Clostridioides difficile Infection

Written By Kimberly Valenta, MD

Basic Information

  • Clostridioides difficile is a gram-positive spore-forming anaerobe associated with healthcare-associated infectious diarrhea

  • Toxigenic strains are responsible for C difficile infection (CDI)

    • Toxins A and B cause destruction of intestinal epithelial cells (1)

  • CDI is the leading cause of healthcare-associated infectious diarrhea, responsible for nearly half a million infections and contributing to over 20,000 deaths annually (2)

  • C difficile enters the gut following ingestion of spores, which are resistant to many disinfectant techniques used in healthcare settings

  • Cumulative antibiotic exposure prior to hospital admission is the most important risk factor for developing CDI (3)

    • Most classes of antibiotics are associated with some risk, with cephalosporins, carbapenems, fluoroquinolones, and clindamycin carrying the greatest risk (1)

    • Other risk factors include advanced age, extended stay in a healthcare facility, and immunosuppression

    • The incidence of healthcare-acquired CDI has decreased over the past decade, but the incidence of community-acquired CDI has increased (4)

  • Primary colonization with C difficile, both non-toxigenic and toxigenic strains, prior to hospitalization, is associated with a decreased risk of CDI (5)

  • 5% of adults and 15-70% of infants are colonized by C difficile (5), complicating diagnosis

Approach to Diagnosis

  • CDI should be suspected in people ≥2 years of age who present with unexplained, new onset diarrhea (≥3 unformed stools in 24 hours)6 following antibiotic use or in people with healthcare-associated diarrhea

  • Factors that disrupt the gut flora and predispose to CDI (7) include:

    • Antibiotic exposure

    • Age >65 years (8)

    • Prior hospitalization

    • Long-term care residence

    • Prior CDI

    • Immunosuppression, including chemotherapy and intravenous immunoglobulin therapy

    • Inflammatory bowel disease

    • Recent gastrointestinal surgery

    • Feeding tube use

    • Multiple comorbidities, including chronic kidney disease and chronic obstructive pulmonary disease (COPD)

  • For children, the risk of CDI varies by age. (6) Before testing, consider consulting a pediatric infectious disease specialist.

    • Neonates or infants ≤12 months of age with diarrhea should not be routinely tested for CDI given the high prevalence of asymptomatic carriage of C difficile

    • Children between the ages of 1 and 2 years with diarrhea should not be routinely tested for CDI until other infectious and noninfectious causes have been excluded

    • Children ≥2 years of age with prolonged or worsening diarrhea should be tested for CDI if they have certain risk factors, including:

      • Inflammatory bowel disease

      • Immunodeficiency

      • Gut motility issues

      • History of bowel surgery

      • Recent antibiotic use

      • Recent outbreak in a closed hospital unit

  • When CDI is considered in an adult or child on the basis of clinical presentation, definitive diagnosis requires a positive stool test for C difficile toxins or toxigenic C difficile genes (6)

  • In adults, clinical evidence of pseudomembranous colitis is also satisfactory for diagnosis

  • Stool tests for C difficile

    • Check your institutional guidelines for stool testing criteria and recommended tests

    • Recommended tests include one of the following (6):

      • Nucleic acid amplification test (NAAT) for toxigenic C difficile genes

      • Multistep algorithm testing including enzyme immunoassays (EIAs) for C difficile toxins

    • Stool tests cannot distinguish between asymptomatic colonization and symptomatic infection with C. difficile

      • Stool testing should not be performed on someone who does not have diarrhea

      • People colonized with C difficile without symptoms of CDI should not be treated with antibiotics9

      • If ileus is present, a rectal swab may be used (10)

  • Additional diagnostic assessments and tests that are included as part of the workup include:

    • Physical examination with a focus on the general appearance and vital signs, volume status, and the abdomen

    • Basic laboratory tests to assess disease severity: CBC, CMP

    • Imaging studies may be indicated if testing is inconclusive or if ileus is present

    • Routine endoscopy for diagnosis is not recommended (7)

  • CDI ranges in severity from mild self-limited diarrhea to fulminant disease with risk of sepsis and death

    • CDI classification is loosely based on 3 degrees of severity (11):

      • Mild-moderate

      • Severe

      • Severe-complicated or fulminant

    • Appreciation of disease severity is important because treatment varies accordingly (12)

Table 1. Presentation of C difficile by Disease Severity (13-16)

Differential Diagnosis

 Table 2. Differential Diagnosis: C difficile Infection (17-19)

Approach to Treatment

  • Stop inciting antibiotic agents as soon as possible (6)

  • If suspicion for CDI is high, start empiric therapy while awaiting test results (if a delay in laboratory confirmation is anticipated)

  • Start empiric therapy for fulminant disease

  • Choice of antibiotic regimen depends on CDI severity and whether it’s a first episode or recurrent

  • Three antibiotics are available for treatment of CDI: metronidazole, vancomycin, and fidaxomicin

  • At its extreme, fulminant CDI can lead to bowel perforation, sepsis, shock, end organ failure, and death

    • Patients who present with fulminant disease require admission to an intensive critical care unit, hemodynamic stabilization, subspecialist evaluation including surgery, and antibiotic therapy

    • Surgical management may be required (7)

      • Subtotal colectomy with preservation of the rectum

      • Alternative consideration: diverting loop ileostomy with colonic lavage with subsequent antegrade vancomycin flushes

    • Recommended antibiotic regimen is oral or rectal vancomycin with intravenous metronidazole

    • This regimen is recommended for all fulminant CDI cases, regardless of episode

  • Those who present with milder forms of CDI but have risk factors for more severe forms of the disease should be closely monitored for disease progression

  • Treatment recommendations for a first episode of mild-moderate CDI

    • Metronidazole, vancomycin, and fidaxomicin have similar efficacy rates for cure of mild-moderate CDI (20)

    • Treatment with fidaxomicin has been shown to result in lower recurrence rates and is therefore recommended as the preferred treatment by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) for treatment of a first episode (21)

    • The American College of Gastroenterology (ACG) supports the use of either fidaxomicin or vancomycin for treatment of a first episode due to similar efficacy rates for a cure and the lower cost of vancomycin (7)

    • ACG supports the use of metronidazole for patients with mild-moderate CDI who do not have risk factors for developing severe disease

  • Recommendations for a first episode of severe CDI

    • Treatment with oral fidaxomicin or vancomycin

    • Fidaxomicin is preferred by SHEA/IDSA

    • Vancomycin can be administered rectally if ileus is present

    • Metronidazole is not recommended for patients with severe disease (7,21)

    • Bezlotoxumab is a monoclonal antibody that binds to toxin B; it has been shown to reduce CDI recurrence in patients at high risk of recurrence (22)

  • Recommendation for a second episode of mild-moderate or severe CDI

    • Add bezlotoxumab to the regimen if recurrence occurred within 6 months (21)

    • Fidaxomicin is preferred and vancomycin is acceptable as an alternative (SHEA/IDSA)

    • ACG recommends the following for mild-moderate or severe disease:

      • If metronidazole was used for the first episode, then treat with vancomycin

      • If vancomycin was used for the first episode, then treat with fidaxomicin

      • If fidaxomicin was used for the first episode, then treated with prolonged vancomycin following a taper and pulse regimen

    • Recommendation for third or subsequent episode for mild-moderate or severe disease:

      • SHEA/IDSA recommends

        • Fecal microbiota transplantation (FMT)

        • If FMT isn’t available, select one of the following:

          • Vancomycin

          • Vancomycin followed by rifaximin

          • Fidaxomicin

      • ACG recommends:

        • Fecal microbiota transplantation (FMT)

        • If FMT is available, complete a course of vancomycin then follow with FMT

        • If FMT is not available, treat with a prolonged course of vancomycin or fidaxomicin or rifaximin

Table 3. Treatment Recommendations for CDI by Severity and Episode (6,21)

References

1. Czepiel J, Dróżdż M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019;38(7):1211-1221. doi:10.1007/s10096-019-03539-6

2. Guh AY, Mu Y, Winston LG, et al. Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes. N Engl J Med. 2020;382(14):1320-1330. doi:10.1056/NEJMoa1910215

3. Webb BJ, Subramanian A, Lopansri B, et al. Antibiotic Exposure and Risk for Hospital-Associated Clostridioides difficile Infection. Antimicrob Agents Chemother. 2020;64(4). doi:10.1128/AAC.02169-19

4. Fu Y, Luo Y, Grinspan AM. Epidemiology of community-acquired and recurrent Clostridioides difficile infection. Therap Adv Gastroenterol. 2021;14:17562848211016248. doi:10.1177/17562848211016248

5. Shim JK, Johnson S, Samore MH, Bliss DZ, Gerding DN. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet. 1998;351(9103):633-636. doi:10.1016/S0140-6736(97)08062-8

6. 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;66(7):987-994. doi:10.1093/cid/ciy149

7. 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

8. Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection. J Med Microbiol. 2002;51(5):448-454. doi:10.1099/0022-1317-51-5-448

9. Fishbein SRS, Hink T, Reske KA, et al. Randomized Controlled Trial of Oral Vancomycin Treatment in Clostridioides difficile-Colonized Patients. mSphere. 2021;6(1). doi:10.1128/mSphere.00936-20

10. Curry SR, Schlackman JL, Hamilton TM, et al. Perirectal swab surveillance for Clostridium difficile by use of selective broth preamplification and real-time PCR detection of tcdB. J Clin Microbiol. 2011;49(11):3788-3793. doi:10.1128/JCM.00679-11

11. Poylin V, Hawkins AT, Bhama AR, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Clostridioides difficile Infection. Dis Colon Rectum. 2021;64(6):650-668. doi:10.1097/DCR.0000000000002047

12. Bagdasarian N, Rao K, Malani PN. Diagnosis and Treatment ofClostridium difficilein Adults: A Systematic Review. JAMA. 2015;313(4):398. doi:10.1001/jama.2014.17103

13. Baker SJ, Chu DI. Physical, Laboratory, Radiographic, and Endoscopic Workup for Clostridium difficile Colitis. Clin Colon Rectal Surg. 2020;33(2):82-86. doi:10.1055/s-0039-3400474

14. Boland GW, Lee MJ, Cats AM, Gaa JA, Saini S, Mueller PR. Antibiotic-induced diarrhea: specificity of abdominal CT for the diagnosis of Clostridium difficile disease. Radiology. 1994;191(1):103-106. doi:10.1148/radiology.191.1.8134552

15. Eghbali E, Akhavi Milani A, Shirmohamadi M, Hosseinifard H. CT features of toxic megacolon: A systematic review. Radiography. 2021;27(2):716-720. doi:10.1016/j.radi.2020.10.019

16. Ahmad O, Crawford TN, Arora V, Maskey MK. Laboratory markers predictive of fulminant Clostridioides difficile infection refractory to fluid resuscitation. Infect Prev Pract. 2021;3(2):100127. doi:10.1016/j.infpip.2021.100127

17. Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017;65(12):e45-e80. doi:10.1093/cid/cix669

18. Polage CR, Solnick JV, Cohen SH. Nosocomial diarrhea: evaluation and treatment of causes other than Clostridium difficile. Clin Infect Dis. 2012;55(7):982-989. doi:10.1093/cid/cis551

19. Mengistu DA, Belami DD, Tefera AA, Alemeshet Asefa Y. Bacteriological Quality and Public Health Risk of Ready-to-Eat Foods in Developing Countries: Systematic Review and Meta Analysis. Microbiol Insights. 2022;15:11786361221113916. doi:10.1177/11786361221113916

20. Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev. 2017;3(3):CD004610. doi:10.1002/14651858.CD004610.pub5

21. 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;73(5):e1029-e1044. doi:10.1093/cid/ciab549

22. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017;376(4):305-317. doi:10.1056/NEJMoa1602615

Kimberly Valenta, MD

Physician, home educator, and writer.

https://www.notemedley.com
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