Clostridioides difficile Infections (CDI)

What is CDI caused by?

a toxin-producing, spore-forming, gram-positive, anaerobic bacillus

signs and symptoms of CDI

- abdominal pain, tenderness, cramping, distention, diarrhea

- >3 unformed stools in 24h and stool (+) C. diff toxins

- colonoscopic/histopathologic demonstrating pseudomembranous colitis (PMC)

nonsevere CDI

WBC

severe CDI

WBC >15000 or SCr >1.5

fulminant CDI

hypotension, shock, ileus, megacolon

diagnostic tests for CDI

- C. diff culture

- cell cytotoxicity neutralization assay

- endoscopy

- glutamate dehydrogenase (GDH)

- toxin EIA tests

- nucleic acid amplification test

TAT for GDH

15-45 min

TAT for toxin EIA tests

2 hours

TAT for nucleic acid amplification test

2-3 hours

sensitivity/specificity of GDH

high/low

sensitivity/specificity of toxin EIA tests

moderate/high

sensitivity/specificity of nucleic acid amplification test

high/high

advantages of GDH

fast, expensive, easy

advantages of toxin EIA tests

detects A-B+ strains

advantages of nucleic acid amplification test

fast, highly sensitive/specificity

disadvantages of GDH

poor specificity

disadvantages of toxin EIA tests

increased sensitivity for low-level toxin production

disadvantages of nucleic acid amplification test

false (+) detected in colonizers

reverse 2-step algorithm

step 1: C. diff PCR test

step 2: reflex to EIA toxin test

recommendations for CDI testing from IDSA

- perform on unformed stool only, unless ileus

- do not test stool as test of cure

- limited value and discourages to repeat testing during the same episode of diarrhea

community-onset CDI (CO-CDI)

diagnosed in an outpatient location or

healthcare facility-onset CDI (HO-CDI)

diagnosed in an inpatient location >4 days of hospital admission

community-onset, healthcare facility-associated CDI (CO-HCFA)

diagnosed in an outpatient location or

epidemic strain of CDI

RT 027

RT 027

- associated with higher mortality, poorer outcomes, and outbreaks

- increased virulence factors (toxin A and B, spore formation, antibiotic resistance)

proven efficient agents for CDI treatment

- vancomycin

- fidaxomicin

- metronidazole

dose of vancomycin for CDI treatment

125mg PO QID

dose of fidaxomicin for CDI treatment

200mg PO BID

dose of metronidazole for CDI treatment

500mg PO/IV TID

agents with inadequate data for treatment of CDI

- rifaximin

- tigecycline

- bacitracin

dose of rifaximin for CDI treatment

400mg PO TID

dose of tigecycline for CDI treatment

50mg IV q12h

dose of bacitracin for CDI treatment

25000 units PO QID

recommendations for initial treatment of CDI from IDSA/SHEA

- fidaxomicin 200mg PO BID for 10 days (preferred)

- vancomycin 125mg PO QID for 10 days

- metronidazole 500mg PO TID for 10-14 days (for nonsevere CDI if other agents are not available)

recommendations for initial treatment of nonsevere CDI from ACG

- vancomycin 125mg PO QID for 10 days

- fidaxomiccin 200mg PO BID for 10 days

- metronidazole 500mg PO TID for 10 days (for low-risk)

recommendations for initial treatment of severe CDI from ACG

- vancomycin 125mg PO QID for 10 days

- fidaxomicin 200mg PO BID for 10 days

- fecal microbiota transplantation (FMT)

recommendations for treatment of 1st recurrent episode of CDI from IDSA/SHEA

- fidaxomicin 200mg PO BID for 10 days (preferred)

- fidaxomicin 200mg PO BID for 5 days, and then once every other day for 20 days (preferred)

- vancomycin tapered and pulsed

- vancomycin 125mg QID for 10 days (if metronidazole was used for initial episode)

recommendations for treatment of 1st recurrent episode of CDI from ACG

- vancomycin tapered and pulsed

- fidaxomicin 200mg PO BID for 10 days (unless fidaxomicin was used for initial episode)

recommendations for treatment of 2nd or more recurrent episodes of CDI from IDSA/SHEA

- fidaxomicin 200mg PO BID for 10 days (preferred)

- fidaxomicin 200mg PO BID for 5 days, and then once daily every other day for 20 days (preferred)

- vancomycin tapered and pulsed

- vancomycin 125mg PO QID for 10 days, and then rifaximin 40mg PO TID for 20 days

- FMT

recommendations for treatment of 2nd or more recurrent episodes of CDI from ACG

FMT

recommendations for treatment of fulminant episode of CDI from IDSA/SHEA

vancomycin 500mg PO QID + metronidazole 500mg IV TID + vancomycin 500mg via rectal enema QID (if ileus present)

recommendations for treatment of fulminant episode of CDI from ACG

- vancomycin 500mg PO QID + metronidazole 500mg IV TID + vancomycin 500mg via rectal enema QID (if ileus present)

- FMT

MOA of fidaxomicin

- inhibits bacterial RNA polymerase and spore formation

- narrow spectrum: gram-positive anaerobes only

AEs of fidaxomicin

nausea and/or vomiting, neutropenia

MOA of vancomycin

inhibits cross-linking of peptidoglycan in cell wall

AEs of vancomycin

systemic absorption at higher doses + inflammation, emergence of VRE

vancomycin taper and pulsed regimen

125mg PO QID for 10-14 days

Then 125mg PO BID for 7 days

Then 125mg PO Qday for 7 days

Then 125mg PO evert 2-3 days for 2-8 weeks

MOA of metronidazole

disrupt DNA structure leading to cell death

AEs of metronidazole

- acute: GI, metallic taste

- long-term use: neurotoxicity (peripheral & central)

- emergence of VRE

treatment in patients with severe CDI & not tolerating PO

- metronidazole 500mg IV q6h + [enteral admin of vancomycin by GT or intracolonic vancomycin]

2nd-line/adjuvants for CDI

- rifaximin

- tigecycline

- IVIG

dose and duration of rifaximin for CDI

400mg PO TID for 20 days

dose and duration of tigecycline for CDI

100mg IV x1, followed by 50mg IV q12h

dose and duration of IVIG for CDI

400mg/kg IV x1 (usually infused over 12h)

agents that contribute to risk factors for initial and recurrent CDI

- lincosamides: clindamycin

- macrolides: clarithromycin, erythromycin

- beta-lactams

- fluoroquinolones

- glycopeptides: vancomycin

more risk factors for initial and recurrent CDI

- gastric acid suppressants

- cancer & chemotherapy

- inflammatory bowel disease

- aging

- metabolic disease (BMI, T2DM

- hospitalization

- long-term care facility

MOA of probiotics

- promote conversion of primary to secondary bile acids

- secret compounds that inhibit C. diff vegetation and its toxins

- improve GI epithelial barrier function & immunomodulation

AEs of probiotics

abdominal cramping, nausea, fever, flatulence, taste disturbances, changes in stool consistency

probiotics place in therapy

- dietary supplements (not subject to FDA approval or good manufacturing practices)

- IDSA/SHEA do not recommend routine probiotics for prevention of initial or recurrent CDI

- not supported as evidence-based practice

MOA of fecal microbiota transplantation (FMT)

engraft donor microbiota to recipient, normalizing the gut microbiome and decrease germination of existing C. diff spores

FDA-approved FMT products

- Rebyota

- Vowst

hospital-prepared ("known donor") FMT

not FDA approved; expensive and logistically challenging

When is hospital-prepared FMT allowed?

under the FDA's "enforcement discretion" policy for recurrent CDI

dose of Rebyota

single-dose enema consisting of human stool suspended in 150mL of NS/polyethylene glycol administered rectally

AEs of Rebyota

abdominal pain, diarrhea, abdominal distention, flatulence, nausea

dose of Vowst

4 capsules PO Qday for 3 days

AEs of Vowst

abdominal distention, fatigue, shivering

other AEs and limitations of FMT

- potential transmission of pathogens and altering metabolism of FMT recipients

- logistical challenges (acquisition, storage, billing, reimbursment)

infection control & prevention of CDI

- hand washing

- PPE

- bleach