1. Clostridium difficile Infection
Microbiology
Clostridium difficile (C.diff) is a spore-forming, gram-positive, anaerobic bacillus that produces two endotoxins:toxinA andtoxinB
Pathology:
Clostridium difficile infection (CDI) causesantibiotic-associatedcolitis. It colonizes human intestinal tract after the normalgut flora have been
alteredbyantibiotic therapy.
Clinical presentation:
Ranging fromAsymptomatic carrier to Severe fulminant disease with toxic megacolon.
- Carrier state:about 20% hospitalizedadults are C.diff carriers whoshedC.diff in their stool but donot have diarrhea
o Data ontreatment of asymptomatic carriers are limited and routine treatment is not recommended
- Diarrheawith colitis:waterydiarrhea upto 10 – 15 times dailywithabdominal pain and cramping, low fever, leukocytosis
- Pseudomembranous colitis (PMC):shallow ulcerations onthe intestine mucosal surface, raised yellowor off white plaques upto 2 cm in
diameter scatteredover the colorectal mucosa, bowel wall edema, erythema, inflammation.
o Type 1 PMC: mildest. Inflammation are confined to superficial epithelium
o Type 2 PMC: more severe disruption ofglands, more intense inflammationof basal lamina
o Type 3 PMC: severe, intense necrosis offullthicknessof mucosa.
- Relapse/reinfection:from relapse of initial infecting strainor reinfectionwitha new strain. Relapse > Reinfection
- Fulminant colitis:severe lower quadrant or diffuse abdominal pain, diarrhea, abdominal distention, fever, lactic acidosis,
hypoalbuminemia, andmarkedleukocytosis (WBC~ 40), toxic megacolon (>7cm diameter + severe systemic toxicity), bowel perforation
Risk Factors:
Virtuallyall antibiotics canrisk predispositionto C.diff infection, including Metronidazole andVancomycin
Diagnosis:
Presence of clinicallysignificant diarrhea (definedas 3+ loose stools per dayfor at least 2 days or 10-15 stoolswith fever or nocturnal diarrheaeven
if one dayin duration) or ileus AND either:
- A positive stool test for toxigenic C. diff or its toxins
- Findings of pseudomembranous colitis
Differential diagnosis – Distinguishing diarrhea fromC.diff infection fromother infections:
- Infectious causes:
o S. aureus was animportant cause ofantibiotic associatedpseudomembranous colitis
o Other = Klebsiella, Clostridium perfringens, Candida spp, Salmonella
o Presence of fever AND leukocytosisfavor C.diff
- Non-infectioncauses:
o More of osmotic mechanism:distinguished bycessationof symptoms with discontinuation oforal intake
- Post-infectious irritable bowel syndrome inpatients after successful treatment ofC.diff
o Not relapse of C.diff. Patient mayhave upto 10 waterystools per day
Laboratory indicators
- Stool culture:
o most sensitive, but most associated withfalse-positive results due to nontoxigenic C.diff strains (CDC)
o labor intensive, results available in48 – 96 hours
- PCR assay
o Test for gene encodingtoxinB, highlysensitive andspecific
- Antigendetection
o Rapid test < 1 hours, non-specific
- Toxin testing

2. o Tissue culture cytotoxicityassay
 Detect Toxin B only, required24-48 hours for result, specific, sensitive but lessthan PCR
o Enzyme immunoassay
 Detect toxin A, B, or both. Same-dayassay, easyto perform, but insensitive
Transmission and Prevention
- C.diff is shedin feces. Anysurfacescontaminatedwith feces mayserve as a reservoir for C.diff spores.
- Prevention:
o Use Abx judiciously
o Contact precautions
 Private room
 Gloves, gowns
 Hand hygiene after removinggloves
 Disinfectinganysharedmedicalequipment
Treatment:
Indication for treatment:
- Typical manifestation ofC.diff (diarrhea, abdominal pain, or N/V) ANDa positive diagnostic assayshould receive antibiotics
- Empiric antibiotic is appropriate ifpending resulting of labtests AND clinical suspicionis high (IDSA-SHEA-CDI guideline 26 – C-III)
- Treatment not indicatedif asymptomatic but a positive assay
1) Initialmanagement
- Important to stop the inciting antibiotic as soonas possible. (IDSA-SHEA-CDI guideline 25 – A-II)
- Avoid usingantimotilityagent suchas loperamide. (IDSA-SHEA-CDI guideline 28 – C-III)
- Supportive care: hydration, electrolyte correction, nutritional support.
2) Non-severe/Mild-moderate C.diffinfection: (WBC< 15, Cr < 1.5x premorbidlevel)
- First line:PO Metronidazole 500 mg TID or 250 mg QID (IDSA-SHEA-CDI guideline 29 – A-I)
o IV Metronidazole 500 mg TID iforal is not feasible
- Second line: PO Vancomycin 125 mg QID equallyeffective as 500 mg QID.
o IV Vanco hasno effect onC.diff
- Durationof treatment: 10-14 days. (IDSA-SHEA-CDI guideline 29 – A-I)
o Maydo an additionalweekafter completion for patient with anunderlying infectionrequired prolonged durationfor
a cost of increasedrisk of recurrence.
3) Severe disease management: (WBC> 15, Cr > 1.5x premorbidlevel)
- Supportive care
- Consider surgeryin severelyill patient withserum lactate above 5, andWBC> 50
o Subtotal colectomy (IDSA-SHEA-CDI guideline 32 – B-II)
o Divertingloopileostomyand colonic lavage
- First line:PO Vancomycin125 mg QID with or without IV Metronidazole 500 mg q8 (IDSA-SHEA-CDI guideline 30 – B-I)
o If no clinical improvement, might increase to Vanco 500 mg QID
o If ileus, then
 IV metro 500 mg TID
 PR Vancomycin enema 500 mg in ~100 mL NS q6 (IDSA-SHEA-CDI guideline 31 – C-III)
- Alternative:
o Metronidazole 500 mg PO TID or 250 QID x 14d,
o Fidaxomicin200 mg PO BID.
- Durationof treatment = tailored to clinical circumstances. Those withunderlying infectionrequired prolonged durationof
antibiotic should continue CDI treatment throughout the antibiotic course plus one additional week after its completion
4) Severe complicated disease management (Hypotension/shock, ileus, megacolon)
- Treatment = PO Vancomycin 500 mg QID + IV Metronidazole 500 mg q8
o Discrepancy:Sanford guideline statedIVMetronidazole 500 mg q6

3. 5) Relapse/Recurrent management
- First recurrence:
o Same regimen as initial episode but stratified by severity (IDSA-SHEA-CDI guideline 33 – A-II)
o No recommendationfor preventionof recurrent CDI (IDSA-SHEA-CDI guideline 36 – C-III)
o Consider colonoscopy
o Mild symptoms of recurrence = treat conservativelywithout further antibiotic.
o Non-severe initial recurrence following therapyfor CDI = Metronidazole
o More severe recurrence:
 Basedon the markers of severe disease: Consider Vancomycin, Alternative = Fidaxomicin
- Subsequent recurrence:
o Avoid Metronidazole beyond first recurrence/longterm (cumulative neurotoxicity) (IDSA-SHEA-CDI guideline 34 – B-II)
o Fidaxomicin200 mg PO BID
o Vancomycin 125 mg PO in pulsed + tapered fashion (IDSA-SHEA-CDI guideline 35 – B-III)
 Onlyin Non-NAP1 strains, recurrence was significantlylesswith Fidaxomicin comparedto Vancomycin
 Vancomycintapering:
 Week 1:BID, Week 2:QD, Week 3:QOD, thenevery3rd dayfor 5 doses
 Alternative: After initial Vancomycin, Rifaximin 400-800 mg PO QD dividedBIDto TIDx 2 weeks
o Other options:Fecal transplant, Probiotic, monoclonal antibodies (not yet available inclinicaluse)
Treatment Summary
Initialepisode, mild – moderate WBC< 15, Cr < 1.5x premorbidlevel PO Metronidazole 500 mg TIDx 10-14 days A-I
Initialepisode, severe WBC> 15, Cr > 1.5x premorbidlevel PO Vancomycin125 mg QID x 10 – 14 days B-I
Initialepisode, severe complicated
Hypotension/shock, ileus,
megacolon
PO Vancomycin500 mg QID + IV Metronidazole 500 mg q8
If complete ileus, consider adding rectal installationof
Vancomycin
C-III
First recurrence Same as initial episode A-II
Second recurrence Vancomycintapered and/or pulsed B-III
Monitoring:
- Number of CDI, rate of infection at facility, severityof disease, patient outcomes. Seekhelpfrom localor state healthdep artments
and/or local infectioncontrol experts for outbreaks
- Vancomycin PO/PR:No renal/hepatic dosing. Monitor for adverse events
- Metronidazole: No renal/hepatic dosing. Monitor for adverse events (neurologic symptoms, CBC)
- Rifaximin:hypersensitivityreaction, temperature, bloodinstool. No renal/hepatic dosing
- Fidaxomicin:hypersensitivityreaction, macrolides allergy. No renal/hepatic dosing
Reference
1. KellyCP, Lamont JT. Clostridiumdifficile in Adults:Treatment. http://www.uptodate.com/contents/clostridium-difficile-in-adults-
treatment?source=related_link. Accessed 9/2/2015
2. Cohen SH, GerdingDN, Johnson S,. et al. Clinical Practice Guidelines for Clostridiumdifficile Infectionin Adults:2010 Update bythe
Societyfor Healthcare Epidemiologyof America (SHEA)andthe Infectious Diseases Societyof America (IDSA).
http://www.cdc.gov/HAI/pdfs/cdiff/Cohen-IDSA-SHEA-CDI-guidelines-2010.pdf. Accessed9/2/2015
3. Centers for Disease Control and Prevention. Atlanta, GA. Healthcare-Associated Infection.
http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_faqs_HCP.html. Accessed 9/2/2015