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Diagnosis, Prevention, and Treatment of C. difficile: Current State of the Evidence

Clinician Summary
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Focus of This Summary

This is a summary of a systematic review that evaluated the recent evidence regarding the accuracy of diagnostic tests and the effectiveness of interventions for preventing and treating Clostridium difficile (C. difficile) infection. The systematic review included 93 articles published between 2010 and April 2015. This summary is provided to assist in informed clinical decisionmaking. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.


C. difficile is a Gram-positive, anaerobic, spore-forming bacterium generally acquired through ingestion. Symptoms of C. difficile infection (CDI) can range from mild diarrhea to severe conditions such as pseudomembranous colitis and toxic megacolon that can result in death. The estimated mortality rate for health care-associated CDI ranged from 2.4 to 8.9 deaths per 100,000 in 2011. For people ≥65 years of age, the mortality rate was 55.1 deaths per 100,000.

Effective containment and treatment of CDI depends on accurate and swift diagnosis. CDI is diagnosed using clinical findings and tests such as: (1) nucleic acid amplification using loop-mediated isothermal amplification (LAMP) and the polymerase chain reaction (PCR), (2) tests for disease- generating C. difficile toxins (including immunoassays), and (3) test algorithms (these are two-step procedures: the first step is a fast screen for the presence of the organism using a test such as the glutamate dehydrogenase [GDH] assay; if the first test is positive, a second test for toxins is performed).

Efforts to prevent CDI include antimicrobial stewardship, the use of infection-control strategies such as handwashing, and immune-boosting strategies. Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials to reduce microbial resistance and decrease the spread of infections. Handwashing with soap and water is helpful for removing C. difficile spores, which are resistant to alcohol rubs or hand sanitizer. Measures that improve a patient's immune defenses include the use of probiotics to promote healthy gut flora and the maintenance of balanced nutrition.

Initial treatment of CDI commonly involves the use of oral antimicrobials such as metronidazole and vancomycin. Mild to moderate initial CDI is often treated with metronidazole, while severe initial CDI is often treated with vancomycin. Treatment with metronidazole and vancomycin can be problematic, however, as they have been implicated in the development of vancomycin-resistant enterococci in immunocompromised patients.

CDI recurs in 15 to 35 percent of patients who have had one previous episode and in 33 to 65 percent of patients who have had more than two previous episodes. Diagnosis and treatment of relapsed or recurrent CDI are challenging. Diagnosis of recurrent CDI is based on the recurrence of clinical symptoms, and repeat testing may not be required. Currently, clinicians choose from a variety of antimicrobials, dosing protocols, and adjunctive treatments (such as probiotics and fecal microbiota transplantation [FMT]) to manage relapsed or recurrent CDI.

The current review aimed to update a 2011 review regarding the accuracy of CDI diagnostic tests and the effects of interventions to prevent and treat CDI in adults.


Diagnosis of CDI: Nucleic acid amplification tests have high sensitivity and specificity for diagnosing CDI (high strength of evidence [SOE]). (See Table 1.)

Prevention of CDI: Strategies such as antibiotic stewardship and handwashing campaigns may help prevent CDI (low SOE). Further evidence is needed to confirm that prevention strategies impact patient outcomes such as CDI incidence. (See Table 2.)

Treatment of CDI: Vancomycin is more effective than metronidazole for the initial treatment of CDI (high SOE), while fidaxomicin is more effective than vancomycin for the prevention of recurrent CDI (high SOE). Physicians may take into consideration disease and patient characteristics, effectiveness, potential adverse effects, patient preferences, and costs when choosing an antibiotic to treat CDI. Lactobacillus probiotics, when used as an adjunct to antibiotic therapy, may prevent the recurrence of CDI (low SOE); additionally, probiotics are generally safe in otherwise healthy patients. There is low SOE that FMT may be effective for treating recurrent and relapsed CDI; however, there is consistent positive evidence for its effectiveness in patients with recurrent and relapsed CDI. (See Tables 3, 4, and 5.)

Overview of Clinical Research Evidence

Table 1: Summary of Key Findings and Strength of Evidence for the Accuracy of Diagnostic Tests for C. difficile Infection
Note: Diagnostic testing is recommended in patients in whom there is a suspicion of CDI based on symptoms and history. CDI is suspected in patients with symptoms of diarrhea (≥3 loose stools in 24 hours) or ileus who have additional risk factors (including use of antibiotics or antineoplastic agents in the previous 8 weeks, hospitalization, and older age). Clinicians should consider the possibility of CDI in hospitalized patients who have unexplained leukocytosis. Testing of stool from asymptomatic patients is not recommended. Testing for C. difficile or its toxins should be performed only on diarrheal (unformed) stool, unless ileus due to C. difficile is suspected.*

Diagnostic Test Outcome No. Studies Summary of Key Findings Sensitivity or Specificity (95% CI) Strength of Evidence
CDI = Clostridium difficile infection; CI = confidence interval
* Information drawn from: Cohen SH, 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):431-55. PMID: 20307191.
These are two-step procedures. The first step is a fast screen for the presence or absence of C. difficile using a test such as the glutamate dehydrogenase assay. If the first test gives a positive result, a second test for C. difficile toxins is performed.
Nucleic Acid Amplification Test: loop-mediated isothermal amplification Sensitivity 12 Sensitive for CDI 0.95 (0.90 to 0.97) [evidence high]
Specificity 12 Specific for CDI 0.98 (0.96 to 0.99) [evidence high]
Nucleic Acid Amplification Test: polymerase chain reaction Sensitivity 31 Sensitive for CDI 0.95 (0.93 to 0.96) [evidence high]
Specificity 31 Specific for CDI 0.97 (0.96 to 0.98) [evidence high]
Immunoassays for C. difficile Toxins A/B Sensitivity 58 Not sensitive for CDI 0.70 (0.66 to 0.74) [evidence medium]
Specificity 58 Specific for CDI 0.98 (0.97 to 0.99) [evidence medium]
Tests for Glutamate Dehydrogenase Sensitivity 10 Sensitive for CDI 0.90 (0.78 to 0.96) [evidence medium]
Specificity 10 Not specific for CDI 0.94 (0.89 to 0.97) [evidence medium]
Test Algorithms Sensitivity 11 Not sensitive for CDI 0.73 (0.62 to 0.82) [evidence low]
Specificity 11 Specific for CDI 1.00 (0.99 to 1.00) [evidence low]
Table 2: Summary of Key Findings and Strength of Evidence for Interventions To Prevent C. difficile Infection
Intervention No. Studies Summary of Key Findings Strength of Evidence
CDI = Clostridium difficile infection
** Multicomponent interventions consisted of using multiple prevention strategies to reduce CDI rates (e.g., the simultaneous use of education, isolation, handwashing, contact precautions, and environmental disinfection).
Antibiotic Stewardship 6 Appropriate prescribing practices were associated with decreased CDI. [evidence low]
Handwashing Campaigns 1 Handwashing campaigns reduced CDI incidence (rates fell from 16.75 to 9.49 cases per 10,000 bed days). [evidence low]
Multicomponent Prevention Interventions** 4 Multicomponent interventions were sustainable over several years. [evidence low]
Table 3: Summary of Key Findings and Strength of Evidence for the Effectiveness of Antimicrobials in Treating Initial C. difficile Infections and Reducing Their Recurrence
Antimicrobial Outcome No. Studies No. Subjects Summary of Key Findings Strength of Evidence
CDI = Clostridium difficile infection; CI = confidence interval; NR = not reported; RR = relative risk
§ Limited evidence suggested that there was a lower rate of recurrence in patients receiving fidaxomicin when the infecting organism was a non-epidemic (non-nucleosome assembly protein 1) strain ([evidence low])
Vancomycin vs. metronidazole Initial cure of CDI 4 872 Favors vancomycin: 83.9% vs. 75.7% of patients achieved initial cure (RR 1.08, 95% CI 1.02–1.15). [evidence high]
Prevention of CDI recurrence 4 705 No significant difference: 16.5% vs. 18.7% of patients had recurrent CDI (RR 0.89, 95% CI 0.65–1.23). [evidence medium]
Fidaxomicin vs. vancomycin Initial cure of CDI 2 1111 No significant difference: 87.6% vs. 85.6% of patients achieved initial cure (RR 1.02, 95% CI 0.98–1.07). [evidence medium]
Prevention of CDI recurrence 2 962 Favors fidaxomicin: 14.1% vs. 26.1% of patients had recurrent CDI (RR 0.55, 95% CI 0.42–0.71).§ [evidence high]
Any antimicrobial Treatment effect by disease severity 3 NR Treatment results did not differ by disease severity. [evidence low]
Table 4: Summary of Key Findings and Strength of Evidence for the Effectiveness of Probiotics in Reducing Recurrence of C. difficile Infection
Interventions Compared (as an adjunct to standard antibiotic treatment) Outcome No. Studies No. Subjects Summary of Key Findings Strength of Evidence
CDI = Clostridium difficile infection; CI = confidence interval; RR = relative risk
Lactobacillus vs. placebo Prevention of CDI recurrence 6 1251 Favors Lactobacillus: RR 0.27, 95% CI 0.15–0.49 [evidence low]
Saccharomyces boulardii vs. placebo Prevention of CDI recurrence 6 1244 No significant difference: RR 0.77, 95% CI 0.38–1.54 [evidence low]
Multiorganism probiotics vs. placebo Prevention of CDI recurrence 5 3960 Favors multiorganism probiotics: RR 0.50, 95% CI 0.28–0.88 [evidence low]
Table 5: Summary of Key Findings and Strength of Evidence for the Effectiveness of Fecal Microbiota Transplantation in Treating Recurrent and Relapsed C. difficile Infection
Intervention Studied Outcome No. Studies No. Subjects Summary of Key Findings Strength of Evidence
CDI = Clostridium difficile infection; RCT = randomized controlled trial
Fecal microbiota transplantation Resolution of diarrhea and prevention of relapse 3 RCTs and 23 case series 751 Resolves diarrhea and prevents relapse in patients with recurrent CDI [evidence low]

Strength of Evidence Scale††

High: [evidence high]
High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

Moderate: [evidence medium]
Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.

Low: [evidence low]
Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.

Insufficient:[evidence insufficient]
Evidence is either unavailable or does not permit a conclusion.

†† The overall evidence grade was assessed based on the ratings for the following domains: study limitations, directness, consistency, precision, and reporting bias. Other domains were considered, as appropriate: dose-response association, plausible confounding, and strength of association (i.e., magnitude of effect). For additional details on the methodology used to assess strength of evidence, please refer to: Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol. 2010 May;63(5):513-23. PMID: 19595577.

Table 6: Adverse Effects Associated With Interventions Used To Prevent and Treat C. difficile Infection
Note: The adverse effects listed here have been drawn from the systematic review and from U.S. Food and Drug Administration (FDA) labels.

Intervention Adverse Effects
RCT = randomized controlled trial
  • Abdominal pain, nausea, vomiting, diarrhea, headache, loss of appetite, and metallic taste in the mouth.
  • Rare but serious adverse effects include neurotoxicity, seizures, or neuropathy with long-term use.
  • Abdominal pain, nausea, and low serum-potassium levels.
  • Abdominal pain, nausea, vomiting, anemia, neutropenia, and gastrointestinal bleeding.
  • No adverse effects were reported in studies in which probiotics were used as adjunctive treatment.
  • Fungemia has been reported in critically ill and immunocompromised patients with use of Saccharomyces.
Fecal Microbiota Transplantation
  • Adverse effects reported in the RCTs include diarrhea, cramps, belching, nausea, and constipation.
  • Rare adverse effects include secondary infection and microperforation of the colon.

Gaps in Knowledge and Additional Issues

  • Future research should include studies to identify subgroups of patients who derive the most benefit from the various treatments for CDI.
  • The costs of the antibiotics used to treat CDI vary significantly. Fidaxomicin is significantly more expensive than vancomycin and metronidazole.
  • The use of probiotics and FMT as adjuntive or alternative treatments for CDI needs additional research.
  • The FDA has specific guidance on FMT as treatment for CDI and on the role of donors and stool banks. The guidance is available at

What To Discuss With Your Patients and Their Caregivers

  • The role that use or overuse of antibiotics, including those used to treat CDI, may play in the development of CDI
  • The available antibiotic treatments for CDI and the evidence for their effectiveness and adverse effects
  • That probiotics may be helpful in preventing recurrent CDI and that patients should be aware that there is wide variation in the quality of over-the-counter probiotics
    • Some manufacturers provide information on the potency and stability of their products.
  • For patients with recurrent CDI that is difficult to treat, the benefits and harms of FMT for reducing the risk of relapse and that patients will be referred to a center with expertise in this procedure for treatment
  • The importance of cleaning hands frequently with soap and water (and not hand sanitizer) to prevent the spread of CDI spores
    • C. difficile spores are resistant to alcohol hand rubs and other routinely used antiseptics.


The information in this summary comes from Butler M, Olson A, Drekonja D, Shaukat A, Schwehr N, Shippee N, Wilt TJ. Early Diagnosis, Prevention, and Treatment of Clostridium difficile: Update. Comparative Effectiveness Review No. 172. (Prepared by the Minnesota Evidence-based Practice Center under Contract No. 290-2012-00016-I.) AHRQ Publication No. 16-EHC012-EF. Rockville, MD: Agency for Healthcare Research and Quality; March 2016.

This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Geetha Achanta, Ph.D., Daniel Musher, M.D., Frank Domino, M.D., and Michael Fordis, M.D.