Clostridium Difficile is a Gram-Positive, Anaerobic, Toxin-Producing, Spore Forming Bacteria
Toxin A (Enterotoxin): causes increased intestinal permeability and fluid secretion -> does not result in colitis/diarrhea alone
Toxin B (Cytotoxin): causes intense colonic inflammation -> this is the clinically important toxin which is associated with colitis/diarrhea
Hypervirulent Strain NAP1/BI/027: more resistant to antibiotics and produces more toxin
Has Been Implicated in Outbreaks Since the Early 2000’s
May Account for Recent Increase in Incidence and Disease Severity (Lancet, 2005) [MEDLINE] (NEJM, 2005) [MEDLINE]
Risk Factors
Antibiotic Use
General Comments
Antibiotic Use is the Most Commonly-Recognized Risk Factor for Clostridium Difficile Colitis
Antibiotics
Carbapenems (see Carbapenems, Carbapenems): one of the highest risk class of antibiotics identified in systematic review/meta-analysis, OR = 1.84 (J Antimicrob Chemother, 2014) [MEDLINE]
Second-Generation Cephalosporins: one of the highest risk class of antibiotics identified in systematic review/meta-analysis, OR = 2.23 (J Antimicrob Chemother, 2014) [MEDLINE]
Third-Generation Cephalosporins: highest risk class of antibiotics identified in systematic review/meta-analysis, OR = 3.20 (J Antimicrob Chemother, 2014) [MEDLINE]
Fourth-Generation Cephalosporins: one of the highest risk class of antibiotics identified in systematic review/meta-analysis, OR = 2.14 (J Antimicrob Chemother, 2014) [MEDLINE]
Clindamycin (see Clindamycin, Clindamycin): one of the highest risk antibiotics identified in systematic review/meta-analysis with OR = 2.86 (J Antimicrob Chemother, 2014) [MEDLINE]
Fluoroquinolones (see Fluoroquinolones, Fluoroquinolones): one of the highest risk classes of antibiotics identified in systematic review/meta-analysis with OR = 1.66 (J Antimicrob Chemother, 2014) [MEDLINE]
Penicillin Combinations(see Penicillins, Penicillins): one of the highest risk antibiotics identified in systematic review/meta-analysis with OR = 1.45 (J Antimicrob Chemother, 2014) [MEDLINE]
Epidemiology: age appears to be correlated with both the frequency and severity of Clostridium Difficile infection
May Be Related to Decreased Immune Response or Other Comorbid Disease (Which Increase the Likelihood of Hospitalization and/or Antibiotic Use)
In a 2002 Quebec Outbreak, Frequency of Clostridium Difficile was Noted to Be 10x Higher in Patients ≥65 y/o, as Compared to Younger Adults (CMAJ, 2005) [MEDLINE]
Meta-Analysis of Gastric Acid Suppression (Am J Gastroenterol, 2012) [MEDLINE]
Probable Association Between PPI Use and Clostridium Difficile Infection: risk is further increased by concomitant use of antibiotics and PPI’s
H2-Blockers May Carry Lesser Risk of Clostridium Difficile Infection
United States Food and Drug Administration 2012 Review of Published Literature and Drug Safety Communication Regarding the Risk of Gastric Acid Suppression on the Incidence of Clostridium Difficile Infection [LINK]
Most Studies Suggest an Increased 1.4-2.75x-Increased Risk of Clostridium Difficile Infection with PPI Use, as Compared to Patients without PPI Use
Meta-Analysis Studying the Association Between PPI and Clostridium Difficile Infection (Clinical Gastroenterology and Hepatology, 2012) [MEDLINE]
PPI was Associated with a 2x-Increased Risk of Clostridium Difficile Infection
Retrospective Case-Control Study Studying PPI Use and Clostridium Difficile Infection (Mayo Clin Proc, 2013) [MEDLINE]
Duration of PPI Use was Significantly Associated with Clostridium Difficile Infection
Systematic Review and Meta-Analysis Studying the Association Between H2-Blockers Use and the Risk of Clostridium Difficile Infection (PLoS One, 2013) [MEDLINE]
Association Between H2-Blockers and Clostridium Difficile Infection: risk appears to be highest in hospitalized patients receiving antibiotics
Retrospective Cohort Analysis Studying PPI Use and Recurrent Clostridium Difficile Infection in Hospitalized Patients (Am J Gastroenterol, 2013) [MEDLINE]
Among Hospitalized Patients with Clostridium Difficile Infection, Receipt of PPI’s Concurrent with Clostridium Difficile Treatment was Not Associated with Recurrence of Clostridium Difficile Infection
Recurrence of Clostridium Difficile Infection was Significantly Associated with Black Race, Increased Age, and Increased Comorbid Disease
Other
Cancer
Chemotherapy: the association with cancer chemotherapy and Clostridium Difficile infection may be related to the antimicrobial effect of chemotherapies or immunosuppression
GDH Antigen is an Essential Constitutively-Expressed Enzyme Produced by All Clostridium Difficile Isolates: however, the detection of GDH cannot differentiate toxigenic from non-toxigenic strains
Testing for GDH is Useful as an Initial Screening Step in a Multistep Testing Paradigm (Followed by EIA for Clostridium Difficile Toxins A and B on Specimens Which are GDH-Positive)
Testing for Clostridium Difficile Toxins A and B is More Specific
Technique
Laboratory Turnaround Time: <1 hr
Sensitivity: good
Specificity: low (since the detection of GDH cannot differentiate toxigenic from non-toxigenic strains)
Stool Enzyme Immunoassay (EIA) for Clostridium Difficile Toxins A and B
Rationale
Most Clostridium Difficile Strains Produce Both Toxins A and B: although some strains produce only one of the toxins
While Only Toxin B is Important as a Cause of Clinical Symptoms, Testing for Both Toxins by EIA Has a Higher Sensitivity than Testing for Toxin B Alone
Technique
Clostridium Difficile Toxin Degrades at Room Temperature: may degrade to the point of being undetectable within 2 hrs after collection
Assay for Clostridium Difficile Toxins A and B
Laboratory Turnaround Time: hours
Sensitivity (for Both Toxins A and B): 75%
At Least 100-1000 pg of Toxin Must Be Present for a Positive Test Result
Specificity (for Both Toxins and B): 99%
Stool Polymerase Chain Reaction (PCR) for Clostridium Difficile Toxin Genes
Rationale
Real-Time PCR Detects One or More Genes Which are Specific to Toxigenic Clostridium Difficile Strains
Gene for tcdB Encodes for Toxin B
Because PCR Can Detect Toxigenic Strains, But Does Not Test for Active Toxin Production, it May Detect Asymptomatic Carriers: therefore, it should be used to test liquid stool from patient with high clinical suspicion on infection
Indications
Further Testing After Positive EIA for Clostridium Difficile Glutamate Dehydrogenase
Technique
Laboratory Turnaround Time: 1 hr
Sensitivity: high (higher than EIA and comparable to that of the cytotoxicity assay)
Specificity: >95%
False-Negative Results
Delayed Processing of Stool Specimen
Testing in Patient Who Has Already Been Empirically Treated for Clostridium Difficile
No Role in the Diagnosis of Clostridium Difficile (Ann Clin Microbiol Antimicrob, 2006) [MEDLINE]
Sensitivity (as Compared to Clostridium Difficile Toxin Assay): 30%
Specificity (as Compared to Clostridium Difficile Toxin Assay): 74.9%
Positive Predictive Value (as Compared to Clostridium Difficile Toxin Assay): 13.2%
Negative Predictive Value (as Compared to Clostridium Difficile Toxin Assay): 89.3%
Anaerobic Stool Culture with Toxin Testing of Isolated Clostridium Difficile (see Stool Culture, Stool Culture)
Rationale
Most Sensitive Diagnostic Method: although culture cannot differentiate toxin-producing strains from non–toxin-producing strains
Considered to Be the Gold Standard Testing Modality
Technique
Stool Culture on Selective Media with Toxin Testing of Isolated Clostridium Difficile
Laboratory Turnaround Time: useful for epidemiologic studies, but is too slow to be clinically useful
Cell Culture Cytotoxicity Assay
Rationale
Has Been Used a Gold Standard Test
Technique
Addition of Prepared Stool Sample (Diluted, Buffered, and Filtered) to Monolayer of Cultured Cells: Clostridium Difficile toxin exhibits a cytopathic effect
Suspicion of Alternate Diagnosis Other than Clostridium Difficile Colitis: colonoscopy is not necessary in patients with a typical clinical presentation, positive stool studies, and response to appropriate treatment
Probiotics Colonize the Gastrointestinal Tract Temporarily: they produce bacterial acids and peptides, as well as compete with other microbes for nutrients and epithelial adhesion
Probiotics Secrete Acids Which Decrease the pH of the Gastrointestinal Environment
Probiotics Secrete Toxins Which Inhibit the Growth of Clostridium Difficile: in animal models, Lactobacillus and Saccharomyces Boulardii inhibit the growth of Clostridium Difficile
Probiotics Inhibit the Binding of Clostridium Difficile Toxins to Intestinal Epithelial Cells
Probiotics Modulate Both the Innate and Adaptive Immune Systems by Stimulating Toll-Like Receptors
Adverse Effects
Bacteremia/Fungemia: small number of cases have been reported (although none in clinical trials) with the use of probiotics
Probiotics Most Commonly Associated: Sachharomyces Boulardii, Lactobacillus Rhamnosus GG
Most cases were immunocompromised, had severe comorbidities, had recent surgery, and/or had prolonged hospitalization
Two cases of Sachharomyces Boulardii fungemia have been reported in patients who were not receiving this probiotic, but acquired it via transmission from a healthcare worker caring for a patient who was taking Sachharomyces Boulardii
Intestinal Ischemia (with Increased Mortality): has been associated with the use of probiotics in the setting of acute pancreatitis
Clinical Efficacy
Systematic Review and Meta-Analysis of Probiotics in the Prevention of Clostridium Difficile (Ann Intern Med. 2012) [MEDLINE]
Moderate Quality Evidence Suggests that Probiotics Produces a Large Reduction in the Risk of Clostridium Difficile without Clinically Important Adverse Events
Review of Role of Probiotics in the Prevention of Clostridium Difficile Infection (Clin Infect Dis, 2015) [MEDLINE]
Data Conflict with Regard to the Efficacy of Probiotics in the Prevention of Clostridium Difficile Infection
Recommendations
Probiotics May Be Considered as a Preventative Measure
Treatment
General Measures
Discontinuation of the Offending Antibiotic
Contact Isolation with Hand Washing: to prevent spread
Hand Washing is More Effective Than Alcohol Hand Sanitizer in Eliminating Spores: spores are inherently resistant to alcohol
Alternative Agent: alternative if intolerant to metronidazole or no improvement in 5-7 days on metronidazole therapy
Pharmacology: macrocyclic antibiotic which is bacteriocidal against Clostridium Difficile
Fidaxomicin has a narrower antimicrobial spectrum than metronidazole or vancomycin, resulting in less disruption of the normal colonic anaerobic microflora
Administration: 200 mg PO BID x 10 days
Severe Disease
American College of Gastroenterology (ACG) Guidelines (Am J Gastroenterol, 2013) [MEDLINE]
Indications (As Adjunctive Therapy): in conditions where vancomycin PO may not be tolerated or where the transit of vancomycin PO to colon may be impaired
Fecal Transplant Results in the Recipient Intestinal Microbiota Becoming Similar to that of the Donor and Clinical Resolution Within 14 Days: dominated by Bacteroides strains and an uncharacterized butyrate producing bacterium (J Clin Gastroenterol, 2010) [MEDLINE]
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines (Clin Microbiol Infect, 2014) [MEDLINE]
Fecal Transplant Results in the Recipient Intestinal Microbiota Becoming Similar to that of the Donor and Clinical Resolution Within 14 Days: dominated by Bacteroides strains and an uncharacterized butyrate producing bacterium (J Clin Gastroenterol, 2010) [MEDLINE]
Other Treatments
Monoclonal Antibodies Against Clostridium Difficile Toxin
Actoxumab
Pharmacology: monoclonal antibody against Clostridium Difficile toxin A
Clinical Efficacy
MODIFY I/MODIFY II Trials of Bezlotoxumab and Actoxumab in C Diff Colitis (NEJM, 2017) [MEDLINE]
Actoxumab was Used in MODIFY I Trial, But Not in MODIFY II Trial, Due to Lack of Efficacy in the Interim Analysis
Retrospective Study of Intravenous Immunoglobulin in Clostridium Difficile Colitisi (Am J Infect Control, 2007) [MEDLINE]: no clinical benefit with IVIG
Systematic Review of Intravenous Immunoglobulin in Clostridium Difficile Colitis (Int J Infect Dis, 2009) [MEDLINE]: may be beneficial in recurrent severe disease, but data quality is poor
Small Case Series Suggest that Rifaximin May Be Beneficial Following Vancomycin Therapy for Recurrent Clostridium Difficile Colitis: however, exposure to rifamycins prior to the development of Clostridium Difficile colitis is a risk factor for rifampin-resistant Clostridium Difficile infection
Tigecycline (Tygacil) (see Tigecycline, Tigecycline): although tigecycline has been used in severe disease refractory to standard therapy, its use it not currently recommended
Monitoring of Therapy
Repeat Stool Clostridium Difficile Toxin PCR: repeat testing is not indicated in asymptomatic, recovering patients
Stool Assays May Remain Positive in 50% of Cases for as Long as 6 wks After Completion of Therapy (Am J Gastroenterol, 2002) [MEDLINE]
Prognosis
Mortality Rate
References
General
Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet. 2005 Sep 24-30;366(9491):1079-84 [MEDLINE]
An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005 Dec 8;353(23):2433-41. Epub 2005 Dec 1 [MEDLINE]
Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173(9):1037 [MEDLINE]
Risk Factors
Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Archives of Internal Medicine 2010; 170 (9): 784–90. doi:10.1001/archinternmed.2010.89 [MEDLINE]
Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107(7):1011 [MEDLINE]
United States Food and Drug Administration 2012 Review of Published Literature and Drug Safety Communication Regarding the Risk of Gastric Acid Suppression on the Incidence of Clostridium Difficile Infection [LINK]
Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis. Clinical Gastroenterology and Hepatology 2012; 10 (3): 225–33 [MEDLINE]
Proton Pump Inhibitors and the Risk for Hospital-Acquired Clostridium difficile Infection. Mayo Clin Proc. 2013 Oct;88(10):1085-1090. Epub 2013 Sep 5 [MEDLINE]
The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis. PLoS One. 2013;8(3):e56498 [MEDLINE]
Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013 Sep;68(9):1951-61. doi: 10.1093/jac/dkt129. Epub 2013 Apr 25 [MEDLINE]
Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol. 2013 Nov;108(11):1794-801. Epub 2013 Sep 24 [MEDLINE]
Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014 Apr;69(4):881-91. doi: 10.1093/jac/dkt477. Epub 2013 Dec 8 [MEDLINE]
Prevention
Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012 Dec 18;157(12):878-88 [MEDLINE]
Clinical review: Probiotics in critical care. Critical Care 2012; 16:237 DOI: 10.1186/cc11382
Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498 [MEDLINE]
Prevention of Clostridium difficile Infection With Probiotics. Clin Infect Dis. 2015 May;60 Suppl 2:S122-8 [MEDLINE]
Diagnosis
Is Fecal Leukocyte Test a good predictor of Clostridium difficile associated diarrhea? Ann Clin Microbiol Antimicrob. 2006;5:9 [MEDLINE]
Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498 [MEDLINE]
Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015 Jan;313(4):398-408 [MEDLINE]
European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2016 Aug;22 Suppl 4:S63-81. doi: 10.1016/j.cmi.2016.03.010. Epub 2016 Jul 25. [MEDLINE]
Treatment
Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769 [MEDLINE]
Clinical outcomes of intravenous immune globulin in severe clostridium difficile-associated diarrhea. Am J Infect Control. 2007;35(2):131 [MEDLINE]
A prospective study of risk factors and historical trends in metronidazole failure for Clostridium difficile infection. Clin Gastroenterol Hepatol. 2008;6(12):1354 [MEDLINE]
The role of immunoglobulin for the treatment of Clostridium difficile infection: a systematic review. Int J Infect Dis. 2009 Nov;13(6):663-7. doi: 10.1016/j.ijid.2008.11.012. Epub 2009 Jan 30 [MEDLINE]
Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2010;44:354–360 [MEDLINE]
Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis. 2011;53(5):440 [MEDLINE]
Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498 [MEDLINE]
European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014 Mar;20 Suppl 2:1-26. doi: 10.1111/1469-0691.12418 [MEDLINE]
Clostridium difficile infection: a review of current and emerging therapies. Ann Gastroenterol. 2016 Apr-Jun;29(2):147-54. doi: 10.20524/aog.2016.0006 [MEDLINE]
In C difficile infection, adding IV bezlotoxumab to standard antibiotics reduced recurrence at 12 weeks. Ann Intern Med. 2017; 166:JC53. doi: 10.7326/ACPJC-2017-166-10-053 [MEDLINE]
Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615 [MEDLINE]