Clostridioides difficile Infection

Question 1

Problems with Antibacterial Therapy

Answer 1

• Superinfection
• Bacterial
• Fungal
• Alteration of Normal Flora
• Overgrowth of commensal / opportunistic organisms
• Skin / Mucous membranes - Candida
• Candida Vaginitis
• Oral Thrush
• Candida Skin Infections
• Candida in Blood Stream

• GI Tract
• Diarrhea (3.2 - 29%)
• Clostridioides Difficile-Associated Diarrhea (CDAD)
(Pseudomembranous Colitis)

Question 2

What is Clostridioides difficile?

Answer 2

• Gram-positive anaerobe
• Produces spores and toxins
• Ubiquitous in nature
• Important transmissible nosocomial pathogen
• Spreads primarily through person-to-person transfer
via fecal-oral route and environmental contamination
of surfaces with C. difficile or its spores

Question 3

______is the primary pathogen
causing antibiotic-associated colitis
• Can result in significant morbidity and mortality

Answer 3

Toxin-producing C. difficile

Question 4

Epidemiology

Answer 4

Colonization found in ~ 1-3% of healthy people (3-26% of adult
inpatients in acute care hospitals)
• 43% ↑ in incidence of CDI and 189% ↑ in multiple recurrent CDI in the
United States from 2001-2012
▫ 0.63 per 1,000 person years in 2012
• Incidence of healthcare-associated CDI in Canada 4.3 per 10,000
patient-days in 2015 (down from 5.9 in 2009)

Question 5

C. difficile-associated Diarrhea (CDAD)

Answer 5

• Normal flora in colon is disrupted
• All antibacterials implicated
• Fluoroquinolones, clindamycin, and 3 rd generation
cephalosporins particularly troublesome
• C. difficile attaches to receptors in the gut epithelial cell, proliferate and toxogenic strains may release toxins
(Toxins A and B)
• Toxin B highly pathogenic, essential for virulence
• Toxins cause inflammation and vasoconstriction, leading to the development of pseudomembranous colitis ± necrosis
• Symptoms - diarrhea, fever, abdominal pain, dehydration etc.

Question 6

Clinical Manifestations of CDAD

Answer 6

• Onset typically 5 -10 days after start of antibacterial therapy, but may occur as long as 10 -12 weeks following antibacterials (index of suspicion)
• Unformed stools (i.e., watery diarrhea that takes the
shape of the container)
• *≥ 3 episodes in 24 hrs may be brief and self-limited orcholera-like with > 20 very liquid stools /day.

• Blood in stools is rare
• Fever (30 - 50%)
• Leukocytosis (50 - 60%) (>15 x 109/L)
• Abdominal pain or cramping (20 - 33%)
• Asymptomatic carriage (possibly protective)

Question 7

Complications of CDAD

Answer 7

• Dehydration
• Electrolyte disturbances
• Hypoalbuminemia
• Toxic megacolon
• Bowel perforation
• Hypotension
• Renal failure
• Sepsis, septic shock
• Death

Question 8

Risk Factors for CDAD

Answer 8

• Age – Older adults (> 65 yrs)
• Antimicrobial Tx (>90% occur post-Abx Tx)
- the more abx received, the higher ther risk
- the longer duration of tx, the increased risk
(ceph 2nd gen or higher, fluoroquin high risk) (mod risk with penicillins)
• Hospitalization
• Cancer chemotherapy
• Severe underlying illness
• Manipulation of GIT
• ?H2 Receptor Blockers / Proton Pump Inhibitors

Question 9

risk management

Infection Prevention and Control

Answer 9

Contact precautions (gloves (Strong, High) and gown (Strong, Moderate))
• Private room and washroom for patient (Strong, Moderate)
• Wash hands with SOAP & WATER (Weak, Low)
• Alcohol rubs do not inhibit/remove spores
• Proper disinfection of surfaces with approved
disinfectants (Strong, Moderate)
• >5,000 ppm Chlorine-containing solutions one of the most effective disinfectants
• Spores may persist for weeks-months on surfaces

MOXIFLOXACIN IS WORST FOR C DIFFICILE (GUT ANAEROBES WIPED OUT AND LEADS TO C DIFF TAKING OVER) > CIPRO > LEVO

Question 10

Pharmacists CAN have an impact!
Antimicrobial stewardship (Good practice)

Answer 10

• Minimize frequency, duration, and number of
antimicrobials prescribed (Strong, Moderate)
• Restriction of
• 3rd generation cephalosporins,
• fluoroquinolones, and
• clindamycin use may be particularly useful
(Strong, Moderate)
• Discontinue inciting antimicrobial therapy as soon as
possible (Strong, Moderate)

Question 11

Diagnosis of CDAD

Answer 11

• Diarrhea
• ≥ 3 unformed stools (that take the shape of the
container) in ≤ 24 hours
AND ≥1 of the following:
• Positive stool test for C. difficile or its toxins
• Evidence of pseudomembranous colitis
• This criteria should be used for diagnosing initial and recurrent episodes (unless paralytic ileus is present)

Question 12

start clock when ceftriaxone ends, vanco start

Diagnosis of CDAD
tests

Answer 12

• Stool Culture (72 hrs) – GOLD STANDARD
• Not practical to use routinely
• NAATs such as PCR to detect toxin genes the preferred test (are superior to the enzyme immunoassays for toxins A+B)
• Glutamate dehydrogenase (GDH) is a newer screening test for C. difficile that can be used with 2 or 3-step testing along with testing for toxins A + B (has a high sensitivity, but low specificity)

Question 13

Approach to CDAD Patient

dont give loperamide, let toxins out

Answer 13

• Discontinue all unnecessary antimicrobials
• Discontinue and avoid antiperistaltics
• Determine if this is an initial or recurrent episode
• Patient care with severe CDAD should include
• Intravenous fluid and electrolyte resuscitation
• Venous thromboembolism prophylaxis
• Oral or enteral feeding should be continued unless patient has a paralytic ileus (fermentable carbohydrates useful for normalizing
the microbiota)
• Use of probiotics not currently recommended (limited data of effectiveness and potential risk of bloodstream infection)

Question 14

Initial Episode

Criteria

Answer 14

• Symptoms of CDAD

* NO positive C. difficile test results in the last 8 weeks

Question 15

Recurrent Episode

Answer 15

• Up to 25% of treated CDAD patients have a recurrence
• Recurrences may be due to relapse with original strain or re-infection with new strain
• Criteria:
• Symptoms of CDAD
• ≥ 1 positive C. difficile test result in the last 8 weeks

Question 16

approach to cdad pt
• If this is an initial episode or the patient’s 1st recurrence,
determine the severity of the episod

Answer 16

• Mild-moderate:
• Leukocytosis (WBC <15.0 x 109 cells/L) AND
• SCr < 130 µmol/L
• Severe:
• Leukocytosis (WBC >15.0 x 109 cells/L) or
• SCr ≥ 130 µmol/L
• Severe, complicated (fulminant):
• Hypotension, shock, ileus, and/or megacolon

Question 17

Therapeutic Options

Metronidazole

Answer 17

Metronidazole
-≥ 85% abs following oral dose
• Affects other gut bacteria
•AE: Peripheral neuropathy (uncommon), Darkened urine 
Initial Treatment Response ++ 
Recurrence Risk ++

Question 18

Vancomycin

Answer 18

• Negligible abs following oral dose
• Affects some gut bacteria
• Minimal systemic AE
Initial Treatment Response ++ +
Recurrence Risk ++ 

capsules now a regular benefit

Question 19

Fidaxomicin

Answer 19

• Minimal abs following oral dose
• Limited activity against other gut bacteria
• Minimal systemic
Initial Treatment Response ++ +
Recurrence Risk ++ 

• A new macrocyclic antibacterial
• Not absorbed from GI tract
• Bactericidal against C.difficile
• Prolonged post-antibiotic effect against C. difficile
• Limited activity against normal gut flora
• Preserves Bacteroides groups in fecal flora
• Already seeing elevated MIC to fidaxomicin due to a
mutation in RNA polymerase B
• Expensive

Question 20

Treatment Recommendations: Initial Episode

mild-mod

severe, uncomp

severe, comp

Answer 20

Mild to moderate (non-severe)
• Vancomycin 125 mg po QID x 10 days (Strong, High), or
• Fidaxomicin 200 mg po BID x 10 days (Strong, High), or
• If above two not available (or cost prohibitive):
▫ Metronidazole 500 mg po TID x 10 days (Weak, High)

Severe, uncomplicated
• Vancomycin 125 mg po QID x 10 days (Strong, High), or
• Fidaxomicin 200 mg po BID x 10 days (Strong, High)

Severe, complicated (fulminant)
• Vancomycin* 500 mg po/NG QID x 10-14 days (Strong, Moderate), AND
• Metronidazole 500 mg IV Q8H (Strong, Moderate)
* If ileus present, consider additional rectal instillation of vancomycin (Weak, Low)

Question 21

Treatment Recommendations: Recurrence
First Recurrence
Second or Subsequent Recurrence

Answer 21

First Recurrence
• Vancomycin 125 mg po QID x 10 days if metronidazole was used for initial episode (Weak, Low), or
• Prolonged tapered and pulsed vancomycin regimen if a standard regimen was used for initial episode (e.g., 125 mg po QID x 10-14 days, then BID x 7 days, then daily x 7 days, then q48-72h for 2-8 weeks) (Weak, Low), or
• Fidaxomicin 200 mg po BID x 10 days if vancomycin was used for the initial episode (Weak, Moderate
DO NOT USE METRO FOR MORE THAN 2 RECURRENCES

Second or Subsequent Recurrence
• *Vancomycin in a tapered and pulsed regimen (Weak, Low), or
• Vancomycin 125 mg po QID x 10 days, followed by rifaximin 400 mg po TID x 20 days (Weak, Low), or
• Fidaxomicin 200 mg po BID x 10 days (Weak, Low), or
• Fecal microbiota transplantation (Strong, Moderate)

Question 22

Not Recommended

Answer 22

• Repeat testing (within 7 days) during same episode of
diarrhea (Strong, Moderate)
• Routine identification of asymtomatic carriers (Strong, Moderate)
• Probiotics (limited data to support and may cause blood stream
infection) (No recommendation)
• Adding cholestyramine or rifampin to ↓ risk of recurrence
• Use of antiperistaltic agents

Question 23

Vancomycin vs Metronidazole

Answer 23

• Systematic review – 4 trials (872 patients) comparing
vancomycin 125 mg QID to metronidazole 250-375 mg QID
• Metronidazole associated with lower sustained symptomatic
cure

Question 24

Fidaxomicin vs Vancomycin

Answer 24

• Fidaxomicin dose 200mg q12h x10days
• Vancomycin 125mg q6h x 10days
• Rates of clinical cure with fidaxomicin noninferior to
vancomycin (Intention to treat analysis 88.2%vs
85.8%), per-protocol (92.1% vs 89.8%)
• Fewer recurrences with fidaxomicin group 15.4% vs
25.3% P=0.005 (but not followed to 90 days)
• Fidaxomicin significantly lower rate of recurrence of
C.difficile diarrhea with non-North American Pulsed
Field type 1 strain
• Adverse event profile similar

Question 25

Probiotics to Prevent CDAD

Answer 25

• Two meta-analyses in past in JAMA and Annals of
Internal Medicine showed probiotics prevent antibiotic
associated diarrhea and C. difficile infections
• But studies small and heterogenous

PLACIDE study from UK
• 5 hospitals, 68 medical and surgical units >17,000 patients
>65 yrs of age
• Patients all hospitalized and taking an antibiotic
• Randomly assigned to take a microbial preparation
(lactobacilli and bifidobacteria x 21 days) or placebo
•* At 8 weeks: No difference in rates of diarrhea or
C.difficile (but ↑ flatus/bloating)

Question 26

Fecal Microbiota Transplant

Answer 26

• Stool is taken from a healthy individual (with rigorous screening of the donor’s blood and stool for common bacterial and viral enteropathogens)
• Routes of delivery:
▫ oral capsules
▫ nasoduodenal tube
▫ endoscopy (upper or lower)
▫ Enema
• Treatment success rates range from 77-100%

• 2 small RCTs compared FMT to antibacterial therapy
(vancomycin) for recurrent CDI
• Both were stopped early due to overwhelming benefit in the
FMT arms (Sustained resolution at 10 weeks: 81% vs 31%; and
90% vs 26%)

Question 27

Rifaximin

Answer 27

• RCT (68 patients): following 10-14 days of vancomycin or
metronidazole, randomized to rifamixin 400 mg po TID vs placebo for
20 days
• Recurrent diarrhea in 21% vs 49% (p = 0.0018, NNT 4)
• Recurrent CDI in 15% vs 31% (not significant)

Question 28

Bezlotoxumab

Answer 28

• Monoclonal antibody against C. difficile toxin B
• Addition to antibacterials may reduce recurrence of CDI
• 2 RCTs (2,655 patients) with primary or recurrent CDI receiving standard
of care therapy (metronidazole, vancomycin, or fidaxomicin)
• Sustained cure through 12 weeks: 64% vs 54% (p < 0.05)

Question 29

• JP is a 70 year old ♀ who presents to the urgent care clinic complaining
of abdominal discomfort and diarrhea that she describes as “severe”.
She rates the abdominal discomfort as 7/10. She states that she has been having around 8-10 very loose stools a day for the past two days.
She does not think that she has noticed any blood in her stools. On exam, her temperature is 36.9ºC, BP 110/74, HR 98, RR 22, O2 sat 96%
on RA. Her WBC count is 11, SCr 90 Her abdomen is not tender or painful with palpation. Her medications include the following: candesartan, metoprolol, pantoprazole, bisacodyl, colchicine, and
acetaminophen. She received a course of moxifloxacin just under a month ago and has had no other recent antibacterials. She has no medication allergies.

Answer 29

confounder: bisacodyl, laxative
colchicine
if you discontinue before sending specifmen
if C. diff positive, can treat with vanco

not mild as older pt

check if she still needs pantoprazole
decrease future risk of C. diff infection