Transcript
Speaker: Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound provides comprehensive critical care programs to hospitals across the country.
Speaker: To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Speaker: And now your host, Dr. Sergio Zanotti.
Speaker: The coscritoides, formerly Clostridium difficile infection, also known as CDI or C. diff, is a common and potentially lethal hospital-acquired infection.
Speaker: Today, we will discuss evidence-based management of severe and fulminant CDI in the intensive care unit.
Speaker: Our guest is Dr. Max Adelman.
Speaker: Dr. Adelman is a member of the Division of Infectious Diseases Department of Medicine at Emory University School of Medicine in Atlanta.
Speaker: Dr. Adelman is the lead author of a recent concise definitive review on the topic in critical care medicine.
Speaker: Max, welcome to Critical Matters.
Speaker: Thanks so much for having me.
Speaker: Happy to be here.
Speaker: As we were discussing before we started recording, it's refreshing to talk about an infection that starts with a C and is not COVID, at least in the last year.
Speaker: But I found that as we were preparing for the podcast that the memo didn't get to me, I guess, but they changed the name once again of this disease.
Speaker: Can you tell us a little bit about that before we start?
Speaker: Yeah, absolutely.
Speaker: I think the...
Speaker: the taxonomists are getting their hands on a lot of different infections.
Speaker: So there might be a lot of infectious diseases that we know well, whose names are changing, but I think we all grew up knowing the C. diff is clostridium difficile, but it's actually changed to clostridioides, but still at least it begins with a C. So we can still keep calling it C. diff and not get too confused.
Speaker: And that works.
Speaker: I agree.
Speaker: C. diff is what everybody refers to it.
Speaker: And, uh,
Speaker: I find this a very important topic to cover for many reasons that you'll cover in the epidemiology, but also I think it's a great example of how something that is very frequent, very common in our practice still has layers of depth and still present sometimes with some challenges that might go a little bit out of what most people consider ordinary.
Speaker: So Max, maybe we could start at the epidemiology
Speaker: and how does C. diff stack up within other hospital-acquired infections to begin with?
Speaker: Yeah, that's a great question.
Speaker: So C. diff is the most common hospital-acquired infection.
Speaker: We think there are about a half million cases of C. diff in the United States per year, and about half of them are hospital-acquired.
Speaker: So a good chunk actually start out in the community.
Speaker: And that rate has been increasing in the past several years, but still about at least half and probably even more than that are hospital acquired.
Speaker: So really something important that all hospitalists and certainly all intensivists should feel pretty comfortable with and pretty comfortable taking care of these patients because we certainly see a lot of them and it's more common than really any other hospital acquired infection.
Speaker: And it's very interesting that in many ICUs,
Speaker: when teams are looking at performance improvement and quality measures, hospital-acquired infections in the form of VAPs, in the form of CAUTIs and CLABSIs are very commonly targeted, yet C. diff, despite being the most common one, is only a problem when they have big outbreaks.
Speaker: But it seems that this is something that we should probably be having our hand on at all times just based on the frequency.
Speaker: Yeah, I absolutely agree.
Speaker: And I think with...
Speaker: things like VAP and CAUTI, it's kind of easy to identify the inciting factor, you know, either being the endotracheal tube or the urinary catheter.
Speaker: And it's a little bit harder to take away the antibiotics from some of these folks who need them.
Speaker: And that really, as we'll get to, is the most important risk factor for C. diff.
Speaker: So I think unlike some of those other hospital-acquired infections, it's a little bit harder to kind of
Speaker: pinpoint one specific thing that we can work on.
Speaker: And certainly antimicrobial stewardship is very important, but it's a little bit harder to change that in a lot of these critically ill patients.
Speaker: So I certainly understand that.
Speaker: Absolutely.
Speaker: I wanted to ask you, Max, if you could maybe make some comments on the difference between a C. diff infection that requires care in the ICU versus C. diff infections that occur in patients who are in the ICU.
Speaker: from an epidemiology, but also outcomes perspective?
Speaker: Yeah, I think they're, you know, they're potentially two somewhat different diseases.
Speaker: A lot of us think about the patients who come in, who come into the ICU with C. diff and they're very sick with shock, fulminant colitis.
Speaker: And it's pretty easy to identify these patients.
Speaker: I think in many cases, um,
Speaker: And that's going to be about 5% to 15% of folks who are hospitalized with C. diff will end up in the ICU.
Speaker: On the other hand, it's the patients who are already in the ICU and they develop diarrhea.
Speaker: And like so many of our ICU patients do because of whatever reason, really, it's actually pretty infrequent that these patients have C. diff.
Speaker: Diarrhea is pretty common, as everyone knows, in the ICU, and really only a minority, about 10 or 15 percent of patients with diarrhea in the ICU have C. diff, so it can be pretty hard to identify.
Speaker: And certainly the outcomes are really driven by how critically ill these folks are.
Speaker: And a lot of the patients who come into the ICU with C. diff are very sick, and at least 20 to 30 percent of those folks go on to die, so it certainly carries a lot of morbidity and mortality.
Speaker: And I think that's an important aspect to reemphasize that despite C. diff being very common as a hospital acquired infection, in those cases that are the ones we're going to be discussing today that result in an ICU admission, the morbidity and mortality is quite significant.
Speaker: Yep.
Speaker: Absolutely.
Speaker: The other question I had along this topic relates to readmissions.
Speaker: Obviously, a big topic in value-based care for hospitalized patients.
Speaker: Could you tell us a little bit about readmissions within the context of C. diff?
Speaker: Yeah, readmissions are very common and certainly common in a lot of our patients who are in the ICU.
Speaker: Among patients who survived their initial hospitalization with C. diff, about a quarter of them are readmitted in the month.
Speaker: And, um,
Speaker: I think in the majority of those readmissions are due to CDI recurrence.
Speaker: So even if we feel like someone is getting better from their C. diff, they've made it out of the ICU, they've made it out of the hospital.
Speaker: I think it's really important to remember that these are still really critically, you know, these patients are chronically ill and they have high
Speaker: high potential for readmission and other negative outcomes.
Speaker: So there are still patients who really need to be watched closely and could get very sick again.
Speaker: I want to go into the discussion of risk factors.
Speaker: And you obviously mentioned the single most important one earlier with antibiotics, but maybe we can dive in that a little bit deeper, Max.
Speaker: So if we can start talking about risk factors from the perspective of antibiotics and what do we know
Speaker: about the different types of antibiotics or the different factors that actually increase risk for patients developing C. diff and why?
Speaker: Absolutely.
Speaker: I think this is a really important topic for C. diff and certainly near and dear to my heart as an infectious diseases doctor.
Speaker: I think we all kind of have this association with fluoroquinolones and clindamycin as conferring the highest risk for C. diff.
Speaker: Those antibiotics certainly carry high risk, but those risks were shown mainly in studies of outpatients with C. diff.
Speaker: Other studies have looked at risk among hospitalized patients.
Speaker: And really, the antibiotic class that rises to the top is cephalosporins, mainly third and fourth generation cephalosporins.
Speaker: That's going to be ceftriaxone and cefepine mainly.
Speaker: So really in hospitalized patients, a lot of our hospitalized patients are on those antibiotics and those really seem to confer the highest risk.
Speaker: Certainly other antibiotics like beta-lactam combinations such as peptazo, carbapenems confer high risk as well.
Speaker: And really the main reason these antibiotics drive risk is because they have the largest impact on the gut microbiome.
Speaker: So we know that
Speaker: C. diff can colonize the microbiome of patients, especially once they're hospitalized, and then killing off other gut commensals allows the C. diff to kind of take over the intestinal microbiome and ultimately allows it to establish infection and cause clinical disease.
Speaker: So really, these antibiotics are the main drivers behind C. diff and
Speaker: you know, a lot of our hospitalized patients and critically ill patients certainly need antibiotics, and they can obviously be life-saving, as we all know, but it's important to remember this potential outcome and the mechanism by which that happens.
Speaker: Would it be fair, Max, to say that there is a class effect?
Speaker: So you mentioned some of the cephalosporins, for example, that obviously are associated with a higher risk.
Speaker: There's also a
Speaker: spectrum effect.
Speaker: So the broader the antibiotic, the most likely it is to be associated with C. diff.
Speaker: And finally, I guess you mentioned there's also probably a dose response, right?
Speaker: The longer you are, the higher number of antibiotics, the more likely.
Speaker: Would that be a good way to think about it?
Speaker: Absolutely.
Speaker: I think those are all really excellent points.
Speaker: And really, if you remember the mechanism that the way we develop C. diff is by killing off
Speaker: the other gut microbiomes that kind of crowd out the C. diff, the more antibiotics you give, the broader they are, and the longer you give them for, the more likely you are to kill off the rest of the gut microbiome that's really preventing the C. diff from taking over.
Speaker: So we know from other studies, it's been well demonstrated that
Speaker: giving broad spectrum antibiotics when a narrow spectrum antibiotic would be just fine increases your risk for C. diff.
Speaker: So for example, if you start a patient on vancomycin and cefepime when they have septic shock, and then a few days later, the blood cultures come back with a pan-susceptible E. coli, we know that at that point, the best way to lower risk for C. diff is by narrowing
Speaker: the antibiotics to the narrowest antibiotic possible.
Speaker: So perhaps something like ceftriaxone in that case would be better than, for example, continuing the cefepime because the cefepime is going to have more effect on the gut microbiome and kill off more of the bacteria that can crowd out the C. diff.
Speaker: So certainly I think minimizing antibiotics in, you know, however you can, whether that's narrow spectrum or less duration is helpful for lowering C. diff risk.
Speaker: And the effect that you described, Max, is a very important reminder for clinicians of the importance of deescalating.
Speaker: A lot of times because of inertia or because we want to be on the safe side, we tend to keep antibiotics a little bit longer, broad, despite having positive or negative cultures that could help us deescalate.
Speaker: And this is a specific and very clear example of how you might be harming a patient by having that behavior.
Speaker: Yeah, absolutely.
Speaker: I mean, this is, I think, one of the biggest clinical decisions that intensivists and infectious diseases doctors really have to make on a day-to-day basis.
Speaker: And it can certainly be difficult when you're faced with a critically ill patient.
Speaker: But I think really re-examining every day whether the patient needs the broad-spectrum antibiotics or not is really the best thing to do for them.
Speaker: And
Speaker: we know it can lower their risk of many adverse outcomes.
Speaker: And C. diff is really one concrete example of how we can help patients by narrowing their antibiotics and really thinking about that on a day-to-day basis.
Speaker: Max, so we talked about one end of the spectrum, which is really the use of broad-spectrum antibiotics, which is very common in the ICU.
Speaker: Could you comment of the risk of C. diff in patients that might be undergoing surgery and are receiving
Speaker: pre-op antibiotics.
Speaker: Is there any thoughts on how to manage that best, and is that something that could increase their risk?
Speaker: So certainly even narrow-spectrum perioperative antibiotics have been clearly shown to increase risk for C. diff.
Speaker: Certainly not as much as broad-spectrum antibiotics for longer duration, but
Speaker: Even, you know, every dose of antibiotics is going to increase a patient's risk.
Speaker: So most patients, I think, will be fine and certainly benefit from perioperative antibiotics, but it will increase C. diff risk.
Speaker: So probably something important to think about for the subset of patients who are at higher risk for C. diff, whether they've already had a few recurrences or they have other risk factors.
Speaker: It might not necessarily change your risk.
Speaker: your perioperative antibiotic prescribing practices, but it might make you think about whether they need that, you know, that extra dose that you sometimes keep on just to be on the safe side.
Speaker: Certainly, I think that's something worth thinking about in patients who are at higher risk.
Speaker: Before we talk a little bit about patient characteristics that are associated with higher risk or worse disease, could you comment on gastric acid suppression by PPIs?
Speaker: That's been a common
Speaker: commonly cited a risk factor, and some people have argued against GI prophylaxis with PPIs because of this.
Speaker: What's the current state of evidence?
Speaker: It's a really good question, and I think another question that's really important for patients in the ICU.
Speaker: So PPIs have been associated with C. diff for about 10 years now.
Speaker: A lot of the early studies that showed this increased risk of C. diff
Speaker: were conducted in the community.
Speaker: And this led to an FDA warning for PPIs.
Speaker: But more recent data, and there was a really good meta-analysis that looked at randomized clinical trials of use of PPIs in the ICU for other indications, such as bleeding prophylaxis.
Speaker: And they did a secondary analysis of C. diff risk and actually found that in these RCTs, PPIs didn't include
Speaker: increased risk of C. diff.
Speaker: So I think for me, that's pretty strong evidence that, you know, perhaps in the outpatient setting where patients are on PPIs for weeks or months or kind of indefinitely, that might increase their C. diff risk, but really probably isn't a big factor in, you know, the days to weeks we're looking at when patients are in the ICU.
Speaker: So I don't think it should be a major factor in deciding whether to prescribe a PPI for an ICU patient or not.
Speaker: Excellent.
Speaker: And that is a change a little bit, like you said, of more relevant perhaps and newer evidence to suggest that the impact might not be as severe as we thought.
Speaker: But like you said, super important and relevant to what we do in the ICU since we prescribe PPIs to our mechanically ventilated patients on a very frequent basis.
Speaker: Yes, absolutely.
Speaker: The last aspect of risk factors, if you could share with us a little bit on your thoughts on
Speaker: patient characteristics in terms of contracting C. diff, but also are there any patient characteristics that are associated with a more likely severe or fulminant case of C. diff?
Speaker: Yeah, the patient characteristics that really are associated with both contracting C. diff and worse outcomes from C. diff, unfortunately, they really look like the patient characteristics
Speaker: for most of our folks who end up in the ICU, especially the medical ICU.
Speaker: So these are patients with diabetes, chronic kidney disease, malignancy.
Speaker: These are all risk factors for development of C. diff.
Speaker: Some studies have indicated that age is a risk factor, and I've
Speaker: think it still might be.
Speaker: One good study that I looked at from about a year or two ago didn't find any difference in age between ICU patients with and without C. diff.
Speaker: So I think the jury may still be out, but I wouldn't be surprised if age was an independent risk factor for C. diff acquisition.
Speaker: And then really, in addition to the risk factors I already mentioned, I think another big risk factor that is a little bit unique to C. diff is
Speaker: C. diff specifically is IBD.
Speaker: So patients with IBD we know are certainly at significantly increased risk for adverse outcomes once they develop C. diff.
Speaker: Excellent.
Speaker: But to move on to the next section, it seems that the really take-home message here is that the one factor that has the highest impact on developing C. diff and happens to be the factor that we have control over is the use of antibiotics.
Speaker: So judicious
Speaker: use of antibiotics, good stewardship with antibiotics is probably the single most important aspect of care that the intensivist can control in trying to decrease the risk of their patients contracting C. diff.
Speaker: Yeah, I definitely agree, and I really like how you put that.
Speaker: It's not only the most important factor, but really our one modifiable risk factor.
Speaker: So really important to consider antibiotics every day and whether they can be discontinued or narrowed.
Speaker: Excellent.
Speaker: Let's talk a little bit before we go into the clinical presentation of fulminant C. diff and what does that entail, but how do we make the diagnosis?
Speaker: And that, again, seems quite simple, but yet sometimes can be difficult.
Speaker: So can you tell us a little bit of the types of tests and then how do we utilize them at the bedside and how do they perform?
Speaker: I totally agree that this, like many things in medicine and many infectious diseases diagnoses, it seems like it should be relatively simple, but frequently isn't.
Speaker: I think the key thing to know about the tests for C. diff, and we can talk in a little bit about who best to use them on, but there's really
Speaker: two things you want to ensure.
Speaker: First, you want to see if there's actually C. diff present.
Speaker: And we know that for other infections such as VAP or CAUTI, as we've discussed before, that just having the organism present in either an endotracheal aspirate or urinary culture, that doesn't mean that they're causing disease.
Speaker: But certainly they have to be there before they can cause disease.
Speaker: So the first step in testing for C. diff, you want to see if the C. diff organism is actually there.
Speaker: So there are two main ways to do that.
Speaker: The first is a nucleic acid amplification test or a PCR for toxin encoding genes.
Speaker: So if this is positive in this dual sample, that'll tell you that the C. diff is actually present.
Speaker: Similarly, you can perform
Speaker: a test for glutamate dehydrogenase, which is an enzyme that's produced by C. diff.
Speaker: So if that's positive, that also tells you that the C. diff is there.
Speaker: So if one of those tests is positive, you know that the patient has the C. diff organism, but that doesn't tell you if it's causing disease.
Speaker: So the Infectious Diseases Society of America and many other places recommend that if you have a positive either nucleic acid amplification test
Speaker: or a glutamate dehydrogenase enzyme, you then go on to test for production of a toxin, which is required to have clinical disease.
Speaker: So really, most places are requiring or suggesting this two-step process.
Speaker: First, you see if the organism is there.
Speaker: And then if it's there, you test for presence of a toxin, which is actually needed to have clinical disease.
Speaker: But certainly, this can be tricky.
Speaker: A lot of patients have
Speaker: presence of the organism, usually identified by a positive nucleic acid amplification test, and then a negative toxin test.
Speaker: That can really indicate either colonization with the organism, or we know that the toxin tests aren't 100% sensitive.
Speaker: So a negative toxin test doesn't necessarily rule out disease, and that's
Speaker: you know, an important place where clinical gestalt and determination is necessary for deciding whether this represents colonization or actually active disease.
Speaker: Would it be fair to say that two strategies or approaches that we could utilize to overcome this lack of sensitivity with a toxin especially and trying to differentiate colonization from ruling out, let's say, an infection would be to
Speaker: testing obviously based on clinical suspicion first.
Speaker: I mean, you don't just test in everybody, right?
Speaker: Because a whole bunch of people are going to be colonized.
Speaker: And B, is there any value in increasing the number of times we test or the number of tests that we do to increase the sensitivity?
Speaker: Those are both really good questions.
Speaker: I think the first part I definitely agree with that we should really only be testing unless patients have alias, which I think those patients really fall into a different camp.
Speaker: But really, patients shouldn't be tested unless they're having at least three loose stools in a 24-hour period.
Speaker: And even patients who are having three loose stools in a 24-hour period, in the ICU especially, there are a lot of reasons for diarrhea.
Speaker: So we should be checking to see if they're on tube feeds or stool softeners or laxatives.
Speaker: And if they are really only testing for C. diff,
Speaker: if you think there's a strong clinical suspicion otherwise.
Speaker: If not, then it probably makes more sense to add fiber, for example, to thicken the stools or to hold the laxatives and then see if the diarrhea persists and only testing for C. diff if it does.
Speaker: The second part, in terms of repeat testing with an initial negative test, I think the
Speaker: nucleic acid amplification tests are sufficiently sensitive, especially in patients who are having copious diarrhea, that if those are negative, it's pretty good at ruling out C. diff in these patients.
Speaker: So I don't think there's a standard recommendation to retest folks who have an initial negative test as long as they are having diarrhea.
Speaker: Okay, that's important.
Speaker: And you did mention ILEAS.
Speaker: So maybe it might be a good time to talk about the patient who has ILEAS.
Speaker: And what do we do then?
Speaker: Yeah, this can certainly be very challenging.
Speaker: I think the key point in diagnosing C. diff in patients with ileus, as most intensivists do, is really just to maintain a high degree of suspicion.
Speaker: It's obviously hard or impossible to collect a stool sample from these patients to know if they have C. diff.
Speaker: So you really just have to put it in the clinical context and really for any hospitalized patient who newly develops ileus, C. diff should be high on the list of potential causes for this.
Speaker: We can use adjuncts such as CT scans to see if there are clinical signs of colitis, for example, although that again, it really isn't particularly specific.
Speaker: But there really aren't many diagnostic tests that are going to help diagnose C. diff in patients with ileus.
Speaker: And in terms of colonoscopy, there's typical findings, but probably not a routine test that we would do to diagnose C. diff, right?
Speaker: It's usually more of an incidental finding as they're working or doing something else.
Speaker: Can you comment on that, Max?
Speaker: Yeah.
Speaker: So colonoscopy isn't recommended in suspected cases of C. diff just for the reasons you mentioned.
Speaker: It's not really helpful in ruling in or out the diagnosis.
Speaker: Pseudomembranous colitis might be present in slightly above half the cases, so not particularly sensitive or specific.
Speaker: It does carry risk of complications, including sedation, colonic perforation.
Speaker: So we don't routinely recommend C. diff, excuse me, FMT in cases of suspected C. diff, but certainly pseudomembranous colitis may be there if
Speaker: the patient is getting a colonoscopy for another reason, or in cases of delivery of FMT, as we'll discuss later, you can certainly see pseudomembronous colitis as well.
Speaker: Excellent.
Speaker: So I would like to spend a little bit of time on the clinical presentation or the clinical spectrum.
Speaker: So obviously you talked about an important number of patients who can be colonized, which are not active infections.
Speaker: There might be even in patients outside of the ICU or people who contract C. diff in the ICU, diarrhea is the main symptom.
Speaker: But could you give us more details of how we start progressing into what some call severe C. diff and then fulminant C. diff and what characterizes or defines those?
Speaker: Absolutely.
Speaker: And these are really important because the different clinical severity is really what's going to drive your treatment decisions.
Speaker: Once you get, as C. diff gets more severe, the first category is severe C. diff, which is defined by either a white count greater than 15,000 or a serum creatinine greater than 1.5.
Speaker: Even beyond that, which is fulminant C. diff, which is really important to intensivists.
Speaker: And that's defined as C. diff with any of hypotension, shock, megacolon,
Speaker: or alias.
Speaker: So these are really the patients that probably most folks are thinking about now, the really critically ill patients who have one of these severe complications from C. diff that really puts them at a quite high risk of mortality.
Speaker: And I believe that it's important to spend a little bit of time and reemphasize the fulminant is, like you mentioned, probably easier to recognize.
Speaker: But
Speaker: A lot of times what I worry about is that patient who's becoming sick, but we haven't really identified them as being as sick, and maybe we might lose our window of intervening.
Speaker: But it seems that as somebody develops C. diff, if they're outside of the ICU or we're evaluating somebody with C. diff, and their white count starts going up and their cranny starts going up, we probably should be paying more attention to those patients as their likelihood to be moving in the wrong direction.
Speaker: Yeah, certainly, you know, as with many infectious diseases, early institution of proper antibiotics and proper adjunctive measures is really helpful in preventing adverse outcomes.
Speaker: So as an infectious diseases doctor, you know, we think a lot about which
Speaker: which antibiotics to institute, but certainly this is another, C. diff is another great example of where multidisciplinary management is really important in terms of fluid resuscitation and collecting, excuse me, correcting electrolyte abnormalities and organ impairment.
Speaker: These patients who are starting to slip into severe fulminant C. diff really deserve to be, um,
Speaker: treated pretty aggressively up front, thinking about antibiotics and adjunctive measures that can perhaps prevent them from developing even more severe disease.
Speaker: Max, a heuristic or a pattern that has been ingrained in my clinical mind for years now is intubated patients, ileus, very high Y count, more than 20,000, 30,000, 40,000, like immediately think C. diff.
Speaker: Is there any validity to that?
Speaker: Is that something that is useful, you think?
Speaker: You know, I think that's probably a good mental model.
Speaker: I don't know off the top of my head, or I don't know if there's been evidence to suggest how often patients develop, you know, white counts between 15 to 20,000, 20 to 30.
Speaker: Certainly, the higher, the worse, and the higher is going to make you think more about C. diff.
Speaker: But I think really keeping C. diff high interdifferential for any patient who might meet criteria is going to help missing some cases and is going to prevent any significant morbidity or mortality associated with C. diff.
Speaker: So I think the cases you're describing are certainly the ones that are going to get all of our attention and probably the ones that are going to be
Speaker: most tricky and most likely to have really bad outcomes.
Speaker: So those are certainly good ones to remember.
Speaker: But keeping C. diff pretty high on the differential for even more subtle presentations, I think, will help doctors take really good care of these patients.
Speaker: Excellent.
Speaker: So why don't we dive into treatment?
Speaker: And you mentioned, obviously, first step related to antibiotics.
Speaker: And I would imagine that involves what to stop, but also what to start.
Speaker: Right.
Speaker: Right, exactly.
Speaker: So a few things are really important in managing C. diff patients.
Speaker: And we talked before about limiting antibiotics for patients who are at risk of C. diff.
Speaker: Certainly, if patients require systemic antibiotics and develop C. diff, trying to, again, discontinue or narrow the systemic antibiotics is really helpful.
Speaker: You know, that's obviously not always possible in every patient, but certainly something to think about daily.
Speaker: And again, once patients develop C. diff, but once they develop C. diff, the quarterstone antibiotic is really oral vancomycin for everyone.
Speaker: This is
Speaker: very safe, effective, limited systemic absorption, although there are some patients who could develop systemic levels of vancomycin, but in general, quite safe and not associated with many of the adverse outcomes that we think of with IV vancomycin and is really widely available and a great treatment for C. diff.
Speaker: Could you comment on the dosing of oral vancomycin?
Speaker: I know there's a traditional dose of 250, but some people recommend using higher doses.
Speaker: Yeah, I think this hasn't been entirely rigorously studied, so it's a little bit hard to know.
Speaker: There's thought that giving a higher dose of 500 milligrams oral every six hours is
Speaker: could lead to higher intracolonic levels, especially among patients who might have alias.
Speaker: So they're likely to have less drug delivery to the distal colon, where the C. diff is really causing most of the issues.
Speaker: So that's really the thinking behind giving this higher dose of 500 Q6.
Speaker: Some studies indicate that even at lower doses, 250 or 125, you're still getting colonic concentrations of well above the MIC.
Speaker: So there's some thought that you might not need that 500 Q6, but it's still guideline recommended, at least in the United States, and still probably the standard of care to give high-dose vancomycin for patients with severe or fulminant C. diff.
Speaker: And this doesn't apply to patients without severe or fulminant C. diff, but to give them that high dose to make sure they're getting really high intracolonic levels.
Speaker: And those patients with either megacolon or ileus,
Speaker: Are rectal deliveries of vancomycin useful and utilized?
Speaker: Yeah, I think they are still standard of care, again, for the same, thinking of the same reason.
Speaker: We really don't know how much of that oral vancomycin is making it all the way to the distal colon.
Speaker: It seems like even if a little bit is trickling down there, that's probably going to get above the MIC.
Speaker: But without really knowing how much is there,
Speaker: it probably makes sense to give them rectal retention enemas of vancomycin to make sure you're getting the drug right to where it needs to go and killing off the C. diff spores right where they're causing disease.
Speaker: So I think that would still be recommended or is recommended, I should say, for patients with alias or toxic megacolon.
Speaker: And because of the lack of absorption, you could utilize both at the same time.
Speaker: Is that correct?
Speaker: You can.
Speaker: You certainly can.
Speaker: I think there are some cases where patients do develop actually systemic absorption, which I'm not sure is very widely known.
Speaker: And this is really a risk in patients with end-stage renal disease and significant colonic inflammation where they actually are getting some systemic absorption of vancomycin.
Speaker: So I think it's reason to be a little bit cautious in patients, like I said, with ESRD,
Speaker: and they're getting a PO and rectal vancomycin, if they're needing both of those at high doses for a long time, it's probably worth at least thinking about checking a serum vancomycin level to make sure they're not getting much systemic absorption.
Speaker: Again, the risks, you always have to weigh the risks and benefits, but it's at least worth thinking about for patients who are getting long courses of rectal and oral vancomycin, thinking about whether they could be absorbing some systemically.
Speaker: And what's the standard duration?
Speaker: So I guess you start with 10 days is what I have always done, but in some cases you might need to do a little bit longer.
Speaker: Is there any current recommendations on duration?
Speaker: Has this been studied?
Speaker: There really aren't any current recommendations and there really aren't any trials evaluating this.
Speaker: A lot of the data in fulminant C. diff is extrapolated from less severe forms of C. diff.
Speaker: Right now, the standard practice is to kind of start with 10 days and then see how things are going.
Speaker: And certainly, if patients are still having bad disease after 10 days, you can either extend the vancomycin course or consider switching to other antibiotics.
Speaker: I think that's
Speaker: you know, 10 days is probably a good place to start.
Speaker: And then you can kind of take it from there in terms of how the patient's responding and whether they might need more vancomycin or switching to a different agent altogether.
Speaker: Excellent.
Speaker: And Max, could you comment on the role of metronidazole in these patients?
Speaker: Yeah, metronidazole, you know, is unlike vancomycin, it's given IV.
Speaker: So the thinking is that, you know,
Speaker: Actually, I should take a step back.
Speaker: I think, you know, we used to give oral metronidazole for non-severe forms of C. diff.
Speaker: And even now, in the last version of the IDSA guidelines in 2018, vancomycin is recommended first for really all patients with C. diff.
Speaker: So every patient with C. diff should be on oral vancomycin unless there's a really compelling reason not to do so.
Speaker: For patients with severe and fulminant C. diff,
Speaker: The current practice is to add on intravenous metronidazole.
Speaker: And the thinking there is that if the patient has ileus and they might not be getting a lot of vancomycin into their colon, that because the metronidazole is given systemically, you are going to reach high intraclonic levels of metronidazole.
Speaker: So that is certainly standard practice to add on IV metronidazole in addition to the oral vancomycin for severe and fulminant C. diff.
Speaker: And I think certainly what I still do and what I imagine most folks still do, there have been a few recent large retrospective studies that have kind of called this into question and haven't shown that this improves clinical outcomes.
Speaker: So I think this might be changing a little bit in the next few years, but for now, I do think it's still standard of care and probably still recommended to give IV metronodazole in addition to the oral vancomycin for patients with very severe C. diff.
Speaker: So clearly, the oral vancomycin and the IV metronidazole are first-line therapy, what we should be doing in all our patients.
Speaker: Could you comment on some of the drugs that maybe have a much more niched approach for refractory cases or when we should use them that perhaps are not as common?
Speaker: And that includes a couple of antibiotics like fidaxamycin and the tegacycline, but also some monoclonal antibodies and IV immunoglobulins.
Speaker: Yeah, so like you said, Sergio, really all patients should be on vancomycin and probably metronidazole.
Speaker: And then if they have ileus or toxic megacolon, they should be given rectal vancomycin as well.
Speaker: Fidoximycin is another antibiotic that's used more widely in Europe.
Speaker: It is available in the United States.
Speaker: Its use has been limited a little bit by its cost, but it does actually in non-severe C. diff have improved outcomes in terms of decreasing recurrence mainly and perhaps mortality and cure improvement as well.
Speaker: So Fidoximycin is certainly something to consider.
Speaker: There haven't been any studies that primarily evaluated it in severe and fulminant C. diff, but there is some hint that it might be at least as good, if not perhaps a little bit better than vancomycin in severe C. diff, although I don't think we can say that definitively at this point.
Speaker: So vancomycin is certainly still the standard of care.
Speaker: But fidoxomycin might be something you consider if the patient isn't responding to vancomycin after a few days and they're not sick enough at that point to necessarily need a fecal microbial transplant or surgery.
Speaker: Tiga cyclin has also made it into the 2018 IDSA guidelines.
Speaker: I don't think I've ever used this or really seen it used.
Speaker: It's a really poorly tolerated antibiotic, and its use was really just based on a few case series.
Speaker: So I don't think there's much of a role for tigacyclin, which is the other antibiotic that people sometimes talk about using for C. diff.
Speaker: Bezlatoximab is a monoclonal antibody against toxin B, which is the main C. diff toxin that really causes disease and is virulent.
Speaker: This, the main benefit of bezotoximab is that it decreases C. diff recurrence.
Speaker: So it might be something to think about for your patients who already have recurrent C. diff or are at high risk of developing recurrence.
Speaker: But it's really not going to be kind of a standalone therapy for C. diff.
Speaker: Similarly, IV immunoglobulin might have some of the same benefits, but really isn't used that much for C. diff and definitely carries risks for ICU patients, including a large volume of administration.
Speaker: So I think the takeaway is that for patients not responding to initial therapy and you don't think they're quite sick enough yet to need FMT or surgery, maybe think about switching to fidoxamizam.
Speaker: Excellent.
Speaker: So let's dive into FMT.
Speaker: We had talked about it here and there, but could you first tell us what does FMT stand for and how does it work and who should we be thinking to use it in?
Speaker: Yeah, thanks.
Speaker: I'm sorry if I didn't define this before, but FMT stands for fecal microbiota transplant.
Speaker: And as we discussed before,
Speaker: The main pathogenesis of C. diff is that the quote-unquote good or commensal gut bacteria are killed off by antibiotics, which allows C. diff to colonize the intestines and then kind of take over and cause disease.
Speaker: FMT really attempts to reverse that process by instilling feces from a healthy donor into a person with C. diff.
Speaker: you can recolonize their intestines with this beneficial commensal bacteria and hopefully crowd out the C. diff spores.
Speaker: And this has been really, really well demonstrated for recurrent or, let's say, refractory C. diff cases, you know, maybe not folks in the ICU, but outpatients who just keep coming back and back with C. diff that really won't go away despite antibiotics.
Speaker: FMT is really clearly indicated for those patients and is really over 90% cure rate.
Speaker: So really the standard of care for those patients.
Speaker: In patients with fulminant or severe disease in the ICU, a few recent studies have shown that FMT may improve outcomes compared to antibiotics alone, including vancomycin.
Speaker: So I think this is a really promising
Speaker: therapy for patients who are sick enough to end up in the ICU.
Speaker: I think there's still a lot we don't know, as you alluded to, specifically which patients to give FMT to.
Speaker: And it seems to be that, you know, this shouldn't be first line, at least not quite yet.
Speaker: And I think there's kind of this window of when patients are
Speaker: haven't yet responded to initial therapy, including usually vancomycin and metronidazole, when they might benefit from FMT.
Speaker: But I think this is really still one of the main questions that needs to be defined in terms of C. diff care is which patients benefit from FMT and when they benefit.
Speaker: Excellent.
Speaker: And I guess that the third weapon we have therapeutically to treat
Speaker: C. diff directly is surgery for those fulminant cases that are not responding.
Speaker: Can we first maybe talk about timing of involvement of surgery, timing of surgery, and then what are the types of operations that people have utilized for these patients?
Speaker: Yeah, I really like how you phrased that question, kind of distinguishing the timing of involvement of surgery from timing of surgery itself.
Speaker: And I think, as a lot of your listeners will know, involving surgery early on is usually to the patient's benefit.
Speaker: And the idea is that the surgeons can have some time to prepare for surgery, potentially, if it's needed.
Speaker: But certainly, they can follow serial abdominal exams, get a sense of the patient, and kind of watch their clinical exam evolve over time.
Speaker: I know many surgeons usually aren't happy when you call them in only once the patient has perforated their colon.
Speaker: So probably a good idea to think about getting surgery involved early, at least to see the patient.
Speaker: if the patient is critically ill.
Speaker: So I think probably anyone with ileus or megacolon, or as you mentioned before, you know, really high white counts or severe abdominal pain or lactic acidosis, those are probably all patients who should have a surgical consult.
Speaker: Whether or not they ultimately need surgery is a different question, but probably a good idea to think about calling surgery pretty early in those patients' course.
Speaker: And then
Speaker: when to do surgery specifically.
Speaker: I mean, this is, I think, a really hard question, and I'm certainly not a surgeon, so I can't give personal thoughts or opinions on this.
Speaker: And I imagined if you asked 10 different surgeons, you'd get 10 or 12 or 15 different answers.
Speaker: But I think similar to FMT, there's this idea that there's
Speaker: kind of an optimal surgical window for C. diff.
Speaker: And this is after patients haven't responded to initial treatment.
Speaker: So you certainly want to, unless they're very, very sick, give them a shot to respond to the usual antibiotics we give.
Speaker: But you don't want to let them get too sick.
Speaker: That surgery won't be beneficial and they'll have an unacceptably high surgical mortality.
Speaker: So I think
Speaker: This idea of maybe between day two to seven or so, some studies have suggested that a lactate between 2.2 and 5 is kind of the ideal surgical window.
Speaker: So I think that kind of reflects this clinical sense that the patient is sick and quite sick.
Speaker: but not too sick that they won't even benefit from surgery.
Speaker: And this is really hard to define.
Speaker: And similar to C. diff, I think deserves more, excuse me, similar to FMT, I think deserves more rigorous perspective study.
Speaker: But clearly identifying those patients who are sick and might need surgery early is important to get the team involved.
Speaker: And like you said, this narrow window makes it difficult because if you wait too long,
Speaker: then it's probably surgery that's not going to make a difference.
Speaker: And that's also, I believe, something that our surgeons are not going to be very happy being called at that stage.
Speaker: Right.
Speaker: Exactly.
Speaker: So I think, like you said before, potentially calling surgery early is usually in the patient's benefit.
Speaker: You know, the surgeons are really the ones with the clinical expertise, and they've seen a lot of these cases and know when it might still be in the patient's benefit to intervene.
Speaker: And in terms of the type of surgery, obviously none of us are surgeons, but traditionally people have done total abdominal colectomies, but it seems that now loop biliostomies are a little bit more popular as well.
Speaker: Could you comment on what the data shows on these?
Speaker: Yeah, so like you said, total abdominal colectomy was really the primary surgery that was done until about 10 or so years ago.
Speaker: There was a retrospective study published about 10 years ago that showed that loop ileostomy, where they actually connect the ileum without resecting it, and then that allows you to give integrated vancomycin flushes through the ileostomy.
Speaker: They showed that that had improved mortality compared to total abdominal colectomy.
Speaker: Other studies since then haven't been as definitive as to whether loop ileostomy has a mortality benefit.
Speaker: I think this is a really hard thing to study.
Speaker: Certainly, it would be tough to randomize patients to one of these two interventions, and there's obviously a lot of differences between the patients who you might take for a total colectomy or a loop ileostomy.
Speaker: In talking to some surgeons, it seems that the loop ileostomy allows for much easier subsequent reanastomosis than the total abdominal colectomy.
Speaker: So that seems to be the one that's probably preferred.
Speaker: It's much less invasive and it allows for subsequent reanastomosis.
Speaker: So if the patient can undergo that,
Speaker: That should probably be the procedure of choice.
Speaker: But certainly, I think more important is having an experienced surgeon come evaluate the patient and decide whether surgery is in their best interest.
Speaker: And then if so, which of the two surgical techniques would be best for the patient?
Speaker: Absolutely.
Speaker: And the one thing that also you mentioned, obviously, is when a patient progresses to a point of perforation, it's late.
Speaker: even if they go to surgery at that point, their options are limited and probably they're going to end up with a total abdominal colectomy regardless.
Speaker: Right.
Speaker: If they have complications like perforation or necrosis or large areas of ischemia, at that point, it seems like it would be better to do the total abdominal colectomy, which is another great reason to involve the surgeons earlier, potentially preventing the patient from progressing to that point.
Speaker: Excellent.
Speaker: Well, I think that the last area from the clinical management that I think is worth discussing and emphasizing is prevention.
Speaker: And I think especially after a year plus of N95s and a lot of alcohol, it might be good to remind people what prevention looks like in C. diff.
Speaker: Yeah, that's a very, very good point.
Speaker: C. diff prevention looks a little different from COVID prevention, and both very important.
Speaker: Really, the cornerstone of C. diff prevention, as we've talked about before, is limiting antibiotics.
Speaker: But now everyone is expert in doing that.
Speaker: So let's say you've limited antibiotics and your patient still develops C. diff.
Speaker: The main way to prevent C. diff from spreading to other patients in the unit is by the standard infection control practices that we all know and love.
Speaker: So these involve using a single-use gown and gloves, even though some places are getting rid of those for MRSA and certain gram-negative, resisting gram-negative infections.
Speaker: I don't think those will go away for C. diff anytime soon.
Speaker: So certainly using single-use gown and gloves.
Speaker: Single-use stethoscope is really important as well.
Speaker: And then once you leave the patient's room, cleaning with soap and water, because we know that
Speaker: the alcohol-based hand sanitizers really don't do a good job of killing the C. diff spores.
Speaker: It's really crucial to wash with soap and water.
Speaker: So those are really the cornerstones for preventing C. diff and hopefully not having it become an outbreak in your ICU.
Speaker: Excellent.
Speaker: Well, we would like to end, Max, with some questions that are unrelated to the clinical topic.
Speaker: That's a tradition in the podcast.
Speaker: Would that be okay?
Speaker: Yeah, absolutely.
Speaker: So the first question relates to books.
Speaker: And is there a book or books that have influenced you the most or that you have gifted most often to others?
Speaker: That's a good question.
Speaker: I've had a little more time to read in this past year with the pandemic.
Speaker: You probably get, I don't know if you've had, you probably get the same response from a lot of the ID doctors you have on the podcast, but
Speaker: I think the book, The Hot Zone, really stuck with me and is timely now.
Speaker: This was about an Ebola outbreak in a primate facility in Virginia in the early 90s.
Speaker: And it was really, really well written and reported and kind of did a great job, I thought, of bridging science and public health and making it accessible for a wide audience.
Speaker: But I think the idea that these infections really are never that far from us in this
Speaker: was kind of a wild idea 20 or 30 years ago when the book was written.
Speaker: And now we've seen it, unfortunately, really play out in the past year, year and a half.
Speaker: So this was a book that really, really stuck with me.
Speaker: And I think, you know, really started my love of infectious diseases and viral infections and really a fascinating book for anyone who hasn't read it.
Speaker: Probably not the escapist literature that some people might be looking for in the COVID era, but definitely a really good, well-written and exciting read.
Speaker: Absolutely.
Speaker: And we will link this in the show notes, but a book that I agree, I had a lot of time or read a lot more during the last 12 months that I've read in a long time, even though I definitely try to dedicate a lot of time to reading, but a book that was recommended to me by another infectious disease colleague that really was quite interesting during, especially during the context of COVID, was a book on the great influenza pandemic from 1918.
Speaker: I think it's by Barry.
Speaker: which also intertwines the whole history of the pandemic with the history of medicine in the United States, the initiation of John Hopkins Medical School and how it became a science in the United States and really a fascinating story.
Speaker: But I'm sure that I had not read the hot zone, but what was remarkable for me was that a pandemic over a hundred years ago, Max had so many dynamics that were exactly the same of what we saw here.
Speaker: And it's just speaks to human behavior, right?
Speaker: That never changes.
Speaker: I totally agree.
Speaker: I think, yeah, as much as we all wish it will change, you know, as a result of COVID, I think when the same thing happens, whenever it does, and hopefully it's, you know, not for at least another hundred years, a lot of the same things will be will happen again.
Speaker: So I think that's a really great point.
Speaker: The second question relates to beliefs.
Speaker: And is there something that you believe to be true in medicine or in life that most other people or many other people don't believe or don't behave as they believe?
Speaker: That's a really good question about beliefs.
Speaker: Actually, I just came across something today, and I've heard about this a few times recently, including from an unnamed family member, and that's this idea of manifesting.
Speaker: I don't know if you've heard of this, but it seems to be this idea that you can kind of make something come true just by believing in it or thinking about it enough to
Speaker: Like my family member was saying, you know, you could, for example, manifest getting a new job or getting a promotion or something like that.
Speaker: And I know I'm probably preaching to the choir, talking to a group of scientists, but this to me just, you know, seems kind of to go against the
Speaker: the core ideas of, you know, hard work and really working at something to make it happen.
Speaker: And it really doesn't seem to me like it should have any place in our modern society, but I guess it, it kind of just ties into the general anti-science attitude in our, in our population that, you know, I think is a problem and is, you know, been more of a problem in the past few years.
Speaker: And certainly, as you said, you know, might've contributed to, to making this pandemic worse than it had to be.
Speaker: And it's interesting because I often think of maybe the contrary of manifesting in terms of not having ideas lead me to a different way of being or acting, but actually starting with actions that ultimately change the way I think.
Speaker: If you start acting like a leader, all of a sudden you become a leader, right?
Speaker: As you start acting like a scientist and asking the right questions and being very, very, very,
Speaker: very hesitant and accepting things that are apparent initially, you might start becoming more of a scientist.
Speaker: But it is definitely an interesting discussion.
Speaker: And like we mentioned, same dynamic in 1918.
Speaker: The war against science was present there.
Speaker: The war against science is present now.
Speaker: And it just seems to speak to the polarity that we have now in society, but definitely very interesting topics.
Speaker: Yep.
Speaker: I like that way you put it of kind of flipping it on its head and start
Speaker: know start with the outcome and then it'll it'll drive your thoughts too so i really like how you put that so the last question max relates to what would you want every intensivist that's listening to you our audience and a fact or quote to know as a departing thought well i'm sorry to to make it too id related um and i certainly don't envy any intensivist you all have an incredibly difficult job but i think
Speaker: For me, the one thing that I really think clinically is important is the diagnosis of urinary tract infection.
Speaker: And for me, this is just a big bugaboo of mine, let's say.
Speaker: And I really think UTI is a diagnosis of exclusion.
Speaker: So sorry to leave it on a very ID-specific note.
Speaker: But if I could take away urine cultures, I probably would.
Speaker: And, you know, UTI is a really hard diagnosis to make.
Speaker: And I think it's usually not what is was driving any any major pathology.
Speaker: So I love it because it came out of out of right field.
Speaker: I wasn't expecting that, but I love it because that would be a great PSA for every hospital to have in the parking lot for all the doctors to see, right?
Speaker: I totally agree.
Speaker: UTI is a diagnosis of exclusion.
Speaker: That could be my tagline.
Speaker: I'd be happy if that was on my gravestone.
Speaker: That's a perfect place to stop.
Speaker: Max, I want to thank you for your time, for sharing your expertise.
Speaker: I look forward to talking more with you, having you back on the podcast, talk about other ID critical care related topics.
Speaker: And also hope we all have the opportunity to see each other soon in conferences and as we emerge from this pandemic to get to interact again in person.
Speaker: Thank you so much, Sergio.
Speaker: I really appreciate it.
Speaker: And that sounds great to me too.
Speaker: Take care.
Speaker: Bye.
Speaker: Thank you for listening to Critical Matters, a sound podcast.
Speaker: Make sure to subscribe to Critical Matters on Apple or Google Podcasts and share with your network.
Speaker: Sound's transforming the way critical care is provided in hospitals across the country.
Speaker: To learn more, visit www.soundphysicians.com.
