Advances in Microbiome-Based Therapies for Recurrent C difficile Infection - Episode 3

Challenges in the Management of CDI

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Andrew Skinner, MD, reviews challenges in managing CDI, as well as the treatment guidelines from IDSA, SHEA, and ACG.

Stuart Johnson, MD: Andrew, what are some challenges in managing CDI [C difficile infection] and why does it have such a high recurrence rate?

Andrew Skinner, MD: One of the challenges in managing in CDI is, as Candace pointed out, there's a lot of recurrence when we come to this as well. So, a lot of the data shows that after the first episode of C difficile infections…about 25% of those individuals will end up with a recurrence and with each subsequent recurrence, that number keeps increasing. And one of the biggest challenges that we're noticing with this is that our current guidelines, which is antibiotic-based for the most part, is the antibiotics are great at killing the vegetated bacteria, but not so much the spores and those spores are what can end up contributing toward these recurrence infections as well as that these individuals will clear out the vegetated bacteria, but with the spores persisting. And then with the continued disruption to the microbiota, it allows for the spores to regerminate, causing subsequent infections as well.

Stuart Johnson, MD: Right. And so the spores are a real tricky aspect of C diff.

Andrew Skinner, MD: Definitely a tricky aspect. And that's where some of the hopeful future we are, is kind of deal with these spores.

Stuart Johnson, MD: And some of the issues are, is this a reactivation of spores that are within the colon residual spores, or are they picked up again from the environment, or what's your take on that?

Andrew Skinner, MD: It's going to be a bit of a mix as well. And in the individuals who end up having a subsequent recurrence within weeks after they've finished up those treatments, those are likely going to end up being residual spores at that point. There is some data to suggest though that individuals further and further out, they are picking up different strains of the C diff as well. And that's leading to a different infection.

Stuart Johnson, MD: Thank you. How is CDI treated and what do the IDSA/SHEA guidelines say and the ACG guidelines? Let's start with the antibiotic treatments for initial episode of CDI. What does the IDSA/SHEA recommend?

Andrew Skinner, MD: The IDSA/SHEA guidelines for initial episodes recommended the preferred agent being fidaxomicin 200 mg twice a day for 10 days with an acceptable alternative if fidaxomicin wasn't available, would be vancomycin 125 mg 4 times a day for 10 days.

Stuart Johnson, MD: Great. And the ACG guidelines are somewhat different. They do recommend vancomycin or fidaxomicin, but they also recommend metronidazole for nonsevere patients at low risk.

Andrew Skinner, MD: Correct.

Stuart Johnson, MD: And they've retained that, whereas the IDSA/SHEA guidelines have relegated metronidazole to secondary considerations, if you will. What about first recurrence? What does the IDSA/SHEA guideline recommend for first CDI recurrence?

Andrew Skinner, MD: For first recurrence, the IDSA/SHEA guidelines start branching out a little bit more in that they're recommending either a standard course of fidaxomicin as I previously described, but they also will recommend a fidaxomicin taper, which is 200 milligrams twice a day for 5 days, and then after that every other day to finish up a 20-capsule regimen. And then another recommendation would be either, again, a standard vancomycin regimen or doing a vancomycin taper. And of note, it is worth mentioning that the IDSA/SHEA guidelines also recommended adjuvant bezlotoxumab therapy at this stage as well.

Stuart Johnson, MD: And bezlotoxumab being the infusion of a monoclonal antibody against toxin B. So adjunctive therapy.

Andrew Skinner, MD: Yes.

Stuart Johnson, MD: Somewhat like FMT [fecal microbiota transplant], if you will. So it's not treatment per se, but it's to prevent recurrence. Second or subsequent recurrences? Does the IDSA have anything to say about that?

Andrew Skinner, MD: Yes, the big addition that after the first occurrence that they had added on, so on top of the previous regimens that I had already mentioned with fidaxomicin taper, the vancomycin taper, they also recommended a fidaxomicin taper with a rifaximin chaser on top of this as well, to where you complete the vancomycin and then follow that, but with a rifaximin course as well. And again, bezlotoxumab is considered an adjunctive therapy at this stage as well.

Stuart Johnson, MD: And then there is, I mention it, we don't see this as often as we used to, but the fulminant CDI.

Andrew Skinner, MD: Yes.

Stuart Johnson, MD: These are patients that are hypotensive, multiorgan failure, their white count may be climbing exponentially as you see the patient and they look, really, septic, I guess.

Andrew Skinner, MD: Yes.

Stuart Johnson, MD: What does the IDSA/SHEA recommend?

Andrew Skinner, MD: For the severe, for fulminate C difficile infections, the recommendation is increasing the vancomycin dose at this point as well. Going up towards the 500 milligrams, 4 times a day, and this is typically given either orally or rectally as well. And on top of that is adding on IV metronidazole and then, as always, an urgent surgical consult.

Stuart Johnson, MD: And the ACG guidelines are similar. They do add this caveat for patients with recalcitrant CDI, that they have been managed with fecal transplant, which is an interesting concept and certainly not available in most centers, but that has been tried, but otherwise they're fairly similar in regards to antibiotic treatment. While antibiotics are the current and standard therapy for CDI, how does their prolonged use in recurrent CDI affect the gut microbiota?

Andrew Skinner, MD: One of the things that we have more evidence for is, how much of the microbiota that are current antibiotics that we used to treat CDI impacted as well. In fact, there was an article out of mSphere in 2021 by Dr Fishbein, [Skye R.S. Fishbein, MD] showing that vancomycin almost had the equivalent impact on the microbiota as some third-generation cephalosporins as well. And also we have further evidence that shows that the longer we're on these street treatments as well, is that it impacts the microbiota to a larger degree. As we said earlier, it's good at treating the vegetative cells, it's not so great at treating these spores. And with that continued alterations with the microbiota from vancomycin tends to lead to further and further recurrences.

Transcript edited for clarity