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Emerging Treatment Options for Recurrent C. Difficile Infection - Episode 1

Clostridioides Difficile Infection Overview and Management

Dr Paul Feuerstadt provides an overview of Clostridioides difficile infection and why it is challenging to manage recurrent C diff infections (rCDI).

Paul Feuerstadt, MD: My name is Dr. Paul Feuerstadt, MD, and I am an assistant clinical professor of medicine at the Yale University School of Medicine and an attending gastroenterologist at the PACT Gastroenterology Center. I’d like to welcome you to this learning session today, a primer covering Clostridioides difficile [C diff] infection with a focus on microbiota-based live biotherapeutic products.

C diff is a major problem in the United States. In fact, it’s estimated that 500,000 individuals will test positive on an annual basis, leading to a significant burden on the health care system, but most importantly, a significant burden on the patient population. It’s estimated that 25% of all individuals who are diagnosed with C diff and receive a standard of care antimicrobial, an appropriate treatment, will recur. Of those who recur, up to 40% will recur again, and up to 60% thereafter as patients get caught in the cycle of recurrence, after recurrence, after recurrence.

Why do so many patients recur? In order to understand recurrences, briefly, we have to understand the basic structure of the life cycle of Clostridioides difficile. There are 2 main phases of C diff; one is the vegetative phase. The vegetative phase is susceptible to gastric acid and alcohol-based hand sanitizers. Plainly stated, if it comes in contact with these things, it gets wiped out. The vegetative phase releases 2 main toxins, toxin A and toxin B, that most commonly stimulate the abdominal pain, diarrheal syndrome, and fevers associated with C diff infection. Alternatively, the spore phase is a much more resistant phase. The spore phase is resistant to gastric acid and alcohol-based hand sanitizers. In fact, the spore phase most commonly remains within a patient’s system after antimicrobial treatment, either being released in the stool causing transmission from person to person, or staying within the system and reconverting back to the vegetative phase, causing a recurrence.

How do individuals get infected with C diff? Classically, they swallow the spore phase; it’s resistant to their gastric acid, gets through their gastric acid into their small bowel, where a process called germination occurs. Germination is the conversion from the spore phase to the vegetative phase. The vegetative phase then multiplies, divides, and multiplies some more as it builds an army of sorts heading toward the colon. But I’m a gastroenterologist, and I think the colon is a brilliant organ, and the colon is a brilliant organ because it has its own defense system, independent of the blood-borne defense system that protects it. What is that defense system? The microbiota or colonization resistance. What classically weakens colonization resistance? Amoxicillin, ampicillin, clarithromycin, fluoroquinolones, and cephalosporins. We weaken the colonization resistance or create a so-called dysbiotic state that allows the C diff to proliferate. The vegetative phase releases those toxins and stimulates the diarrheal syndrome and the symptoms that cause patients to be uncomfortable.

As we understand that basic pathophysiology of C diff infection, we need to contextualize the treatment of C diff infection. The standard treatment of C diff infection involves antimicrobials. Antimicrobials largely control the vegetative phase. However, the spore phase is not usually impacted by these antimicrobials. This is why when patients are on antimicrobials, their symptoms improve. However, that spore phase is largely eradicated by the microbiota, but the microbiota is so-called dysbiotic or weakened prior to C diff infection. In patients with recurrent C diff, their microbiota is even further dysbiotic or further weakened, leading to recurrence after recurrence after recurrence. Why? Because without further intervention, the microbiota needs to regrow itself in order to supplement the deficiencies, and it does it pretty well, but it doesn’t do it very well. As a result of that, those deficiencies persist and patients get recurrent because the score phase is able to reconvert to the vegetative phase.

When we think about antimicrobials, it’s important to go back and understand the guidelines, and the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America [IDSA/SHEA] updated their guidelines in 2021. With this update, there is a new favored treatment for initial infection with C diff. That new favored treatment is fidaxomicin; this given at 200 mg twice daily for 10 days is the preferred treatment of an initial infection. An acceptable alternative is vancomycin, at 125 mg 4 times daily for 10 days. As you’ve noticed, metronidazole has largely been phased out. For an initial infection, metronidazole is only recommended when neither fidaxomicin nor vancomycin are available, the patient’s white blood cell count is less than 15,000, and their creatinine is less than 1.5 mg/dL. For that first recurrence, the IDSA/SHEA guidelines recommend, again, preferred treatment with either fidaxomicin for 10 days, or fidaxomicin 200 mg twice daily for 5 days, followed by 1 tablet every other day, day 7 through 25. An acceptable alternative is vancomycin in a tapered and/or pulsed fashion.

Finally, for patients who fail metronidazole initially, vancomycin at 125 mg 4 times daily for 10 days is recommended. Within this first recurrent group, the first so-called add-on therapy was recommended, and that therapy is a product called bezlotoxumab. Bezlotoxumab is a fully humanized, monoclonal antibody designed to bind toxin B in a very specific way. By doing that, and by infusing bezlotoxumab, it’s a onetime infusion, during the standard of care antimicrobial, recurrence rates might be reduced. That is what the MODIFY-I and MODIFY-II trials show, and that’s how this entered the guidelines. For the second recurrence and beyond, pretty much the recommendations are to use what you haven’t used already, either a fidaxomicin regimen, vancomycin in a taper and pulse regimen as well, or vancomycin and a 10-day treatment course followed by a chaser of rifaximin. Those are the antimicrobials, however, there are 2 add-on therapies for second recurrence and beyond, which is either bezlotoxumab, or fecal microbiota transplantation.

Transcript Edited for Clarity