Clostridium Difficile

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

Fecal Leukocytes (see Fecal Leukocytes, Fecal Leukocytes)

  • 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

Abdominal/Pelvic CT (see Abdominal-Pelvic Computed Tomography, Abdominal-Pelvic Computed Tomography)

  • Findings
    • Ascites (see Ascites, Ascites)
    • Low-Attenuation Colonic Mural Thickening: due to mucosal and submucosal edema
    • Pancolitis
    • Peri-Colonic Fat Stranding

Colonoscopy (see Colonoscopy, Colonoscopy)

  • 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

  • Epidemiology: common

Abdominal Pain (see Abdominal Pain, Abdominal Pain)

  • Clinical
    • Crampy Abdominal Pain: usually in the lower quadrants

Appendicitis (see Appendicitis, Appendicitis)

  • Epidemiology: rare reported cases

Diarrhea (see Diarrhea, Diarrhea)

  • Clinical
    • Watery, Non-Bloody Stool: usually 3 or more per day in symptomatic illness

Hypoalbuminemia (see Hypoalbuminemia, Hypoalbuminemia)

  • Epidemiology: may occur with severe colitis

Intestinal Perforation (see Intestinal Perforation, Intestinal Perforation)

  • Epidemiology: may occur with fulminant colitis

Protein-Losing Enteropathy (see Protein-Losing Gastroenteropathy, Protein-Losing Gastroenteropathy)

  • 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

Probiotics (see Probiotics, Probiotics)

  • 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

  • Not Recommended

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

  • 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]
  • 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]
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