COMMENTARY

New ACG Guidelines on C difficile Infections: Key Takeaways

David A. Johnson, MD

Disclosures

June 17, 2021

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.

The American College of Gastroenterology (ACG) has published new guidelines to advise clinicians in the prevention, diagnosis, and treatment of Clostridioides difficile infections. These guidelines are meant to supplement those from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America, which were published in 2018.

The ACG guidelines offer a very timely update, and I'd like to give you a quick overview as to what's changed and what I think we really need to know.

Epidemiologic Considerations

Cases of C difficile infection are on the rise, as is well known by anyone involved in clinical care and particularly by those working in a hospital. From 2001 to 2012, the annual incidence of C difficile infection increased by 43%. More importantly, cases of multiply recurrent C difficile infection increased by 188% over that same timeframe. Annually, this translates into approximately 450,000 cases of infection and 14,000 deaths occurring as a result.

Although recent evidence has suggested that there's been a decrease in the national burden of these infections, thanks in part to our increased epidemiologic knowledge, at least in the hospital setting, they remain a point of considerable concern.

There are also additional concerns regarding asymptomatic colonization, which the guidelines' authors point out occurs in 4%-15% of healthy adults, 21% of hospitalized adults, and 15%-30% of residents in long-term care facilities. Therefore, when you start testing in the absence of diarrhea, it's important to keep in mind that some of these people may have a colonization.

Another major concern is that 35%-48% of the new C difficile infection diagnoses are now associated with community risks. Apart from antibiotic treatment, key risk factors for community-acquired infection include Caucasian race, cardiac disease, chronic kidney disease, and — importantly — inflammatory bowel disease (IBD).

Probiotics' Failed Promise

When it comes to the question of whether probiotics are of value in preventing primary C difficile infections, the answer is decidedly no. The guidelines note that this is a conditional recommendation with moderate-quality evidence. They also offer a strong recommendation against the use of probiotics as secondary prevention against recurrent infections, given the very low quality of evidence.

Probiotics is a $40-billion-a-year industry which is poorly regulated and has very little data to support it. So when it comes to the use of probiotics, even for the treatment of antibiotics-related diarrhea, the recommendation is no. In fact, probiotics may actually prolong the normal recolonization of patients after antibiotic courses.

Diagnosing C difficile

There are several different assays available for diagnosing these infections. Enzyme immunoassays can recognize the toxins A and B produced by the organism. They are very easy to use. Nucleic acid amplification testing (NAAT) is a polymerase chain reaction test. The standard test is glutamate dehydrogenase, which is an enzyme produced in large amounts by both toxigenic and nontoxigenic C difficile strains. Although this is an important screening test, we must recognize that positive glutamate dehydrogenase tests require confirmation of a toxic genetic strain by either enzyme immunoassays or NAAT.

In fact, no single diagnostic test can offer 100% accuracy (although having two negative tests does make C difficile infection unlikely). As such, the authors point out that the decision to treat should really be based on clinical evidence.

You also don't have to retest patients who are otherwise asymptomatic after treatment, particularly in the absence of diarrhea. As reported in one study, up to 56% of patients have prolonged shedding of C difficile as much as 4 weeks after their treatment, despite having resolution of diarrhea. Another study showed that new-onset postinfection irritable bowel–type syndrome occurs in up to 25% of patients. For such cases of diagnostic uncertainty, the authors recommend scoping the patients. If the colon is endoscopically and histologically normal, then C difficile is not likely to be accountable for the diarrheal symptoms.

Treatment Recommendations

When it comes to the treatment of C difficile, oral vancomycin has been considered the gold standard by most people, although there's also a clear role for fidaxomicin and metronidazole.

For initial episodes of nonsevere C difficile infections, the authors recommend oral vancomycin at 125 mg four times a day, fidaxomicin at 200 mg twice daily, or oral metronidazole for 500 mg three times a day, all of which can be given for 10 days. However, it should be noted that metronidazole is not well tolerated at that dose and may be problematic for some patients.

The authors qualified severe C difficile as occurring in patients who have either a white blood cell count of ≥ 15,000 cells/mm3 or a creatinine level of > 1.5 mg/dL. In such patients, the guidelines recommend beginning, once again, with vancomycin at 125 mg four times a day or fidaxomicin at 200 mg twice a day, both for 10 days. Findings indicate that increasing the dose of vancomycin in patients with severe C difficile doesn't seem to produce superior results.

The dose recommendation is escalated, however, in fulminant C difficile, which is defined the same way as severe infection but with the addition that the patients also have hypotension, shock, ileus, or megacolon. These are patients in a very medically dire circumstance.

Here, the recommendation is to achieve adequate volume resuscitation and give them 500 mg of oral vancomycin every 6 hours for a period of 48-72 hours. This can perhaps be combined with parenteral metronidazole, as these patients can have concomitant dual therapy. You can then reevaluate them, and if they're still not doing well, consider fecal microbiota transplantation (FMT).

Expanding the Candidates for FMT

Another potentially practice-changing aspect of these guidelines relates to the use of FMT.

This is something we clearly consider for recurrent disease, but also something the authors recommend for severe and fulminant C difficile refractory to antibiotic therapy.

FMT can even be safely administered in patients with toxic megacolon, which the authors suggest could be done via colonic insulation beyond the splenic flexor, with gentle CO2 insufflation so as to avoid air distention and careful advancement of the scope.

In those circumstances where there's a pseudomembrane, the authors recommend repeating the FMT every 3-5 days until resolution, concomitantly administering antibiotics (vancomycin or fidaxomicin) after the FMT for as long as the pseudomembrane is present, continuing antibiotics for 5 days after the pseudomembrane is resolved, and then repeating the FMT for a final time.

Treatment of Recurrent Cases

In cases of recurrent C difficile, the authors suggest using a tapering dose of vancomycin, which is certainly in line with the standard following the first recurrence. Initial recurrence is experienced by approximately 20% of patients, although those numbers go up very quickly, essentially doubling with each episode of recurrence.

Once the patients have sustained clinical cure, the guidelines state that vancomycin is the only antibiotic that's really been studied. There are no industry trials with fidaxomicin in this particular circumstance.

Strategies for Preventing Recurrence

Once patients have had a second or further recurrence, the authors recommend that they should go straight to FMT to prevent more recurrences. This is a strong recommendation based on moderate-quality evidence. This is a standard that most of us already use.

FMT should be delivered through the colonoscope. The authors did cite that there have been a number of cases of fatal aspiration pneumonia in patients receiving FMT via nasoenteric tube, which they recommend avoiding in these high-risk patients, especially when patients are fairly toxic and lying flat.

FMT should be repeated if the patients relapse after initially undergoing this procedure. Treatment with a second FMT is reported to have a 95% success rate.

For patients who have relapsed and aren't candidates for FMT, the question is whether you should give them a sustained treatment. The authors recommend that oral vancomycin be given daily for a minimum of 8 weeks. For chronic suppression, they also suggested that vancomycin be given at 125 mg once daily. But remember that this was supported only for high-risk patients who are not candidates for FMT via colonoscopy.

Primary prevention has been demonstrated with placebo-controlled trials for fidaxomicin and vancomycin. The guidelines also cite data in very high-risk patients who have undergone either a renal transplant or a bone marrow transplant, in which oral vancomycin used as secondary prophylaxis has shown success. These are things that should be considered if the patients are at a significant high risk or require frequent or ongoing courses of antibiotics. They can be given concomitant treatment until they have finished their antibiotic course.

The guidelines also speak to the potential role for bezlotoxumab, a fairly new product released in 2016. It's a human monoclonal antibody that binds to toxin B and prevents it from entering the GI cell layer, thereby preventing colonic cell damage. Bezlotoxumab has been well studied. There is good evidence that it prevents relapse. However, it's extremely expensive. One 1000-mg vial costs approximately $4500. The recommended dose is 10 mg/kg, so the amount you're taking from that vial will increase in higher-weight patients.

Clinical trials of bezlotoxumab showed that it yielded the greatest benefits in those aged 65 years or older with at least one of the following risk factors: They had their second episode of C difficile within 6 months, they were immunocompromised, or they had severe C difficile. The authors recommended that these high-risk patients should potentially be considered for what is, again, a very expensive drug.

Managing Patients With IBD

Patients with IBD have an approximately fivefold increased risk of developing C difficile. They're also more likely to have community-acquired C difficile. We really do need to keep our guard up in this patient population.

In evaluating these patients, the guidelines recommend they receive vancomycin at 125 mg four times a day, but for a minimum of 14 days rather than 10 days. This was a strong recommendation based on low-quality evidence.

They also recommend that immunosuppressive therapy for patients with IBD should not be held during any course of C difficile treatment in the setting of disease flare. The escalation of therapy may be considered if these patients show no signs of symptomatic improvement. The takeaway message is to not withhold immunosuppressive therapy in patients with IBD.

These guidelines provide lots of new information and a tremendous number of valuable points. I strongly recommend that you read them, as they have practice-changing implications that should influence how you treat C difficile infection in your patients. I certainly learned a lot from reading them.

I hope this has been helpful.

I'm Dr David Johnson. Thanks again for listening, and I look forward to speaking with you soon.

David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.

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