Clostridioides difficile Infection: Update on Management


Am Fam Physician. 2020 Feb 1;101(3):168-175.

  Patient information: A handout on this topic is available at

Author disclosure: No relevant financial affiliations.

Guidelines for the diagnosis and treatment of Clostridioides difficile infection have recently been updated. Risk factors include recent exposure to health care facilities or antibiotics, especially clindamycin. C. difficile infection is characterized by a wide range of symptoms, from mild or moderate diarrhea to severe disease with pseudomembranous colitis, colonic ileus, toxic megacolon, sepsis, or death. C. difficile infection should be considered in patients who are not taking laxatives and have three or more episodes of unexplained, unformed stools in 24 hours. Testing in these patients should start with enzyme immunoassays for glutamate dehydrogenase and toxins A and B or nucleic acid amplification testing. In children older than 12 months, testing is recommended only for those with prolonged diarrhea and risk factors. Treatment depends on whether the episode is an initial vs. recurrent infection and on the severity of the infection based on white blood cell count, serum creatinine level, and other clinical signs and symptoms. For an initial episode of nonsevere C. difficile infection, oral vancomycin or oral fidaxomicin is recommended. Metronidazole is no longer recommended as first-line therapy for adults. Fecal microbiota transplantation is a reasonable treatment option with high cure rates in patients who have had multiple recurrent episodes and have received appropriate antibiotic therapy for at least three of the episodes. Good antibiotic stewardship is a key strategy to decrease rates of C. difficile infection. In routine or endemic settings, hands should be cleaned with either soap and water or an alcohol-based product, but during outbreaks soap and water is superior. The Infectious Diseases Society of America does not recommend the use of probiotics for prevention of C. difficile infection.

Clostridioides difficile (formerly Clostridium difficile) is an anaerobic, spore-forming, gram-positive bacillus identified in 1978 as the primary cause of antibiotic-associated diarrhea and pseudomembranous colitis.1 The rate of C. difficile infections increased from 13 to 14.2 cases per 1,000 adults between 2011 and 2015; it is now the most commonly reported nosocomial pathogen in the United States.2 Health care costs associated with C. difficile infection were estimated at $4.8 billion for acute care facilities in 2008.3 This article discusses recently updated guidelines for the diagnosis and treatment of C. difficile infection.

 Enlarge     Print


Clinical recommendationEvidence ratingComments

A two-step algorithm should be used to guide diagnostic testing for Clostridioides difficile infection: enzyme immunoassay for glutamate dehydrogenase and toxins A and B, followed by nucleic acid amplification testing if initial results are indeterminate. For patients likely to have C. difficile infection based on clinical symptoms, either nucleic acid amplification testing or the two-step algorithm is appropriate.6


Guideline recommendation based on low-quality, small diagnostic studies

Oral vancomycin and fidaxomicin (Dificid) are preferred over metronidazole for initial episodes of C. difficile infection.6,25


Recommendation from an evidence-based practice guideline and large disease-oriented study

Fecal microbiota transplantation is recommended for patients with multiple recurrences of C. difficile infection in whom appropriate antibiotic therapy has been ineffective.6,27,28


Based on practice guidelines and consistent findings from small randomized controlled trials evaluating diarrhea

Antibiotic stewardship reduces rates of C. difficile infection.6


Guideline recommendation based on low- to moderate-quality longitudinal cohort studies

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to

The Authors

show all author info

ANNE MOUNSEY, MD, is a professor of clinical medicine in the Department of Family Medicine at the University of North Carolina, Chapel Hill....

KELLY LACY SMITH, MD, is an assistant professor of clinical medicine in the Department of Family Medicine at the University of North Carolina.

VINAY C. REDDY, MD, MPH, is an assistant professor of clinical medicine in the Department of Family Medicine at the University of North Carolina.

SARAH NICKOLICH, MD, is an assistant professor of clinical medicine in the Department of Family and Community Medicine at the Penn State Health Milton S. Hershey Medical Center, Hershey, Pa.

Address correspondence to Anne Mounsey, MD, University of North Carolina School of Medicine, 590 Manning Dr., Chapel Hill, NC 27514 (email: Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


show all references

1. Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med. 2006;145(10):758–764....

2. Healthcare Cost and Utilization Project. Clostridium difficile hospitalizations 2011–2015. August 16, 2018. Accessed April 12, 2018.

3. Lessa FC, Winston LG, McDonald LC; Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(24):2369–2370.

4. Brown KA, Fisman DN, Moineddin R, et al. The magnitude and duration of Clostridium difficile infection risk associated with antibiotic therapy: a hospital cohort study. PLoS One. 2014;9(8):e105454.

5. Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57(5):2326–2332.

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.

7. Henrich TJ, Krakower D, Bitton A, et al. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis. 2009;15(3):415–422.

8. Reveles KR, Pugh MJ, Lawson KA, et al. Shift to community-onset Clostridium difficile infection in the national Veterans Health Administration, 2003–2014. Am J Infect Control. 2018;46(4):431–435.

9. Centers for Disease Control and Prevention. Surveillance for community-associated Clostridium difficile—Connecticut, 2006. MMWR Morb Mortal Wkly Rep. 2008;57(13):340–343.

10. Barbut F, Petit JC. Epidemiology of Clostridium difficile-associated infections. Clin Microbiol Infect. 2001;7(8):405–410.

11. Shaughnessy MK, Micielli RL, DePestel DD, et al. Evaluation of hospital room assignment and acquisition of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2011;32(3):201–206.

12. Carter GP, Rood JI, Lyras D. The role of toxin A and toxin B in Clostridium difficile-associated disease: past and present perspectives. Gut Microbes. 2010;1(1):58–64.

13. Heinlen L, Ballard JD. Clostridium difficile infection. Am J Med Sci. 2010;340(3):247–252.

14. Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70(4):298–304.

15. Ma GK, Brensinger CM, Wu Q, et al. Increasing incidence of multiply recurrent Clostridium difficile infection in the United States: a cohort study. Ann Intern Med. 2017;167(3):152–158.

16. Figueroa I, Johnson S, Sambol SP, et al. Relapse versus reinfection: recurrent Clostridium difficile infection following treatment with fidaxomicin or vancomycin. Clin Infect Dis. 2012;55(suppl 2):S104–S109.

17. Cohen SH, Gerding DN, Johnson S, et al. 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;31(5):431–455.

18. Rao K, Berland D, Young C, et al. The nose knows not: poor predictive value of stool sample odor for detection of Clostridium difficile. Clin Infect Dis. 2013;56(4):615–616.

19. 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):1963–1973.

20. Schutze GE, Willoughby RE; Committee on Infectious Diseases; American Academy of Pediatrics. Clostridium difficile infection in infants and children. Pediatrics. 2013;131(1):196–200.

21. Crobach MJ, Planche T, Eckert C, et al. European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2016;22(suppl 4):S63–S81.

22. Rodriguez C, Van Broeck J, Taminiau B, et al. Clostridium difficile infection: early history, diagnosis and molecular strain typing methods. Microb Pathog. 2016;97:59–78.

23. Kawamoto S, Horton KM, Fishman EK. Pseudomembranous colitis: spectrum of imaging findings with clinical and pathologic correlation. Radiographics. 1999;19(4):887–897.

24. Abujamel T, Cadnum JL, Jury LA, et al. Defining the vulnerable period for re-establishment of Clostridium difficile colonization after treatment of C. difficile infection with oral vancomycin or metronidazole. PLoS One. 2013;8(10):e76269.

25. Barkin JA, Sussman DA, Fifadara N, et al. Clostridium difficile infection and patient-specific antimicrobial resistance testing reveals a high metronidazole resistance rate. Dig Dis Sci. 2017;62(4):1035–1042.

26. Cornely OA, Crook DW, Esposito R, et al.; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281–289.

27. Khoruts A, Rank KM, Newman KM, et al. Inflammatory bowel disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2016;14(10):1433–1438.

28. Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. 2016;165(9):609–616.

29. Rokas KE, Johnson JW, Beardsley JR, et al. The addition of intravenous metronidazole to oral vancomycin is associated with improved mortality in critically ill patients with Clostridium difficile infection. Clin Infect Dis. 2015;61(6):934–941.

30. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections [published correction appears in Clin Infect Dis. 2011;53(12):1312]. Clin Infect Dis. 2011;53(5):440–447.

31. Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever [published correction appears in N Engl J Med. 2010;363(16):1585]. N Engl J Med. 2008;359(18):1932–1940.

32. Hu MY, Katchar K, Kyne L, et al. Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology. 2009;136(4):1206–1214.

33. Bakken J. Staggered and tapered antibiotic withdrawl with administration of kefir for recurrent Clostridum difficile infection Clin Infect Dis. 2014;59(6):858–861.

34. Bezlotoxumab (Zinplava) for prevention of recurrent Clostridium difficile infection JAMA. 2017;318(7):659–660.

35. Jury LA, Guerrero DM, Burant CJ, et al. Effectiveness of routine patient bathing to decrease the burden of spores on the skin of patients with Clostridium difficile infection. Infect Control Hosp Epidemiol. 2011;32(2):181–184.

36. Oughton MT, Loo VG, Dendukuri N, et al. Hand hygiene with soap and water is superior to alcohol rub and antiseptic wipes for removal of Clostridium difficile. Infect Control Hosp Epidemiol. 2009;30(10):939–944.

37. Jabbar U, Leischner J, Kasper D, et al. Effectiveness of alcohol-based hand rubs for removal of Clostridium difficile spores from hands. Infect Control Hosp Epidemiol. 2010;31(6):565–570.

38. Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;(12):CD006095.

39. Suez J, Zmora N, Zilberman-Schapira G, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174(6):1406–1423.e16.

40. Kothari D, Patel S, Kim SK. Probiotic supplements might not be universally-effective and safe: a review. Biomed Pharmacother. 2019;111:537–547.

41. Winslow BT, Onysko M, Thompson KA, et al. Common questions about Clostridium difficile infection. Am Fam Physician. 2014;89(6):437–442. Accessed July 23, 2019.

42. Schroeder MS. Clostridium difficile–associated diarrhea. Am Fam Physician. 2005;71(5):921–928. Accessed July 23, 2019.



Copyright © 2020 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions

More in AFP

Editor's Collections

Related Content

More in Pubmed


Jan 2022

Access the latest issue of American Family Physician

Read the Issue

Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.

Sign Up Now

Navigate this Article