2021 American College of Gastroenterology Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections

The American College of Gastroenterology (ACG) released updated clinical guidelines on the prevention, diagnosis, and treatment of Clostridioides difficile infections (CDI), which was recently published in The American Journal of Gastroenterology. These guidelines represent the official practice recommendations of the ACG and indicate the preferred approach to the management of adults with CDI.

The researchers used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to develop 23 clinical guidelines on the prevention, diagnosis, and treatment of CDI. In instances where the evidence was not applicable to the GRADE process but there was a consensus of significant clinical value, 8 key concepts were developed based on expert consensus.

Prevention

The ACG committee does not recommend probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention). They also do not recommend probiotics for the prevention of CDI recurrence (secondary prevention). The panel determined that there is limited evidence on use of probiotics for the primary prevention or secondary prevention of CDI.

Diagnosis and Classification

According to the first key concept statement, only individuals with symptoms suggestive of active CDI should be tested (3 or more unformed stools in 24 hours). Data on the optimum threshold for testing for CDI is lacking because reports of diarrhea are often subjective and confounded by other illnesses or medications.

To help distinguish colonization from active infection, CDI testing algorithms should include both a highly sensitive and a highly specific testing modality. The diagnosis of CDI is not always straight forward. In cases of diagnostic uncertainty, expanded diarrhea workup including colonic biopsy to evaluate for alternative etiology of symptoms, such as microscopic colitis or inflammatory bowel disease (IBD), may be clinically valuable. The investigators assert that if the colon is normal endoscopically and histologically, CDI is not likely to be the source of diarrheal symptoms.

Treatment

For an initial episode of nonsevere CDI, the committee recommends either oral vancomycin 125 mg 4 times daily for 10 days or oral fidaxomicin 200 mg twice daily for 10 days. These recommendations are based on ample data that support the effectiveness of vancomycin and fidaxomicin as primary treatments in nonsevere CDI.

For the treatment of an initial nonsevere CDI in low-risk patients, oral metronidazole 500 mg 3 times daily for 10 days may be considered. The use of metronidazole in patients with first occurrence and nonsevere disease remains controversial. Previous research suggests vancomycin may be more effective than metronidazole, while fidaxomicin is superior to vancomycin in curing symptoms. However, differences in effectiveness are not considerable, and the cost of metronidazole is much lower compared with the other 2 antibiotics. Overall, all 3 agents can be beneficial as first-line treatment of initial nonsevere CDI.

For initial therapy of severe CDI, the committee recommends either vancomycin 125 mg 4 times a day for 10 days or fidaxomicin 200 mg twice daily for 10 days. Based on previous studies, 10-day treatment courses for both vancomycin and fidaxomicin appear sufficient for most patients with CDI. Though, it should be noted that metronidazole should not be used for the treatment of severe CDI. Metronidazole has been shown to be inferior compared with vancomycin in multiple randomized controlled trials (RCTs) and cohort studies.

Patients with fulminant CDI should undergo medical therapy. This includes adequate volume resuscitation as well as treatment with 500 mg of oral vancomycin every 6 hours daily. Combination therapy with parenteral metronidazole 500 mg every 8 hours may also be considered.

In patients with an ileus, the addition of vancomycin enemas (500 mg every 6 hours) may be useful. In cases of paralytic ileus, the addition of intravenous metronidazole might be helpful, as transit of oral vancomycin might be impaired, whereas therapeutic concentrations of intravenously administered metronidazole in the inflamed colon are more likely to be attained.

In a key concept statement, the researchers suggest that for patients who need surgical intervention, either a total colectomy with an end ileostomy and a stapled rectal stump or a diverting loop ileostomy with colonic lavage and intraluminal vancomycin be used depending on factors such as clinical circumstances, the patient’s estimated tolerance to surgery, and the surgeon’s best judgment. According to published surgical guidelines, for fulminant CDI, surgeons may choose either total colectomy or diversion without colectomy based on their best judgment.

Fecal microbiota transplantation (FMT) should be considered for patients with severe and fulminant CDI refractory to antibiotic therapy, especially, when patients are determined to be poor surgical candidates. The authors note that, “Optimally, FMT should be considered for those with severe and fulminant CDI after 48-72 hours of maximum medical therapy because it is significantly less invasive without the risks associated with surgery and the burden of postoperative recovery.”

For patients experiencing a first recurrence following an initial course of fidaxomicin, vancomycin, or metronidazole, tapering/pulsed-dose vancomycin is suggested. For patients experiencing a first recurrence following an initial course of vancomycin or metronidazole, fidaxomicin is recommended. For the treatment of a first recurrence of CDI, another course of antibiotics is generally required and the choice of treatment is determined by what was used to treat the initial episode.

Prevention of Recurrence

For patients experiencing their second or further recurrence of CDI, FMT is recommended to prevent further recurrences. FMT is recommended to be delivered through colonoscopy or capsules for the treatment of recurrent CDI (rCDI). If other methods are not available, delivery by enema is suggested. For patients experiencing a recurrence of CDI within 8 weeks of an initial FMT, repeat FMT is suggested. FMT has been found to be a safe and effective therapy for rCDI. The committee also recommend closely following up with patients post FMT to evaluate their responses. Patients can be examined in the clinic or via telephone within a week of the procedure to assess for symptoms of recurrence or adverse events.

Long-term suppressive oral vancomycin may be used to prevent further recurrence in patients with rCDI who are not candidates for FMT, who relapsed following FMT, or who need ongoing or frequent courses of antibiotics. For chronic suppression, the researchers suggest vancomycin at a dose of 125 mg once daily, which controls symptoms and prevents recurrence in most patients. However, some patients continue to experience loose stools at a dose of 125 mg once daily. Thus, twice daily or three times daily dosing of vancomycin may be required.

In patients with a history of CDI who are at an increased risk for recurrence, to prevent further recurrence, oral vancomycin prophylaxis (OVP) may be considered during subsequent systemic antibiotic use. When prescribing OVP, using low-dose vancomycin 125 mg once daily is suggested. In most cases, this treatment is continued until 5 days following completion of systemic antibiotics.

Bezlotoxumab (BEZ) may be considered for the prevention of CDI recurrence in patients who are at an increased risk for recurrence. Based on a previous study, the committee does not recommend the use of BEZ in patients with a history of heart failure. They also recommend that BEZ should be used with caution in patients with severe underlying cardiovascular comorbidities.

Provided there is an appropriate indication for their use, the researchers advise against discontinuation of antisecretory therapy in patients with CDI. The investigators assert that the effects of antisecretory therapy on CDI risk are very small compared with known CDI risk factors. Discontinuing antisecretory therapy may leave acid-related upper gastrointestinal (GI) diseases untreated and subsequently put patients at an increased risk for harm.

Special Populations

In patients with IBD presenting with an acute flare associated with diarrhea, CDI testing is recommended. The authors report that, “[D]etection of CDI in an acute flare of IBD and administration of effective antimicrobial therapy often leads to favorable outcomes; therefore, testing is recommended in any patient with acute onset of or worsening of IBD symptoms.”

In patients with IBD and CDI, vancomycin 125 mg by mouth 4 times a day for a minimum of 14 days is suggested. Based on clinical experience and favorable safety, the committee recommends a longer than standard 10-day treatment course of vancomycin, with a minimum of 14 days of treatment.

In a key concept statement, the investigators note that immunosuppressive IBD therapy should not be held during anti-CDI therapy in the setting of disease flare. If there is no symptomatic improvement with treatment of CDI, escalation of therapy may be considered. When CDI is diagnosed, anti-Clostridioides difficile antimicrobial therapy should be initiated in conjunction with continued maintenance of IBD therapy. If clinical symptoms do not improve after 3 days, immunosuppressive therapy should be optimized or escalated to treat the underlying active IBD.

In patients with IBD, FMT should be considered for rCDI. Patients with IBD are known to be at increased risk of developing rCDI. In numerous single-center and multicenter retrospective cohorts, FMT has been shown to be useful in patients with IBD. Data supports the notion that FMT is as safe and well tolerated in patients with IBD as in those without.

In a key concept statement, the committee recommends using vancomycin to treat pregnant and peripartum patients with CDI and breastfeeding patients with CDI. Mothers can continue to breastfeed during CDI treatment and oral vancomycin is recommended. According to the authors, “Vancomycin is not absorbed and, given its large molecular weight, would not be expected to enter breast milk and any drug that got into the breast milk would not be absorbed by the infant’s gut.”

According to the final key concept statement, vancomycin or fidaxomicin is suggested to be used as a first-line treatment of CDI in patients who are immunocompromised. These individuals are known to be at an increased risk of acquiring CDI, having multiple CDI recurrences, and developing a complex clinical course.

Conclusions

The study authors conclude that CDI will remain a common and difficult clinical problem. The goal of the ACG’s review was to supply evidence-based and clinically meaningful guidelines for the diagnosis, management, and prevention of CDI. While these guidelines are meant to be broadly applicable, they should not be considered the only approach to clinical scenarios.

Table 1. Summary and Strength of GRADE Recommendations for the Management of Clostridioides difficile

Prevention

1. We recommend against probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention) (conditional recommendation, moderate quality of evidence).

2. We recommend against probiotics for the prevention of CDI recurrence (secondary prevention) (strong recommendation, very low quality of evidence).

Diagnosis

3. CDI testing algorithms should include both a highly sensitive and a highly specific testing modality to help distinguish colonization from active infection (conditional recommendation, low quality of evidence).

Treatment

4. We recommend that oral vancomycin 125 mg 4 times daily for 10 days be used to treat an initial episode of nonsevere CDI (strong recommendation, low quality of evidence).

5. We recommend that oral fidaxomicin 200 mg twice daily for 10 days be used for an initial episode of nonsevere CDI (strong recommendation, moderate quality of evidence).

6. Oral metronidazole 500 mg 3 times daily for 10 days may be considered for treatment of an initial nonsevere CDI in low-risk patients (strong recommendation, moderate quality of evidence).

7. As initial therapy for severe CDI, we recommend vancomycin 125 mg 4 times a day for 10 days (strong recommendation, low quality of evidence).

8. As initial therapy for severe CDI, we recommend fidaxomicin 200 mg twice daily for 10 days (conditional recommendation, very low quality of evidence).

9. Patients with fulminant CDI should receive medical therapy that includes adequate volume resuscitation and treatment with 500 mg of oral vancomycin every 6 hours daily (strong recommendation, very low quality of evidence) for the first 48 to 72 hours. Combination therapy with parenteral metronidazole 500 mg every 8 hours can be considered (conditional recommendation, very low quality of evidence).

10. For patients with an ileus, the addition of vancomycin enemas (500 mg every 6 hours) may be beneficial (conditional recommendation, very low quality of evidence).

11. We suggest FMT be considered for patients with severe and fulminant CDI refractory to antibiotic therapy, particularly, when patients are deemed poor surgical candidates (strong recommendation, low quality of evidence).

12. We suggest tapering/pulsed dose vancomycin for patients experiencing a first recurrence after an initial course of fidaxomicin, vancomycin, or metronidazole (strong recommendation, very low quality of evidence).

13. We recommend fidaxomicin for patients experiencing a first recurrence after an initial course of vancomycin or metronidazole (conditional recommendation, moderate quality of evidence).

Prevention of Recurrence

14. We recommend patients experiencing their second or further recurrence of CDI be treated with FMT to prevent further recurrences (strong recommendation, moderate quality of evidence).

15. We recommend FMT be delivered through colonoscopy (strong recommendation, moderate quality of evidence) or capsules (strong recommendation, moderate quality of evidence) for treatment of rCDI; we suggest delivery by enema if other methods are unavailable (conditional recommendation, low quality of evidence).

16. We suggest repeat FMT for patients experiencing a recurrence of CDI within 8 weeks of an initial FMT (conditional recommendation, very low quality of evidence).

17. For patients with rCDI who are not candidates for FMT, who relapsed after FMT, or who require ongoing or frequent courses of antibiotics, suppressive oral vancomycin may be used to prevent further recurrences (conditional recommendation, very low quality of evidence).

18. OVP may be considered during subsequent systemic antibiotic use in patients with a history of CDI who are at high risk for recurrence to prevent further recurrence (conditional recommendation, low quality of evidence).

19. We suggest BEZ be considered for prevention of CDI recurrence in patients who are at high risk for recurrence (conditional recommendation, moderate quality of evidence).

20. We suggest against discontinuation of antisecretory therapy in patients with CDI, provided there is an appropriate indication for their use (strong recommendation, very low quality of evidence).

Special Populations

21. We recommend CDI testing in patients with IBD presenting with an acute flare associated with diarrhea (strong recommendation, low quality of evidence).

22. We suggest vancomycin 125 mg by mouth 4 times a day for a minimum of 14 days in patients with IBD and CDI (strong recommendation, very low quality of evidence).

23. FMT should be considered for rCDI in patients with IBD (strong recommendation, very low quality of evidence).

Table 2. Summary of Key Concept Statements for the Management of Clostridioides difficile

Diagnosis and Classification

1. Only individuals with symptoms suggestive of active CDI should be tested (3 or more unformed stools in 24 hours).

2. We recommend the following criteria, which are predictive of unfavorable outcomes, be used to classify severe CDI at the time of diagnosis: white blood cell count >15,000 cells/mm³ or serum creatinine >1.5 mg/dL.

3. We recommend defining fulminant infection as patients meeting criteria for severe CDI plus presence of hypotension, shock, ileus, or megacolon.

Treatment

4. We suggest that for patients who require surgical intervention, either a total colectomy with an end ileostomy and a stapled rectal stump or a diverting loop ileostomy with colonic lavage and intraluminal vancomycin, be used depending on clinical circumstances, the patient’s estimated tolerance to surgery, and the surgeon’s best judgment.

Special Populations

5. Immunosuppressive IBD therapy should not be held during anti-CDI therapy in the setting of disease flare and escalation of therapy may be considered if there is no symptomatic improvement with treatment of CDI.

6. We recommend using vancomycin to treat pregnant and peripartum patients with CDI.

7. We recommend using vancomycin to treat breastfeeding patients with CDI.

8. We suggest vancomycin or fidaxomicin be used as first-line treatment of CDI in patients who are immunocompromised.

Disclosure: Some study authors declared affiliations with the industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol. 2021:116(6);1124-1147. doi:10.14309/ajg.0000000000001278