Updated Guidelines on Management of Clostridioides difficile Infection in Adults

Diarrhea is common in the intensive care unit (ICU), often without obvious cause. Dehydration, malnutrition, hemodynamic instability, electrolyte imbalances, burns, skin breakdown, infections, intestinal ischemia, antibiotic or other medication induction, and enteral feeding are common causes of diarrhea in the ICU. Clostrididioides difficile infection (CDI) occurs in about 4% of ICU patients, causing fulminant colitis and death in nearly 60% of symptomatic critically ill patients.^1-3 Staying abreast of the evidence-based advancements to CDI management is imperative for all ICU professionals.
 
For decades we have known that the longer a critically ill patient stays in the ICU, the higher the likelihood of acquiring and being colonized with C difficile.⁴ Although the adjusted estimate for CDI burden in the United States has decreased by 24% (462,100 cases annually) from the prior report, first CDI recurrences have remained unchanged. It will be interesting to see how the incidence of CDI has been affected by the COVID-19 pandemic. The increase in global hand hygiene, personal protective equipment, and limited patient and people interactions may cause an incidence reduction. However, prolonged hospitalizations, longer mechanical ventilation durations, disruption in gastrointestinal flora by proton pump inhibitor prophylaxis and enteral feeding in mechanically ventilated patients, and increased antibiotic exposure caused by the virus may very likely counteract this reduction.
 
In 1995, clinical practice guidelines for CDI were first published to assist clinicians in diagnosis, monitoring, and management.⁵ In 2010 and again in 2017, the guidelines were updated dramatically.^6,7 In 2021, the Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHAE) again updated their recommendations. ICU professionals should be aware of the significant updates.⁸
 
Here is a summary of the key changes:
 
1. What is the preferred therapy for an initial CDI episode?
In the 2010 guidelines, metronidazole was the drug of choice for an initial episode of mild to moderate CDI, and oral vancomycin with or without metronidazole was recommended for severe, complicated CDI. In 2017, the IDSA/SHAE guidelines strongly recommended either vancomycin or fidaxomicin over metronidazole for an initial CDI episode and removed the severity scale. Metronidazole was suggested only in settings of nonsevere CDI where vancomycin or fidaxomicin was limited. The revised guidelines, based on four newly released randomized controlled trials, now suggest fidaxomicin rather than the alternative standard, vancomycin, because of the increased sustained response after therapy, fewer CDI recurrences, and comparable initial CDI clinical cure following fidaxomicin therapy without increased drug-related adverse events or change in mortality. For fulminant (previously termed severe, complicated to include patients with shock, ileus, or megacolon) CDI, vancomycin is still recommended rather than fidaxomicin.
 
2. What is the preferred therapy for recurrent CDI episodes?
In 2010, the guidelines recommended the same regimen as for the initial episode. Metronidazole was discouraged after the first recurrence. Vancomycin, using a tapered and/or pulse regimen, was the preferred strategy. In 2017, the guidelines again recommended vancomycin as a tapered and pulse regimen (rather than repeating a 10-day course), vancomycin followed by rifaximin, or fidaxomicin. Metronidazole was no longer preferred. In 2021, the guidelines now suggest fidaxomicin rather than intracolonic vancomycin to improve sustained response after therapy.
 
3. Should monoclonal antibodies be used in CDI treatment?
Bezlotoxumab is a monoclonal antibody that targets toxin B produced by C difficile. It was found to be effective in preventing CDI after the completion of the 2017 CDI guidelines.⁹ The 2021 guidelines now suggest bezlotoxumab, as a one-time infusion, as an adjunct to standard-of-care antibiotics for recurrent CDI episodes within six months rather than standard-of-care antibiotics alone. Bezlotoxumab should be used with caution in patients with congestive heart failure.
 
4. Are there any changes regarding the use of fecal microbiota transplantation?
Essentially, no. However, it should be noted that since the 2017, three separate safety alerts have been published by the U.S. Food and Drug Administration. Two alerts pertain to Escherichia coli transmission from donor to transplant recipients, and the other documents concern for SARS-CoV-2.
 
The 2021 guidelines did not update recommendations for diagnosis, CDI management in children, isolation measures, or infection control and prevention.
 
Given the emergence of new, relevant evidence, IDSA and SHAE will determine the need for guideline revisions every two years. As critically ill patients possess many of the risk factors for developing severe CDI, ICU professionals must have a high index of suspicion and maintain vigilance to prevent and rapidly treat the disease using the latest evidence-based recommendations.

References 

1. Lawrence SJ, Puzniak LA, Shadel BN, Gillespie KN, Kollef MH, Mundy LM. Clostridium difficile in the intensive care unit: epidemiology, costs, and colonization pressure. Infect Control Hosp Epidemiol. 2007 Feb;28(2):123-130. https://pubmed.ncbi.nlm.nih.gov/17265392/
2. Grundfest-Broniatowski S, Quader M, Alexander F, Walsh RM, Lavery I, Milsom J. Clostridium difficile colitis in the critically ill. Dis Colon Rectum. 1996 Jun;39(6):619-623. https://pubmed.ncbi.nlm.nih.gov/8646945/
3. Kyne L, Merry C, O'Connell B, Kelly A, Keane C, O’Neill D. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing. 1999 Mar;28(2):107-113. https://pubmed.ncbi.nlm.nih.gov/10350405/
4. Clabots CR, Johnson S, Olson MM, Peterson LR, Gerding DN. Acquisition of Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. J Infect Dis. 1992 Sep;166(3):561-567. https://pubmed.ncbi.nlm.nih.gov/1323621/
5. Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva Jr, J. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995 Aug;16(8):459-477. https://pubmed.ncbi.nlm.nih.gov/7594392/
6. Cohen SJ, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010 May;31(5):431-455. https://pubmed.ncbi.nlm.nih.gov/20307191/
7. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):e1-e48. https://pubmed.ncbi.nlm.nih.gov/29462280/
8. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021 Jun 24;ciab549. https://doi.org/10.1093/cid/ciab549
9. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017 Jan 26;376(4):305-317. https://pubmed.ncbi.nlm.nih.gov/28121498/