oh, I see. Okay.

Jame: 10:59

the thing to know is that ionized drugs can't diffuse through a lipid bile layer. So the lipid bile layer is specifically to keep out ionized molecules. But ionized drugs do do that. So if you've got, say an acid, which still has its, his, its spare hydrogen ion attached to it. It's not ionized, and then it will diffuse across the limit. Whereas if it's given up that h and it's negatively charged, it's not going to do that. But it can combine with free h plus in order to become, acidified and then can move across. And the reverses being true for basis. So protonated basis can't cross lipid bio layers. So yeah, that's brings me to the four methods by which things transit the gi epithelium into the bloodstream, and the first of which is passive diffusion. And most small molecules, less than 500 Daltons that aren't strongly ionic do that.

Callum: 11:59

And what's adult?

Jame: 12:00

Dalton's a unit of measurement that's a 12th of a carbon atom.

Callum: 12:04

So it's a measurement Of molecular

Jame: 12:06

molecular, it's a measurement of molecular size. Most mul molecules are measured in killer Daltons.'cause they're bigger than a thousand

Callum: 12:12

Yeah. So less than 500 Daltons is quite a small, smaller drug.

Jame: 12:16

it is, yeah. So small drugs will cross that. And ionized drugs and lipophilic drugs, things like steroids they will pass just through a lipid bile layer as if it doesn't exist. And then the second way that a small molecule can get across, if you're lipo, so if you're a proteinated base or you're a, a acid that gave up its h plus is that you can do something called facilitated diffusion. And so this is where protein will help the. Molecule cross, and it will happen across an electro concentration gradient. And at this point, Callum, I have to tell you about SLCs. Do you know what SLCs are?

Callum: 12:52

Yes, they're saute carrier transporters. Of course, I know that everyone knows that

Jame: 12:57

okay. Fair enough.

Callum: 12:59

I.

Jame: 12:59

Fine. You probably have heard of OTT transporters though in the kidney. Sometimes this is, way that drugs can interact. For example, rabid is sometimes given alongside Baal Lactams to boost their plasma concentration. And we're doing that more and more down in nado, shoing infirmary South. How it works is that prop acid is preferentially excreted outside of, in the oat transporter out into the urine. And that means that the Beal Liam is not. And so the Beal Liam level stays high in the plasma. so OAT stands for organic ion transporter, and there's OCTs, which are organic cation transporters, and organic ion transporters or oats will carry deprotonated acids. So star acids that have given up in ES plus and OCTs will carry protonated bases. And th this group, there's about 350 of them saute, carrier transporters. They're divided into oats and OCTs, and they do some other stuff as well, which we're gonna come onto. But if they're passively just helping a a small molecule get across a lipid bile layer, it will do so by moving it from where there's lots of them to where there's little of them. And so that will help diffusion across into the bloodstream. And then the third method is active transport. And you probably, know about active transport involves the use of energy or an exchange of ions or code transport of a negatively charged ion with a positively charged thing or vice versa. There, there's two kinds. One is primary and usually that's actually doesn't have a big. That does isn't involved in drug uptake. It's mostly the influx of drugs from specific body compartments or cells out of outta that compartment. But secondary active transport is how OID drugs tend to be absorbed. And SLCs do this as well. Again, it's across pre-existing electrochemical gradients, and they will be co transported with a suitably ionized thing. So our example for this from the antibiotic world is hydrogens will be co transported with beta Liam antibiotics, which are negatively charged. And then the last transport mechanism is pinocytosis. So this is the endocytosis or occasionally the exocytosis of large molecules where the cell membrane will invaginate and then just suck up proteins that happen to be in the local area, or occasionally some receptor mediated the endocytosis. And then they will be pinched off into a iCal, and that iCal could then transport across the cell and go into the bloodstream. This is more important in places like the blood brain barrier, where otherwise there's tight junctions that prevent diffusion of the antibiotic or the drug into the brain for obvious reasons. But yeah. Any questions on that, Carl?

Callum: 15:50

So just to summarize,'cause I am, that is quite a lot. That is new to me or I haven't thought about in a long time.

Jame: 15:57

more information than you need to know, but why don't you go through the table at the

Callum: 16:00

yeah, so there's four, four methods of transit of drugs and we're thinking specifically about transiting the GI epithelium into the bloodstream, but this is sort of general principles anyway. Okay. So it's four methods. Method one is passive diffusion, so that's small molecules, less than 500 daltons that are lipoic and are not ionic. Then there's number two facilitated diffusion. So that's small molecules, less than 500 daltons that are lipo phobic and are ionic drugs. So your deprotonated acids and your protonated bases. And that's carried out by your SLCs. So saute carrier transporters. The third one is active transport. That's your ionized drugs. And there's two types. One is primary active transport, which is mostly flx and secondary active transport. And that's how most ionized drugs are absorbed. And that's again, carried out by your SLCs saute, carrier transporters. And those are made up of your oats and your OCTs. And they're co transported. And then the final one is Penoc Cytosis, and that's where your large molecules are transported. And that's mainly across tissue barriers, either the blood brain barrier and endo or exocytosis.

Jame: 17:27

like we said, the, this is probably more information than you need to know but I think it's interesting to, good to have a refresher of exactly how stuff is getting in to, to the to bloodstream. And then the last thing that we're going to talk about is first pass metabolism. And a small amount of this happens in the gut epithelial before entering the portal vein, but most of it occurs in the liver, and that's done almost exclusively by CYP four 50 iso enzymes in the hepatocytes. So the drug will diff as it's passing through the liver, it diffuses into the hepatocytes, gets metabolized, and then, gets broken down. But some of it will not, and some of it will just pass through and then hit the bloodstream. And that is what you're measuring when you measure the plasma availability.

Callum: 18:16

Yeah.

Jame: 18:17

So that's it for part one. Part two is gonna be a talk about. We're gonna talk about oral antibiotic bioavailability, in general. So now we've talked about all that basic stuff.

Callum: 18:29

Yeah. Space. That was the basics. Yeah. That wasn't all complicated.

Jame: 18:34

well basic signs? Let's say Cal, what are the differences between oral and IV sort of antibiotics?

Callum: 18:41

Yeah, so I guess oral antibiotics by nature need to be soluble. So you want, so that you can actually absorb them, need to be acid stable so they can get past your stomach acid and they need to be lipid soluble so they can get through the gut easily.

Jame: 18:57

Lipid soluble, but

Callum: 18:58

preferably, yeah, these are all preferences, whereas IV or doesn't matter if they're, so they can be acid labile'cause they don't need to go through the stomach acid. They don't need to have high solubility. So they can be low solubility and they can be lipo. So it doesn't really matter. It is more important, thinking about what an oral antibody needs to be. So it's got a lot more hurdles to get through than an IV one, which is, basically it's got an Uber straight to where it needs to go.

Jame: 19:25

Yeah. Yeah. And I suppose actually that, there, there are antibiotics which are Given oral lab, but also given iv, and they can be, they don't need to be acid labile, but the kind of antibiotics that are only available iv, it tends to be because they're acid labile or lipo. And so the oral root is just not suitable,

Callum: 19:45

You might have different formulations.

Jame: 19:47

for example.

Callum: 19:48

So obviously a lot of like drug approval, getting a drug formulation ready is about, do you have a coaching on your tablet to protect the drug on the inside? Or, can it be as a liquid? So it's often that

Jame: 19:59

I've not talked about this here actually, but exhaustion can be a hands by enteric coating, which is aspirin and omeprazole and all that are enteric coated and that's

Callum: 20:08

obviously a lot more

Jame: 20:09

more likely to pass the stomach.

Callum: 20:11

Yeah. There's a lot of complexity about how do you get drugs suitable and make them up in terms of formulation. But there's some general principles.

Jame: 20:19

totally. So here's the meat of the episode Callum. What drugs are highly bioavailable And first I think I need to define what that means. And so I think of highly bioavailable as this. If the oral route is available, those drugs will be just as good orally as if they were iv. And as a very general rule of thumb. Anything more than 70% bioavailable is probably going to be just as good as if you had given it intravenously. Now, that's not based on any hard science or anything, Callum, but the very rough cutoff is at 70, basically because ciproflox bioavailability is 70 and there's reasonable data suggests that it's as good IV as the disorder. So if it's more than 70% bioavailable, it's probably good to go. And once you go below that, the next drug that I've got in the list here is Penicillin V or Oxy methyl penicillin. It's 60% bioavailable and it's not really considered to be highly bioavailable, when people talk about it. So I've got what I did Callum, was I went through every drug that is available in the BNF. So apologies to non UK listeners. There will be some drugs that you use all the time that are not featured in this list, but

Callum: 21:47

those oral catalyst, sporin you've got that we don't get

Jame: 21:50

Yeah, exactly. And although Keitel is available in the in the uk, I didn't include it, but actually it's bioavailability is 90% same as Keflex. And then what I did was I sought out the bioavailability where I could, I included the the bioavailability as stated in the Ucast document for that drug. And those ones that were in Ucast, I bolded Cal. So you'll see there that Minocyline is bold, but Lela isn't. That's'cause Lela's bioavailability wasn't stated in uca. And so I found another source.

Callum: 22:22

there's a James referring to a table in the prep notes, which can be found in the link on the.

Jame: 22:27

Yeah. And so listeners I've applied a traffic light. Nomenclature. So green is highly bioavailable. Orange is intermediate and red is not very but there are curiosities down at the bottom of that table that I'll tell you about shortly cal. So I'll we'll just list them.

Callum: 22:43

We gonna alternate or we, we don't have any bacteria

Jame: 22:47

do you know what actually we've finished our noling, the non fermentors mini seeds, but I'm sure the loyal listeners would love an alternating reading of the drug and then the bioavailability as a number'cause that will make them feel like this is a continuation

Callum: 23:01

I think there's, there's quite a few listeners that can't tell us apart very easily.

Jame: 23:04

Oh God. Is that true? Do you think?

Callum: 23:05

we do an alternate, I've heard this, so when we do an alternating list, they think it's just one person's meeting.

Jame: 23:11

Oh my God,

Callum: 23:12

Think different voice. Oh my god.

Jame: 23:14

We have very different accents. Callum.

Callum: 23:16

It is totally different. We from one end of Scotland and I'm from the other. I'll start'cause then you get to say nla. How

Jame: 23:22

fine.

Callum: 23:23

do I sacrifice myself Levofloxacin 100,

Jame: 23:28

Esli 194 On Toin 95 or Greater

Callum: 23:35

Trimethoprim. 90 or greater

Jame: 23:38

Cotrimoxazole. 90 or Greater

Callum: 23:41

Doxycycline. 90 or greater.

Jame: 23:44

Metronidazole. 90 or Greater

Callum: 23:47

Moxifloxacin 90

Jame: 23:49

Clindamycin 90.

Callum: 23:52

Kein, 90

Jame: 23:54

Tetracyclines. 80 to 90

Callum: 23:57

Chloramphenicol 85

Jame: 24:01

amoxicillin. 80 to 85.

Callum: 24:04

Amoxicillin Clavulanate, 80 to 85 slash 64.

Jame: 24:11

PIV Macin. 75.

Callum: 24:14

Ciprofloxacin 70,

Jame: 24:18

And now we're onto the moderately bioavailable penicillin. V or Phenoxy, methyl penicillin. 60.

Callum: 24:25

Flu Oxacillin 60.

Jame: 24:28

Shout out to Luke. Clarithromycin. 55.

Callum: 24:33

Now we're onto the

Jame: 24:35

Lowly. Bioavailable. Yeah.

Callum: 24:37

Kro. Axial 40,

Jame: 24:41

Kefi 40

Callum: 24:43

azithromycin, 37

Jame: 24:46

Phosphomycin, 33 to 44,

Callum: 24:49

arithromycin, 20 to 45.

Jame: 24:53

and that's it. So like I say, anything bold comes from Ucast. Everything else I've gotten from the, usually the SPC of the drug is found on medicines.org.uk. So

Callum: 25:06

of product characteristics. Is that what

Jame: 25:08

yeah, I think so. I think so. So when I look at that table, column, a, it's a thing of beauty. Do you know I think this should be put on every wall at every hospital with the, with a poster that says, points to it and says, prescribe orally you idiots. But B, we've got loads of highly bioavailable options, don't we? not so many beta-lactams, like enough to be going on with it's good, right? But

Callum: 25:35

I'm just laughing about

Jame: 25:37

at what?

Callum: 25:38

what's coming up.

Jame: 25:40

Oh, fine. Well, I'll just jump to it, will I, Callum? This is listeners, this has tickled Callum Pink when he, uh, uh, saw this. So when I'm teaching this to the medical students, what I like to say is that you're highly a bioavailable. Antibiotics tend to start with a C, so, well, another alternating list for your loyal listeners, Kexin

Callum: 26:04

Chloramphenicol

Jame: 26:05

Ciprofloxacin, and the other quinolones.

Callum: 26:07

Clindamycin

Jame: 26:09

MCL and amoxicillin.

Callum: 26:12

Cotrimoxazole

Jame: 26:13

Clever old lali

Callum: 26:16

Crusher of Clostridia Metronidazole.

Jame: 26:19

and cyclines of Tetra

Callum: 26:23

So you can see that all those antibiotics very clearly begin with C. we're not taking any further questions at this time.

Jame: 26:31

Thank you very much, Callum. so not in the

Callum: 26:33

questions or comments about that list, please do not email us at idiot Podcasting.

Jame: 26:38

So not in that list are things like Tmm, niton and fib, but those are more, I can say they're more UTI drugs. and so the next table that I've got is I've just, for the sake of learning,

Callum: 26:49

We actually, I can fix the list to include those three.

Jame: 26:53

can you?

Callum: 26:54

Yeah.

Jame: 26:55

How?

Callum: 26:56

I'm just gonna end the end. Cystitis, drugs, MPRM, nitrofuran to and mci.

Jame: 27:02

God dammit. That's amazing. Callum.

Callum: 27:05

Thank you. That's the best feedback I've had so far

Jame: 27:07

Oh, that's really good. I am included. I'm gonna do that actually the next time I'm teaching this. fine. And so I've included here the a breakdown of the of the drugs that we've just mentioned by class. And all of the anti-D NA agents are highly bioavailable quinolones and cotrimoxazole and mprm. For protein synthesis, it's a bit fuzzier. So basically the macrolides are not highly bioavailable. Everything else is. and then the Beal at times, it's really for highly bioavailable, it's really just a mocks Keflex and pici. The cla laic acid would be considered medium bioavailability, but actually you don't need an awful lot of clave, laic acid to get this maximal effect. So even though it's absorption is only about 64%, it's probably the, you should still consider MCL to be highly bioavailable when you're using it, if you know what I mean. And the the last table I've got here is a list sorted by indication where I've included more the drugs that we mostly use for each indication. And again, color coding by bioavailability for chest skin and urine. So that's something that the listener can take a look at, if they so choose in the prep notes,

Callum: 28:22

So what you've done is you've said for each antibiotic and then it's bioavailability, and then you've put a plus next to it, if it can be used for that. That's organ system infection.

Jame: 28:35

Yeah. And basically it's what I would use for those organ systems. So say for, say for chest, you could use tcl. I would not, but it is optional, it is something that can be used. And then Keflex in Chloramphenicol clarithromycin cotrimoxazole, levofloxacin, the Minow or Doxy cycle and moxifloxacin. So those are things that you could use for skin, soft tissue infection. There's a bunch of those there that I wouldn't really want to use. But, you could do it,

Callum: 29:05

So, so James, are there any caveats to absorption?

Jame: 29:09

Callum, as a matter of fact, there are so the first is to point out that amoxicillin absorption is ible. And for the average person after 750 milligrams, no more of that is, is likely to be getting in to the patient. And for Keflex, and as well, the maximum amount you can absorb Orley is about four grams. A actually, I just looked this up in the BNF we were discussing using high dose kexin for skin and soft tissue in our ambulatory setting. And, you know, the maximum that you can give is 1.5 grams four times a day. So six grams a day of Kexin. So

Callum: 29:47

As in, that's, the maximum listed on the BNF.

Jame: 29:50

Yeah. Yeah. But the range is high.'cause as you can give CareFlex in 250 twice a day or something like that, or, and it'll, it'll cure your UTI, but we are using it for skin soft tissue. So the whereas with UTIs, it will concentrate into the urine at high enough levels with skin soft tissue you're relying on the plasma levels to do that. We were looking and yeah, you can give six grams, but actually most people won't be able to absorb more than four grams in 24 hour period. So bear that in mind when you're thinking about how to use it. We tend to use, when I'm using the high dose, I call high dose something like one gram three times a day. Yeah. That's what I would use. And then lastly, we need to talk about the Macrolides calendar, because if you look, go back and look at the first table that I put together, clarithromycin bioavailability is about 55. And Azithromycin is 37 and Erythromycins 20 to 45,

Callum: 30:43

Yeah, that surprised me a bit because often when we're saying OMO and it was like there's no reason to give the Clarity iv. Just give it oral

Jame: 30:52

But you are still entitled to see that Callum.

Callum: 30:55

but because you're like immediately you'd be like, oh, it's not well absorbed orally, so we need to give IV.

Jame: 31:00

Yeah. That's not true though. And so there are exceptions to this. Bioavailability is not everything where, is what I'm saying, because distribution matters and the macrolides distribute disproportionately to the intracellular space, which is where all of their pathogens happen to be. And so if you think about your, your respiratory atypicals, they're all intracellular pathogens, Legionella, mycoplasma, clam dola. You might want something that concentrates into the intracellular space and macrolides do that. And so there's been, there's sort of circumstantial data, I think, for clarithromycin that giving IV or giving orally doesn't make a difference so that 55% that's absorbed, that's enough to give the maximal effect.

Callum: 31:45

Yeah.

Jame: 31:46

and so I'm not sure that I would say with that a erythromycin that's the case. But for Azithro and Clary, it does seem to be fine. Yeah,

Callum: 31:54

the rationale for giving macrolides orally and it being okay is because they concentrate into cellularly. So if you're treating something that's an extracellular pathogen, then do we need to be worried about giving clarithromycin?

Jame: 32:06

maybe I don't know that I don't think I've got the data to support an assumption one way or the other. Callum.

Callum: 32:11

but I guess your point is that although we've just spoken through oral bioavailability, that isn't the sum total of the story and All of it matters. And it also all matters where the organism is in the body, like what body site you're trying to get to. And it also matters about, other bug factors,

Jame: 32:33

Yeah. And that brings me to my last point, Callum, which is that some of these UTI drugs don't have very good absorption at all. Phosphomycin, a third of the oral dose, if you're given three grams, only one gram is getting in. That's not very good at all. But Fosso CIN concentrates into the urine and so do you know a bunch of the other ones? Pici, Trimeth, they're all highly bioavailable as well. They the. Get into the urine. And so they're useful for UTI, but even the highly bioavailable ones that I mentioned, so ferone trimeth improvement, they don't get great plasma levels.

Callum: 33:11

Yeah.

Jame: 33:12

So for that reason, they are discounted for the treatment of pyelonephritis because in order to get good kidney levels, you need to get good plasma levels. but they're useful for UTI. So even though they're highly bioavailable, you wouldn't necessarily want to use them for systemic infection.

Callum: 33:30

Which comes back to the whole, when you look in guidelines and they say for un, like they give different recommendation. So they'll say, you can use this first cystitis, but you can't use it for a more complicated UTI, like pyelonephritis are similar because in that case you want to have a more systemic treatments. So the fact that it concentrated to the urinary tract may be fine, but that's why you might see different agents per, recommended for different conditions because it comes back to pk.

Jame: 33:58

And I guess I, I wanted to finish off this episode, Callen, by talking about the effects of food.'cause I think this is a cause of some confusion. And certainly I wasn't clear on on everything before I started researching for this episode. So I went back to those SPCs and and just saw that for for each drug what the recommendations were or what the effective absorption was, I didn't look at the. Pills, the patient information leaflets.'cause usually they said the same thing regardless of the evidence, which is take with food. And I think that's'cause when you do that, you reduce the chances of gi side effects with whatever the drug is. But that didn't necessarily correlate with the effects of absorption. yeah. So the, I've divided them into three categories here. One is take on an empty stomach, one is take with food, and the other is no recommendation at all. And I've, below this is another table that we're not going to through, which has the very precise recommendations and then a couple of other notes for each individual antibiotic. So for example, there's a note for the tetracyclines that you know, with, if you take'em with dairy or antacids, then the drug will We'll bind the the metal that's in the antacids form an insoluble complex, and then will absorption will be impaired. We've covered that a little bit in the pregnancy episode. But tetracycline is chelate metal ions and their absorption is affected by that. But anyway, the returning to the more simple table, the things that you would want to take on an empty stomach would be penicillin, flu, oxacillin, azithromycin, and phosphomycin. And when we say an empty stomach, we mean either take an hour before food or two hours after food. So that's what an empty stomach means. There's ones that you want to take with a meal. And so that would be Comox, socl, erythromycin metronidazole or Nitro andone. And most of those are to minimize side effects as opposed to having a significant effect on absorption. So you see that amoxicillin is in the, it doesn't matter group, it's because the GI side effects that you sometimes get with clavulanic acid can be mitigated with food. And then the third category is none, and that's everything else. That we've, that I've not mentioned so far. So amoxicillin, peril, and Keflex, and tetracycline, clarithromycin, clindamycin, lin, Linox, traeth, and quinolone. Yeah. So I think depending on your setting that absorption stuff and you know how to take with food, sometimes that will be dealt with by a pharmacist who's counseling the patient. Worthwhile to know a little bit about, Whi which drugs in particular need to be taken with food and without.

Callum: 36:37

So obviously some of that is, is quite in depth and maybe a bit complicated. And generally speaking, when we're prescribing an antibiotic we'll be given a dose recommendation by BNF or guidelines or whatnot. And so this is maybe explaining some of the rationale behind some of those decisions. So of all the stuff that you've just talked about for what is the key message that you would have for people?

Jame: 36:59

I think the key message. Is the thing that I said at the start when we were talking about the table with the traffic like system, if it is highly bioavailable, I would push for an oral switch as soon as practical. I basically never prescribe, these drugs IV unless the oral route is compromised. And I, furthermore, Callum think that a lot of the time a drug will be started IV because people are worried about, sepsis and things like that. And then after the first dose, you're not contributing anything so I think after the first dose of IV really giving con extra doses IV are not really contributing that much. And yet we have this dogma in our heads. A, the IV is superior to oral, and I think we've contributed to a little bit to knocking that down, but b, that you need to give IVs for a couple of days and then switch. When the patient's better onto an oral dose, which might be a lower dose. And I don't hold that. So I have a couple of patients under my care right now. I'm on service at the moment for general medicine in Na, Infirmary, Southern Wing, and there's a couple of people on Cottam ol, and I'm using that as a, don't know really what the infection is. They need broad spectrum cover, but they're old, so I don't want to give a, a broad spectrum Beal lot time. So they're on Cotran and they're on an iv, but the second they start being able to swallow and eat and drink again, I'm switching them to pills because I don't believe that Como cell nine 60 BD is more effective IV than it is only. So that's an example. And there was somebody who had, they were put on cosla and I let that happen for they, it already happened basically. But then I switched them to orals when I saw them. And the juniors that I was rounding with were like, don't you need to wait a couple of days? And so I said I don't think so. I think that as long as the patient is absorbing and they're not in septic shock, then oral medication should be fine for this patient. So that's where I think, because every time that you give a dose of antibiotics, there's an opportunity for stewardship and, reducing the course length so that they're exposed to less antibiotic. That's one way to do it. And oral switching is another way to do it.

Callum: 39:38

Wow. I feel like I've just had a one-to-one tutoring session from the pharma team himself, Jay McCray. So thanks. I feel like we should talk about something I know more about at some point, so that I feel like the

Jame: 39:54

to redress the balance. Yeah. I should say there, at this point, before we go to the outro, if anybody disagrees with any of this stuff or knows that I've made an error with this let me know idiots podcasting@gmail.com and I'll do my best to correct it,

Callum: 40:09

Unless it's related to the mnemonic, in which case we don't wanna hear.

Jame: 40:13

The mnemonic is enshrined

Callum: 40:16

of practice. Yeah. Yeah. Clever old Lili

Jame: 40:22

Yeah, cyclings of Tetra.