Epidemiology
- Clostridium Difficile Infection is the Most Common Health Care-Associated Infection in US Hospitals
Microbiology
- Clostridium Difficile is a Member of Clostridium Genus (see Clostridium, Clostridium)
- 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]
- Cephalosporins (see Cephalosporins, Cephalosporins)
- 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]
- Sulfamethoxazole-Trimethoprim (Bactrim, Septra) (see Sulfamethoxazole-Trimethoprim, Sulfamethoxazole-Trimethoprim): one of the highest risk antibiotics identified in systematic review/meta-analysis with OR = 1.78 (J Antimicrob Chemother, 2014) [MEDLINE]
Advanced Age
- 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]
Gastric Acid Suppression
- Agents
- Clinical Data
- 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
Physiology
Asymptomatic Clostridium Difficile Carriage
- Asymptomatic Clostridium Difficile Carriage Occurs in 20% of Hospitalized Patients
- Clostridium Difficile is Shed in the Stool without Clinical Symptoms (Diarrhea, etc)
- Asymptomatic Clostridium Difficile Carriage Occurs in 50% of Patients in Long-Term Care Facilities
Diagnosis
General Comments
Clinical Data
- Systematic Review of Diagnostic Clostridium Difficile Testing in Adults (JAMA, 2015) [MEDLINE]
- Laboratory Testing Cannot Differentiate Asymptomatic Colonization from Symptomatic Infection
- Diagnostic Testing Should Be Performed Only in Symptomatic Patients
- Single-Step PCR Testing on Liquid Stool
- Sensitivity: 86-92%
- Specificity: 94-97%
- Multistep PCR Testing on Liquid Stool
- Sensitivity: 68-100%
- Specificity: 92-100%
Stool Enzyme Immunoassay (EIA) for Clostridium Difficile Glutamate Dehydrogenase (GDH) Antigen
- Rationale
- 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
- More Sensitive than EIA
- Lack of Standardization
- Laboratory Turnaround Time: 2 days
- Findings
- Ascites (see Ascites, Ascites)
- Low-Attenuation Colonic Mural Thickening: due to mucosal and submucosal edema
- Pancolitis
- Peri-Colonic Fat Stranding
- Indications
- 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
- Findings
- Pseudomembranous Colitis Appearance: variably present
- In Addition, Pseudomembranes May Be Also Seen with Other Infectious Colitis (Salmonella)
Clinical Manifestations-Clostridium Difficile Colitis
General Comments
- Presentation is Variable: ranges from asymptomatic carriage to fulminant colitis
Dermatologic Manifestations
Hematologic Manifestations
Gastrointestinal Manifestations
Abdominal Distention
- Clinical
- Crampy Abdominal Pain: usually in the lower quadrants
- Epidemiology: rare reported cases
- Clinical
- Watery, Non-Bloody Stool: usually 3 or more per day in symptomatic illness
- Epidemiology: may occur with severe colitis
- Epidemiology: may occur with fulminant colitis
- Epidemiology: uncommon
- Physiology: protein losing enteropathy in the absence of fulminant colitis
- Colonic Inflammation with Resulting Loss of Albumin
Small Bowel Involvement
- Epidemiology: rare reported cases
- Typically Occurs in Older Patients or Patients with Multiple Comorbid Conditions
- Some Cases Occur in Patients with Prior Colectomy or Ileostomy
Toxic Megacolon
- Epidemiology: xxx
- Clinical: xxx
- Treatment: xxx
Infectious Manifestations
Renal Manifestations
Rheumatologic Manifestations
- Reactive Arthritis (see Arthritis, Arthritis)
- Epidemiology: rare reported cases
- Soft Tissue Infection
- Epidemiology: rare reported cases
Prevention
- Rationale
- 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
- Intravenous Fluid/Electrolyte Resuscitation
- Treatment of Sepsis (see Sepsis, Sepsis)
Anti-Motility Agents
Mild-Moderate Disease
American College of Gastroenterology (ACG) Guidelines (Am J Gastroenterol, 2013) [MEDLINE]
- Metronidazole PO (Flagyl) (see Metronidazole, Metronidazole)
- First-Line Agent
- Pharmacology: bacteriostatic
- Notably, stool metronidazole levels decrease as colonic inflammation subsides
- Administration: 500 mg PO TID x 10 days
- Risk Factors for Metronidazole Failure (Clin Gastroenterol Hepatol, 2008) [MEDLINE]
- Presence of Clostridium Difficile Colitis on Admission
- Recent Cephalosporin Use
- Transfer from Another Hospital
- Vancomycin PO (see Vancomycin, Vancomycin)
- Alternative Agent: alternative if intolerant to metronidazole, pregnant/nursing, or no improvement after 5-7 days of metronidazole therapy
- Pharmacology: bacteriostatic
- In contrast to metronidazole, vancomycin maintains high stool concentrations throughout the course of therapy
- Administration: 125 mg QID x 10 days
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines (Clin Microbiol Infect, 2014) [MEDLINE]
- Metronidazole PO (Flagyl) (see Metronidazole, Metronidazole)
- First-Line Agent
- Pharmacology: bacteriostatic
- Notably, stool metronidazole levels decrease as colonic inflammation subsides
- Administration: 500 mg PO TID x 10 days
- Risk Factors for Metronidazole Failure (Clin Gastroenterol Hepatol, 2008) [MEDLINE]
- Presence of Clostridium Difficile Colitis on Admission
- Recent Cephalosporin Use
- Transfer from Another Hospital
- Vancomycin PO (see Vancomycin, Vancomycin)
- Alternative Agent: alternative if intolerant to metronidazole, pregnant/nursing, or no improvement after 5-7 days of metronidazole therapy
- Pharmacology: bacteriostatic
- In contrast to metronidazole, vancomycin maintains high stool concentrations throughout the course of therapy
- Administration: 125 mg QID x 10 days
- Fidaxomycin (Dificid, Dificlir) (see Fidaxomicin, Fidaxomicin)
- 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]
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines (Clin Microbiol Infect, 2014) [MEDLINE]
Severe and Complicated Disease
American College of Gastroenterology (ACG) Guidelines (Am J Gastroenterol, 2013) [MEDLINE]
- Vancomycin PO (see Vancomycin, Vancomycin)
- Administration: 500 mg PO QID x 10 days
- Vancomycin Enema (see Vancomycin, Vancomycin)
- 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
- Administration: 500 mg in 100-500 ml normal saline PR QID
- Adverse Effects: vancomycin can be absorbed through the inflamed colonic mucosa and cause systemic toxicity in patients with renal failure
- Metronidazole IV (Flagyl) (see Metronidazole, Metronidazole)
- Indications: recommended as adjunct to vancomycin PO
- Rationale: due to presence of ileus, there may be significantly delayed passage of oral antibiotics from the stomach to the colon
- Pharmacology: fecal concentrations in the therapeutic range can be achieved due to the biliary and intestinal excretion of metronidazole
- Administration: 500 mg IV TID
- Surgical Consultation: however, the optimal timing of surgery is uncertain
- Indications
- Multi-Organ System Failure
- Necrotizing Colitis
- Perforation/Impending Perforation
- Peritoneal Signs (see Peritonitis, Peritonitis)
- Severe Ileus (see Ileus, Ileus)
- Toxic Megacolon
- Procedures
- Subtotal Colectomy with Ileostomy: with rectal sparing
- Diverting Loop Ileostomy with Vancomycin Colonic Lavage
European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines (Clin Microbiol Infect, 2014) [MEDLINE]
- Vancomycin PO (see Vancomycin, Vancomycin)
- Administration: 125 mg PO QID x 10 days
- Fidaxomicin (Dificid, Dificlir) (see Fidaxomicin, Fidaxomicin)
- Alternative Agent
- Administration: 200 mg PO BID x 10 days
- Surgical Consultation: however, the optimal timing of surgery is uncertain
- Indications
- Multi-Organ System Failure
- Necrotizing Colitis
- Perforation/Impending Perforation
- Peritoneal Signs
- Severe Ileus (see Ileus, Ileus)
- Toxic Megacolon
- Procedures
- Subtotal Colectomy with Ileostomy: with rectal sparing
- Diverting Loop Ileostomy with Colonic Lavage with Vancomycin
Recurrent Disease
General Comments
- Definition of Recurrence: initial resolution on appropriate therapy with recurrence of colitis within 8 wks
- Incidence of Recurrence: 10-20%
- After Initial Recurrence: incidence of further recurrence increases to 40-65%
- Majority of Recurrences are Due to Relapse with Original Strain, Rather Than Reinfection
- Factors Contributing to Recurrence
- Additional Courses of Antibiotics: prolonged antibiotic courses increase the risk of recurrence (Clin Infect Dis, 2011) [MEDLINE]
- Advanced Age
- Chemotherapy
- Lower Levels of IgG Against Toxin A: suggest impaired immune response
- Prior Episode of Recurrent Clostridium Difficile Colitis
- Prolonged Hospital Stay
- Proton Pump Inhibitors (PPI) (see Proton Pump Inhibitors, Proton Pump Inhibitors)
American College of Gastroenterology (ACG) Guidelines (Am J Gastroenterol, 2013) [MEDLINE]
- First Recurrence
- Repeat Same Antibiotic Used for Initial Episode
- Second Recurrence
- Third Recurrence
- Fecal Microbiota Transplantation + Vancomycin PO (see Vancomycin, Vancomycin)
- 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]
- First Recurrence
- Second Recurrence
- Third Recurrence
- Fecal Microbiota Transplantation + Vancomycin PO (see Vancomycin, Vancomycin)
- 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
- Bezlotoxumab (Zinplava) (see Bezlotoxumab, Bezlotoxumab)
- Pharmacology: monoclonal antibody against Clostridium Difficile toxin B
- Clinical Efficacy
- MODIFY I/MODIFY II Trials of Bezlotoxumab and Actoxumab in C Diff Colitis (NEJM, 2017) [MEDLINE]
- Bezlotoxumab Add-On Therapy Decreased the Recurrence Rate in Both Primary/Recurrent C Diff Colitis
- Trial of Addition of Bezlotoxumab to Standard Antibiotic Therapy in C Diff Colitis (Ann Intern Med, 2017) [MEDLINE]
- Bezlotoxumab Add-On Therapy Decreased the Recurrence of C Diff Colitis at 12 wks
Anion-Binding Resins
- Pharmacology: bind to Clostridium Difficile toxin
- Clinical Efficacy: may be beneficial as adjuncts for recurrent infection
- Agents
- Administration: need to be given at least 2-3 hrs apart from vancomycin (since they bind vancomycin)
Other
- Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin, Intravenous Immunoglobulin)
- Clinical Efficacy
- 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
- Probiotics (see Probiotics, Probiotics): no clear clinical benefit
- Rifaximin (Rifagut, Xifaxan, Zaxine) (see Rifaximin, Rifaximin)
- 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
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]
- Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009; 15:285–289 [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]