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
- H2 Histamine Receptor Antagonists (H2-Blockers) (see H2-Histamine Receptor Antagonists, H2-Histamine Receptor Antagonists)
- Proton Pump Inhibitor (PPI) (see Proton Pump Inhibitors, Proton Pump Inhibitors)
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

Cancer
Chemotherapy: the association with cancer chemotherapy and Clostridium Difficile infection may be related to the antimicrobial effect of chemotherapies or immunosuppression
Enteral Feeding (see Enteral Nutrition, Enteral Nutrition)
Gastrointestinal Surgery
Hematopoietic Stem Cell Transplant (HSCT) (see Hematopoietic Stem Cell Transplant, Hematopoietic Stem Cell Transplant)
Hospitalization
Obesity (see Obesity, Obesity)
Severe Illness

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

Cellulitis (see Cellulitis, Cellulitis)
- Epidemiology: rare reported cases

Hematologic Manifestations

Leukocytosis (see Leukocytosis, Leukocytosis)
- Epidemiology: may occur with severe colitis (with WBC count >40k)

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

Bacteremia (see Bacteremia, Bacteremia)
- Epidemiology: rare reported cases
Fever (see Fever, Fever)
Sepsis/Septic Shock (see Sepsis, Sepsis)

Renal Manifestations

Acute Kidney Injury (AKI) (see Acute Kidney Injury, Acute Kidney Injury)
- Epidemiology: may occur in severe cases
- Physiology: due to dehydration

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]

Vancomycin PO (see Vancomycin, Vancomycin)
- Administration: 125 mg (or 500 mg) QID x 10 days

European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Guidelines (Clin Microbiol Infect, 2014) [MEDLINE]

Vancomycin PO (see Vancomycin, Vancomycin)
- Administration: 125 mg QID x 10 days
Fidaxomicin (Dificid, Dificlir) (see Fidaxomicin, Fidaxomicin)
- Alternative Agent
- Administration: 200 mg PO BID x 10 days

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
  - Hartman’s Pouch
  - Ileostomy (see Ileostomy, Ileostomy)
  - Ileus (see Ileus, Ileus)
  - Toxic Megacolon
- 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
- Pulsed or Tapered Vancomycin PO Regimen (see Vancomycin, Vancomycin)
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
- Vancomycin PO or Fidaxomicin PO (see Vancomycin, Vancomycin and Fidaxomicin, Fidaxomicin)
Second Recurrence
- Pulsed Vancomycin PO Regimen (see Vancomycin, Vancomycin): administration of vancomycin every few days
- Tapered Vancomycin PO Regimen (see Vancomycin, Vancomycin): stepwise decrease in vancomycin dose over a period of time
- Fidaxomicin Standard Regimen (see Fidaxomicin, Fidaxomicin): alternative
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
- Cholestyramine (Questran) (see Cholestyramine, Cholestyramine)
- Colestipol (Colestid, Cholestabyl) (see Colestipol, Colestipol)
- Tolevamer: polystyrene sulfonate
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]
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]