23. The ID:IOTS guide to Carbapenems

Callum and Jame provide an overview of the Carbapenem class of antibiotics discussing: what they are; their spectrum of action (looking in particular at what they don't cover); resistance; how to use them; and side effects.

This site has a useful summary of the new formulation of carbapenems and their spectra:
http://www.microbiologynutsandbolts.co.uk/the-bug-blog/new-sweets-on-the-market-but-will-these-new-flavours-live-up-to-their-vibrant-colours

Here is the NEJM paper on Tebipenem Jame mentions:
https://www.nejm.org/doi/full/10.1056/NEJMoa2105462

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Transcript

 23. The IDIOTS Guide to Carbapenems 

Jame: Callum, I know what's coming, so I'm not sure I want to ask this, but how are you doing? 

Callum: I'm carb loading. I'm eating crisps. I always upend the packet to get the last few crisps. I carb append them. Are you happy? 

Jame: I'm not sure I'd describe it as happy, but I think we could all move on. Is it? 

Callum: Now my jokes are scripted by James, so. 

Jame: Funny that you should mention that Callum, because what are we talking about today? Carbapenems. Yeah, carbapenems. Everyone's favourite antibiotic, if you don't [00:01:00] know what you're doing. 

Callum: And if you do, to be honest. 

Jame: Yes, we're going to round out the beta latams by finishing with the carbapenems. We've previously talked about the penicillins. 

Yes. The Kevla Sporins we've mentioned Astrinam, which is in its own little class, and the last group to talk about are the carbapenems. So we'll talk a little bit about, you know, what they are and what they're covering. Talk about the spectrum, resistance mechanisms, how you should be using them, and we'll finish off with side effects. 

Callum: So, James, what is the structure of the carbapenems? 

Jame: Okay, so carbapenems, structurally they're very similar to the penicillins. There's kind of two main differences. The first is that in sort of position one of the beta lactam ring, instead of a sulfur atom, there's a carbon atom, and the molecule overall is sort of unsaturated. 

 [00:02:00] The main, the other big sort of difference that they've got is that they don't have a very big side chain when compared to the other beta lactams, your penicillins, your keflasporins. And because of that reason, they're not particularly allergenic. We've talked before about penicillin allergy and beta lactam allergy and how usually what you're allergic to is Not the belatham ring itself, but the side chain. 

Well, with carbapenems, there's not very much of a side chain at all. And so they are not particularly allergenic, which makes them good for use in penicillin allergic patients. It means they can be used relatively safely. They're sort of divided into two groups. Chemically, one group, one only contains ertopenem and group two contains all the other carbapenems that you've ever heard of. 

So do you want to list some off, Calum? What are the two that we mostly use? Let's start with them and then we'll mention the others. [00:03:00] 

Callum: So the two we use. Very commonly really are meropenem and ertopenem. More rarely are used imipenem, cilostatin, and doropenem. And then finally, relatively new antibiotics are used infrequently, mainly for drug resistant isolates as imipenem, cilostatin relabactam, and meropenem vaburabactam. 

Jame: Yeah, I suppose that the one that we use most commonly in Nadosh Royal Infirmary would be Meropenem. I, whenever I'm thinking about carbapenems, rightly or wrongly, I don't know how you feel about this, Carl, I think about that as the default carbapenem. And then. I think about what the others have or don't have as are relative to Meropenem's attributes. 

So, for example, we'll talk about this in a moment, but Ertopenem is once a day, whereas Meropenem's three times a day. I kind of [00:04:00] consider that the default number of times that you might give a carbopenem, not least because that's also the number of times a day you would give a Meropenem Cylostatin and Doropenem. 

 But Ertopenem also doesn't have pseudomonas, whereas meropenem does, and I sort of regard, , having pseudomonas as a fundamental quality of carpopenems, but it's one that ertopenem lacks. But because I think of meropenems as the kind of type drug for the class, I'm thinking of carpopenems as being anti pseudomonal in their effects. 

In terms of the other drugs, we don't really have direct experience of them. I've never used doropenem and imipenem xylostatin. Usually if you're, if you've got a carbapenem on the books at your hospital, it will be Meropenem or Imipenem xylostatin, usually [00:05:00] not both, there's not really much of a reason to have both of them on your list. 

People might be wondering what Celastin or xylostatin is, well Imipenem is metabolized in the kidney actually by something called dihydropeptidase 1. Xylostatin is a dihydropeptidase 1 inhibitor, it competes with Imipenem for being processed by this enzyme. And so by in doing so prevents imipenem degradation, prolongs its half life. 

So you don't see imipenem without xylostatin. So sometimes people talk about imipenem, but you will always prescribe it as imipenem xylostatin in combination. And then rounding out this sort of core four would be dodopenem. And dodopenem is You know, a carbapenem that I think is more commonly used in the US, but I think less and less there have been a couple of head to heads with imipenem xylostatin and [00:06:00] those trials resulted in less cure in the doropenem group and more mortality. 

And there's not even particularly an advantage with dosing. They're still three times a day, just like imipenem xylostatin, just like meropenem. So I'm not sure what the advantage would be. Of of using daughter penham. If a loyal listener knows, maybe they could write in idiots, podcasting at gmail. 

com. It's also doesn't even have an FDA license for treating pneumonias, which is kind of interesting. Whereas the others do and are, you know, used for treating pneumonias, particularly ventilator acquired pneumonia, for example, with regularity in, in need of infirmary. Those are the sort of core four carbapenems that are in common use. 

There are a couple of sort of new formulations on the block, and Callum mentioned these. These are imipenem xylostatin with relebactam. This is a beta lactamase inhibitor that is related to tasobactam. [00:07:00] And it is a class A and C, but not D, beta lactamase inhibitor. So 

Callum: what's a beta lactamase and what does the class A and C mean? 

We'll tell you next episode, we're going to do beta lactamase. 

Jame: Yeah, we're not going to cover it now. But just suffice it to say that this kind of prolongs or extends the spectrum of activity of imipenem considerably. And then meripenem vabor bactam is another. A combination of meropenem with a beta lactamase inhibitor and Vabrobatin in particular inhibits KPC carbapenemases. 

So those in the know will know that there are kind of five big carbapenemase enzymes. KPC, standing for Klebsiella pneumoniae carbapenemase, we mentioned it briefly last week, is one commonest carbapenemase. And so something that inhibits KPC. And [00:08:00] it means, therefore, that you can still use meropenem would come in handy in quite a lot of situations. 

And so this formulation of meropenem vaborbactam has been developed. Callum, talk about the spectrum of carbapenems. What do they cover? 

Callum: Yes, I think this is a common question that you get posed as an infection specialist by colleagues is it's often jokingly done, but they're just. You know they boil down the treatment of infection to, well, why don't you just use Tazosin for everything. 

 Or the more extreme is, , why don't we just give everybody Meropenem. And now there's, , various reasons. I think one, Meropenem doesn't, and carbapenems don't work for all infections. And two , if we use our, essentially our, Some of our best antibiotics for everything and we'll drive up resistance and then we won't be able to use them. 

So stewardship is [00:09:00] really a big part of carbapenems because they are really good and they have a really broad spectrum. And for that reason, it's almost easier to say what they don't cover rather than what they do because they have very broad gram positive, gram negative and anaerobic cover. So intrinsic resistance to carbapenems exists. 

Has coined the term, stay alert, Elizabeth. So yeah, that stands for Stenotrophomonas multifilia, Aromonas species, and Elizabeth Kingia, Meningoseptica. And Elizabeth King was a very famous American microbiologist. It's named after her. It's a gram negative organism. 

Yeah, 

Jame: these are all gram negatives. They just happen to have intrinsic resistance to carbapenems. 

Callum: You don't see Elizabeth Kingia that often clinically and aeromonas is really a kind of waterborne infection. Sometimes you see it in wound infections. Stenotrophomonas, however, you do quite commonly seen causing hospital acquired [00:10:00] infections, particularly in patients With chronic respiratory disease, you've had a lot of antimicrobial exposure and, , essentially we've killed all their normal flora and they get colonized as senatrophomonas and it can be really problematic because there's limited therapies for it, which I won't go into now, but carbapenem's you know, you often give people the carbapenem and then the stenotrophomonas starts brewing in the respiratory samples. 

 Other intrinsic resistance examples, so imipenem serratia species and proteae are intrinsically resistant to imipenem, but not to the others. Carbapenems in general, in terms of gram positives, don't have good enterococcal cover. And there's some debate on that, but in general, if you're, treating someone and you're worried about intracochal infections, like I'd say intra abdominal infection or some sort of hospital choir, they've got lines, then you would add in something like vancomycin, use vancomycin, meropenem would be [00:11:00] quite a common combination. 

Jame: The other big gram positive that it wouldn't cover would be MRSA. For reasons mentioned prior, if you've got a target modification, which is the underlying cause of MRSA, then all beta latams are essentially out. That PBP is no longer going to be targeted by carbapenems. 

Callum: Now, other things that carbapenems don't work against that works on inhibiting cell wall synthesis. 

So organisms that don't have a cell wall, so Plamenophila pneumoniae and Systachy Coxiella burnetti or Q fever Mycoplasma pneumoniae all wouldn't be covered. So just something to think about if you're got patients at risk of say an atypical pneumonia, and then those are important causes of those that you wouldn't be covering of just a mirror Meripenem or another carbapenem and then specifically for ertopenem. 

So people say that there's a hole in the middle of ertopenem [00:12:00] and it's an ape. There's other ways of remembering as well, but A P E are three letters in the middle of ertopenem and they stand for Acinetobacter species, Acinetobacter bomonii, Pseudomonas And intraocular. So ertapenem doesn't have any activity against them, really. 

 The ertapenem doesn't have any activity against Pseudomona full stop. Whereas Meropenum and Imipenem often, but not always have activity against Pseudomona. 

Jame: Yeah. So I guess that those overview of what they don't cover those intrinsic resistances there you're really talking about Meropenem and Ipen slatin spectrum there and. 

, that's quite a long list that you've said. Meropenem covers just about everything else, or carbapenems cover just about everything else. So like all your gram positives that you've, we've gone through, the gram negatives that we're about to go through, it's got great anaerobic cover. It covers just about [00:13:00] everything, except these things. 

Stuff without a cell wall. Stuff that's intrinsically resistant, the Stalite Elizabeth organisms, and there's a couple of intrinsic resistances to Serratium Proteus, to Emapenum, and Enterococcus, again, you wouldn't trust, but that's about it, , so for most of the stuff that we're trying to treat, Acarbapenum would cover just about everything. 

Callum: There's other organisms that have intrinsic resistance aren't really that clinically important. 

Jame: True. Bacillus cereus. Cereus. Yeah. , barely ever needs treatment. That's the common cause of food poisoning that lasts about 24 hours. 

Callum: Intrinsic resistance. What about acquired resistance? This is the big concern with these. 

We're going to we're quite fortunate in Scotland that we have very low rates of acquired carbapenem resistance, but other parts of the world are not so fortunate. And it is a major [00:14:00] issue. Most common the encountered problem will be carbapenemases. And James touched on that earlier on when he talked about carb Klebsiella pneumoniae carbapenemase. 

 We're not going to go into that detail because we're going to do a whole episode on it. It's a big topic. 

Jame: Yeah. Yeah. We'll talk about beta latinamases next week or next episode. Beta latinamases are hydrolytic enzymes which break up the beta latinam ring, thus inactivating whatever drug they're targeting at. 

Carbapenemases are a particular class of beta latinamases. They are a worsening problem world over, mostly because of overuse of carbapenems. They're really interesting. They're a bit difficult to wrap your head around, but we will talk about them later. 

Callum: Other things you can get acquired resistance, so you could get non carbapenemases. 

Carbapenemase, beta lactamases, so basically beta lactamases that don't break down carbapenems. But sometimes if you get that and some other mechanism of resistance, so say hormone loss, which is the way the [00:15:00] antibodies get into the cell. Yeah, this is an 

Jame: example of resistance mechanisms building on each other. 

So if you just had an AMPC organism, carbapenem would work. If you just had an organism that had lost proteins, it probably still would work. But if you have two of them on top of the other, because although AMPC is not a carbapenemase, for example, just take it for example, it still has a little bit of activity. 

It just won't be enough to actually mean that you can't use the drug anymore. But if you layer that on top of something else, which means that the drug is having a hard time getting into the into its target site, then you can get resistance developing. 

Callum: So in general, I don't think we've spoken, said this before, but there's four main types of drug resistance, which is efflux pumps. 

 So the cell of the bacteria pumps the antibiotic out of the cell inactivation of the antibiotic substance. So that's enzymes usually. [00:16:00] So that's like the carbapenemases target bypass. So that's where they just say, we're going to. We don't need that. We're going to do something else. So for example, vancomycin resistance in intracocci and in target modifications. 

So they again, change change the target so that the antibiotic doesn't bind to it. Yeah, like MRSA. There we go. Cause it's got a different penicillin binding protein. 

Jame: Lastly there are some resistance mechanisms specific to Pseudomonas and Arthrocannabinol. 

Callum: Yeah. So ertapenem. Has no activity against Pseudomonas from the get go. 

Pseudomonas can have carbapenemases. It can also just through up regulated efflux pumps become meropenem resistant, and that's very common. And it can become resistant to imipenem by having poor loss of something called OPRD. So you often see [00:17:00] pseudomonas isolates becoming resistant to meropenem, and it doesn't necessarily mean it's got a carbapenemase. 

In our lab, we have a set of rules where we say, , if it's got meropenem resistance and also resistance to a couple of other things, I think it's peptaz and or keftazidine, and then you would go ahead and look for a carbapenemase. But most of the time you say it's just due to upregulated defunct. 

How do we use carbapenems or how? When do we not use them? I guess there'd be another question. 

Jame: Well, I think here we need to lay the groundwork there for people that unless you're using them as part of an established protocol or that on the advice of infection specialist or a microbiologist, you probably shouldn't be using them at all. 

 So these are in the WHO classification of access, [00:18:00] watch and reserve antibiotics. These are very much reserve antibiotics. Carbapenemases are, carbapenemases producing organisms are becoming a worse and worse problem. They have a not insignificant C. diff risk associated with them. The more we use them, the less we will be able to use them in the future. 

So I don't think that unless you are an infection specialist, you should be using them at all. In terms of how we use them, they would be sort of considered first line if you were dealing with an ESBL or an abc producing organism, which meant that you. Which meant that you couldn't use other beta lactams that you might normally use, penicillins, keflasporins, or peptaz, things like that. 

Or you didn't want to use or didn't have access to things like temosilin or astrenan, which we've discussed in our weird beta lactams episode. [00:19:00] 

Callum: Yes. So part of a protocol on the advice of infection specialists. So when would you consider using it? You said ESBLs, Amp Cs. What else? 

Jame: Well, for erythropenia in particular, because it's once a day, there is it can be used in the OPAT setting. 

And so that's , a reason that erythropenia is used quite a lot. If you've got an organism which is keftraxone resistant, let's say, or say the patient has an allergy and you need to use once a day antibiotics, well erythropenia is an option that you could use there. Okay. Thanks. It's interesting, when you have access to OPAT settings, which use 24 hour infusions of antibiotics, and that means that they are then able to use things like, you know, tazosin, for example your, the use of vertapen drops a little bit. 

And that's the circumstances where I'm working at the moment, but in [00:20:00] other places where you're still, you know, the patient comes in once a day, they get an IV infusion, they leave, they come back, you know, traditional standard OPAT, eryopenem can be quite useful for treating kind of complicated UTIs, for example, whereas stuff like meropenem, because there's three times a day, you can't really do that very easily. 

Callum: Yeah. Well, you can get Meripenem on a 24 hour pump as well. 

Jame: You can do, yeah. And actually the guy Mark Chrislip, who used to run the Pusscast, he still has a a podcast called A Goblet of Puss, in which it's like three to five minute kind of cases that he's been dealing with. And I've just been diving through the back catalog. 

And he did mention at one point he had a complicated infection where he, For some reason, he couldn't use air to pen in the he operates in America. So there was some sort of billing issue and patient had kids. So they couldn't come into hospital. They couldn't go to a nursing facility to get daily antibiotics. 

So what he did was he [00:21:00] gave her Maripenem. With probenicid to prolong the activity of the meropenem so that he was getting meropenem once a day, which normally you would never do, but giving it with probenicid to delay its excretion and achieved clinical cure that way. And there have been kind of moves to try and use things like. 

You know, this is not a carbapenem thing, but trying to use things like cefazolin and other antibiotics with prevenicid so that they could be used kind of once a day and almost in like an OPATI setting or in nursing homes, for example, to increase the number of drugs that we've got that we can give, you know, one shot. 

Once a day, and then it will have 24 hours of activity. The other thing that we probably should mention is that there are oral carbapenems on the horizon. So all of the carbapenems we've mentioned so far, they're all IV only. There are actually a couple [00:22:00] of carbapenems which are can be given orally although they're not given orally very a lot, but these are drugs which only have a license in Japan. 

They are Biapenem and Panepenem but more recently there is a drug called Tebepenem, and the loyal listener may have heard about this because there was a New England Journal of Medicine article published comparing oral Tebepenem with IV erthopenem once a day for complicated urinary tract infections. 

It's a non inferiority study and the endpoint was, it was achieved non inferiority the oral tebupenem and this got published in Negem. I think a lot of people thought that was, , quite interesting and quite nice to have another option for treating complicated UTI unless you were an infection specialist or microbiologist, in which case [00:23:00] you thought, Oh God, people are going to get their hands on oral carbapenems now. 

And the stewardship implications of that are pretty probably keeping a lot of people up at night. And at least myself, one of the. Advantages, in air quotes, of having something that's only IV means that when you're prescribing it, it has to be in certain scenarios, , in hospital, in, as part of OPAT. 

Having tebupenem available to does not fill me with joy, let's say. 

Callum: Yeah, I do. I do worry. I don't think it's about that setting. I think it's about settings where you can, that should just go to the pharmacist and say, I want this drug and buy it. I think that's where the real worry is going to be. So we've talked a bit about how to use them. 

And I guess the setting, the general setting is, you know, you're going to be using them in patients who have either confirmed or you suspect. Drug resistance. That's generally where we're going to be using it is patients that have, you know, hospital acquired infections in particular, or are there reasons to make you think this [00:24:00] person's at risk or another option would be, you know, someone who's incredibly unwell, maybe it's got a septic shock, there might be an ICU and you really can't risk not covering something. 

So you want really broad coverage. Often there's phone calls. to discuss patients who are unwell. And it's, I think one of the most difficult conversations to have with a clinical team, you know, I've got this patient there, they're unwell, although they may be not in septic shock, but maybe they've got bad pneumonia and they've been on Tazosin or Coloxaclav and we want to give them Meropenem. 

And because it is such a good drug and it has a good spectrum of activity It's really hard to say no, because you know, everybody knows it's probably a, you know, a good treatment option. All those individual discussions and patients add up to having this big weight of selection pressure for drug resistance. 

[00:25:00] And so you're really, In all these discussions, I find it, I find that really hard when someone's like, I want to give this individual patient meropenem and often it might be better for them. Although it does come a risk, , the more of your, the wider spectrum of antibacterial you give, then the more at risk you become of things like candidal infection. 

And that might just be, , a bit of mucosal candidiasis, but it might be something invasive, like a candidemia or otherwise. And you're wiping out a lot of the flora, so I often make that argument and often say, , actually, let's just wait and see, , if they're not that well, if they're in shock, then I think it's quite reasonable to escalate. 

Jame: Well, I mean, if it's been less than 24 hours, like sometimes those calls come up and the patients had one dose. Yeah. And you think, well, like antibiotics, people think that antibiotics work instantly. No, they don't. They take 24 to 48 hours to work. And that means that if the patient is going to die within that next 24 hours, there's [00:26:00] nothing you can do about it. 

 And that's a hard fact for clinicians to accept. I don't, certainly don't like the idea that there's nothing I can do to stop someone from dying. But that's the situation that you find yourself in a lot of the time. 

Callum: , you sometimes find yourself on the other end of the phone saying, actually, it sounds like this patient is very unlikely to survive. 

And it's giving them, , a carbapenem best thing to do. It's this sort of mentality of, well, we should just try everything. And, actually have to be like, is this realistic medicine? , you're giving the meropenem to feel like you're doing something, but actually it's futile. 

Jame: And that can go like two ways, can't it? It can go the, you want to give a carbapenem, but what you should be doing is pulling out. And sometimes it's worth a go. And, , the way that I justify this to myself is if the patient does die, all the carbapenem resistant bugs are going to die with them. 

[00:27:00] And so I If they do die, I'm probably not going to be contributing to the hospital's burden of carpepenemes producing organisms. 

Callum: I don't know if it's quite as simple as that, because you only give antibiotics, we know they're in the environment and then they're in the drain and, , is that more of the use rather than 

Jame: If there is always the chance that they are infected with something that the current antibiotics aren't treating. 

And, , that's Obviously, particularly a problem in intensive care, the intensive care population, but it can be also a problem in the old exposed to lots of health care, , elderly population. And so, although I, , I think we should be stewards for carbapenems, , upon discussion with the clinical team suggested carbapenems, a trial of carbapenems, give it 24 hours, that kind of thing to see if the patient does clinically improve. 

And sometimes people just need one more day. 

Callum: I think there's a lot more to say about antimicrobial stewardship and it's probably something we should speak about on its [00:28:00] own. 

Jame: Yeah. Cause it's not just about saying no, it's about making a decision that's in the patient's best interest, but balancing that with the interests of future patients. 

That's how I try and can give meropenem and vancomycin and metronidazole and ambazome, and you would cover just about every organism that walks upon the earth. But that's not what we do to people. 

Callum: Disinject 

Jame: them with detergent whilst you're at it, James. Yeah, exactly. I mean the ultimate cure of infection is a tactical nuclear strike because that eliminates absolutely everything within its blast zone. So that in many ways, the ultimate antibiotic, but there's no point. I feel 

Callum: like there's some, I think like Stenitrofamona, , some bacteria will be able to survive. 

Something 

Jame: would get through. That's 

Callum: right. Pseudomonas. 

Jame: But you know what I mean? Like you can give broad spectrum antimicrobial therapy to everyone, but then you are going to produce new problems. Resistance down the line, and side effects of those [00:29:00] antibiotics. Speaking of which, Callum, the side effects of carbapenems? 

Callum: I had a very good medical consultant when I was a student, and he said that every drug's got the same side effects to start off with. I think I've said this in an episode before, but it's 

Jame: Oh, so you have, what are they again? 

Callum: GI upset. Rash? Rash. Oh, allergy. Allergy. 

Jame: Although, yeah, although as stated, carbapenems are not particularly allergenic, people do get allergic to them. And the loyal listener may want to recall that the cross reactivity between carbapenems and the other beta lactamases is equivalent to the background incidence of people randomly becoming allergic to unrelated drugs, so there's not a lot of cross reactivity at all. 

 In terms of other side effects yes, diarrhea, phlebitis at the injection site, about 4%. That was interesting, I didn't realize that. A mild derangement [00:30:00] of the LFTs is reasonably common at 6%. In terms of stuff that you might see in the blood, it can cause eosinophilia on its own and it can cause eosinophilia as part of the dress syndromes. 

That's drug reaction with eosinophilia and systemic symptoms. This is a severe reaction, which would be a reason for discontinuing the carbapenem and never giving the patient another carbapenem ever again can cause neutropenia with prolonged use particularly. So you sometimes see that in the oat setting. 

 Don't you cal? And then the other thing to mention, which yes. is true of all beta lactams, but is commonly, reasonably commonly seen with carbapenems is they can lower your seizure threshold. So we like carbapenems because they cross the blood brain barrier, but that has a side effect, which is that there's, you've never a lot of beta lactams sitting around in your head or changing the mechanics of how action potentials are propagated in neuronal tissue. 

 Penicillin also penetrates the blood brain barrier quite nicely, but high doses of [00:31:00] penicillin are associated with seizures. Outside of the ITU population, this risk is really low, and in particular with ertypenin and imipenem xylostatin, the risk is quite low compared to, say, meropenin, but even with meropenin, you would not be seeing this commonly, apart from in an intensive care setting where they're using, , say, two grams three times a day for a prolonged period of time in a prone patient, as in a patient who's prone to getting seizures, not a patient who's lying on the stomach. 

Callum: So we've talked about what carbapenems are, we made a really terrible pun, we talked about their spectrum of activity and what they don't cover, we talked about how to use them, in particular how to try not to use them, but they are very good. And finally, we ended up with side effects. 

Jame: That's it. So thank you very much for listening questions, comments, suggestions. 

Why don't you send them into idiotspodcastingatgmail. [00:32:00] com. Fancy writing a five star review? Why don't you put that in your podcast app of choice? Until next time, I'm Jane. I'm Callum. See you then.