87. ID:IOTS guide to Tetracyclines

Join Jame and Callum on this episode about the  ultimate 4 rings of power: Tetracyclines. The swiss army knife of antibiotics. We talk through the history, uses, mechanism, PK/PD and resistance.

Become a pharmacophile as you learn something about pharmacophores.

Shows notes for this episode here

Transcript

Jame: 0:18

Callum, how are you doing?

Callum: 0:21

I'm good. I've been doing a lot of cycling recently. I'm an avid, cyclist. I've got a new bike.

Jame: 0:26

How many wheels has it got, Callum?

Callum: 0:28

four

Jame: 0:29

Wow, do we have a name for that, Callum?

Callum: 0:32

call it a Tetra is one of the words for

Jame: 0:34

Yes, everybody knows that, Callum. Just get on with it.

Callum: 0:37

So this is like a Tetra

Jame: 0:39

And what a coincidence that is, Callum.'cause what are we talking about today? Yes, ladies and gentlemen is the idiots guy to tetracyclines our first drug episode in a while.

Callum: 0:51

We've been missing them. The pharmacologist and and James has been burst. I guess we had all the pharmacokinetic

Jame: 0:57

Absolutely. I was happy enough with that. But now it's time to talk about these are of increasing importance in the difficult to treat gram negative world. Are they not?

Callum: 1:07

Yes.

Jame: 1:08

Yes, they are. Alright. Let's get on with it, Callum, will we?

Callum: 1:14

Yes.

Jame: 1:15

Okay. Will I take you a little bit through the history?

Callum: 1:21

Yes.

Jame: 1:25

So these are Tetracyclines are a class of antibiotics that were discovered in the 50s. Their origin is initially from the Streptomyces species, where we also get aminoglycosides, if I remember rightly. Streptomycin is from there. And there's some natural ones, and through variations of various groups that we attach onto the pharmacophore of tetracyclines, as in pharmacophore meaning the central structure which is common to all members of the drug class. By attaching various chloromethyl and hydroxyl groups you can vary the PK and PD not so much the spectrum of activity until you get into the the more modern examples.

Callum: 2:08

Why are they called tetracyclines?

Jame: 2:10

Because they have a four ring central structure on which various hydroxyl and nitrate groups hang, or sorry, yeah aminyl groups re recording a central four ring structure of which hang various hydroxyl and nitrile groups. They are divided into generations, roughly. I guess people don't really think about this very much. But actually the first member discovered was oxy tetracycline. And then through variation removing of presumably an oxy group they found the drug which gives the class its name, tetracycline. That was in 1953. And then very quickly the second generation ones, these are semi synthetic and done by various kind of manipulations followed. And they were Domeclacycline in 1957, Doxycycline in 1967, and Minocycline in 1972. And there it stayed for a long time until people started doing some more variation with the chemical structure in the sort of 90s and early 2000s. And that gave us the third generations, which we're going to cover separately, Callum. But for the record, they are the glycol cyclins, only one of which has entered clinical practice, and that's tigecycline and then the aminomethyl cyclins, which presumably have amino and methyl groups added to them. And that would be aravacycline, omadacycline, and something called saracycline, which I've not really heard very much at all. about Calum. Aravacycline and Armada are mentioned a lot more. In fact, Aravacycline is mentioned quite heavily in the IDSA difficult to treat gram negative guidance in the relevant areas. How do they work, Calum? What's their mechanism of action?

Callum: 3:56

Yeah, the I remember as a very junior doctor, one of the microbiology consultants quizzing me on this and I had to draw up on a board and I still find it a bit confusing, but the main mechanism of action for this is, inhibition of protein synthesis. And the way it does that is it reversibly binds to the 30S subunit of the rRNA

Jame: 4:17

and just as an aside, the other antibiotic class which binds the 30S subunit of ribosomal RNA? Yeah

Callum: 4:25

I'm going to glycosides.

Jame: 4:27

also from the Streptomyces species. It's weird, right? Yeah.

Callum: 4:31

Yeah, I don't know if you've thought about that before. And by reversibly binding to the 30S subunit of rRNA, that prevents tRNA binding to the ribosome mRNA complex. Long story short, inhibits protein

Jame: 4:45

Hmm.

Callum: 4:45

And on that 30S subunit, they bind at the major binding site, which is called the RNA. TET1 or TET1, and there's also five minor binding sites of the 16S rRNA Significance of these are unclear, and you'll have heard us talking about 16S RNA before, or the 16S ribosome. And that's something that we often sequence in bacteria for diagnostics. And basically that's the ribosomal RNA in the 30S subunit of the whole ribosome, if that makes

Jame: 5:17

Yeah.

Callum: 5:18

Some other binding so that some of them find the 50 s subunit impairing function and and they alter cytoplasmic membrane leading some cell content leak. So there's not just one mechanism action, but I think the most important thing to remember is really impair protein synthesis. And to get into the bacterial cell, it complexes with magnesium and then transports through two transporters, OMPF and OMPC. And then once it's in, it dissociates from magnesium to get through the inner membrane. And then the recomplex of magnesium. So magnesium is an important part of it. I don't know if that has any sort of therapeutic indications. I haven't been aware of that.

Jame: 5:52

I don't think so. Okay. Yeah. And then in terms of how they, how they get into the human, most of them are oral. Some of them are IV, like Tigecycline is IV only. Doxycycline can be given IV, and actually there is a supplier who's now providing it to the UK, but for years it was only available as oral. There are only two that can go in IM, tetracycline and oxytetracycline. And I think before we move on as to how we're using it, Cal, I think I'd be remiss if I didn't point out that there are other non antibicrobial uses for Tetracyclines and the first is anti inflammatory, and so it's known that they've got these anti inflammatory properties, which is why dermatologists like to use them in acne patients. A lot of the time they'll use oxytetracycline for that. And the presumed mechanism of action is by inhibition of matrix metalloproteinases. And the, there's association between that and inhibition of MMP by tetracyclines and decreased production of TNF alpha, IL 6, IL 1b, so that those kind of pro inflammatory cytokines. And then the other use is that demeclocycline, and this is possibly where the only time that you will have seen demeclocycline being used, is that it has a direct anti ADH activity in the kidney. It blocks V2 vasopressor receptor expression. And if you do that, you don't claw back water from your urine. And so you get diuresis. And sodium is then concentrated. And in fact, Domeclacycline is not particularly used as an antimicrobial. It's main use case is for the treatment of refractory hyponatremia. Callum, why would we give tetracyclines?

Callum: 7:43

There's a lot, a long use case for tetracyclines. And as I guess, one of the, one of the things that you might come across as an infection specialist is this rare syndrome or actually not very common syndrome called doxycycline deficiency

Jame: 7:57

Ha.

Callum: 7:59

I'm just going to spoil it for everybody. It's not real, but it's just a term that we use because doxycycline a really wide spectrum of action and use case. And it is a real useful

Jame: 8:10

the sort of syndromes first that it's got an for, at least in the BNF, and then we'll talk about the bacteria that we can use it for.

Callum: 8:18

Do you want to alternate? We don't have a list of organisms to do

Jame: 8:21

We certainly do have a list of organisms, Callum. Much

Callum: 8:23

yeah, but you've only given the genus names, you've not given the whole organism names, so it's not a list of organisms.

Jame: 8:28

Just read the syndromes, Callum.

Callum: 8:32

Okay, so we've got sinusitis, lower respiratory tract infection bronchiectasis or COPD flares, skin soft tissue infection, mild diabetic foot infection or leg ulcer, human or animal bites in the penile penilegic patient, non gonococcal urethritis, so thinking of things like chlamydia, and pelvic inflammatory disease, and rarely UTI.

Jame: 8:54

Yeah, uncommonly, but as we need something to treat ESPLE coli in the urine, I think people are turning to Doxy more. It depends if you have it on your card, your antibiotic testing cards. Do we still have it up in Nadosh North on the gram negative card? Has it been removed? Hmm. Okay. And then I've got here a list of just the bacteria that doxycycline has an indication for. And I went through, did a deep dive in the literature. And I, I think Callum it's time for a classic Jame and Callum alternate reading of these organisms. Do you want to start?

Callum: 9:31

Yes. So we're going to say the organism type. We'll go gram positive and

Jame: 9:34

Yeah.

Callum: 9:36

gram positive staphylococci,

Jame: 9:37

Pneumococci

Callum: 9:38

so on. Okay.

Jame: 9:40

Actinomyces

Callum: 9:43

A typical lower respiratory tract infection, mycoplasma,

Jame: 9:46

Clamidophila

Callum: 9:48

legionella ish,

Jame: 9:50

Gram negatives influenzae Gram negatives ESBL E. coli UTI

Callum: 10:00

UTI, controversial. They've got a link to that in the

Jame: 10:04

late to our urine drug prime notes Burkholdania pseudomallei Helicobacter pylori

Callum: 10:13

And STIs? Syphilis. Gonorrhea.

Jame: 10:18

Animal vectors Brucella

Callum: 10:22

Bartonella.

Jame: 10:23

bernettii

Callum: 10:24

Ankycella

Jame: 10:26

Leptospira, Yersinia pestis.

Callum: 10:31

Tick factor. Borreliosis. Borreliolosis, such as lyme relapsing

Jame: 10:39

Rickettsiales, such as Rocky Mountain spotted fever, typhus, scruptyphus, anaplasma, and ehrlichia.

Callum: 10:45

Other, such as Whipple's disease and

Jame: 10:48

And anthrax. And then we're not even done. That's just the bacteria. We've got some parasitic. So I'll take them. That's malaria both as PEP and as treatment in combination with quinine. And various filarial infections. Filarial are thread like worm infections. And they do that by killing a endosymbiont called volbachia, which is essential for the the worm survival. And then finally, Callum other as an anti inflammatory are,

Callum: 11:16

acne vulgaris,

Jame: 11:18

keep going,

Callum: 11:20

rosacea, periodontitis, bullous emphempha, bullous pemphigoid, and hydrogenitis

Jame: 11:26

yeah, I think, I, I would put money that that is the widest spectrum of action of any antimicrobial. It's got parasites, it's got worms, it's got, funny gram negatives, it's got gram positives, it's got everything here. Stuff without a cell wall.

Callum: 11:47

I guess I'm just thinking there we look at 16S for diagnosis because it's highly conserved, but there's variation between species. And I guess maybe that's part of it, is that the ribosome is such a basic building block of your cell that it's quite hard to have radically different, penicillin binding proteins, you can just mess around with that a little bit and become resistant.

Jame: 12:06

Perhaps, The resistance mechanism would support that, point of view.

Callum: 12:09

Lot in there. I guess that, we're going to talk about resistance in a second, but it's not going to cover all streptococci,

Jame: 12:16

We'll talk about resistance in a wee sec. Yeah, so a little bit about the pharmacokinetics now.

Callum: 12:20

Nice table you've got here,

Jame: 12:22

it has been stolen and improved upon from our one table to rule them all, the Idiot's Guide to Antibiotic pharmacokinetics which, I still think I might produce that as a poster if people want to buy it. If people are interested give us a you gmail. com or at the top of the episode description there is now a button to text us and if you want to text us you can and we will get that and be able to reply to you. It's all about engagement column. But the yeah, so I've got the PK data here for the main sort of offenders. So we've got tetracycline, doxy, minow and Ecic, anti cyclone. They're all fairly highly bioavailable, with the exception of Eclo, which is 60 to 80%. And Tiggy, which is not available apart from tetracycline. They're all. lipophilic, so they've got a fairly high volume of distribution. So the the sort of range between about, say, 50 to 90 for, tetracycline to doxy and minocycline is 84, all the way up to about 440 for ticlocycline. It's extremely lipophilic and you get very low plasma levels at all. Protein binding is mid to high. It's quite high for stuff like minocycline and doxy, which are the main things that we would be using in clinical practice. And metabolism is predominantly hepatic or not at all. And excretion is divided, 30 to 40 percent renal. for tetracycline and doxy, only about 10 percent for minocycline. So if I was using it in the urinary tract, I probably wouldn't use minocycline. And then hepatic and GI for the rest. And in terms of half lifes, they vary about 12 hours for Doxy, 6 hours for Minil, 13 to 31 for Tegacycline, that kind of thing. So that, and that influences dosing most of, Doxy and Minil in particular can be usually dosed once daily. It's interesting the the

Callum: 14:26

halflife of tigecyclinee is longer than the others, but we dose that twice

Jame: 14:30

Yeah, I think that's to try and get halfway decent levels in in tissue and, it was probably just the approved regimen. But you're right, half life between 13 and 31 hours. It's a bit of an aberration. The PD, Callum?

Callum: 14:46

So the pharmacodynamics, so your target is the area under the curve over the MIC. Having more time over MIC rather than CMAX. And, penetrant, so it gets well into tissues, things like acidic fluids, endovial fluid, pleural fluid, bronchial secretions. So that, they've got general, because of that high volume of distribution and the fact that most of them apart from tetracycline and lipophilic, they're very good at getting into places that are somewhat difficult to get into normally. Minocyclines, you've written here minocycline, liver and

Jame: 15:18

Yeah, It's got slightly better penetrance into the liver and gallbladder than the others in the class.

Callum: 15:24

Because it's got more hepatic clearance.

Jame: 15:25

I think so, yeah. And the other place that it gets into better is the CNS. And so if you're treating CNS infection say, we just had a Nicardia case. Oh God, that's not on the list actually, I better add it. We had Nicardia. Case, and locally we don't actually do minocycline testing, but Colindale do, the health security agency, Central Laboratory in London. If you send the sample off for typing they'll do that, and this guy, for various reasons he had poor kidney function, so we didn't want to necessarily use cotrim for a long period of time. And also he had iron deficiency anemia, so Kotrim and Lanezolid were both probably not ideal long term, and those are the sort of things that we would use for anacardia. But minocycline is also an option as long as it's sensitive, and so we were going to send it off for testing and then, see what we got.

Callum: 16:15

We use Doxycycline for quite a few CNS infections, like CNS Lyme, and it's not inferior in clinical trials, so I don't It's just because you don't need that much levels.

Jame: 16:23

I think that in terms of getting a, better, better peak in the target tissue, minocycline would be better, but I mean you're right, the evidence base is much better for DOCSY for something such as syphilis and Lyme disease, if you're treating stuff there, yeah. But remember, when you do that for Lyme, isn't the dose 200 twice daily? It's not to be sniffed at. It's not a standard dosing. You're using quite a high dose. We talk about the side effect profile. Yeah. In terms of side effects, I've tried to divide them into what's, common and uncommon. And by body type. In terms of common side effects, GI stuff is what we worry about. So nausea and vomiting. Less common would be You know, epigastric pain, or dyspepsia. And the one that we tell all patients about is esophageal ulceration. Doxycycline tablets can get lodged in the throat. And if they do, they can erode through and cause an esophageal rupture. It's not very common, but it does happen. They're occasionally associated with mucosal candidiasis as well. And so for this reason, we recommend people sit upright when they're taking it, and take a drink of water with it too. And so sometimes that requirement renders it unsuitable for some patients. And then in for skin effects, Callum, do you want to

Callum: 17:46

Yeah, so the main thing that you'll need to warn people about and it's particularly relevant if people are taking it as, say, malaria prophylaxis, is that it gives, certainly in some people, but most people, to a small degree, photosensitivity. So you need to warn people not to go out in the sun without wearing very high fat or sun cream or covering up completely. And, yeah, I think that's an easy thing to forget about, particularly in Scotland in the winter. But people do travel and yeah, I had a case recently where someone hadn't been warned about that and had a really severe, skin reaction from it and it was pretty horrible.

Jame: 18:20

was I can't remember why he was taking it, but he was But he was black Caribbean and he'd never worn sunscreen in his life. And then he went home and then came back with sunburn. And he was like I've got a sunburn for the first time in my life. And I was like I did warn you. And that was because of doxy and you're right. If you're having it in the UK and certain times of the year, it's just a complete non issue, but like you say, people do travel. And. Particularly if somebody's taking it for malaria prophylaxis and they've got very fair skin, it's probably not suitable for them. And you would use something else, like mefloquine or atavacron proguanol.

Callum: 18:57

So that's a

Jame: 18:58

other skin stuff?

Callum: 18:59

effect. Hyperpigmentation is another one. So I think this is with more prolonged use. I haven't really seen this as a major issue. I don't know if you've

Jame: 19:06

Me neither, but it was listed in the SPC as a common side effect, but I'm with you, I've never seen it actually. Anything

Callum: 19:12

I think I've. Yeah, so uncommon risks of vaginal infection, so I guess, candidal, and bacterial vaginosis like any antibiotic. And then risk low or unknown, paracesia, so altered sensation in the hands, feet, or the nose. And then something called photo oncolysis, which I guess is discoloration of the fingernails.

Jame: 19:31

And then the last common side of it would be headache, which again, I don't see all that much, and I use a lot of Doxy, but, it's there. And then uncommonly you might see drowsiness, dizziness, ataxia, tinnitus, visual disturbance, anything really. What about tooth discolouration? Cal?

Callum: 19:49

Just briefly on the headache. I have seen the other people have this, and it's associated, Tepstecans are associated with, I think it's a normal pressure hydrocephalus, and so it is a, it's a risk that's worth being aware about. I don't routinely warn people about it, but, if someone comes back with a bad headache then, think it's worth considering.

Jame: 20:06

What about teeth and bones? Calum? What about discolouration of the teeth? Mhm.

Callum: 20:10

we worry about a lot in children. And the idea is that because, tetracyclines collate into calcium and other sort of heavy metals, it's meant to bind to the calcium in teeth and you lead to this sort of yellow or gray discoloration and it's or maybe brown and it's it's, permanent and it can, also lead to, effects on the enamel. So enamels, hypoplastic get demyelization and can affect the skeletal growth. Now, obviously, it doesn't really matter what colour your bones are because they're underneath your skin and muscle, but your teeth are very visible, that's the enamel effect is really the one that people worry about because of the sort of cosmetic,

Jame: 20:44

yeah. And this is another reason that you can't take tetracycline with antacids because they will just bind the magnesium or aluminium. Anything with, that's able to donate two electrons to it, so calcium is Ca2 and magnesium is Mg2 it'll just bind. This is less of an issue with doxycycline than it is with the earlier generation tetracyclines. I don't know if it's also an issue with minu or etc. But actually, short courses in pregnant patients or kids. There's some good, uh, sort of recent articles are saying that actually short courses can be used without consequence in kids. It was longer courses and the use of tetracycline and oxytetracycline earlier that were really associated with the tooth discoloration.

Callum: 21:32

Yeah. Yeah, so that's covered in more detail in episode 56,

Jame: 21:36

Yes, in our pregnancy breastfeeding episode, and then lastly, just wrapping up

Callum: 21:41

rare again, it's, we're looking at like more risk unknown or low, at least, things like cholestasis, jaundice, and very rarely, basically most drugs are very rarely associated with, fulminant liver failure, acidosis and shock.

Jame: 21:55

and then in terms of renal they can be associated with acidosis and polyurea polydipsia. I don't, I've, I've literally never seen any of this stuff. There's one other thing to mention, Calum, is that in the UK we use doxycycline hyclate. That's what all the tablets are. There is another formulation called doxycycline monohydrate, which I think is more commonly used in the US, and that is associated with fewer GI side effects than doxycycline hyclate.

Callum: 22:24

Talked about sometimes in MDTs where we're like, this person can't tolerate doxycycline and there's very few other treatment options. Then we talk about monohydrate, but then it becomes apparent that it's quite difficult to access.

Jame: 22:34

very difficult to source. We'd probably have to get it from the US or Europe or someplace like that, but yeah. There are other things that you can do. And then just a little note of comparison between doxycycline and minocycline. The, in terms of side effect profile, that doxy will cause more GI side effects, whereas mino will cause more dizziness hepatic dysfunction. It's associated with more autoimmune. Disease and it's more allergenic. And if you had the choice between the two, you would use Doxy. But, if you need to, for some reason, use Minocycline, then that's fine. And, in particular, the CNS pension with Mino is more more reliable. And then lastly, Cal, let's talk about resistance. So I've included the UCAS breakpoints in the prep notes, but I don't think we're going to go through them. But the resistance mechanisms I think are quite interesting.

Callum: 23:27

Yeah. So there's three main mechanisms as my understand, and they're all easily transportable on mobile genetic elements, so it's fairly easy for that to be transferred from bacteria to bacteria, even species to species. so the first, I'll take the first one, I is efflux pumps. so James linked to, the Pseudomonas episodes where he went into a deep dive about how efflux pumps, work. But essentially for tetracyclines, the, there's these, um, Group of eox pumps called the major facilitator, super family. They're MFS and they're the main class of pumps. There's lots of other ones as well. And the mechanism of action. So they, basically they're drug and ine antiporters, so they exchange the tetracycline for a proton ine. And there's for tetracycline, there's, there's fairly reported, and it depends on the organism type, which ones are reported. And they're usually called like Tet something. So Tet, A, B, K, and L are the main ones. And they're not, it's not universal. Some of them have effect on the earlier classes. So like tetracycline, doxycycline, minocycline, and then they don't have an effect on the later generations, like tigacycline or rafacycline, which shows the value of these newer drugs in treating resistancing. So just because it's resistant to the earlier ones, if it's an efflux pump, then it might actually still be sensitive to your later generation tetracyclines.

Jame: 24:45

Yeah true.

Callum: 24:46

So the second one, don't take

Jame: 24:48

Yeah, the second one is ribosomal protection. And these are, Either 16S RNA binding site mutations, which you will get with things like strep pneumoniae cutobacterium acnes, and helicobacter pylori, or ribosomal protein mutations which you will get in enterococci, staph aureus, neisseria and klebsiella pneumoniae. And then I suppose the other method of ribosome protection is the ribosomal protection proteins, the last example, there, there are proteins like TETM and TETO. You see this in Campylobacter jejuni and venae streptococci. And what they do is they catalyze GTP dependent release of tetracycline from the ribosome. So the tetracycline binds onto its site and then it gets released. and they encourage or increase the rate of release. There are 12 of those currently documented, but the third gens, your Tiggy, Irava, and Amanda Cyclone and Sara Cyclone are resistant to that resistance mechanism. So that's good. And lastly, Kal? The third resistance

Callum: 25:52

mechanism is enzymatic degradation. They're also known as tetracycline destructases.

Jame: 25:59

name.

Callum: 26:00

yeah, it's an awesome name. And for example, that is TET X, which is also a cool name. And that adds on a hydroxyl group to the drug at a C11A position between the B and the C ring. So there's four rings, A, B, C,

Jame: 26:12

Yeah, which annoyingly go from right to left.

Callum: 26:15

And, they bind between B and C and have a covalent inactivation of drug. So yeah, we've rapid run down through the, we've done a four times speed cycle, you might call it a tetracycle through the, tetracycline

Jame: 26:28

What a way to bookend this episode, Callum, but yeah.

Callum: 26:33

I'm going to do a quick summary of what we've learned. Because we know that helps you memorize things. We talked about tetracyclines, we made some bad jokes. James took us through, James? James took us through the classes in evolution through time. They bind to the 30S subunit of rRNA, and that inhibits protein synthesis. They've got a wide spectrum of action of different syndromes and bacteria, some parasites, anti inflammatory. Most of them are lipophilic, apart from tetra, which is hydrophilic. And, we talked about the common adverse drug reactions. and penetrance into different tissues. And then the free resistance mechanisms we went over were efflux pumps, ribosomal protection, and enzymatic degradation. And all of this is very well summarized on the Notion page, which is where we've got our show notes the link for this episode show notes is in the episode description on your podcast player of choice,

Jame: 27:29

Lovely. Thank you very much. See you next time.

Callum: 27:32

Cheerio.

Jame: 27:33

Oh, and don't worry about covering Tigi, Arava, Nomada, because we're going to do that in detail next episode.

Callum: 27:43

I'm mad. We're not covering it this time.

Jame: 27:45

Okay.