Yamaki - clostridioides difficile

Clostridioides difficile

• gram-positiv bacillus (rod), strict anaerobe

• spore-forming

• some are toxin producing (A & B)

• in 1970s discovered as a cause of pseudomembranous colitis and antibiotic-associated colitis

• fecal-oral route transmission

C. difficile epidemiology

• accounts for 20-30% of cases of antibiotic-associated diarrhea

• stool carriage of C. difficile reaches 16-35%

• occurs in community ~7/100,000 people

• ~500,000 infections/yr

  • mortality 29,000/yr

CDI rates and mortality increase with ________

increased patient age

CDI new epidemic

• in US ↑incidence continues to increase as well as severity:

  • ↑ toxic megacolon

  • ↑ colectomy

  • ↑ refractory to therapy, relapse

• now considered by CDC as a major public health threat

• Orange County has one of the highest C. diff rates in California

possible reasons for increased CDI incidence and severity

• changes in underlying host susceptibility

• changes in antimicrobial prescribing

• new strain with increased virulence/resistance

• changes in infection control practices

BI/NAP1/027 strain

distinctions from typical C. diff strains:

• hyper-production of Toxin A/B

• 3rd, binary toxin

• hypersporulation

• Fluoroquinolone resistance

disease pathogenesis

C. difficile ingested —>

C. diff spores germinate in the intestine —>

in the large intestine, C. difficile-associated disease can arise if the normal flora has been disrupted by antibiotic therapy —>

toxin A & B production leads to colon damage ± pseudomembrane

why do taking antibiotics lead to CDI

• primary bile acids (cholic acid, taurocholic acid) trigger C diff spore germination

  • primary bile acid made by liver —> intestine

  • normal flora in GI convert primary to secondary bile acids

• secondary bile acids suppress C diff growth and toxic production

  • promote healthy GI normal flora

intracellular modifications by TcdA and TcdB

risk factors

• advanced age (≥ 65 yrs)

• prior hospitlizaiton

• resides in skilled nursing facility

• prior C. difficile infection

• immunosuppression

• medications:

  • antibiotics — clindamycin, fluoroquinolones, 3rd gen cephalosporins, long duration of therapy

  • PPIs

  • prolonged corticosteroid use

  • chemotherapy

“C. diffogenicity”of various ABX

red = more likely to cause CDI

green = less likely to cause CDI

disease presentation — general signs/symptoms

• diarrhea ≥3 times a day

• cramps/abdominal pain

• fever

• leukocytosis

• inflammation on colonic biopsy

• toxic megacolon

• dehydration/electrolyte imbalance

disease presentation — mild/moderate, severe, extremely severe

*KNOW EXTREMELY SEVERE

complications

• dehydration

  • electrolyte imbalances

• hypoalbuminemia

• AKI

• toxic megacolon or pseudomembraneous colitis

• sepsis

• death

diagnosis

• PCR detection — highly sensitive, may detect colonization

  • appropriate sample testing is necessary

• diagnosis should NOT be made on lab test alone, but needs to consist of the entire clinical picture including additional patient objective data (WBC, PE, symptoms, etc)

treatment

• fidaxomicin (Dificid) PO

• vancomycin (Vancocin) PO

• metronidazole (Flagyl) PO/IV

primary treatment 1st line

Fidaxomicin (Dificid) PO

• used for mild/moderate/severe infections and recurrent infection (fidaxomicin is superior for recurrent infections)

• very narrow spectrum macrocyclic lactone (macrolide), non-systemic

• 200 mg PO q12h x 10d

Vancomycin (Vancocin) PO (NOT IV)

• used for mild/moderate/severe/fulminant infections and recurrent infection

• 125 mg PO q6h x 10d, can give higher dose (250 mg), in severe give 500 mg

• poor absorption no need for monitoring levels

• OR 500 mg in approximately 100 mL normal saline per rectum every 6 hrs as a retention enema

alternative treatment (2nd line)

metronidazole (Flagyl) PO/IV

• mild/moderate CDI metronidazole 500 mg PO q8h 10-14 day (if cannot take vanco or fidaxomicin) NO longer 1st line

• severe complicated infection fulminant colitis give 500 mg IV q8h with vancomycin 500 mg PO q6h, or 500mg enema q6h

guidelines — mild/moderate and severe

guidelines — fulminant (severe complicated)

recurrent / refractory disease

expect a number of relapses

• recurrence — usually within 1 week up to 8 weeks after Rx DC’ed in 20% of atients

  • recurrent CDI: defied as CDI occurring within 8 weeks after a previous episode resolved with treatment

  • sustained cured: is defined as no recurrence of symptoms up to 12 weeks after the previous episode

• ~1/2 of relapse are technically reinfection due to new strains of C. difficile

risk factors for recurrence

• ≥ 65 yrs of age

• receiving one or more systemic antibacterial drugs (during the 12-week period after treatment of CDI)

• having one or more episodes of CDI within the 6 months

• immunocompromised

• clinically severe CDI

• infected with hypervirulent strain (ribotypes 027)

recurrent / refractory treatment

• vancomycin taper & pulse dosing

  • 125 mg 4 times per day for 10-14 days, 2 times per day for a week, once per day for a week, and then every 2 or 3 days for 2-8 weeks

• fidaxomicin (Dificid) — 10 days of 200 mg PO BID is NOT inferior to 10 days vancomycin PO 125 mg QID

recommended treatment for first recurrence

recommended treatment for second recurrence

Bezlotoxumab (Zinplava) IV

DISCONTINUED

• monoclonal antibody against toxin B

• used as adjunctive therapy to prevent recurrence in patients at risk

• NO antibacterial activity —> NOT for treatment alone

• given as 10mg/kg one-time IV dose while being treated for CD

• very expensive (thousands of $)

what should NOT be given as treatment?

• along with C. difficile treatment, systemic antibiotic therapy should be DC’ed if possible

  • de-escalate to less “C. diffogenic” antibiotic

• NEVER give anti-motility / anti-diarrheal drugs (e.g., Lomotil - diphenoxylate and atropine - or loperamide)

recurrent / refractory treatment (non-antibiotic treatments)

• Vowst (fecal microbiota spores, live-brpk)

  • FDA-approved PO microbiome therapeutic to prevent C. diff recurrence

  • does NOT treat C. diff

  • take 2-4 days AFTER finishing C. diff treatment

• Rebyota (fecal microbiota spores, live-jslm)

  • FDA-approved rectal admin (PR) microbiome therapeutic to prevent C. diff recurrence

  • does NOT treat C. diff

  • take 1-3 days AFTER finishing C. diff treatment

• stool transplant (FMT)

  • recommended after 2 recurrences (3 CDIs)

  • 30 grams donor blended w/ 150 mL nS then given by PO, G-tube, enema, and colonoscopy delivery

• probiotics — some evidence in prevention

  • NOT recommended by 2018 guidelines

  • many hospitals have implemented probiotics for patients on ABX

infection control

• wash hands

  • DO NOT rely on hand sanitizers (EtOH)

• patient isolation — follow protocols

• antibiotic selection/control

• prophylactic metronidazole and vancomycin NOT recommended per guidelines

  • prophylactic Vanco 125 mg PO q12h if on ABX