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Clostridium difficile
Aka: Clostridium difficile, Clostridiodes difficile, Pseudomembranous colitis, Pseudomembranous Enterocolitis
- See Also
- Diarrhea
- Infectious Diarrhea
- Chronic Diarrhea
- Health Care-Associated Infection
- Background
- First recognized in 1978 as a cause of Antibiotic-Associated Diarrhea in 1978
- Clostridium difficile was reclassified as Clostridiodes difficile in 2016
- Initially included in genus Clostridium due to shared properties
- Later reclassified to be included in a completely different Bacterial family, Peptostreptococcaceae
- New genus was named Clostridiodes to preserve similar naming (C. Diff) and reduce clinician confusion
- Epidemiology
- Incidence
- U.S. Adults: 14 cases per 1000 persons
- Marked increase from the 65 per 100,000 in 1991, and 156 per 100,000 in 2003 in U.S.
- Most common nosocomial infection in the United States
- Mortality:
- Of >450,000 cases per year, nearly 30,000 died in 2011 (6% mortality)
- References
- Kelly (2008) N Engl J Med 359(18): 1932-40 [PubMed]
- Pathophysiology
- Obligate, anaerobic, Gram Positive, spore-forming bacillus
- Causes Secretory Diarrhea and mucosal injury with colitis
- Two toxins are typically produced
- Enterotoxin A (accompanies Toxin B in some cases)
- Cytotoxin B (present in all cases)
- New virulent epidemic strain: NAP1/B1/027
- Strain responsible for the 5 fold increase in C. difficile infections from 1999 to 2007
- Toxin A/B levels are >16 fold higher than other strains
- Produces binary toxin in addition to typical toxins A and B
- Higher rate of associated toxic Megacolon
- Highly Fluoroquinolone resistant
- Sequence of infection
- Normal colonic Bacteria disturbed (e.g. antibiotics)
- Exposure to C. difficile
- C. difficile is acquired in health care settings in 94% of cases
- However presentation is delayed until after hospitalization in 75% of cases
- C. difficile is commensal in only 3% of patients
- C. difficile survives in hospital room >40 days
- Occupying a room of a prior patient with C. difficile more than doubles the C. difficile risk
- Flushing a toilet in a C difficile patient's room disperses contaminated bioaerosol throughout room
- Wilson (2020) Infect Control Hosp Epidem, published online
- Colonization occurs in 7 to 26% of acute care facilities
- Colonization risk increases for each day of hospitalization
- Occurs in 50% of those hospitalized >4 weeks
- Colonization is community acquired in 41% of cases
- More common young, female with few comorbidities and less severe infection
- Occurs without antibiotic exposure frequently
- Khanna (2012) Am J Gastroenterol 107(1): 89-95 [PubMed]
- Colonization with Clostridium difficile
- Asymptomatic (carrier state)
- Up to 15% of healthy adults are colonized with C difficile
- Asymptomatic patients account for >50% C. difficile colonization cases
- As many as 63% of healthy newborns are colonized with C. difficile
- Most strains in infants are non-toxic, and likely due to peripartum hospitalization
- Symptomatic (typically symptoms start 3-7 days after exposure)
- Mild Diarrheal illness or
- Severe illness (Pseudomembranous colitis)
- Risk Factors
- Highest risk patients
- Older patients over age 64 years old, and especially over age 70 years
- Risk of C. difficile infection increases 2% for each year over age 18 years old
- Debilitated patients
- Immunocompromised patients
- Includes Hematopoietic Stem Cell Transplant and Solid Organ Transplant
- Cystic Fibrosis patients (high risk for fulminant infection)
- Obesity
- Chronic Kidney Disease (esp. Serum Creatinine >2)
- Gastrointestinal conditions
- Enteral feeding
- Gastrointestinal surgery
- Small Bowel Obstruction or Adynamic Ileus
- Inflammatory Bowel Disease
- Cirrhosis
- Acid suppression
- Proton Pump Inhibitors (e.g. Omeprazole)
- Highest risk as they raise gastric pH most significantly
- H2 Blockers (e.g. Ranitidine)
- Less risk than with Proton Pump Inhibitors
- Consider stopping indefinately following diagnosis of Clostridium difficile (due to higher risk of recurrence)
- Corticosteroid use
- Recent antibiotic use within last 3 months (especially last 7-10 days)
- General
- All antibiotics can cause C. difficile Diarrhea (even single dose perioperative antibiotics)
- Broad-spectrum agents are highest risk
- Risk increases with combination antibiotic regimens, frequent dosing and longer therapy duration
- Most common antibiotic causes
- Clindamycin
- ClindamycinOdds Ratio 16
- More common cause again since resurgence for MRSA management
- Fluoroquinolones (e.g. Ciprofloxacin, Levofloxacin)
- FluoroquinoloneOdds Ratio 5.5
- Emerging as very common cause
- Broad-spectrum Cephalosporins
- Odds Ratio 5.7
- Ampicillin or Amoxicillin (most common cause in United States)
- Odds Ratio 2.7
- Macrolides (e.g. Erythromycin, Azithromycin)
- Odds Ratio 2.7
- Less common antibiotic causes
- Tetracycline antibiotics (e.g. Doxycycline)
- Sulfonamides (e.g. Bactrim)
- Trimethroprim
- Rare antibiotic causes
- Parenteral Aminoglycosides
- Metronidazole (used for treatment)
- Vancomycin (used for treatment)
- References
- Brown (2013) Antimicrob Agents Chemother 57(5): 2326-32 +PMID:23478961 [PubMed]
- Symptoms
- Asymptomatic carrier state is common
- Megacolon may be present without Diarrhea
- Inflammatory Diarrhea (variably present)
- Timing
- Incubates for 2-7 days after colonization
- Most cases occur on days 4-9 of antibiotic course
- Onset <14 days after antibiotics in 96% of cases
- All cases occur within 3 months of antibiotics
- Olson (1994) Infect Control Hosp Epidemiol 15:371 [PubMed]
- Characteristics
- Frequent, watery Bowel Movements to profuse Diarrhea up to 20-30 stools daily
- Foul, characteristic odor may be present, but not shown in studies to be sensitive or specific
- Rao (2013) Clin Infect Dis 56(4):615-6 [PubMed]
- Mucus and occult blood often present
- Acute inflammatory symptoms (<50% of cases)
- Fever
- Crampy Abdominal Pain
- Decreased appetite
- Malaise
- In severe cases, Pseudomembranous colitis and toxic Megacolon occurs
- Melana and Hematochezia are uncommon (although occult blood in stool is more often present)
- Extraintestinal symptoms
- Asymmetric Oligoarticular large joint Arthralgia
- Labs: Diagnosis
- Indications: Screening
- At least 3 unformed stools in 24 hours (required)
- Antibiotic use in last 3 months
- Inflammatory Bowel Disease with acute exacerbation
- Contraindications to testing
- Formed stool (no Diarrhea)
- Recent Laxative use
- Testing for cure in asymptomatic patients (following treatment of active infection) is NOT recommended
- Children <12 months of age
- Infants are frequently and asymptomatically colonized with C. difficile
- Children 1-2 years old with prolonged Diarrhea, no other causes and who have risk factors may be tested
- One-Step Clostridium difficile testing
- Clostridium difficile PCR (preferred)
- Best test efficacy and recommended by American College Gastroenterology
- Increased risk of overdiagnosis of asymptomatic carrier state (esp. in lower probability cases)
- Clostridium difficile A and B toxin ELISA
- Largely replaced by PCR testing (however may be used in combination to reduce risk of over-diagnosis)
- Preferred over Clostridium difficile culture, and widely available
- Test Sensitivity: 75-95%
- Test Specificity: 83-98%
- Available within 2 hours of obtaining sample
- Aldeen (2000) Diagn Microbiol Infect Dis 36(4): 211-3 [PubMed]
- Multi-step protocols
- Glutamate dehydrogenase (GDH) Antigen
- Highly sensitive and rapid assay for Antigen produced by all C. difficile isolates
- Positive tests are then reflexed to PCR or ELISA testing (see above)
- Labs: Markers of Severe Infection
- Hypoalbuminemia
- Lactic Acidosis
- Complete Blood Count
- Leukocytosis variably present (<50% of cases)
- White Blood Cell Count may be greater than 20,000
- White Blood Cell Count greater than 30,000 is related to C. difficile in 25% of cases
- Imaging: Abdominal XRay
- Dilated colon: >7 cm in greatest diameter
- Small Bowel dilation or air-fluid levels may be present
- Mucosal edema or thumbprinting may also be present
- Diagnostics
- Endoscopy (Flexible Sigmoidoscopy or Colonoscopy)
- Not recommended in most cases
- May be indicated if diagnosis is unclear
- Findings: Mucosal lesions with pseudomembranes
- Differential Diagnosis
- Antibiotic intolerance (resolves off antibiotics)
- Infectious enteritis
- Acute Gastroenteritis
- Amebic Dysentery
- Klebsiella oxytoca
- Like Clostridium difficile, causes Antibiotic-Associated Diarrhea, that may be hemorrhagic
- Improves after stopping antibiotics and NSAIDs
- Inflammatory Bowel Disease
- Ischemic Colitis
- Evaluation: Severe Infection Criteria
- Severe infection criteria risk stratify management (e.g. Vancomycin selection for treatment)
- High risk patients of severe, fulminant disease (with 2 or more of the following risk factors)
- Age over 60 years old
- Temperature >38.3 C (100.9 F)
- Albumin <2.5 g/dl
- Leukocytosis with White Blood Cell Count >15,000/L
- Serum Creatinine >50% increase over baseline or >1.5 mg/dl
- Pseudomembranous colitis on endoscopy
- Intensive Care unit management
- Zar (2007) Clin Infect Dis 45(3): 302-7 [PubMed]
- Management: General Measures
- Discontinue antibiotic
- Diarrhea resolves in up to 25% of cases with stopping
- If antibiotic required, choose one with lower risk
- Indications to start antibiotics immediately (empiric)
- Older patients
- Multiple comorbid conditions
- Antibiotics can not be discontinued
- Severe disease
- Persistent Diarrhea
- Dysentery (fever, Leukocytosis)
- Avoid and stop medications that could worsen condition
- Proton Pump Inhibitors
- Opioid
- Antidiarrheal agents
- Cholestyramine (Questran)
- Binds Vancomycin and Metronidazole in the Intestine lowering their efficacy against C. difficile
- Do not retest for toxin post-treatment if asymptomatic
- May be positive, but does not require treatment
- Management: Adults
- Fidaxomicin (Dificid)
- Considered first-line, preferred over Vancomycin due to lower recurrence rates
- Dose: 200 mg orally twice daily for 10 days
- Advantages
- Narrow spectrum antibiotic (C. difficile, Staphylococcus, Enterococcus)
- Does not affect Gram Negative Bacteria including normal bowel flora
- High efficacy (90% cure rate, similar to Vancomycin)
- Lower C. difficile recurrence rates than with Vancomycin
- Minimal systemic absorption
- Disadvantages
- Very expensive ($3000 to $4300 for a 10 day course)
- Vancomycin
- Precaution: Only effective for C. difficile if dosed orally or rectally
- Indications
- As of 2018, a first-line agent for C. difficile, replacing Metronidazole even in mild-moderate cases
- Drug of choice for severe C. difficile infection
- Still with risk of promoting Vancomycin resistance
- Had been very expensive ($600-800 per course)
- Inexpensive if pharmacist compounds the intravenous form into oral formulation
- As of 2021, Vancomycin capsules are $75 to 300 per course
- Firvanq oral Vancomycin solution is also available $125 per course
- Dose: 125-500 mg orally (or rectally) four times daily for 10-14 days (10 days is often sufficient)
- Use low dose (125 mg) in most patients
- Studies suggest 125 mg four times daily is as effective as higher doses
- Use high dose Vancomycin 500 mg four times daily with Metronidazole in severe, fulminant disease
- Consider using via rectal retention enema in ileus
- High dose enteral doses may require serum Vancomycin level monitoring (esp. Kidney disease)
- Extended course may be used for persistent Diarrhea
- See Vancomycin recurrence protocol below
- Bezlotoxumab (Zinplava)
- Monoclonal Antibody against C. Difficile
- Consider in the prevention of recurrent infection (adjunctive to antibiotics) if at least one risk factor for recurrence
- Age 65 years or older
- Immunocompromised state
- Severe C. Difficile infection
- Dose: 10 mg/kg IV infusion over 60 minutes
- Risk of worsening Congestive Heart Failure
- Metronidazole
- No longer recommended by IDSA as first line protocol for mild to moderate Clostridium difficile
- Replaced by Vancomycin as first-line agent
- Resistance is growing and may approach 30% in some regions
- IDSA shifted to recommending oral Vancomycin as first-line in 2018
- Not recommended for c. difficile recurrence treatment
- If repeated after was used for prior management, neurotoxicity risk
- Metronidazole has historically been preferred for mild to moderate infection (WBC <15k, creat<1.5 mg/dl)
- Metronidazole is much lower cost (~$20/course) than oral Vancomycin (~$400/course)
- May still be a reasonable alternative in mild-moderate first cases in younger patients (author opinion)
- Dose
- Typical: 500 mg orally every 6-8 hours for 10-14 days
- Lower dose: 250 mg orally q6 hours for 10-14 days
- Parenteral dose: 500 mg IV q8 hours for 10-14 days
- Management: Child
- Mild to Moderate disease: Metronidazole (Flagyl)
- Metronidazole 7 mg/kg (maximum 500 mg) orally three times daily for 7-10 days
- Severe disease: Vancomycin
- Vancomycin 5 mg/kg (to maximum 125 mg) every 6 hours for 7-10 days
- Management: Recurrence
- Recurrence risk doubles with each episode
- Initial recurrence risk is 20-30% (typically within 2 months)
- After third episode, recurrence is virtually assured
- Recurrence risk factors
- Prolonged antibiotic use
- Prolonged hospitalization course
- Diverticulosis
- Multiple comorbid illnesses
- Elderly patients
- Immunocompromised
- Management
- Vancomycin is preferred antibiotic for recurrence management
- Metronidazole is not recommended for recurrence due to neurotoxicity risk
- Fidaxomicin (Dificid)
- Start: 200 mg orally twice daily for 10 days
- Next: 200 mg orally once every other day for 20 days
- Vancomycin taper
- Start 125 mg orally four times daily for 10-14 days,
- Then 125 mg orally twice daily for 7 days
- Then 125 mg orally daily for 7 days
- Then 125 mg orally once every 2-3 days for up to 8 weeks
- Vancomycin AND Rifamaxin
- Vancomycin 125 mg orally four times daily for 10 days and THEN
- Rifaxamin 400 mg orally three times daily for 20 days
- Bezlotoxumab (Zinplava)
- Monoclonal Antibody against C. Difficile
- Indicated in the prevention of recurrent infection (adjunctive to antibiotics) if last infection in prior 6 months
- Dose: 10 mg/kg IV infusion over 60 minutes
- Risk of worsening Congestive Heart Failure
- Probiotics
- Precautions
- Avoid if Immunocompromised (risk of Septicemia)
- Take Probiotics 2 hours after antibiotic dose
- Saccharomyces boulardii
- Dose 250 mg PO bid to tid for 1 month
- Has also been used with Vancomycin 500 mg PO qid
- Lactobacillus (Culturelle)
- Fecal transfer (Stool transplant, fecal bacteriotherapy, intestinal microbiota transplant)
- Indicated in 3 or more recurrent episodes of C. difficile (or refractory cases to Vancomycin, Fidaxomicin)
- Healthy donor (e.g. spouse) with normal fecal flora
- Sample typically introduced via Nasogastric Tube or similar
- Small volume fecal amount (25 grams) sufficient to reestablish normal flora
- Long term cure rates approach 92%
- Gough (2011) Clin Infect Dis 53(10): 994-1002 [PubMed]
- Brandt (2012) Am J Gastroenterol 107(7): 1079-87 [PubMed]
- Management: Fulminant disease (high mortality rate)
- Indications
- Intractable colitis, toxic Megacolon or bowel perforation
- Severe Leukocytosis (e.g. White Blood Cell Count to 30,000)
- Serum Lactate >5
- Multi-system organ failure or other shock-like state
- Management
- Metronidazole IV 500 mg every 8 hours AND
- Vancomycin 500 orally four times daily AND
- Vancomycin enema 500 mg in 100 cc NS q6 hours
- Delivered by foley in Rectum, 30 cc balloon
- Balloon inflated for 60 minutes after dose
- Colectomy may be indicated in the most severe diseases
- Prognosis
- Findings of improvement (assess on day 5)
- Fever resolves within first 2 days
- Diarrhea resolves within first 4 days
- Recurrence rates
- After episode 1: Recurrence in up to 25%
- After episode 2: Recurrence in up to 65%
- Complications
- Toxic Megacolon
- Bowel perforation
- Dehydration
- Electrolyte abnormality
- Prevention
- Avoid Proton Pump Inhibitors (or other acid suppression such as H2 Blocker use) unless absolutely indicated
- Antibiotic Stewardship
- Antibiotic Stewardship decreases c. difficile infection rates by >50%
- Dancer (2013) J Antimicrob Agents 41(2): 137-42 [PubMed]
- Avoid broad-spectrum antibiotic use if possible
- Narrow antibiotic spectrum based on ongoing findings such as culture results
- Use antibiotics only when indicated, and no longer than the necessary duration
- Probiotic Indications
- Recurrent C. difficile (see above)
- Concurrent use with antibiotics (start while patients hospitalized)
- Dosing
- Start within 1-2 days of antibiotic initiation
- Continue for 5 days beyond antibiotic course
- Take 2 hours after each antibiotic dose
- Probiotic species appear to be equally effective
- Saccharomyces boulardii (e.g. Florastor)
- Lactobacillus (e.g. Culturelle)
- Multiple studies demonstrate significant reduction in C. difficile infection following antibiotic use
- Hempel (2012) JAMA 307(18): 1959-69 [PubMed]
- Hickson (2007) BMJ 335(7610): 80 [PubMed]
- Gao (2010) Am J Gastroenterol 105(7): 1636-41 [PubMed]
- Goldenberg (2017) Cochrane Database Syst Rev (12):CD006095 [PubMed]
- Prevent Clostridium difficile spore spread
- Spores are resistant to Alcohol, antibiotics and antiseptics
- Chlorhexidine and soap are effective
- Contact Isolation of patient
- Use personal protective gear including Hand Hygiene, gowns and gloves
- Use disposable stethoscopes and Thermometers
- Continue contact precautions for at least 48 hours after Diarrhea has resolved
- C. difficile should not share a bathroom with other people in hospital or at home
- Bathroom and kitchen surfaces should be cleaned with bleach solutions
- Practice good hygiene
- Hand Washing with soap and water
- Hand sanitizers (e.g hand gels) are not effective against Clostridium difficile
- C. difficile survives outside colon as spores that are antibiotic, heat and acid resistant
- Disinfect surfaces and equipment with sporicidal disinfectants
- Bleach
- Alkaline glutaraldehyde
- Ethylene oxide
- Disinfecting Ultraviolet light system (used in combination with surface cleaners)
- References
- (2018) Presc Lett 25(4)
- Herbert (2012) EM:RAP C3 2(4): 3
- Suntharam (2006) First 24 hours, Park Nicollet Lecture
- Cagle (2022) Am Fam Physician 105(3): 262-70 [PubMed]
- Hsu (2014) Am Fam Physician 90(6): 377-82 [PubMed]
- Jabbar (2003) Prim Care 30(1):63-80 [PubMed]
- Johnson (2021) Clin Infect Dis 73(1): e1029-44 [PubMed]
- Kyne (2001) Gastroenterol Clin North Am 30(3):753-77 [PubMed]
- Hookman (2009) World J Gastroenterol 15(13): 1554-80 [PubMed]
- Mounsey (2020) Am Fam Physician 101(3): 168-75 [PubMed]
- Schroeder (2005) Am Fam Physician 71(5):921-8 [PubMed]
- Winslow (2014) Am Fam Physician 89(6): 437-42 [PubMed]