T5 - IE4 - Gastroenterology - Yamaki - Clostridium Difficile

C. diff

Clostridioides difficile

Clostridioides difficile is a ______-________ __________, strict __________

- gram positive bacillius [rod]

- (strict) anaerobe

Clostridioides difficile forms ________

- (forms) spores

Clostridioides difficile some are ______ producing

- toxin (producing)

A&B

Clostridioides difficile was discovered as a cause of _______________ ______ and ___________-__________ colitis

- pseudomembranous colitis

- antibiotic-associated (colitis)

Clostridioides difficile: ______-______ route transmission

- fecal-oral (route transmission)

Epidemiology of

Clostridioides difficile: accounts for _____-____% of cases of antibiotic-assoicated diarrhea

- 20-30(% of cases of antibiotic-assoicated diarrhea)

Epidemiology of

Clostridioides difficile: stool carriage of C. difficile reaches ___-_____%

- 16-35(%)

Occurs in community ~7 / 100,000 people

Epidemiology of

Clostridioides difficile: mortality

~14,000 people / year

Epidemiology of

Clostridioides difficile: __________ rate amongst the elderly

- rising (rate amongst the elderly)

CDI

clostridiodes difficile infection

CDI rates and mortality increased with __________ ___________ _____

- (mortality increased with) increased patient age

CDI rates and mortality chart

older the patient, the higher the mortality in C Diff

Epidemiology of

Clostridioides difficile: in US, incidence continues to __________, as well as ________

- increase

- (as well as) severity

Increased toxic megacolon, colectomy, refractory to therapy, relapse

Epidemiology of

Clostridioides difficile: in US, incidence continues to increase, as well as severity

Increased toxic megacolon

Increased colectomy

Increased refractory to therapy, relapse

Epidemiology of

Clostridioides difficile: now considered by CDC as a _______ _______ _______ threat

_________ _______ has the highest C diff rate in California

- MAJOR public health (threat)

- Orange County (has the highest C diff rate in California)

Epidemiology of

Clostridioides difficile - possible reasons for INCREASED CDAD incidence and SEVERITY

changes in underlying host susceptibility

changes in antimicrobial prescribing

new strain with increased virulence / resistance

changes in infection control practices

CDAD

Clostridium difficile-associated diarrhea

Epidemiology of

Clostridioides difficile - possible reasons for INCREASED CDAD incidence and SEVERITY:

Changes in underlying ______ ________ and _________ ______

- (underlying) host susceptibility

- antimicrobial prescribing

Epidemiology of

Clostridioides difficile - possible reasons for INCREASED CDAD incidence and SEVERITY:

New strain with __________ _________ / _________

- (New strain with) increased virulence / resistance

Epidemiology of

Clostridioides difficile - possible reasons for INCREASED CDAD incidence and SEVERITY:

Changes in __________ ________ practices

- infection control (practices)

Epidemiology of

Clostridioides difficile - BI/NAP1/027 strain

distinctions from typical C. diff strains

- hyper-production of Toxin A/B

- 3rd, binary toxin

- hypersporulation

- fluoroquinolone resistance

Epidemiology of

Clostridioides difficile - BI/NAP1/027 strain distinction from typical C. diff strains: _______-___________ of Toxin A/B

- Hyper-production (of Toxin A/B)

Epidemiology of

Clostridioides difficile - BI/NAP1/027 strain distinction from typical C. diff strains: 3rd, binary _______ and __________

- (3rd, binary) toxin

- hypersporulation

Epidemiology of

Clostridioides difficile - BI/NAP1/027 strain distinction from typical C. diff strains: ____________ resistance

- fluoroquinolone (resistance)

Disease pathogenesis of C. Diff figure

Disease pathogenesis of C. Diff: C. diff ingested -> C. diff spores ___________

- (spores) germinate

In the large intestine, C. difficile-associated disease can raise if the normal flora has been disrupted by antibiotic therapy

Toxin A & B production leads to colon damage ± pseudomembrane

Disease pathogenesis of C. Diff: In the large intestine, C. difficile-associated disease can raise if the normal flora has been ___________ by __________ therapy

- disrupted

- (by) antibiotic (therapy)

Toxin A & B production leads to colon damage ± pseudomembrane

Disease pathogenesis of C. Diff: Toxin A & B production leads to...

colon damage ± pseudomembrane

TcdA and TcdB

disrupt epithelial barrier, cause cell death and induce inflammation

Fulminant

occurring with great intensity; refers to severe pain with sudden onset

"Severe +"

Intracellular modifications by TcdA & TcdB Figure

Intracellular modification by TcdA & TcdB

breakdown of tight junctions and epithelial integrity (toxins destroy epithelial cells)

glycosylation and inactivation

serum level increases and neutrophils in area which causes diarrhea

Risk factors for C. Diff

advanced age (≥ 65 years)

prior hospitalizations

resides in SNF

Prior C. Diff infection

Immunosuppression

Risk factors - MEDICATIONS

antibiotics

- clindamycin

- fluoroquinolones

- 3rd generation cephalosporins

- carbapenems

- long duration of therapy

proton pump inhibitors

prolonged corticosteroid use

chemotherapy

Risk factors - MEDICATIONS (antibiotics)

clindamycin

fluoroquinolones

3rd generation cephalosporins

carbapenems

long duration of therapy

______ suppression and __________ lead to higher C. diff risk

- Acid (suppression)

- antibiotics (lead to higher)

Acid suppression and antibiotics with C. Diff Risk Chart

C. diff presentation - general signs and symptoms

Diarrhea ≥ 3 times a day

Cramps

fever

leukocytosis

inflammation on colonic biopsy

toxic megacolon

dehydration / electrolyte imbalances

ileus

obstruction of the ilium

Disease presentation of C. Diff chart

Disease presentation of C. Diff - mild/moderate toxin associated infection

supportive data:

- ~6 stools

- WBC < 15

- Scr < 1.5 mg/dL

symptoms

- cramps

- lower abdominal discomfort

physical exam

- slight abdominal distention

Disease presentation of C. Diff - mild/moderate toxin associated infection (supportive data): ___ stools, WBC ___ _____, Scr ___ ____ mg/dL

- ~ 6 (stools)

- (WBC) < 15

- (Scr) < 1.5 (mg/dL)

Disease presentation of C. Diff - mild/moderate toxin associated infection (symptoms)

cramps

lower abdominal discomfort

Disease presentation of C. Diff - mild/moderate toxin associated infection (physical exam)

slight abdominal distention

Disease presentation of C. Diff - severe toxin associated infection

supportive data:

- ~10 stools daily

- fecal occult blood

- WBC > 15

- Scr > 1.5 mg/dL

Symptoms

- nausea

- weight loss

- dehydration

- WBC

- low grade fever

Physical exam

- abdominal tenderness / distension

Disease presentation of C. Diff - severe toxin associated infection (supportive data): ____ stools daily, positive _______ ________ blood, WBC ___ _____, Scr ___ ______ mg/dL

- ~10 (stools daily)

- positive (fetal occult) blood

- (WBC) > 15

- (Scr) > 1.5 (mg/dL)

Disease presentation of C. Diff - severe toxin associated infection (symptoms)

Nausea

Weight loss

Dehydration

WBC

Low grade fever

Disease presentation of C. Diff - severe toxin associated infection (physical exam)

abdominal tenderness / distention

Disease presentation of C. Diff - FULMINANT colitis (extremely severe)

supportive data:

- severe diarrhea or possibly decreased due to toxic megacolon

- WBC > 15

- Scr > 1.5 mg/dL

- Shock

- Ileus

Symptoms

- lethargy, fever/chills

- tachycardia

- WBC

Physical exam

- severe lower abdominal distention / tenderness

Disease presentation of C. Diff - FULMINANT colitis (extremely severe) - supportive data: _______ diarrhea or decreased due to _______ _______

WBC: ___ _____; Scr ___ ____ mg/dL; shock and obstruction of ilium (________)

- severe (diarrhea)

- (decreased due to) toxic megacolon

- (WBC:) > 15

- (Scr) > 1.5 (mg/dL)

- ileus

Disease presentation of C. Diff - FULMINANT colitis (extremely severe) - symptoms

lethargy

fever / chills

tachycardia

WBC

Disease presentation of C. Diff - FULMINANT colitis (extremely severe) - physical exam

SEVERE lower abdominal distension / tenderness

Complications of C. diff

dehydration

- electrolyte imbalances

hypoalbuminemia

AKI

toxic megacolon or pseudomembranous colitis

sepsis

death

Pseudomembranous colitis figure

A: regular

B: pseudomembranous colitis

Toxic Megacolon X-Ray Figure

FT is a 67 y/o male with NKDA, that was admitted 3 days ago on 3/7/20 for CAP. Today (3/10) FT has had 8 bowel movements that were unformed. He also is complaining of abdominal pain and cramping. WBC were initially trending down (9.2k WBC yesterday), however today they increased to 14.3k and has a fever of 102.4F.

Labs today:

Na 139 mEq/L

K 3.8 mEq/L

Cl 102 mEq/L

Co2 18 mEq/L

BUN 26 mg/dL

Scr 1.1 mg/dL

WBC 14.3 k/cmm

Neut 79%

Bands 6%

Hgb 13.1 g/dL

Hct 43%

Put 230 k/cmm

AST 36 IU/L

ALT 22 IU/L

Alb 4.0 g/dL

T. bili 0.3 mg/dL

Glu 118 mg/dL

Ca 9.3 mg/Dl

Mg 2.1 mg/Dl

Current medications:

Atorvastatin 20mg q24h

Ceftriaxone 1g IV q24h

Azithromycin 500 mg IV q24h

Levofloxacin 500 mg IV q24h

Metoprolol succinate 50 mg q24h

Pantoprazole 40 mg q24h

What are signs/symptoms and risk factors for Cdiff?

FT is elderly (67 y/o), 8 bowel movements (unformed)

- abdominal pain / cramping

- WBC increased to 14.3k

- febrile

Meds (risk factors):

- ceftriaxone (3rd generation)

- pantoprazole

- levofloxacin

Bristol stool chart

Diagnosis - bristol stool chart for C. diff

Stool sent for lab testing if ≥ 3 type 6 or 7 stools

Type 6

- fluffy pieces with ragged edges, a mushy stool

Type 7

- watery, no solid pieces, entirely liquid

Diagnosis - bristol stool chart for C. diff: stool sent for lab testing if ___ ___ type 6 or 7 stools

- ≥ 3 (type 6 or 7 stools)

Diagnosis - Bristol stool chart for C. diff: stool sent for lab testing if ≥ 3 type ___ or ___ stools

- 6

- 7 (stools)

Bristol Stool Chart - Type 6

fluffy pieces with ragged edges, a mushy stool

Bristol Stool Chart - Type 7

watery, no solid pieces (entirely liquid)

Diagnosis - Bristol stool chart for C. diff: also note that these patients should present without being on _________ or ______-_________

- (without being on) laxatives

- tube-feeding

Laxatives and tube-feeding will have type 6 or type 7 presentation

Diagnosis for C. Diff should not be made on lab tests alone, but needs to consist of the ________ ______ ______ including additional patient objective data

- entire clinical picture

e.g., WBC, PE, symptoms etc.

Diagnosis for C. Diff Lab Testing

PCR for toxigenic genes (high sensitivity, high specificity)

Gold Standard: Cytotoxin assay (high sensitivity, high specificity)

Diagnosis for C. Diff Lab Testing - PCR for toxigenic genes - highly sensitive but ONLY detects ______________, cannot distinguish between ________ infection and __________ carriage

- (ONLY detects) colonization

- (cannot distinguish between) active (infection)

- asymptomatic (carriage)

Cytotoxin assay is the GOLD standard

Diagnosis for C. Diff Lab Testing - GOLD standard

Cytotoxin Assay

May take several days for results

Diagnosis for C. Diff Lab Testing - GOLD standard: cytotoxin assay may take ___________ days for results, requires _______ _________ ________

- several (days for results)

- (requires) tissue culture facility

Diagnosis for C. Diff Lab Testing - PCR for toxigenic genes, results are _________

- (results are) rapid

However, cannot distinguish between active infection and asymptomatic carriage; more expensive than ELISA so needs criteria prior to testing

Nurse sends a stool sample to microbiology lab for C. difficile testing

What are the results needed in PCR and ELISA to confirm C. diff?

PCR testing - Toxin A/B (+)

ELISA testing - Toxin A/B detected

If GENE is there (PCR TEST) does not mean toxin is there, so ELISA is sometimes used

Vancomycin PO

VANCOCIN

Oral vancomycin bioavailability is __________, thus it sits in the intestine to treat ____ _________

- (bioavailability is) low

- (sits in the intestine to treat) C. Difficile

Thus, low absorption and does not need renal adjustment UNLIKE IV vancomycin

Oral vancomycin has ______ ________ due to low bioavailability and does _____ _______ renal adjustment unlike IV vancomycin

- low absorption (due to low bioavailability)

- NOT need (renal adjustment)

No need for monitoring

Initial episode of C. diff (non-severe / mild-moderate treatment) - first line

Vancomycin PO (125 mg QID or NGT for 10 days)

Fidaxomcyin 200 mg PO BID for 10 days

(initial episode non-severe)

Initial episode non-severe is the same as SEVERE except DO NOT use second-line agents

Initial episode of C. diff (non-severe / mild-moderate treatment) - second line

Metronidazole 500 mg Q8 PO for 10-14 days

Initial episode of C. diff (severe treatment)

ONLY first-line used

Vancomycin PO 125 mg QID or NGT for 10 days

Fidaxomycin 200 mg BID for 10 days

(same as first line non-severe, however non-severe may use second line as alternative)

Initial episode of C. diff (FULMINANT / SEVER COMPLICATED)

Vancomycin 500 mg PO QID or by NG tube

- if ileus, consider adding rectal instillation of vancomycin (500 mg in ~100 mL NS)

IV metronidazole 500 mg Q8H should be administered together with ORAL or RECTAL vancomycin, particularly if ileum is present

First recurrence of C. diff treatment: use a ____________ ________ and __________ vancomycin regimen if a standard vancomycin regimen was used for initial episode

- prolonged tapered

- pulsed (vancomycin regimen)

e.g., 125 mg vancomycin QID for 10-14 days, then BID per day for 1 week, QD for a week, then once for every 2 to 3 days for 2-8 weeks

First recurrence of C. diff treatment

prolonged tapered and pulsed vancomycin

OR

fidaxomicin 200 mg BID for 10 days if vancomycin was used for initial episode

OR

vancomycin 125 mg QID for 10-14 days if metronidazole was used for the initial episode

Prolonged tapered and pulsed vancomycin treatment

125 mg QID for 10-14 days

then...

BID for 1 week

then...

QD for 1 week

then...

every 2 or 3 days for 2-8 weeks

First recurrence of C. diff treatment: may use the __________ ______ and _______ vancomycin regimen

- prolonged tapered

- pulsed (vancomycin regimen)

First recurrence of C. diff treatment: if vancomycin was used for initial episode may use __________ ______ mg ________ for ____ days

- Fidaxomycin 200 (mg)

- BID

- 10 (days)

First recurrence of C. diff treatment: if metronidazole was used for initial episode use...

vancomycin 125 mg QID for 10-14 days

Second or subsequent recurrence of C. Diff

Tapered and pulsed vancomycin regimen

OR

vancomycin 125 mg QID PO for 10-14 days FOLLOWED by rifaxmin 400 mg PO TID for 10 days

OR

Fidaxomcyin 200 mg PO for 10 days

OR

Fecal Microbiota Transplantation (FMT)

FMT

fecal microbiota transplant

Second or subsequent recurrence of C. Diff - vancomycin + rifaximin regimen

vancomycin 125 mg QID PO for 10-14 days

FOLLOWED by rifaxmin 400 mg PO TID for 10 days

Primary treatment (1st line) - Vancomycin (VANCOCIN - PO - NO IV)

used for mild / moderate / severe infections and recurrent infections

Primary treatment (1st line) - Vancomycin (VANCOCIN - PO - NO IV) dosing

125 mg PO q6H for 10 days, can give higher dose (250 mg)

In severe, patients give 500 mg

Primary treatment (1st line) - Vancomycin (VANCOCIN - PO - NO IV): has ________ absorption so there is ____ _______ for monitoring levels

- poor (absorption)

- no need (for monitoring levels)

Primary treatment (1st line) - Vancomycin (VANCOCIN - PO - NO IV): Other non-PO option

500 mg in approximately 100 mL NS per rectum Q6H as a retention enema

fidaxomicin

DIFICID

Primary treatment (1st line) - Fidaxomicin (DIFICID - PO) is also used for _______ / _________ / _______ infections and _________ infection

- mild / moderate / severe

- recurrent (infections)

Similar to Vancocin

Fidaxomycin is superior for recurrent infections than initial treatment

Primary treatment (1st line) - Fidaxomicin (DIFICID - PO): superior for ___________ infection

- recurrent (infection)

Rather than initial treatment

Primary treatment (1st line) - Fidaxomicin (DIFICID - PO) _______ ________ spectrum

- very narrow (spectrum)

Primary treatment (1st line) - Fidaxomicin (DIFICID - PO) dosing

200 mg PO q12h for 10 days

Alternative treatment (2nd line) - Metronidazole is used in _______ / _________ CDI

- mild / moderate (CDI)

Alternative treatment (2nd line) - Metronidazole (IV/PO) dosing

500 mg PO q8h for 10-14 days (if patient cannot TAKE vancocin or fidaxomicin)

NO longer first line

Alternative treatment (2nd line) - metronidazole (IV/PO) for SEVERE infection / fulminant colitis

Give 500 mg IV q8H WITH

vancomycin 500 mg PO q6h or 500 mg enema 6qh

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