C diff

Question 1

microbiology/etiology

Answer 1

C diff - gram positive, spore-forming*, anaerobic bacillus
part of normal intestitinal flora in 3-5% of healthy adults; colonization rates are higher in hospitalized patients; most common cause of infectious diarrhea in hospitalized patients
Transmitted person-to-person through fecal-oral route; transmitted nosocomially on the hands of personnel and surface contamination in infected patient’s room
66-75% of CDI cases are nosocomial and ≈ 25-33% are community-acquired (no overnight stay in healthcare facility for 12 weeks prior to infection)
Severity ranges from mild diarrhea to fulminant pseudomembranous colitis and toxic megacolon (life-threatening)
Incidence and severity of CDI are increasing; CDI-associated morbidity and mortality are also increasing.
BI/NAP1/027 – more virulent strain of C. difficile; hyper-sporulating and increased production of toxins A and B than previous strains → increase disease severity and mortality; highly resistant to fluoroquinolones; may be refractory to standard therapy

Question 2

definition of C diff infection

Answer 2

(CDI)
Presence of diarrhea in the form of 3 or more unformed (liquid) stools in 24 hours in conjunction with a positive stool test for C. difficile toxins or toxigenic C. difficile or colonoscopic or histopathologic findings revealing pseudomembranous colitis.
Prior antimicrobial use is no longer included in definition

Question 3

pathogenesis of CDI

Answer 3

4 critical components
-Disruption of colonic microflora – normal intestinal flora suppress colonization, overgrowth, and toxin production by C. difficile
-Need source for C. difficile – endogenous flora or exogenous source
-Organism must have potential to produce toxin: Antibiotics may stimulate toxin production, Produces 2 toxins – TcdA (inflammatory enterotoxin) and TcdB (cytotoxin)
Individual risk factors: antibiotic exposure (especially longer exposure and exposure to multiple agents); duration of hospitalization; advanced age (> 65 years); physical proximity to patient with CDI; presence of comorbidity with functional impairment; use of proton-pump inhibitors or H2 antagonists; cancer chemotherapy; GI surgery; immunosuppression; HIV; poor serum antibody response to C. difficile toxins
Median time between exposure to C. difficile and occurrence of CDI is 2-3 days
Pathology
-Colonic and rectal mucosa is edematous, erythematous with distinct, adherent, raised plaque-like pseudomembranes (yellow-white)
-Pseudomembranes consist of fibrin, mucus, necrotic epithelial cells, and leukocytes
-Occur throughout the colon; most prominent in rectosigmoid area

Question 4

signs and symptoms of CDI

Answer 4

Profuse, watery or mucoid green, foul-smelling diarrhea (guaiac-positive in 5-10%)
Cramping abdominal pain
Leukocytosis (> 15,000/mm3 in severe** CDI in blood)
High fevers (103-105°F in severe** CDI)
Hypoalbuminemia (less than 2.5 g/dl in severe** CDI)
Increasing serum creatinine (≥ 1.5 times the pre-morbid level) with renal failure (AKI in severe** CDI)
Toxic megacolon may develop; mortality ≈ 50%

Question 5

clinical manifestations of CDI

Answer 5

Can appear from 2-3 days after the start* of antimicrobial therapy to 3 months after* therapy with the offending agent

Question 6

difference between CDI and AAD

Answer 6

symptoms - CDI often has evidence of colitis; AAD has no evidence of colitis
CT or endoscopy - CDI shows evidence of colitis
results of stool toxin - CDI: positive
epidemiologic - CDI: may be epidemic or endemic; AAD: sporadic
AAD usually resolves with withdrawal of implicated antibiotic
CDI requires oral metronidazole or vanc

Question 7

laboratory diagnosis

Answer 7

need to detect toxin A and B
most common: BD-GeneOhn C diff real time PCR assay – a polymerase chain reaction assay that is rapid, sensitive, and specific

Question 8

treatment considerations

Answer 8

Discontinue treatment with the offending antimicrobial as soon as possible (if possible)
Initiate empiric therapy as soon as a diagnosis of severe or complicated CDI is suspected
Avoid use of peristaltic agents** – may obscure symptoms and precipitate toxic megacolon
Colectomy should be considered for severely ill patients – monitoring serum lactate (≥ 5 mmol/L) and WBC count (≥ 50,000/mm3)

Question 9

treatment of an asymptomatic carrier**

Answer 9

No signs or symptoms

No treatment indicated

Question 10

treatment of mild CDI**

Answer 10

outpatient
Clinical manifestations: Mild diarrhea (3-5 unformed bowel
movements/day, Afebrile, Mild abdominal discomfort or tenderness, No notable laboratory abnormalities
Treatment: Stop predisposing antibiotic, Hydration, Metronidazole 500 mg PO TID, Monitor clinical status

Question 11

treatment of moderate CDI**

Answer 11

clinical manifestations: Moderate, non-bloody diarrhea, Moderate abdominal discomfort or tenderness, Nausea with occasional vomiting, Dehydration, WBC > 15,000/mm3, Scr and BUN above baseline
treatment: Consider hospitalization, Stop predisposing antibiotic, Hydration, Either metronidazole 500 mg PO, TID or first-line therapy with oral, vancomycin 125 mg PO QID for
14 days

Question 12

treatment of severe CDI***

Answer 12

clinical manifestations: Severe or bloody diarrhea, Pseudomembranous colitis, Severe abdominal pain, Vomiting, Ileus, Temperature > 38.9°C, WBC > 20,000/mm3, Albumin under 2.5 g/dL, Acute kidney injury (AKI)
treament: Hospitalization, Oral or nasogastric vancomycin 500 mg QID with or without metronidazole 500 mg IV q8h
OR Fidaxomicin 200 mg PO BID for 10 days instead of vancomycin if risk of recurrence is high

Question 13

treatment of complicated CDI***

Answer 13

Clinical manifestations: Toxic megacolon, Peritonitis, Respiratory distress, Hemodynamic instability
treatment: Antibiotics as for severe CDI, Surgical consult for subtotal colectomy or a diverting ileostomy with vancomycin retention enema
Consideration for fecal microbiota transplantation

Question 14

treatment of first recurrence of CDI

Answer 14

Oral metronidazole 500 mg TID or oral vancomycin 125 mg QID for 14 days OR oral fidaxomicin 200 mg PO BID for 10 days

Question 15

treatment of further recurrence

Answer 15

Vancomycin in a tapered or pulsed regimen OR fecal microbiota transplantation OR fidaxomicin 200 mg PO BID for 10 days

Question 16

metronidazole treatment considerations

Answer 16

Metronidazole – may be considered first-line therapy for initial episode of mild-to moderate CDI
Very active against C. difficile
Well tolerated; significantly less expensive than vancomycin; recent studies suggest decreased efficacy and higher relapse rates compared to vancomycin
Usual dose: 500 mg PO TID for 10-14 days
Bioavailability ≈ 100%; ?adequate concentrations achieved within colonic lumen

Question 17

vancomycin treatment considerations

Answer 17

Recommended for initial treatment of severe, life-threatening cases, when metronidazole fails, or when metronidazole is not tolerated or cannot be used
Concern for development of vancomycin resistant enterococci
Resistance has not been reported in C. difficile
Stool concentrations
-125 mg PO QID → 300 to 1,000 µg/g
-500 mg PO QID → ≥ 2,000 µg/g (average)
Usual initial dosage – 125 mg PO q6h for 10-14 days (may increase to 500 mg q6h in severe, complicated CDI)
Disadvantages – cost; bitter taste

Question 18

example of tapered and pulsed dose therapy for vancomycin

Answer 18

125 mg 4 times daily for 1 week
125 mg 3 times daily for 1 week
125 mg 2 times daily for 1 week
125 mg once daily for 1 week
125 mg every 2 days for 8 days (4 doses)
125 mg every 3 days for 9 days (3 doses)

Question 19

fidaxomicin treatment considerations

Answer 19

Non-absorbable macrocyclic antibiotic, approved by FDA in 2011
More potent in vitro than vancomycin against C. difficile; minimal activity against other gut flora
Dosage: 200 mg twice daily for 10 days (with or without food) – very expensive
Phase 3 comparison to vancomycin for CDI
Significant decrease in recurrence only for non-BI/NAP1/027 strains

Question 20

fecal microbiota transplantation treatment considerations

Answer 20

FMT involves administration of fecal material containing distal gut microbiota from a healthy donor to a patient with CDI with the goal of restoring phylogenetic diversity and microbiota in a normal person.
Potential indications (informed consent required by FDA)
-Recurrent or relapsing CDI – (a) 3 or more episodes of mild-to-moderate CDI and failure to respond to a 6- to 8-week taper with vancomycin with or without an alternative agent (rifaximin, nitazoxanide, fidaxomicin) (b) at least 2 episodes of CDI resulting in hospitalization and associated with significant morbidity
-Moderate CDI with no response to standard therapy for at least 1 week
-Severe or fulminant CDI with no response to standard therapy for 48 hours
Donor may be a spouse, first-degree relative, long-time partner, friend, or unrelated donor
Donor screening – screen for behaviors that may cause increased risk for transmitting infection; may use questionnaire similar to blood donation; donors should be free of diseases or conditions that may be transmissible by stool
Donors should undergo serologic and stool testing within 4 weeks for donation
Stool preparation – must be diluted (tap water, milk, normal saline) and homogenized (blender, manually) and filtered if necessary (gauze, coffee filter, strainer)
Material may be directly infused into the GI tract or placed in gelatin capsules and swallowed; fecal material may be frozen and thawed for later use
Method of instillation – upper GI tract via endoscopy or NG tube, proximal colon via colonoscopy, or distal colon by enema, rectal tube, or sigmoidoscopy.
Associated with rapid response and cure rates ≈ 80-95% in patients with recurrent CDI; patients may require > 1 FMT
Generally well tolerated but a few cases of fatal aspiration pneumonia following FMT have been reported
Material may be purchased commercially

Question 21

monoclonal antibodies

Answer 21

FDA-approved in October 2016 to reduce recurrence of C. difficile infections in patients ≥ 18 years of age who are receiving antibacterial drug treatment for CDI and are at high risk for recurrence
Binds toxin B only (does not bind toxin A)
Not indicated for treatment of CDI
10 mg/kg single dose IV infused over 1 hour (no dose adjustment for renal or hepatic dysfunction)
Caution in patients with history of CHF
Most common adverse events: nausea, pyrexia, headache
Availability: 1000 mg/40 ml single use vial (≈ $4,000/vial)

Question 22

environmental cleaning and dissinfection

Answer 22

Identify and remove environmental sources of C. difficile
Use chlorine-containing cleaning agents or other sporicidal agents
Routine environmental screening is not recommended

Question 23

probiotics

Answer 23

administration is not recommended to prevent or treat CDI in 2010 guidelines; limited data on efficacy; potential risk of bloodstream infection; controversial