1. MANAGEMENT OF CLOSTRIDIUM
DIFFICILE INFECTION (CDI):
A TOPIC REVIEW
Tauhid Ahmed Bhuiyan, PharmD
PGY-1 Resident (Year 1)
Pharmacy Practice Residency
King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy
Education as a provider of continuing pharmacy education. (UAN# 0833-0000-14-039– L01-P, 0833-0000-14-039– L01-T)

2. Objectives
 Familiarize with the background, epidemiology, and
general overview of CDI
 Identify key elements for diagnosing CDI
 Discuss contemporary management strategies of CDI
 Recognize key infection control measures as well as
understand pharmacists’ role in prevention of the
disease
I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

3. Background
 Gram-positive, anaerobic, spore forming organism, first isolated in 1935
 Found in soil, human and animal feces, and food products (e.g. processed
meats)
 Produce two types of toxin
 Toxin A
 Toxin B (primary toxin responsible for CDI)
 Most common causes of hospital acquired infection along with methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococci (VRE)
 Common cause of infectious diarrhea in hospitals and long-term care (LTC)
settings
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

4. Case Definition of CDI
 An episode of CDI is defined as:
 Presence of diarrhea
 Passage of ≥ 3 unformed stool in 24 hours or fewer consecutive hours
 Positive stool test result for presence of toxigenic C. difficile or its
toxins or histopathologic findings demonstrating pseudomembranous
colitis
 Rarely (<1% of cases), a symptomatic patient will present with
ileus and colonic distension with minimal or no diarrhea
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

5. Epidemiology
 C. difficile is recognized as:
 Primary pathogen responsible for antibiotic-associated colitis
 15%-25% of cases of nosocomial antibiotic-associated diarrhea
 Disease burden:
 20%-30% of cases of antibiotic-associated diarrhea
 The cost attributed to CDI in the US varies from $2470.00−$3669.00
per episode
 According to Center for Disease Control (CDC)
 C. difficile causes diarrhea links to 14,000 deaths each year
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455
Silva M. Einstein 2012; 10(1):105-9
Clostridium Difficile Infection. www.cdc.gov

6. Surveillance Definition
 Community onset, healthcare facility-associated (CO-HCFA)
 Symptom onset in the community or within 48 hours of hospital admission + discharge
from healthcare facility within the previous 4 weeks
 Hospital onset, healthcare facility-associated (HO-HCFA)
 Onset of symptoms >48 hours after admission or <4 weeks after discharge from health
care facility
 Intermediate
 Symptom onset occurs in the community between 4-12 weeks after discharge from a
hospital
 Community associated
 Not discharged from healthcare facility in the previous 12 weeks
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

7. Natural History
CDAD: Clostridium Difficile Associated Diarrhea
HCW: Health Care Worker http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement
/infectious-disease/clostridium-difficile-infection

8. Pathogenesis
http://www.cdiff-support.co.uk/about.htm

9. Etiology
 Exogenous
 Transmission through
 Fecal-oral route
 Person to person spread
 Fomites
 Hospital equipment or furniture
 Endogenous
 Small amount found in natural flora in the small intestine
 Exposure to antibiotic suppresses natural flora “niche”
for C. difficile to flourish
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

10. Risk Factors
Major risk factor Likely risk factor
Age >64 years Immune compromised (e.g. AIDS, cancer)
Recent hospitalization Consumption of contaminated food products
Increased length of hospital stay Inflammatory bowel disease
Long term care (LTC) facility
residence
Use of proton-pump inhibitors
Antibiotic exposure Gastrointestinal endoscopic procedures
Contact with active carriers
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

11. Complications of Severe CDI
 Dehydration
 Electrolyte
disturbances
 Hypoalbuminemia
 Toxic megacolon
 Hypotension
 Renal Failure
 Systemic inflammatory
response syndrome
(SIRS)
 Bowel perforation
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

12. Diagnosis

13. Clinical Presentation
 Symptomless carriage—mild or moderate diarrhea–fulminant
and sometimes fatal pseudomembranous colitis
 Watery diarrhea is the cardinal symptom accompanied by
 Lower abdominal pain and cramping (20%-33%)
 Fever (30%-50%)
 Leukocytosis (50%-60%)
 Patient with severe disease may develop colonic ileus or toxic
dilatation with minimal or no diarrhea
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

14. Assessment of Severity
Clinical definition Supportive clinical data
Mild to moderate
 Leukocytosis with WBC< 15,000
cells/μL
 Serum Creatinine (Scr) < 1.5 X baseline
Severe
 Leukocytosis with WBC ≥ 15,000
cells/μL
 Scr ≥ 1.5 X baseline
Severe-complicated
 Hypotension or shock, ileus, toxic
megacolon
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

15. Laboratory Investigations
 Confirmatory test
 Stool examination
 Other test for disease severity
 Complete blood count (CBC)
 Electrolytes
 Albumin levels
 Serum lactate levels

16. Stool Tests
Test
Sensitivity
(%)
Specificity
(%)
Advantages Disadvantages
Cell Cytotoxicity Assay 80-90 99-100
Considerably high
sensitivity and specificity;
considered as gold
standard
Takes 24-48 hr to complete;
requires tissue culture
facility; cost; detects only
toxin B
Enzyme Immunoassay
(EIA) Toxin test
65-85 95-100
Fast (2-6 hr), easy to
perform, high specificity
Lack of sensitivity than cell
cytotoxicity assay; detects
both toxin A and B
Stool Culture 90-100 98-100
Most sensitive, essential
for epidemiologic studies
Takes 2-5 days to complete;
labor intensive; not specific
for toxin-producing bacteria
Latex Agglutination
Assay for Glutamate
Dehydrogenase (GDH)
58-68 80-96
Fast, inexpensive, easy to
perform
Poor sensitivity and
specificity needed to
establish diagnosis; requires
confirmatory test
PCR assay toxin gene
detection
92-97 100
Excellent sensitivity and
specificity compared with
cytotoxin assay
Not in routine practice
Aberra FN. et al. Clostridium Difficile Colitis. www.medscape.com. March 17, 2014

17. Imaging
 Endoscopy
 Not generally used in making initial diagnosis
 Used in high suspicion despite normal stool tests or ileus
secondary to CDI
 Findings of pseudomembranes are not specific but
sensitive to CDI diagnosis
 Computed tomography (CT)
 Suggestive of CDI include bowel wall thickening, peri-
colonic stranding
 Dilated colon may indicate severe-complicated CDI
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

18. Management

19. Goals of Therapy
 Short term:
 Resolution of signs and symptoms of CDI infections
 Progression of the disease
 Long term:
 Prevention of recurrences

20. General Measures
 Supportive care and careful management of fluid
and electrolyte
 Discontinuation of unnecessary antimicrobial
therapy
 Avoidance of anti-motility agents
 Reviewing of PPI use
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

21. Treatment
 Pharmacological
 Agents with activity against C. difficile organisms
 Non-pharmacological
 Fecal Microbiota Transplantation (FMT)
 Surgical Management

22. Pharmacological Agents
Approved Unapproved/Unlabeled
Vancomycin Metronidazole
Fidaxomicin Nitazoxanide
Rifaximin
Immunotherapy

23. Treatment Guidance (Adults)
Clinical Definitions Recommended Treatment
Initial episode, mild or
moderate
Metronidazole, 500 mg orally every 8 hours for
10-14 days
Initial episode, severe
Vancomycin, 125 mg orally every 6 hours for
10-14 days
Initial episode, severe,
complicated
Vancomycin 500 mg orally every 6 hours +
Metronidazole 500 mg every 8 hours
intravenously (IV)
Note: consider adding rectal instillation
First recurrence Same as initial episode
Second recurrence Vancomycin tapered and/or pulse regimen*
First 2 weeks: 125 mg PO q6h
Third week: 125 mg PO BID
Fourth week: 125 mg PO daily
Next 2-8 weeks: 125 mg every 2 to 3 days
*
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

24. Metronidazole
 Inexpensive, widely used as a first-line treatment for CDI
 Compared to vancomycin alone:
 Similar efficacy for mild to moderate infection
 Not recommended beyond the first recurrence/long term
therapy; “possible cumulative neurotoxicity”
 Only 6%-15% excreted in stool
 Adverse effects:
 Nausea, disulfiram-like reaction, metallic taste, peripheral
neuropathy
 Not routinely recommended for use in children or in women
during lactation or pregnancy
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

25. Vancomycin
 First FDA approved labeled indication for treatment of CDI
 More expensive than metronidazole; minimal oral absorption
 Use is discouraged as initial treatment to decrease selection
pressure for the emergence of VRE
 Usage:
 When metronidazole is found to be ineffective
 If metronidazole is contraindicated or not well tolerated
 Initial treatment option of severe CDI
 For severe complicated CDI, higher dose (250-500 mg 4 times a day)
is used as a supplemented therapy along with IV metronidazole
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

26. Comparative Effectiveness
 Initial Cure:
Drekonja DM. et al. Ann Intern Med. 2011;155:839-847

27. Fidaxomicin (Dificid®)
 FDA approved (2011) for indication of C. difficile-associated
diarrhea (CDAD)
 Narrow spectrum macrocyclic antibiotic that targets bacterial
RNA polymerase
 Activity against gram-positive aerobic and anaerobic organisms
 Dose & duration: 200 mg by mouth twice a day for 10 days
 Safe and effective for the first episode of C. difficile infection,
however, there is limited evidence for recurrent infection
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

28. Initial Episode of Mild-to-Moderate CDI
 Fidaxomicin (200 mg twice daily) was compared to oral
vancomycin (125 mg 4 times daily) in 2 randomized control
trials (RCT) for duration of 10 days
 Both trial found fidaxomicin noninferior to vancomycin in
terms of clinical cure
 Fidaxomicin was also associated with a lower recurrence rate
within 28 days of clinical cure relative to vancomycin
Louie TJ et al. N Engl J Med 2011; 364:422-431

29. Pharmacokinetic Advantage
 Minimal systemic absorption after oral administration
 >92% excreted in the feces as unchanged drug and
metabolites
 Concentrations in feces substantially exceed the 90%
MIC of C. difficile
 Postantibiotic effects against C. difficile in clinical
studies range from 6-10 hours
Lexi-Comp OnlineTM , Lexi-Drugs Multinational , Hudson, Ohio: Lexi-Comp, Inc.; September 19, 2014

30. Alternative Agents
 Nitazoxanide
 Rifaximin
 Immunotherapy
 Probiotics

31. Nitazoxanide
 Antiparasitic agent, active against C. difficile
 Musher et al. compared nitazoxanide in at 2 durations to
metronidazole in a prospective, randomized, double-blinded
study involving 142 patients with CDI
 Results showed that nitazoxanide is as effective as metronidazole with
similar response rate (90% vs. 82%) and recurrence rates ( 18% vs.
23%)
 Lacks long term safety and efficacy data
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

32. Rifaximin
 Used as an adjunct to treat patient with multiple CDI
recurrences
 Course is given in a form of “rifaximin chaser” (400 mg orally
for 14 days)
 A recent RCT found that rifaximin was similar to vancomycin
(57% vs. 64%) in attaining clinical success and was non-inferior
in resolution of diarrhea (80% vs. 81%) and recurrence (9%
vs. 14%)
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

33. Immunotherapy (IVIG)
 Variable success
 No RCT trials showing benefit of IVIG for CDI
 Its mechanism may relate to antibodies against C. difficile
toxin A and toxin B
 In a large, randomized, controlled trial of monoclonal antibody
against C. difficile toxin A and toxin B in addition to antibiotic
therapy
 Rate of recurrence rate was lower among patient treated with
monoclonal antibody (7% vs. 25%; p <0.001)
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

34. Probiotics
 Goal is to repopulate the colonic microflora
 Commonly used species Lactobacillus,
Bifedobacterium, and Saccharomyces
 Currently has no role in the primary prevention of
CDI
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

35. Non-pharmacological Treatment

36. Fecal Microbiota Transplantation (FMT)
 Alternative to standard antibiotic therapy to treat recurrent
CDI
 Restoration of colonic flora with the use of intestinal
microorganisms from a healthy donor (via infusion of a
liquid suspension of stool)
 A systemic review of 317 patients with recurrent CDI treated
via FMT found overall success rate of 92%, with 89% of
patients responding after a single treatment
Khanna S. et al. Ther Adv Gastroenterol 2014; 7(2):72-86

37. Surgical Management
 Indicated for treatment of refractory CDI not
responding to medical therapy, or for fulminant colitis
or toxic megacolon
 Traditional surgical approach—subtotal or total
colectomy
 Poor outcome with mortality as high as 50%
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

38. Recurrent CDI
 Major drawback in management of CDI
 Occurs 20%-25% of patients after first dose
 Defined as “occurrence of symptomatic diarrhea or
abdominal pain, with positive stool test within 56
days of previous episode after interim symptom
resolution”
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

39. Management of Recurrent CDI
Khanna S. et al. Mayo Clin Proc. 2012; 87(11):1106-1117

40. Infection Control Measures
 Hand hygiene
 Contact precautions
 Glove use
 Gowns
 Isolation rooms or cohorting
 Environmental cleaning, disinfection, or use of disposables
 Patient room, equipment between uses
 Elimination of rectal thermometer usage
 Use of hypochlorite for disinfection
Cohen SH. et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455

41. “Three Big Role”
 Identify potential risk factors
 Evaluate antibiotic usage
 Education

42. Summary
 Clostridium difficile is a Gram-positive, anaerobic, spore forming organism
that produces two types of toxin: A & B
 Major risk factors of CDI include elderly (age >64 years), antibiotic
exposure, recent hospitalization or LTC facility residence
 Toxin detection assay such as cell cytotoxic assay or EIA are considered as
suitable alternatives
 Metronidazole is considered as first line for initial episode of mild-to-
moderate infection and should not be used beyond first recurrence
 Vancomycin is reserved for severe CDI and the dose is 125 mg PO 4 times
a day for 10-14 days

43. Summary
 Fidaxomicin has been shown to be non-inferior to vancomycin
in terms of clinical cure in addition to lower rates of
recurrences, however, use is limited by high cost
 Alternate agents such as, nitazoxanide, rifaximin, IVIG, or
probiotics, do not get used routinely in clinical practice due to
lack of substantial evidence
 Non-pharmacological management such as FMT, or surgery is
indicated in the case of multiple recurrences or refractory CDI
 Proper hand hygiene and contact precautions are considered
to be the cornerstone when it comes to infection control and
nosocomial transmission

45. Self Assessment Questions????

46. Q1: Identify the CORRECT statement regarding
Clostridium difficile infection (CDI):
a) It caused by aerobic, Gram-negative bacilli
b) The primary toxin responsible for causing the
infection is toxin A
c) It is a common cause of infectious diarrhea in the
community
d) Use of broad spectrum antibiotic is responsible for
most CDI cases

47. Q2: Which of the following is one of the means of
acquiring CDI?
a) Alteration of gut flora using antibiotic
b) Fecal-to-oral transmission
c) Through contaminated environment
d) All of the above

48. Q3: Case
 R.J is a 65 year old female who was recently discharged
from hospital after being treated for hospital acquired
pneumonia. For past 2 days R.J has been passing watery
stool for >3-4 times a day. She was brought to the
Emergency and was diagnosed with CDI. Which of the
following treatment regimen is appropriate for R.J?
a) Vancomycin 125 mg PO 4 times a day for 10-14 days
b) Fidaxomicin 200 mg PO twice a day for 10 days
c) Vancomycin 500 mg orally every 6 hours + Metronidazole 500
mg every 8 hours intravenously
d) Metronidazole 500 mg orally every 8 hours for 10-14 days
e) None of the above

49. Q4:Which of the following statement is FALSE
regarding management of CDI?
a) Oral vancomycin is initial treatment option for
severe CDI
b) Fidaxomicin is FDA approved for treatment of CDAD
c) Rifaximin is used as adjunct to treat multiple CDI
recurrences in the form of “rifaximin chaser”
d) Use of Probiotics has clinical role in the primary
prevention of CDI
e) None of the above

50. Q5: Which of the following is FDA approved for
treatment of C. difficile?
a) Vancomycin
b) Metronidazole
c) Fidaxomicin
d) Vancomycin + Fidaxomicin