1. C. difficile update: Implications for antibiotic stewardship
Brenda L Tesini, MD

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I have no conflict of interest disclosures
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3. Objectives Appreciate pathophysiology of C. difficile
Review updated testing and treatment options
Understand role of antibiotic stewardship in prevention and management of C. difficile infections

4. Question 1
What is the main modifiable risk factor for developing C.diff infection?
Age
Diabetes
Antibiotics
Probiotic use
Smoking status

5. Question 2
Which antibiotics are first line agents for the treatment of C.diff infection (choose 2)?
Metronidazole
Fidaxomicin
Doxycycline
Vancomycin
Bezlotoxumab

6. Question 3
Which are ways that you can help prevent C.diff infections in your residents?
Audit for appropriate treatment
Identify inappropriate antibiotic use
Identify inappropriate PPI use
All of the above

7. Outline Review pathophysiology of C.difficile infection
Discuss current diagnostic and treatment guidelines
Explore opportunities for your role in preventing of C.difficile infections

8. C. difficile Infections: Top CDC Priority
Top 3 URGENT drug-resistant bacterial threats per CDC
Most common healthcare-associated infection in the US
Recurs in 1 out of 5 patients
Source: CDC Report “antibiotic Resistance Threats in the United States, 2013”
Miller BA et al. ICHE 2011

9. C. difficile Infections: impact to patients
1 out of 11 patients >65 yo with HA-CDI will die w/in 30 days of dx
Nearly 500,000 cases annually
Over 100,000 cases in LTCF*
29,000 deaths
450,000
29,000
$4,800,000,000
Source: CDC Report “antibiotic Resistance Threats in the United States, 2013”
2011 estimate
*LTCF: long term care facilities
Miller BA et al. ICHE 2011; Lessa FC et al. N Engl J Med 2015

10. Impact to health care system
Most common microbial cause of healthcare-associated infections in the US
1 out of 11 pateints >65 yo with HA-CDI will die w/in 30 days of dx
Over $4.8 BILLION /year in excess health care in acute facilities alone
2/3 of infections associated with hospital stay
Nearly as many cases occurred in nursing homes as hospitals

11. Impact to long term care facilities (LTCF)
2/3 of C.difficile infections associated with hospitalization
¼ of those cases will present when at LTCF

12. MMWR 61(09);157-622012. Data from Emerging Infections Program, 2010

13. CDI Incidence in LTCF
Crude and adjusted annual long-term care facility onset Clostridium difficile infection incidence rates across 10 US sites,
Gugh AY, et. Al AJIC 2018

14. Age impacts mortality 85+ years 75-84 years 65-74 years
CDC, National Center for Health Statistics. Compressed Mortality File on CDC WONDER Online Database, released July Data are compiled from Compressed Mortality File Series 20 No. 2Q, Accessed at on May 4,2018

15. Pathogenesis Change in healthy intestinal flora
Acquisition of C diff spores
Overgrowth of C diff
Toxin production and destruction of intestinal lining

16. Colonization Resistance and Dysbiosis
Protective diverse microbiota
Loss of Diversity and richness
Lumen
The normal microbiome consists of 1000 bacterial species
The microbiota has a beneficial role including
Synthesis of vitamins, fermentation of dietary carbohydrates, development and maturation of the immune system
Competitive exclusion “colonization resistance” of pathogens
Antibiotic lead to the loss of microbial diversity, which occurs in association with:
Loss in abundance of key phyla such as Bacteroidetes, Firmicutes
Loss of key functions/metabolic byproducts that inhibit C. difficile: i.e. loss of colonization pressure
Often observed with a reciprocal increase in Proteobacteria, particularly the Enterobacteriaceae family
Submucosa

17. Exposure to C. diff and Antibody Production
C. difficile
Toxin
Antibody

18. C. difficile Colitis and FMT
Fecal microbiota transplant (FMT)
Cell cytotoxicity

19. Points of intervention
Reduce risk factors
Antibiotic stewardship
Infection prevention
Anti-C diff treatment

20. Antibiotic exposure: the most important C. diff infection risk factor

21. Antibiotic exposure: the most modifiable C. diff infection risk factor

22. Avoiding antibiotics
Avoid antibiotic treatment of asymptomatic bacteruria
Avoid antibiotic treatment of viral respiratory infections
Pro-active wound care to avoid secondary infections

23. Thoughtful use of antibiotics
Choose the most narrow spectrum antibiotics when possible
Clarify antibiotic allergies and “de-label” inappropriate penicillin allergies
Limit duration of antibiotic therapy based on disease-specific guidelines

24. Additional risk factors
Advanced age is another risk factor
Older adults are at higher risk of CDI
Changes to the gut microbiome
Immunosenescence
>80% of CDI deaths are in patients aged ≥65 years
1 of 3 infections in >65 yo
2 of 3 healthcare-associated infections in >65 yo

25. Diagnosis Clinical suspicion of disease Diarrhea
>3 loose stools for >1 day
Takes the shape of the container
Positive laboratory testing
Detection of organism
False positives – pick up colonization
Detection of toxin
False negatives – don’t pick up all infections

26. Appropriate Testing – “diagnostic stewardship”
High rates of asymptomatic colonization
8% of patients upon admission to hospital
Up to 25% of patients during prolonged admission
5-7% of patients in nursing homes
NAAT used alone can increase “infection” rate by 50-80%
Need to use toxin test with NAAT, particularly if no clinical screening for stool submission
Diagnostic testing algorithms based on level of clinical screening

27. Commercial C. difficile Diagnostic Tests
Sensitivity
Specificity
Substance detected
GDH
Immunoassay
(EIA)
High
Low
Common C. difficile antigen
Toxin
Immunoassay (EIA)
Moderate
Free toxins
NAAT (PCR)
Low-moderate
Toxin (tcd A or tcd B) genes
A more recent
large study showed sensitivity of 2 toxEIAs to be 68% to 83% with specificities of
approximately 99%. The overall
poor performance of toxin immunoassays led to the recommendation that these
should not be used as stand-alone tests, but rather as a part of a 2-stage or 3-stage
algorithm
GDH: glutamate dehydrogenase; EIA: Enzyme immunoassay; NAAT: nucleic acid amplification test
Modified from Planche T. et al Infectious Disease Clinics of North America, 2015;29:63-82

28. Two Step Algorithm – can use if no clinical screening
GDH
EIA
NAAT
Negative
Result
No evidence
of CDI
+ve
-ve
Positive
Laboratory
confirmation
Confirmation
No evidence of CDI

29. NAAT – use when clinical screening of samples
Lab rejects formed stool
Patients on laxatives not tested
Lab has no rejection policy
No institutional policy for testing
NAAT
Positive
Result
Laboratory
Confirmation
of CDI
No evidence of CDI
-ve
NAAT
Positive
Result
Laboratory
Confirmation
of CDI
No evidence of CDI
-ve
Confirmed +ve by EIA

30. No consensus on the best laboratory method Multi-step testing:
Diagnosis summary
No consensus on the best laboratory method
Multi-step testing:
NAAT alone
GDH then toxin (by EIA)
GDH then toxin then NAAT if needed
NAAT then toxin
In a carefully screened population, may consider NAAT alone
McDonald et al Clinical Infectious Disease (

31. Treatment – top 5 new points
Discontinue inciting antibiotic
May influence CDI recurrence
Vancomycin or fidaxomicin are the drugs of choice
Metronidazole no longer recommended except for mild disease when access to drug of choice is limited
Due to lower efficacy especially in moderate and severe infection
Fecal microbiota transplant for multiple recurrences
Antibiotic stewardship key for CDI prevention

32. Treatment: Initial episode
Clinical Severity
Treatment recommendation
Change from 2010
Comments
Nonsevere
Vancomycin 125 mg QID OR
Fidaxomicin 200 mg BID
Duration: 10 days
Fidaxomicin added
Metronidazole removed
Duration 10 days only
Metronidazole acceptable alternative if other agents not available
Severe
Metronidazole NOT considered acceptable alternative
Fulminant
Vancomycin 500 mg QID
AND
IV metronidazole 500 mg q8h
If ileus: Consider adding rectal installation of vancomycin
Addition of IV metronidazole particularly important if ileus present

33. Treatment: recurrent episodes
Recurrence
Initial treatment
Treatment recommendation
Change from 2010
Comments
First
Metronidazole
Vancomycin 125 mg QID
x 10 days
Same treatment as initial episode no longer recommended
Vancomycin
Prolonged tapered and pulsed vancomycin OR
Fidaxomicin 200 mg BID
Suggested taper:
125 mg
QID for days, then
BID x 1 week, then
Daily x 1 week, then
Every 2-3 days for 2-8 weeks
Second
Any
FMT
Addition of fixadimicin and FMT
Can consider rifaximin 400 mg TID x 20 days instead of vancomycin taper

34. Vancomycin vs Metronidazole
All Cause 30-day Mortality
Vancomycin: improved mortality in moderate to severe disease
Not definitively shown in all studies
Exclusion of metronidazole remains controversial
Stevens et al. JAMA Int Med 2017

35. Vancomycin vs. Fidaxomicin
Recurrence within 4 weeks:
Vancomycin 26%
Fidaxomicin 13%
Cornely OA, et al. Lancet Infectious Diseases 2012;12:

36. Cost comparison Antibiotic Dose / Formulation
Outpatient Ave wholesale price per 10-day course
metronidazole
500 mg PO q8h (tabs)
500 mg PO q8h (suspension)
500 mg IV q8h (500 mg bag)
$21 $
$32-75
Vancomycin
125 mg PO q6h (125 mg cap)
500 mg PO q6h (250 mg cap)
125 mg PO q6h (suspension)
500 mg PO q6h (suspension) $ $
$64
$255
Fidaxomicin
200 mg PO q12h (tabs)
$4418

37. Bezlotoxumab – secondary prevention
General risk of recurrence is around 25%
Recued recurrence in pre-defined high risk groups
Around 10% reduction
Not included in IDSA/SHEA guidelines based on limited evidence
Reduced readmission rates

38. Prevention – role of proton pump inhibitors
Clinical association btwn use and risk of CDI
Lack of robust studies to determine causality
Discontinue unnecessary PPIs
Need to determine individual patient’s risk vs benefit
Consider H2-blocker instead in appropriate patients

39. Prevention – probiotics and alternatives
Lack of evidence to support probiotics
No FDA-approved formulation
Cannot recommend for primary prevention
Seldom harmful
Alternatives
Yogurt
Kefir
Bakken CID 2014

40. Prevention – antibiotic stewardship program
Restriction of fluoroquinolones
Resistant strains decreased in prevalence
Associated with decrease in highly pathogenic NAP1 strain
Develop guidelines for diagnosis and treatment of common infections
Urinary tract infections
Pneumonia
Skin & skin structure infection
Use local antibiogram data to guide empiric antibiotic choices
Limit 3rd generation cephalosporin use
Avoid fluoroquinolones

41. How YOU can prevent harm from CDI
Audit for appropriate treatment
Identify inappropriate antibiotic use
Identify inappropriate PPI use

42. Question 1
What is the main modifiable risk factor for developing C.diff infection?
Age
Diabetes
Antibiotics
Probiotic use
Smoking status

43. Question 2
Which antibiotics are first line agents for the treatment of C.diff infection (choose 2)?
Metronidazole
Fidaxomicin
Doxycycline
Vancomycin
Bezlotoxumab

44. Question 3
Which are ways that you can help prevent C.diff infections in your residents?
Audit for appropriate treatment
Identify inappropriate antibiotic use
Identify inappropriate PPI use
All of the above