34: Febrile Digest - Enterococcus in IAI, Pharmageddon

Sara Dong: 00:00:08

Hello everyone.

Sara Dong: 00:00:09

Welcome to Febrile- a cultured podcast about all things infectious disease.

Sara Dong: 00:00:13

I am your host, Sara Dong, a Med-Peds ID fellow.

Sara Dong: 00:00:16

I'm back with our newest Febrile Digest, which are these newer, shorter episodes that will be space for us to learn about different ID related items or questions.

Sara Dong: 00:00:25

And so the Febrile case-based episodes are going to continue to come out every other week, but now we have these bonus Digest episodes in the gap weeks for more content.

Sara Dong: 00:00:34

So today I'm joined by Scott Crabtree and we're going to chat about a common ID curbside or consult question, and some exciting news about a MedEd resource called Pharmageddon.

Sara Dong: 00:00:45

Scott, can you tell us a little bit about yourself?

Scott Crabtree: 00:00:47

Thanks for having me on.

Scott Crabtree: 00:00:48

So I'm currently an Assistant Professor at UC Davis in Sacramento, California.

Scott Crabtree: 00:00:54

I've been practicing independently for about maybe five or six years now.

Scott Crabtree: 00:00:58

I did my residency, uh, initially with the Air Force in San Antonio, then, uh, they allowed me to separate for a few years, go up to Dartmouth Hitchcock in New Hampshire for my fellowship.

Scott Crabtree: 00:01:09

And then I went back to the military for a initial five years for my service commitment.

Scott Crabtree: 00:01:15

They freed me up and I've been at UC Davis ever since, where I do a lot of clinical medicine, clinical infectious disease, and including antibiotic stewardship and infection.

Sara Dong: 00:01:25

Great.

Sara Dong: 00:01:26

And we're going to get into a little bit more Pharmageddon at the end of the show.

Sara Dong: 00:01:30

I'll start us off by asking this question that I think it actually comes up pretty often.

Sara Dong: 00:01:35

I've noticed that sometimes people call when they really want a patient to go home because they noticed that they look in an intra-abdominal abscess culture, which has been drained, and the culture show Enterococcus.

Sara Dong: 00:01:47

And that's what we're going to talk about today.

Sara Dong: 00:01:49

This question of when do we treat enterococcus in intra-abdominal infections?

Sara Dong: 00:01:54

So I, I don't think that's a very, a totally clear yes or no answer.

Sara Dong: 00:01:58

And I wanted to hear what your thought process is and how you think about this question.

Scott Crabtree: 00:02:04

Yeah, it's definitely a common question and a, in a tricky question.

Scott Crabtree: 00:02:07

Um, one that we get both on the consult service and the stewardship service, uh, usually as you said, when they are about to go out the door.

Scott Crabtree: 00:02:16

I would say that there, there is an easy version of the question, which is, do we need to cover it empirically at all?

Scott Crabtree: 00:02:22

Because with the intraabdominal infections, you know, there's hypothetically a whole host of organisms that we can encounter that we don't routinely cover for.

Scott Crabtree: 00:02:32

And I think when it comes to Enterococcus, there is quite a bit of data out there, including good randomized clinical trial data using antibiotic regimens that both have Enterococcal coverage and those that don't.

Scott Crabtree: 00:02:43

Those all fairly consistently seem to show that, especially in low risk individuals, that the outcomes are about the same, but in scenarios where we do have cultures and we do grow it.

Scott Crabtree: 00:02:54

Then that's where things I think are a lot more gray.

Scott Crabtree: 00:02:57

Looking at those same clinical trials, we do see a, that Enterococcus is encountered, like we would expect, but it is in a small portion of, of cases, you know, only probably about 10 to 20% and most people who don't have risk factors for it.

Scott Crabtree: 00:03:12

So then the sub-analyses that they do, if they do try to look at that question specifically on where the outcome is in the cases where the cultures have grown Enterococcus, they're, they're often under powered to see a statistically meaningful result.

Scott Crabtree: 00:03:25

That said, most of the trials don't seem to suggest a difference in outcomes.

Scott Crabtree: 00:03:31

But, it does leave it a little open-ended.

Scott Crabtree: 00:03:33

So as often the case in infectious disease, when we don't have clinical trial data, we return to our observational studies, which are usually easier to do, can really focus on the, the question we have in mind.

Scott Crabtree: 00:03:46

When it comes to those studies, the biggest problem we then encounter is this, all the, uh, all the variables that go into managing an intraabdominal infection, which is, you know, which part of the abdomen, which organ system is actually involved, what kind of source control was utilized, was it considered effective or not, whole lot of things.

Scott Crabtree: 00:04:06

And it's hard to control for all those variables.

Scott Crabtree: 00:04:08

That said, there clearly, I would say from my perspective, it seems to be association with potentially worse outcomes people who have Enterococcus in their cultures, but it's still pretty open as to whether a targeted antibiotics makes a significant clinical impact or not.

Sara Dong: 00:04:27

Yeah.

Sara Dong: 00:04:27

Great.

Sara Dong: 00:04:28

Um, so in the Consult Notes for this episode, we will put links to these prior trials, uh, that compared these regimens that were active against Enterococcus for community acquired intra-abdominal infection versus those that were not.

Sara Dong: 00:04:43

And so generally this was a combination comparing a group of patients who received pip-tazo versus something like cipro + metronidazole uh, and really none of the papers- so Cohn from 2000, and then there's a handful of papers from the nineties.

Sara Dong: 00:05:01

None of these really showed a clear advantage to treating Enterococcus in the, like you were saying, low-risk community acquired intra-abdominal infection setting.

Sara Dong: 00:05:12

We do have IDSA intra-abdominal infection guidelines that are archived now but are from 2010.

Sara Dong: 00:05:20

And we have another set of guidelines that are put out by the Surgical Infection Society that were revised.

Sara Dong: 00:05:27

They actually contributed to the IDSA guidelines originally.

Sara Dong: 00:05:31

Could you talk a little bit about what those guidelines recommend in these settings?

Scott Crabtree: 00:05:36

Yeah, no, the IDSA guidelines are, I think, a really good start.

Scott Crabtree: 00:05:40

And I think they actually kind of highlight the problems and they break it down into community onset hospital onset intraabdominal infections, and then, uh, basically risk of complications and disease severity.

Scott Crabtree: 00:05:52

And where they give their strongest, you know, I-A recommendation is that scenario where we started with is if you are just treating empirically, um, in that you provide citations to all those, uh, randomized clinical trials, which showed there is no benefit.

Scott Crabtree: 00:06:06

Where the guidelines get a little more wishy-washy, is in the latter scenario that we kind of talked on, but the way they break it down is basically kind of a risk-benefit kind of assessment on what is the probability of bad outcomes, if we don't treat this, uh, sufficiently?

Scott Crabtree: 00:06:22

Depending on, you know, getting things like source control and, uh, how sick the patient is.

Scott Crabtree: 00:06:27

And then what's, what's the alternative treatments that you would be offering them?

Scott Crabtree: 00:06:31

And so they do suggest that in some cases, but they're all like II-B, III-B level recommendations, that you might consider treating, particularly in those who are higher risk, such as hospital onset, immunocompromised, post-surgical infections, where the risk appear to be greater.

Sara Dong: 00:06:48

You know this question of whether patients with Enterococcus isolated in abdominal cultures seem to fail more or do worse is interesting.

Sara Dong: 00:06:58

And we'll put some links to the papers that have reported isolation of Enterococcus as a risk factor for treatment and death, uh, which was generally reported in some of the studies from the late nineties and early 2000s..

Sara Dong: 00:07:11

Uh, but in recent years, a couple of things seem to have come out that suggests that maybe there's no difference in how these patients did.

Sara Dong: 00:07:17

And there's one example from a paper by Sanders and others from 2017, that actually did a posthoc analysis of the STOP-IT trial and stratified patients into two groups based on isolation of Enterococcus, and they didn't really see any signs of increased or more severe complications.

Sara Dong: 00:07:36

And, you know, I think if you look at some of those initial trials we've mentioned, some of those patients did find even if they grew Enterococcus and didn't have Enterococcus targeted therapy.

Sara Dong: 00:07:47

I think we're still figuring this question out, but I would say my suspicion would be that these patients do okay even if we don't target the Enterococcus.

Sara Dong: 00:07:57

Obviously you have to take it case by case, but I think for, for most cases, it seems like it probably isn't quite as bad as it was originally billed.

Scott Crabtree: 00:08:10

Yeah, there are definitely, as you mentioned, some, some new research that hasn't, I don't think been incorporated really into either guideline yet.

Scott Crabtree: 00:08:16

Uh, some of which has been observational and some of which was a meta-analysis of, um, the randomized trials.

Scott Crabtree: 00:08:25

The meta-analysis of the randomized trials was, I think posted just this last year in the Surgical Infection Journal.

Scott Crabtree: 00:08:32

Um, unfortunately didn't really break it down though, into those who have confirmed Enterococcal disease versus just empiric use.

Scott Crabtree: 00:08:41

That gives us some additional information because it kind of synthesizes all the prior, evidence, uh, clinical trial evidence.

Scott Crabtree: 00:08:48

But it didn't really focus on the specific question of, of when we do have Enterococcus in our cultures.

Scott Crabtree: 00:08:55

But there was another study, which I think you were alluding to, uh, there were probably multiple ones.

Scott Crabtree: 00:09:00

Maybe some that I'm not familiar with, but one by, Fabre, et al published in OFID just a few years ago that, uh, avoided some of the problems that we've had in that we've, with too small of a sample size.

Scott Crabtree: 00:09:11

They actually had, uh, between the two study arms, over 200 patients with Enterococcal infection, about a third received ertapenem and about uh, two-thirds received pip-tazo.

Scott Crabtree: 00:09:23

Sometimes with, you know, these observational studies, uh, the two study arms are, are different in many ways beyond just the antibiotic, but in this case, they're actually fairly well matched.

Scott Crabtree: 00:09:32

And, while there still could be some confounding, we're not able to identify, the outcomes definitely in that situation, were pretty much the same when it comes to both recurrence and mortality.

Scott Crabtree: 00:09:43

So that certainly would be a, I think, the best evidence we have today that perhaps we don't need to treat it if we see it.

Scott Crabtree: 00:09:50

Just to kind of say how I usually apply to these situations, the whole risk benefit assessment is -- well, what are our alternatives if we are not going to cover the Enterococcus?

Scott Crabtree: 00:10:04

If it's a matter of piperacillin-tazobactam versus ceftriaxone and metronidazole, well, the toxicity risk are fairly similar, the spectrum is for most part, fairly similar, aside from some anti-pseudomonal coverage, uh, that you would additionally get, and both of course all intravenous.

Scott Crabtree: 00:10:20

So by and large, uh, the risk of changing to a regimen that targets the Enterococcus is, is pretty limited.

Scott Crabtree: 00:10:27

And so I would say if you're not really, it's not really costing you much to target it, uh, it may not make a difference, but, you know, perhaps it will, uh, help.

Scott Crabtree: 00:10:36

Conversely if they have, you know, anaphylaxis to penicillins and you can't use pip-tazo or ampicillin uh, to target Enterococcus faecalis, which is what we usually need to target when it comes to these, uh, infections.

Scott Crabtree: 00:10:49

And you've got to use some like vancomycin or something, a wholly different agent, usually wholly additional agent.

Scott Crabtree: 00:10:54

And to me, it is certainly more toxic potentially.

Scott Crabtree: 00:10:57

At least then depending how they've evolved clinically, because usually this point, you have a, a couple of days of clinical response, uh, to their initial empiric treatment.

Scott Crabtree: 00:11:06

If you're doing better, a lot of times, I think you can make a pretty good case for, for, for not doing anything.

Scott Crabtree: 00:11:10

Um, and going back to the IDSA guidelines, um, back from 2010.

Scott Crabtree: 00:11:15

One of their bullet points is even that if, uh, you have someone who's clinically responded and then you find an organism, uh, three days later that is growing culture that is resistant to the appropriate regimen, uh, you know, if you have source control and they've done well, you probably don't need to cover it in most cases.

Scott Crabtree: 00:11:29

And I think that's, uh, a good thing, a good general rule.

Scott Crabtree: 00:11:32

I think that applies into Enterococcus.

Sara Dong: 00:11:34

Yeah.

Sara Dong: 00:11:34

I feel like as a fellow, we get that call more often than I was expecting.

Sara Dong: 00:11:41

Um, so, you know, we, I felt like this was a really nice question for ID fellows and also hopefully for faculty to take a step back for all of us to think about, um, sort of what the evidence was, but we have a range of learners I think that listen to the show.

Sara Dong: 00:11:56

And so I wanted to see, you know, what are your pearls and like high yield take homes thinking about antibiotics and Enterococcus?

Scott Crabtree: 00:12:05

Yeah.

Scott Crabtree: 00:12:05

I think Enterococcus is kind of unique organism.

Scott Crabtree: 00:12:08

That probably could be said about a lot of bacteria, especially if you ask infectious disease physicians.

Sara Dong: 00:12:11

Um, they're all very interesting.

Scott Crabtree: 00:12:15

Yeah.

Scott Crabtree: 00:12:15

I would say one, one thing that I always emphasize is that generally speaking, compared to Staph aureus or Pseudomonas, they are not generally highly virulent organisms.

Scott Crabtree: 00:12:26

Not that it can't cause disease, they certainly can, but, uh, just because they're there, they don't always necessarily need to be treated depending on the clinical context.

Scott Crabtree: 00:12:32

And here, I think we've made a pretty good case that often they don't.

Scott Crabtree: 00:12:36

But the biggest thing with Enterococcus, why it gives us so much heartburn and so many headaches in infectious diseases is the resistance issues, um, particularly because teams and primary, uh, providers often forget they're inherently resistant to a lot of the antibiotics we'd like to use, including all the cephalosporins, which, are, you know, ceftriaxone is the backbone of a lot empiric regimens, as it should be, and it's not going to cover Enterococcus.

Scott Crabtree: 00:12:59

Uh, but even things we'd like to use for UTIs sometimes or for skin soft tissue infections, such as clindamycin, and trimethoprim-sulfamethaxazole , it's resistant to those as well.

Scott Crabtree: 00:13:10

I will also say that they don't often, they aren't reported on sustainability results because it's taken for granted that, uh, it's resistant in everyone should know that., Uh, being aware of that will, will help you, uh, avoid some of common mistakes.

Scott Crabtree: 00:13:25

Um, yeah, and I would only, I think I'd like to point out, uh, with, with learners is that we always focus on the two species of Enterococcus that are the most frequently encountered, Enterococcus faecalis and Enterococcus faecium.

Scott Crabtree: 00:13:37

Though there are a few other Enterococcal species.

Scott Crabtree: 00:13:39

There's kind of two things that keep in mind when you first see them and you're waiting for additional testing results is that Enterococcus faecalis is usually the more aggressive of the two, typically the one that's causes endocarditis and more severe disease, but it's also usually the more susceptible one.

Scott Crabtree: 00:13:57

VRE is almost always Enterococcus faecium uh, whereas Enterococcus faecalis is almost always ampicillin susceptible.

Scott Crabtree: 00:14:05

It gives you some, some useful information, just knowing the species, um, that you can then apply to your patient.

Scott Crabtree: 00:14:12

And as time goes by, uh, it can help kind of guide your management.

Sara Dong: 00:14:16

Yeah, one of our attendings, well I guess I should just shout him out, Howard Gold, he always says, uh, faecium ends with M and it's, more multi-drug resistant.

Sara Dong: 00:14:25

And I think all the fellows, we all remember that.

Sara Dong: 00:14:28

And I don't know if he taught me that or if a fellow who he taught that to taught me that, but, uh, another, uh, way to remember the "M" as a more drug resistant or multi-drug resistant.

Sara Dong: 00:14:41

But I think that's a really great point about thinking about the two species that we see.

Scott Crabtree: 00:14:45

Yeah.

Scott Crabtree: 00:14:46

I think whatever, whatever works and it certainly isn't one way to learn to memorize it.

Sara Dong: 00:14:50

Well, to end, I wanted to hear more about Pharmageddon because I Pharmageddon uh, as ID learners, we obviously like to hear about ways for us to think about antibiotics, but also as a way to teach others.

Sara Dong: 00:15:03

And I'd love to hear about what you've done with Armageddon and, you know, what's coming up with that and ways that you feel like we could use that to incorporate into our teaching.

Scott Crabtree: 00:15:14

So Pharmageddon is, is a simple card game focusing on antibiotics and microbiology.

Scott Crabtree: 00:15:20

It's just another way to learn beyond, you know, flashcards and textbooks.

Scott Crabtree: 00:15:25

Games are an underutilized way of, of learning.

Scott Crabtree: 00:15:28

I think things like games and podcasts and infographics, stuff that you're doing are really, um, help things.

Scott Crabtree: 00:15:35

It's the basic game.

Scott Crabtree: 00:15:36

Uh, and I can just summarize it real fast.

Scott Crabtree: 00:15:38

Essentially, there's, you have two decks, a deck of a bug cards, which are your bacteria and clinical syndromes, and a deck of a drug cards, which is your antibiotics.

Scott Crabtree: 00:15:47

And it can be played, uh, both competitively or cooperatively, uh, and you can even play it alone.

Scott Crabtree: 00:15:52

It's more than just a matching game where you match your, your bug to your drug.

Scott Crabtree: 00:15:57

Really, the goal is to use the best antibiotic, kill the most pathogens, with the least amount of side effects.

Scott Crabtree: 00:16:04

So in that sense, it's actually also a stewardship game and it can be played, uh, in as short as 15, 20 minutes if you want a short game, and it can be played even longer, if you want to do it like the longer.

Scott Crabtree: 00:16:14

The game system is actually pretty simple, so it's easy to learn and you can actually adjust the difficulty depending on whether you're just getting into medicine or if you've been doing it for a while.

Scott Crabtree: 00:16:24

And it's coming out on a Kickstarter, uh, tomorrow actually.

Scott Crabtree: 00:16:27

And the reason we decided to do it on Kickstarter, because if you've ever looked for, uh, medical education games before, uh, you, you may have found a few of them, but there not many out there.

Scott Crabtree: 00:16:37

In part, because it's expensive to make a game, uh, using the print on demand models that most games use and to bring costs down, you really need to, to print in bulk.

Scott Crabtree: 00:16:47

And so that's why we're hoping with the Kickstarter to get enough backers to, to make a nicer product, with some nice art and to get to people at a, to the students and learners at a good price.

Sara Dong: 00:17:00

Yeah.

Sara Dong: 00:17:01

I love it.

Sara Dong: 00:17:01

And I, I love some of the art that you already have for the kickstart.

Sara Dong: 00:17:05

It looks amazing and we need more resources like this for us.

Sara Dong: 00:17:09

We all know that teaching antibiotics is, so much, it's very difficult.

Sara Dong: 00:17:14

I feel like that's the question that we get asked all the time is how do we teach and learn antibiotics?

Sara Dong: 00:17:19

So having as many resources available to us, especially ones that are fun and different and make people excited to learn is a, it's a huge step for, for all of us.

Scott Crabtree: 00:17:30

Yeah.

Scott Crabtree: 00:17:30

I think it's something that requires practice and frequent application.

Scott Crabtree: 00:17:34

And this allows you to apply it over and over again in a bit more fun way than a standardized exam.

Sara Dong: 00:17:42

Thank you so much for coming on the show and teaching us about Enterococcus, but also just a great plug and everyone check out the Kickstarter for Pharmageddon

Scott Crabtree: 00:17:52

Yeah, thank you very much for having me!

Sara Dong: 00:17:53

Thanks for listening everyone.

Sara Dong: 00:17:55

Please check out and support the Pharmageddon Kickstarter, which will be live on March 22nd.

Sara Dong: 00:18:00

Uh, some of the upcoming Febrile Digest episodes will also feature some other ways and guests who were thinking about using games in your ID teaching and learning.

Sara Dong: 00:18:10

Like our other episodes, I'll put links to all the mentioned articles in our Consult Notes.

Sara Dong: 00:18:15

And another quick reminder for the Febrile survey, which we are conducting to better understand how you use Febrile to teach and learn.

Sara Dong: 00:18:21

And I would love your feedback on what you do to improve future episodes.

Sara Dong: 00:18:25

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Sara Dong: 00:18:29

You can find the link to the survey on our Twitter page, on the website or in the description link for this episode.

Sara Dong: 00:18:36

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Sara Dong: 00:18:38

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Sara Dong: 00:18:42

Thanks again for listening.