54. Antibiotics for UTIs

This is the urine antibiotic drug penetrance you never knew you wanted. Jame might be prouder of this than his own children. Callum, as you will be able to tell, remains indifferent*. 

Figure out which antibiotics you can trust, and which you can't. Use the table in the prep notes and links to win arguments, justify treating 'resistant' organisms in the urine, BREAK HEARTS - you name it! 

Enjoy!  

Prep notes for this episode: https://idiots.notion.site/UTI-Drug-Choice-5deb611895254444a040bf78d2003cdb

*To the episode, he thinks Jame's children are delightful. 

Transcript

Jame: 0:00

Hi everyone, welcome to the Idiot's podcast. That's infectious disease insight of two specialists. I'm James, that's Callum. We're going to tell you everything you need to know about infectious disease. Soon may the editing come to this. Continue the taser sun. One day, when the seer piece done, will take our leave and go. Callum James, you remember that time that you got high and mushrooms broke into Wilmildon and urinated all over the net.

Callum: 0:32

I meant to say yes, yes, yes, very clearly.

Jame: 0:38

Yeah, it was very odd. And you know, when the police officer found you he said to you Callum urine P net trance. And that reminds me Callum of today's episode, because we're going to be talking about you in penitence.

Callum: 0:55

I can't understand that joke. What Urinate.

Jame: 1:02

P net trance.

Callum: 1:05

P net trance Oh.

Jame: 1:06

I get it.

Callum: 1:08

Okay, I got it.

Jame: 1:10

And that reminds me Callum, because today's episode is about urine penetrance of antimicrobials, is it not?

Callum: 1:22

That was quite a complicated pun. When did you think it up and how long had that been on your mind? Like half a minute before the episode started? Half a minute, wow.

Jame: 1:31

that's the skills that you can get, only here are probably on the Idiots podcast, the United Kingdom's premier infectious disease podcast. Don't look into that too closely. So anyway, we're going to be talking about urine drug penitence And we've kind of held this back, haven't we? We've done urinalysis, paralysis, we've done urine culture, we've done CAUTI, we've done everything but talk about in depth.

Callum: 1:57

I think only a pharmacologist would say that we've held it back. As if you want to talk about the antibiotics before you've made the diagnosis. We're like well, i don't care what the diagnosis is. Did you know about Pivmus cilinum?

Jame: 2:12

But do you know about Pivmus cilinum? No, let's make the diagnosis first.

Callum: 2:16

I think this is where it should be in our urine series.

Jame: 2:21

All right, all right, all right, fine, okay. So I mean the easiest thing in the world. I mean, really, when you're talking about particularly when you're in early years, you know trainee or pharmacist or you know microbiologist you should just follow whatever your local guidance has to do or what the nice guidance has to do. you know like they've chosen their recommendations with some care usually. But we're going to go a little bit beyond that and talk about the all available options, including what to use when you're back as to the wall and kind of work forward from that.

Callum: 3:03

It's funny when you get to a certain level. You I think you know you saw this thing like just follow the guideline. The guidelines are amazing, and two things come to mind Now. One is that I was reading a guidance recently because someone told me about something. I didn't know what to do, and so I looked at the guidance and the guidance said consult a microbiologist. And I was like no, no, i don't know, i can't consult myself.

Callum: 3:33

And and then the other thing is that guidelines are, you know, useful and particularly for those common problems, but they were always have issues. Not everything was sitting neatly into a guideline and it's just an accumulation of the evidence. So sometimes new evidence comes along and it's not included in your guideline and maybe your practice should change before the guideline gets updated. Or maybe, you know, in your local setting the interpretation of the evidence is going to be different because you've got different epidemiology or whatnot. So guidelines are perfect. I guess it's my point.

Jame: 4:09

And the more senior you get, the more you sort of have to treat them as you know, something for the juniors rather than something that you yourself need to follow A little bit of that is, i think you, unless you've got a good reason not to you, should follow the guidance because yes, absolutely.

Jame: 4:26

But you're earning your money because when the guidelines don't suit the patient, that's a good line to have in your back pocket. You you're taking the responsibility for deviating from that. Yeah, yeah, that's true, i mean so. But in order to do that, you need to have a fairly you know. When we're talking about urinary tract infections, you know, be it a basic lower UTI, an upper UTI, a catheter, a social UTI, any other UTI variant that you care to think of, you need to have a good appreciation of the pharmacology of the antimicrobials that you're going to be using, what's suitable for what and what is not suitable. And so that's kind of what this episode is all about.

Callum: 5:09

Can I just look at the sensitivity report on the, on the, on the culture James, and that'll just tell me exactly what to do. I just, i'll just jump and just say release the culture. Result and we'll say moxicillin, and we'll just use that.

Jame: 5:21

Yes, absolutely. You use 94-an-ton for as many pylonephritis cases as you like.

Callum: 5:28

I put that to nerve.

Jame: 5:31

So moving on from that, So what?

Callum: 5:34

what drug antibiotics? what antibiotics can we use? What are the options? What are the range of things that might be used for urinary tract infections?

Jame: 5:43

Well, when I I taught a load of urology registrars about this a few months ago now and I divided it into beta-lactamins and everything else. And so let's talk about the beta-lactamins first. First you got your, your penicillins, you've got your amoxicillin, your comoxiclav, your pipericillin, tazobactam, and then you've got your, your kind of slightly older ones, like your pythicillinan and t-macillin, and we've covered them in the in the weird lactamins episode. And then, for your kephalosporins, we've got kefazolin and kefalexin, your first generations. You can use kepharoxyne as well, that's the second gen, but usually people just jump to the third generation, really, and use kefraxyl. If you need to anti-sutamolonell cover, you might use kefazidine. This is a very UK-centric approach, by the way. I know that kefalosporins are much more widely used and lots of different ones are used in other countries, but these are the ones that are very commonly used in the UK. And then you've got your carbapenem, your aertapenem, your meropenem. Both are very broad-spread and the aertapenem doesn't cover pseudomonas and meropenem does. And then, lastly, you've got your monobactam. So astreanam is the only commercially available monobactam And it is also covered in the weird lactams episode, and it has a pseudomonal and gram-negative cover but doesn't really cover anything else.

Jame: 7:18

And then, moving on into your anti-DNA, anti-folate class, you've got your quinolones, and so that would be cipro, levo and moxifloxacin. And, as a brief reminder of the spectrum, cipro covers staph, pseudomonas and gram-negative, levo covers pseudomonas and gram-negative, and I think it covers staph as well. And then moxie covers gram-negative and saphorias but does not cover pseudomonas but does cover anyrobes, which makes it useful in different circumstances. And then for your anti-folate, so things that interfere with folic acid metabolism, which is kind of used to create DNA purines, i think it is that would be your trimethyprim, your sulfanmethoxazole, and they are combined together in the drug cutri-moxazole, also called trimisulfa in other parts of the world.

Jame: 8:17

And then in terms of protein synthesis agents, you've really just got one class that's in common use, but we'll talk about others later, but the aminoglycosides, so that's eugenitamycin, tobramycin, anamicicin, and then, lastly, you've got sort of stuff that doesn't fall into those other categories, that's phosphamycin and nitrifurantone. So at least in the UK that's a sort of run through of the kind of drugs that you could use for for UTIs. So obviously very dominated by the beta-lactam and the DNA and antifolate agents there.

Callum: 8:56

Yeah, And maybe there's a comment later on, but we talk about beta-lactam or beta-lactam. is that applying your nutrient infections?

Jame: 9:06

I think that you know, when we talk about beta-lactam or beta-lactam, we're really talking about a desire to restrict beta-lactam use for the most serious infections And, depending on the UTI, that may not necessarily apply. The good thing about all the drugs that we're about to talk about is that basically they all get heavily concentrated in the urine, because here's the advantage of kind of drugs antibiotics most of them are excreted urinary. There are some exceptions, but most of them are getting eliminated through the urinary tract And that means that you get really, really high levels in the urinary tract, even if you don't necessarily get particularly high plasma levels. And, as we'll come on to, getting high plasma levels is kind of important for pylonephritis when you've got renal parenchymal involvement, but not necessarily for lower UTIs as in below the VUJ where you're going to be getting the main the spell.

Callum: 10:19

What VUJ is for us?

Jame: 10:20

A visicoyurotetic junction, so that's the junction that goes between the ureter and the bladder. So that is the kind of crossover point. If you've got an infection above the VUJ, as in in the ureter and the kidneys, then that's an upper UTI or pylonephritis, and if it's below the VUJ then that's a lower UTI or a cystitis or urethritis or proselytis. What have you? So because the renal parenchymal levels in antibiotic basically mimic plasma. So if you've got something that has high plasma levels then, or sufficient levels above the MIC in plasma that they will be effective, then you can use that for an upper UTI, because that's not the case for all antibiotics. So, for an example, tetracycline don't really get high levels in C max and plasma is not particularly high, so they may not be the best option, whereas, say, beta-lattams or quinolones or even stuff like gentamicin, they'll get high enough above their MIC that you'll be able to use them and they'll be considered effective treatments. Kalmar, have you seen the best antibiotic chart in the world? I'll try and include a link to it in the show notes.

Callum: 11:47

Is this the Brand Spellberg website?

Jame: 11:49

No, no, no, It's not, it's unrelated, But basically somebody got every antibiotic on the sort of Y axis and most pathogens on the X axis and they sort of created like a heat map of what was sensitive and what was resistant to it.

Jame: 12:08

It's a bit like what I've got in the show notes here, but I've restricted it and I've sort of UKized it, so it was very American. So their MRSA was resistant to lots of stuff that we would consider our MRSA to be sensitive to, and so I sort of changed it for that reason. But I've sort of included a kind of a heat map in the show notes here that we'll include, and they're, you know, it's a, you know, a color chart based on the traffic like system. So you know, green is almost always sensitive, red is almost always resistant, green, orange is, it depends, and so I've included a link for all the antimicrobials that we've mentioned there and a few others as well. So there's, i included a column for enterococcus And so I've, you know, included things like Linneslid and glycopeptides, that's, vancomycin, tycoplanin, because they are viable options for enterococcus but not for everything else, because almost everything else is gram negative.

Callum: 13:14

So do you want to talk me through this, because there's a couple of things on here that I'm reading and I'm like, hmm, what does he mean by that? Or, and so, yeah, go ahead.

Jame: 13:22

You pick about Calam and then we'll talk about it. Yeah.

Callum: 13:25

And I wonder if it's easier to talk about it by organism. Yeah, go for it. So you know, public enemy or pubic enemy number one? I guess it doesn't really No no, no, that's good stuff, calam.

Jame: 13:39

That's the best pun you've ever made. Oh no, it is in Calam. do not delete that. That is absolute gold. Great work, calam.

Callum: 13:46

Great work all day. It is E coli And essentially in your chart you've basically put everything as green, apart from the ones that we're just saying for enterococci.

Jame: 13:55

Yeah, true, i mean, this is for wild type, so obviously there are differences and your mileage may vary, but basically everything covers E coli, because When we say wild type, it means an organism that doesn't have any acquired resistance And mechanisms. Basically, Yeah, I'm not sure you need to explain wild type, but go ahead.

Jame: 14:17

I think, Yeah, so the You know, basically if you have an antibiotic and it is nitrificancy coli, it's not very much used for you if you're going to use it as empirical cover of E coli. So everything really here has to cover E coli, And so everything that you would choose for E coli does by default almost.

Callum: 14:40

So what about Klebsiella specifically? Well, klebsiella, pneumonia being the most common culprit, i'd say, but there's lots of other Klebsiella, klebsiella. What's different about them from E coli?

Jame: 14:56

The main thing is that they've got constitutive penicillinase. So the E coli will be sensitive to amoxicillin, say, but Klebsiella's will not, because they have this penicillinase that will chew up amoxicillin And because of that you can't use amoxicillin for Klebsiella. And this is kind of why more recent guidelines are kind of circumspect about using amoxicillin as default. Because if you think I think we quoted 10 to 15% of UTIs are because of Klebsiella's. Well, 10 to 15% intrinsic resistance rate And that's just intrinsic resistance. That's not talking about acquired resistance in your E coli population or in your non-E coli, non-klebsiella intrabaturalis. That's a bit too much to use as upfront empirical therapy And so most guidelines and the most recent nice guidance says look, you can use it if you know what's sensitive.

Jame: 15:58

So you basically have to have the anti-biogram by the time you're going to use it. The way that you get around this is that you just add Kaleb-Atlantic acid, and so of course Co-Mosoclav is active against Klebsiella, as well as other things like Pithmasilinam and Piptaz. The Tazobatam is also active against this Penicillinase And Pithmasilinam is just intrinsically resistant to the Penicillinase.

Callum: 16:27

So, moving on from Klebsiella, because I think there's some other small print stuff there about, i think it's worth. We want to look at the chart, you want to look at anything else. So Proteus was the one that we said was at the third big issue. Any problems with that?

Jame: 16:45

A little bit So again with the Proteus vulgaris and Proteus penerai. So these are not the main event Proteuses. So I think Proteus merabilis would be the commonest organism. But vulgaris and penerai are intrinsically resistant to amoxicillin too. And then in terms of thymacillin it's only Proteus merabilis which it is active against, but that's of course most Proteus that are infecting humans. So it would still be kind of broadly useful in that situation. Nitrointone, interestingly, is not active against Proteus merabilis but is active against all the others. So that's kind of a niche little tidbit to know about Nitrointone, that if you've got a P merabilis infection that you can't use it.

Callum: 17:42

It's quite a common cause of particularly catheter, so it's kind of interesting. What about other intrabateralities?

Jame: 17:50

Well, here it gets more variable because of course every other intrabaterality you've ever heard of, apart from E, coli C, lepsium Proteus, is still a pretty heterogenous group. But I mean your mileage will vary with amoxicillin and Pivnosillinam and you wouldn't necessarily intrinsically trust other things like kind of Nitrointone and Tromethoprim unless you knew it was resistant. And so to your first generation Kephalosporin. So you know, you Kephozolin and Kephalexin, you would be reasonable to trust your more broad spectrum choices, so your Betalatam, the Betalatamase inhibitor, your T-macillin, higher generation Kephalosporins, carbopenems as Trinam, but also your amnibalycides and quinolones and Kotramoxazone stuff like that Kind of up front.

Callum: 18:55

So, pending the Antibiotic, So why not just use amoxicillin clavulinate, you know, comoxiclav, for all these organisms apparently?

Jame: 19:05

Well, callum, you sound a lot like whoever designed the antibiotic plan for Nado South, because that's exactly what we do. We basically use Comoxiclav for most infections in general, but also your Nutratum infections and Pylonephritis in particular, and I hate it because it's broad spectrum, it drives antimicrobial resistance. It kind of promotes the formation of Betalatamase resistance genes, both in the hospital and in the community. I think it's just a bad idea. The health security agents they agree with me, because they have classified Betalatamase inhibitors as a watch antibiotic And so we are meant to be using access antibiotics whenever we can, and so that would be things like amoxicillin, nitrifarin, trimethaprim, kotramoxazole and gentamycin. So, you know, using something like Comoxiclav or you know, higher generation Kephalosporins I just think is not justifiable these days And it will take a while for everybody's microguide to catch up with that. But I think, if we're going to be proper antimicrobial steers, that we can't just keep on using this broad spectrum stuff or everything and just say that makes everything better.

Callum: 20:30

Yeah, it's tempting, which is why I'm suggesting it, But I think the principles here, particularly for UTIs, an extremely common infection is that we should be using antibiotics that can have the least impact elsewhere. And you know, as with any patient with an infection, you're constantly weighing up the risks of could this be something resistant And we're not broad enough, versus the harms both to that patient and to the population of using broad spectrum agents where you don't really need to, Because I could just say well, why don't we just give him a carbapenem? You know?

Jame: 21:07

true enough, Yeah. And when I first came down here I was like, well, why aren't you just using PIP tasks for everything? or a carbapenem Like, why are you stopping at Comox, aglav? Why aren't you going on to use the most broad spectrum thing possible? Because you know you would certainly catch more resistant infections that way. So, like, if that's your justification, why are you stopping with Comox? And I think it's just people think of Comox as the friendly, cuddly broad spectrum antibiotic. Do you know what I mean? Like people don't think it does that much harm.

Callum: 21:47

I guess the words at the beginning of Coal were usually quite good, aren't they? Cooperation, coal-tramox is all You know. Maybe it's actually Coal.

Jame: 21:57

I just think that people just have the wrong idea and partially it's because of you. Know what you and me discussed when we were guessing on that episode of February, when we discussed the Scottish approach to antimicrobial stewardship. That was influenced really heavily with by the Vale of Leven disaster and subsequent inquiry And you know Scotland learned its lesson from it and implemented. What I now realize, having come south of the border, is a pretty strict antimicrobial stewardship program. You know it's nationwide And if you know, like if you use Kefraxone or Comoxiclav when it's not absolutely justified, you get wrapped over the knuckles for it. You know, and that just doesn't happen. I don't know.

Callum: 22:49

We really do wrap people over the knuckles about it. It still happens, not perfect, but it only happens a little less. So we talked about intubator alleys. What about pseudomonas, the other thing. So I guess it's making more incapiters than non-capiturized patients.

Jame: 23:05

Yeah, maybe, and certainly more hospital acquired infections, you know it's. You know love of living in drains and sort of jumping onto patients at a moment's notice. And here we run into an issue in that we've got lots of intrinsic resistances. You know, anti-seudomonal penicillins are called such because all the other penicillins aren't particularly effective against pseudomonas, you know. But you've got your papyrus cilentesa bacteria. You've got your keftazidine, so halfway through the third generation you acquire anti-seudomonal activity. So keftazidine and forced genus like kephapine and things like that can be used. Percopenin, no, but other carbapenins, in particular meropenin and amopenicilostatin, yes, and then astrinan, the monobactam, can be used. And then, when it comes to other things, you've got your quinolones and aminoglycosides and maybe a couple of others. We'll talk about them in a sec. For aminoglycosides it's worth noting that UCAST and now also CLSI have dropped the genitomycin pseudomonasargonosa MIC breakpoint. So now, according to those two organizations, genitomycin doesn't work for pseudomonas. If you're wanting to add pseudomonal aminoglycoside you need to use Tobromycin, or if you're in the urinary tract you can use amicatin, and they've got sort of separate breakpoints for the pair of them. And this has actually been pretty well covered in a recent episode of breakpoints, and so I would encourage people to go and look at that and try and include a link to it in the show notes column about it. Basically the— When you're setting breakpoints for a bug-drug combination, there's a golden rule.

Jame: 25:07

The golden rule is that you don't bisect the wild type population. If you can think of the wild type population as like a bell curve, you want your breakpoint to be basically the edge of the bell curve, so maybe the 99th centile or something like that. A big issue with old breakpoints from back in the day, like before people were looking at this in a systematized fashion, is that some of the breakpoints do bisect the wild type population, for example, the Jane to Bison pseudomonas breakpoint that everybody was using. Ucas looked at this and they put out a rash down document and they said look, we can't justify this anymore, we're going to drop it. If you want to use an amygdalaic side, you're going to use Topramison or Amicason. Calsi have followed suit on that, based on some work that US CAST did for them. Now neither big breakpoint setting organization recommended Jane to Bison for pseudomonas. How?

Callum: 26:13

does that work? Obviously, amygdalaic sides are concentrated into urine, so you get much higher concentrations.

Jame: 26:19

Interesting. You should say Calum, because there is a phenomenon that people have been talking about, which is the urinary anti-biogram. People haven't really, as far as I know, the big breakpoint organizations haven't really implemented this yet. But the idea is this As you get such heavy concentration of antibiotics in urine, you may be able to use antibiotics which previously you had considered the organism to be resistant to, purely because it gets concentrated in the urine to such a high amount that it will exceed the MIC of that organism. A great example of this is Gentamicin. Gentamicin gets concentrated to 100 times the plasma level. If you get a plasma level of, say, 10 milligrams per liter you may well get a urinary concentration of 1,000.

Jame: 27:28

That is more than enough to overcome even the upper ends of the wild type population, as you find it. and that was the reason for UCAS and CLSI dropping the Gentamicin MIC. But interestingly they haven't put a Gentamicin urine breakpoint. and that's because they've been doing this thing where UCAS at least have been changing the dosage of the drug depending on whether or not you're going into the urine or not, trying to TDI, but they've not set independent urinary breakpoints for the drugs. But people have talked about it in the literature and published ideas as to how you could go about it, but as far as I can tell it hasn't been adopted by the big breakpoint setting agencies.

Callum: 28:31

Yeah, ucas released a document. We were on UCAS 13, i think they started in 2010. It's basically got all the breakpoints and so on. I probably used the Excel file that opened the most, because I'm constantly referring to it to just get a feel of what can I test, what is the guidance for what dosage is. It's a really amazing document. The thought that comes to my head there is that you're obviously so interested in the pharmacology, i'm interested in the microbiology. Let's go on a field trip to UCAS.

Jame: 29:01

If only. Well, it would be an interesting mini series, wouldn't it? Because I think you're certainly from microbiologists, but I also think that most infection specialists should learn this as well. Learning how UCAS work is kind of important for learning how to use the drugs, because learning that bug-drug combo, i think, is a big bit of our day-to-day kind of working. So, yeah, let me give you another couple of examples.

Jame: 29:31

A calm with a couple of drugs which you may not have thought of as anti-propagation before now. So let's take phosphomycin. No, it's not anti-propagation, jim, but is it, is it? Well, if you can bring yourself to look at the latest UCAS guidance document, you'll see that they have issue guidance that if the MIC is less than the ECOV and the ECOV is less than 256, then you can consider using it for urinary tricepsis, which is a step up, because in the previous UCAS document, i believe, they didn't make any recommendation.

Jame: 30:18

And that's kind of interesting, because this kind of gets into how you set a breakpoint. And again, that episode of breakpoints is they've got this great mini series on breakpoints And they interview a couple of guys from UScast and somebody else works for CLSI. It's very interesting. But the way of setting breakpoints is basically you get some in vitro data. You then get some animal data, if possible, you get some human data and then a committee basically just decides on what the breakpoint is. So at the very end there's this human modification of what the breakpoint is going to be, and that's obviously got its advantages and disadvantages.

Jame: 31:06

But one of the disadvantages I would say is that if you've got in vitro data, that might not be enough to set the breakpoint. So the example that springs to mind is keftazidine. There are no Staph aureus breakpoints for keftazidine, but in vitro it does seem to work. It just depends on whether or not you can get that concentration above the MIC at the target site. And that's always the issue is, you can drop an antimicrobial onto a petri dish and you can kill a bug, but can you do it in lung urine abscess? The advantage with urine retract sepsis is that usually you've got very high concentrations of the antibiotic.

Jame: 31:58

And in the case of phosphomycin.

Callum: 32:00

that's usually true And that's one of the main issues in bug drug combinations in general, which is that we are kind of reliant on organizations at UCAS and CLSI who do an amazing job. But I think that we know that in vitro and in vivo do not equate And there's sometimes things where there's clinical practices that's been happening for years, like gentamicin for pseudomonas, with a clinical experience saying it works, or maybe clinical data, and then an ember saying, oh, in vitro it doesn't work, so you can't use it and we won't recommend and we can't test in the lab, which is sort of reliant you know people are reliant on clinically. And then when you're in the local lab and you're trying to implement UCAS guidance, it becomes a bit tricky to say like well, what are we going to do with this, because that's going to change, and like, how would you speak to clinicians and say like well, we're not going to give you that susceptibility result anymore because we don't have guidance for how to interpret it? And we're like, well, so you're saying that we've been doing it wrong for 30 years? I think that's.

Callum: 33:15

I don't know. I think that the UCAS, you know these organizations are doing their best to provide things that are, you know, correct. But sometimes I wonder if you know clinically I maybe don't. I don't really care about what's precise and exactly correct, if it works.

Jame: 33:37

Yeah, I mean, I'll give you another example, Callan. So Doxocyclin, have you used it? Have you used Doxocyclin for UTIs? Rarely, yes, Rarely.

Jame: 33:53

So those in the know with the literature will know that there are some advocates for use of Doxocyclin as a UTI agent And that's because it's got some pretty good in vitro efficacy against E coli and clebsiela, which, is a reminder, is kind of most UTIs. It's not particularly active against Proteus, It's got variable activity against the other entrobatterials But interestingly it's got some activity against Pseudomonas And I think I've got some examples down here of, yeah, Doxocyclin resistance. So Doxy is not normally considered to be an anti-synomonal because the MIC is usually around about 150. And the plasma MIC that you would get with Doxocyclin there's usually something like four. It's like way, way too low for it to be an effective anti-synomonal. But in the urine, because you get concentration it's about 60% urinary excretion and 40% sort of GI tract You'll get plasma levels of about 300. Sorry, urine levels of about 300. And so that's like more than enough to overcome the MIC of the average Pseudomonas organism And so for that reason you can consider Doxycycline as an anti-synomonal.

Jame: 35:29

But, Kellan, good luck getting a Doxycycline MIC in your local anti-biogram or Pseudomonas, because UCAS haven't published an MIC and therefore you can't really include it in your anti-biogram.

Callum: 35:46

So I guess that's maybe something to think about if you're desperate And there's always going to be scenarios where you need to think outside the box and think like we're really stuck here, so what we're going to do.

Jame: 36:01

Well, true, but I guess the issue there is that you're always going to be going blind, yeah.

Callum: 36:06

Do you know what I mean?

Jame: 36:07

Because you don't have the Doxy MIC to work with. And this is the argument for introducing, like a urine, specific kind of anti-biogram for bugger combinations, because you could include like a phosphamycin and it's also like an MIC for Pseudomonas and for other organisms too.

Callum: 36:32

Safe in the knowledge that once it comes to the urine, most of them are concentrated to really really high levels And we've got some tables in the There's a table in the show, not here, and you've got sort of plasma versus urine, cmax, and what's going through my head there is I don't know if I care about Cmax for these beetle atoms, because it's time over MIC that we're interested in. So do we have any data on that?

Jame: 37:01

Yeah, Really I just included that as a. So the table that you're talking about is pulled almost completely from reference three and I've got the references here in the show notes here. And it's a really brilliant paper which includes a great table which I have cannibalized but not copied because I didn't want to infer no copyright about kind of urine drug levels And as best as what I included here was the maximal concentration of plasma and urine as an indication of the ratio between these two things. So you know, let's just take a moxicillin 500 as an example. So you've got your plasma level of between 6 and 10 milligrams per liter and that will correlate with the urine concentration of between 300 and 1300 milligrams per liter. And that means that you know, i can't don't recall the moxicillin half life, i think it was like two or three hours or something like that.

Jame: 38:31

Essentially, the plasma levels and the urine levels will kind of match, kind of roughly the same as each other, as the bit of the moxicillin that is filtered into the urine is the free component And then the bit that's in plasma that you're measuring also is the free component, and then it sort of gets replenished from the bound to albumin component And so you sort of clear it at a fairly constant rate, and that rate is kind of related to the half life of the drug of choice. And so, really, what I wanted to prove with this table is the height that you're getting to with. So, say the MIC of the organism is like two, say it's even relative resistant, call it four. Well, how many half lives is it going to take to drop from 1200 to four? Do you know? you're going to have really high moxicillin levels in that urine for like a long time, for lots and lots of half lives. And the truth, the same applies for just about every drug that you go down this list.

Callum: 39:55

So what I'm thinking here is that maybe this is a slight tangent is that we use antibiotics and I think that this bit of knowledge is not well known And I maybe didn't. I kind of understood it, but maybe not as well as you just explained it. And so what happens is that we get familiar with antibiotics And I think you know you prescribe an antibiotic and you say, okay, i know how to prescribe a moxilum because I do that all the time in my practice 500 milligrams three times a day done. And then you are in another scenario and then you have to use a moxilum on a different dose And maybe you're like, oh, i'm going to use a moxilum, right, 500 milligrams three times a day.

Callum: 40:38

That's what you do, and you can get away with really small doses of antibiotics when you're shooting a urinary tract infection because it's concentrated so much And what it's so key to be like, well, what is it that you're treating with the antibiotic? And then that will determine the dose. So careful, x has want to come back to you because you know, for a urinary tract infection, maybe 500 milligrams every 12 hours will be fine because it's super concentrated into your new tract infection. If you're being ambitious. I want to treat a bacharumia with it one gram every six hours. You know, you know much higher plasma levels.

Jame: 41:14

Yeah, I would agree with that, particularly with Kefal X, which I think we criminally underuse in the UK, particularly when we're going to rename the podcast to Kefal Tramion fan club.

Jame: 41:26

So we are. But you know, like you've got your, i don't think we should be running through these numbers, think we should just direct people to show notes and they can take their pleas and also have a look at these references to. But for the, for the beta-latins, we'll just gloss over and say that you know, beta-latins get concentrated in the urine in two comical levels. Some of them are more heavily concentrated than others. You know, i was interested to know that Kefal X in one gram, which is an oral Kefal spore, is concentrated much more into your in the Kefazulin one gram, which is IV only. So that would get 700 to 2000 milligrams per liter, whereas Kefal X would get between five and 10,000 soon, like a lot more.

Jame: 42:22

It depends on the pK and the PD of the drug. You know individually, yeah. But then with your quinolones you've got plasma levels, with Cipro 500, of between two and three, so like not very high, nothing to be sniffed at, but urine levels of 200. With gentamicin we've already talked about you know, plasma levels of between sort of four and eight with a relatively small, maybe five milligrams per kilogram dose. But it will get plasma levels of between four and 500.

Callum: 42:57

Quotramox is all is very heavily concentrated to the all are really Yeah, this is boring me, sorry. I guess one thing we should mention is Entrychalki.

Jame: 43:11

So this is the interesting bit about concentration overcoming resistance.

Callum: 43:16

Before you do anything, i think it's worth mentioning that a lot of the time, entrychalki are actually contaminants in urine culture, so it's not 100% absolutely, they truly think they've got Entrychalki infection in urine.

Callum: 43:29

What can you use? Well, yeah, well, they're kind of annoying answer, you know, going back and listen to the Entrychalki episode. But Entrychalki have quite a lot of intrinsic resistance to different antibiotics And they also are fairly good at requiring resistance. So it's one of these organisms that load doesn't make people super sick. It it can sometimes be difficult to treat because there's limited options, true, True.

Jame: 43:54

So what can you use? Well, your number one it should be amoxicillin. Now, we can do this for two reasons. One is that most Entrychalki is amoxicillin sensitive. But two, even if you are treating a amoxicillin resistant organism, be it Entrychium or a amoxicillin are Entrychalis, you can probably overcome whatever the MIC is in the urine, so you can probably still treat it with amoxicillin, regardless of its amoxicillin sensitivity, to the point where some microbiology departments have stopped reporting amoxicillin sensitivity or resistance and just include a canned comment saying you can use amoxicillin to treat this. If you want, contact us if you want an antibiogram or any more details, and they will restrict that.

Callum: 44:57

There's a And do you need to use higher dosers Amoxicillin 500?

Jame: 45:00

500 three times a day will do you fine, and that sounds very interesting It's in the literature. I think I've included one of the links there. So in the show notes there I've got the amoxicillin are Entrychalki Yes, pubmed ID 30766068 for details. Thank you, kelly, for not believing in me.

Callum: 45:27

No, richie, i didn't write that paper, all right.

Jame: 45:32

And then you can of course use, you know called wasaclav PIPTAS if you need to. And then, if you are going to use a carbapenem, the best evidence is with imapenem, and in fact that's the only thing that UCAS issues a breakpoint for. But I think most people think that meriapenem probably covers Entrychalkis also. And then, in terms of other agents, non-badalatum agents, ciprofloxacin has some Entrychalki cover. Entificalis is covered by Nitroferantoin and luckily that causes the lion's share of UTIs but not other Entrychalki. There's variable covered with Phosphamycin, and then you've got your kind of niche, only Entrychalki agents. So Linneslid, vancomycin if it's not a VRE, vancomycin gets concentrated quite well into the urn, it's its main source of excretion. So you've got good levels there. And then Ticacycline as well, the much maligned Ticacycline, but actually you can use it for your Nutrativations if you absolutely need to. Cb.

Callum: 46:47

Yeah, so that's that sort of chart of all the different organisms and the antibiotics and the urine drug concentrations. What else do you want to talk about?

Jame: 47:01

I mean I guess we could talk about the indications, the recommendations by kind of nice and Aspid and IDSA. We've sort of taught about them previously in our DCR gram negative kind of episodes and in previous.

Callum: 47:17

Unifracting Facts episodes.

Jame: 47:20

I don't think so as well. I think this when you're following the nice and Aspid guidance, the nice guidance, in particular this episode really if you're an infection specialist and you're running into infection where the nice guidance doesn't apply, Yeah, that's true.

Callum: 47:39

I asked at the beginning is urinary tract infection definitely something where we can say that beta-lactams are best of lactams, because it has been in some places the sort of historic thing that beta-lactams aren't good for urinary tract infections and that we should be using alternate antibiotics? But you've put in the show notes a study that was looking at oral step down post-bacteremia, in particular for urinary source, and saying that actually oral beta-lactams are fine in this context, because I often see that discussed that we can't use Kefalixin or Moxacillin because they don't reach sufficient concentrations, but this study is suggesting that actually it's.

Jame: 48:21

Well, i mean, i don't really know where this came from. I mean, you and me have heard this, haven't you in Nadosch North, about Kefalixin in particular, and I don't really understand the justification for it And I definitely don't think it's backed up by the evidence. So the JAMA network open paper that I've got here is, i think, a real nice paper, where they compare Ciprofloxacin, cotramoxazole and I think it's Comosoclav for step down therapies. They've received, i think, something like 72 hours of IV therapy for gram negative-battery-mia from a UTI from a urine source and they compare all three And really there's not much of a difference between them in terms of 30-day mortality.

Callum: 49:24

I feel like shorter is better as a field of research and microbios as constantly advancing and maybe on the horizon will be like actually you only needed the three days of IV to get effective therapy for the battery-mia. So maybe the reason there's no difference is because they were already effectively treated. But I think it is useful to say these drugs are effective. In terms of the duration we talked about there's a bit on the catheter associated with UTI, but generally so. In the UK a nice guidance suggests three days for a non-pregnant female and for all our indications, seven days treatment for a UTI And for pylentophytes. They say seven days, although they do say you use four days, seven days, unless you're using trimephram.

Callum: 50:11

Yeah, why is?

Jame: 50:11

that, In which case it would be 14 days.

Callum: 50:15

Why is it that they recommend 14 days for trimephram?

Jame: 50:19

I think it's because they don't really trust trimephram to get the job done And I can sort of understand their thinking, because I don't really trust trimephram in pylentophytes either. But I wonder if that's because of a historical eminence-based opinion rather than an evidence-based opinion.

Callum: 50:44

Yeah, because I feel like when I first started practicing medicine, pylentophytes was 14 days of therapy And now we've moved to seven and potentially we're moving to five. And on the Shorter is Better. Webpage by the Spellburg has summarized the evidence. There's nine RCTs comparing Shorter, saying that it's equal effectiveness, rather than saying one size fits all. When we talk about Shorter therapy, you really need to make sure that you're selecting the right patients for Shorter therapy. And so it's five days and review.

Callum: 51:15

So we're used to thinking about antibiotics. As you know, it must be the certain amount of duration and that's it. But I think it's much better to think about antibiotics as you give the shortest duration that's suitable for that patient. So if the patient is better at five days, they don't need more antibiotics. If they're not better, they potentially do need more. And the particular patients where you need longer is there's some sort of NIDIS or, like you know, point of infection, so that's things like they've got ureteric calculine or stones that organisms could be harbored in. There's some sort of plastic there, so like ureteric stents, catheter, or there's metal or there's a fistula like colovacyclofistula. Other reasons are things like patient factors. So that's you mean compromised host or transplant patients, patients in hematology, oncology, and then other factors might be some drugs, so like things like tuberculosis or fungal, things like Canada usually need a bit longer therapy just because they're, i guess, lower replicating organisms is potentially part of it.

Jame: 52:21

Yeah, and the therapy is less effective against them too. So I mean, i guess I'll say what I do. So if I've got a bog standard vanilla pyloh, i will default five days, unless there's a reason to extend or the patient is battery mick, in which case I will extend seven days because they're then, you know, gram negative battery mia. Again, in the short-term a better table is seven versus 14 days. And just to point out, in the same table for pylonephritis or complicated UTI, it's five or seven days versus 10 or 14. So the shorter refers to the five to seven day period, not the. There's never been a comparison of five versus seven, so we don't know if five is better or non-amphidia to seven, if you see what I mean.

Callum: 53:22

You really need to go read the studies, but I think you know, often with with urinary tract infections, you know the main things that's causing the patient like an uncomplicated infection is their symptoms And a lot we know, actually quite a lot of urinary tract infections will resolve without any treatment. Yeah, so we're looking at this from the antibiotics perspective, but from a, you know, patient perspective. Actually, if you never gave them antibiotics, they may well have gotten better. And the fact that you've given them antibiotics that's not necessarily the reason why they got better. And the flip side is true in the sort of more complicated end of the spectrum.

Callum: 53:59

So in pylonephritis, we know that the sort of natural history of that is that you get a big inflammatory response. You may well continue to have fevers, despite being the right antibiotics, and that can lead to people being worried that they're not getting the right treatment, they're not getting better, and then they extend the therapy because, oh well, they were slow to settle. Actually, if you look at the evidence you give short duration of therapy, even though they may be were slow to settle in terms of fevers and so on, it's no different. So, you know, is that differentiation between what is inflammatory response and what is actually the organism being there and causing infections, still needing antibiotics to be killing it? Yeah, true, wow, well, we've done a real deep dive there, i think, into urinary tract infection. I've certainly learned a thing or two, james, as you've talked through that. I really want to dig out the phosphor mycine for pseudomonas, just like drop that bombshell in some sort of MDT setting in your future. See how people react probably negatively.

Jame: 55:04

Well, at least now you've got you cast advice to kind of back up your assertion. So there's trial evidence out there as well, yeah And whatnot. So yeah, but I mean I guess you know, particularly when it comes to pseudomonas, we've got so few oral options that at least it's nice to have a couple of other tools in your belt. I know that I would you know if a GP phoned up saying you know, i've got a patient who's got a pseudomonas UTI and I can't use a quinolone.

Callum: 55:37

I'm not sure it would leap to phosphomycin or doxycycline, but I guess if they couldn't come to hospital or they didn't want to, and you're really stuck and you've got no other options patients are farmer and they're not leaving their farm.

Jame: 55:56

What do I do? You know? there's at least a couple of things that you can consider.

Callum: 56:02

Is the dose the same as just a three gram porous ashy?

Jame: 56:06

Mm-hmm.

Callum: 56:07

And then once and then. Well although Do you give a higher dose.

Jame: 56:12

Well, if you want to give more, because it's concentration-dependent killing, if you want to give a higher dose, you can just give it more frequently, And particularly for there was that recent trial for phosphomycin for oral step down of pylodifritus or complicated UTI from, I think, Brad Spellberg's group as well.

Callum: 56:36

So actually we're going to rename, not the Kefal-X and Appreciation Society Brad Spellberg, appreciation.

Jame: 56:41

Society, absolutely, but I think it was. The regimen was three grams every alternate day. So normally for UTI you would give you know, for women you would give one off, assuming that would last about 72 hours because of the PK of the phosphomycin drug, and for men you would basically repeat at day four and then consider the course finished. But this one, for a complicated UTI, was three grams on every alternate day for six days, you know, to E-Cout seven. So yeah, i think that was relatively effective. I think it was no inferior to their alternative, which was artipenem, i think Wow.

Callum: 57:28

Powerful stuff.

Jame: 57:30

Yeah. So I mean, you know, when you're dealing with UTI, you've got the potential to use some narrow spectrum agents, which will nonetheless be devastatingly effective And, as a stewardship intervention, that's worth considering. Questions, comments, suggestions. Why don't you send them into idiotspodcastingcom? Have a five star review in your pocket, calum, and I would love to have it. Please drop it in your podcast player of choice. We tweet at idiots, underscore pod, and if you want to donate directly to support the show, you may now do so. There's a link in the description. But until next time, i'm Jayne, i'm Calum. Bye.