This document discusses Clostridium difficile, a bacterium that causes antibiotic-associated diarrhea and colitis. It provides details on pathogenesis, risk factors, diagnostic testing, treatment of initial and recurrent infections, prevention strategies, and new treatments under investigation. Key points include the importance of the host immune response, the increasing incidence and severity of "hypervirulent" strains, challenges in treating recurrent disease, and the potential for vaccines and stool transfer therapy.

1. BETH ISRAEL DEACONESS
MEDICAL CENTER
HARVARD
MEDICAL
SCHOOL
Clostridium difficile 2013:
More Difficult Than Ever
J. Thomas Lamont

2. Clostridium difficile
Spore-forming, anaerobic, gram-positive bacillus
Aslam S, et al. Lancet Infect Dis. 2005;5:549-557.
Colored transmission
electron micrograph of
C difficile forming an
endospore (red)

3. The “Difficult” Clostridium
• Discovered by Hall and O’Toole in 1935
in stools of healthy newborns
• Gram positive toxin-producing bacillus,
but harmless to infants
• Identified as cause of antibiotic
associated colitis in 1977
• Now increasing in prevalence and
severity worldwide

4. Pathogenesis of C. difficile diarrhea
Antibiotic therapy
Reduces protective colonic flora
C. difficile spores ingested
Toxins released in lumen
Diarrhea
& colitis

5. Pseudomembranous Colitis

6. “Super C diff”: Variant Strain
• Mutated txcD gene : increased toxins
• Expression of binary toxin
• Resistant to multiple antibiotics
• Increased fecal shedding of spores
• Increased severity, death, recurrence
• Associated with epidemics
NEJM : Dec 2005

7. Pathogenesis: Role of host
immune response
• Infection elicits IgG and IgA response
• Antibodies directed at toxins
• High IgG antitoxin titer protective
• Vaccination in animals very protective

8. Serum IgG antitoxins appear during
Infantile carrier state
Are serum antitoxins protective?
Viscidi et al: J Inf Dis 1983

9. The C. difficile Carrier State
Type Prevalence Possible
Mechanism
Infants <1 yr 50-70 % Lack of toxin
receptors
Hospitalized
adults
14 % High titer serum
antitoxin
Healthy adults < 1% Barrier function of
microflora

10. A 76 yo man with resolving C
difficile…
..Is on his last day of oral metronidazole therapy for
C diff diarrhea . He has not had diarrhea for the
last five days and states that he is back to
normal. On the weekend his PCP ordered a stool
assay for C diff toxins which returns positive.
Which of these actions would you take now ?
1. Continue metro for 10 more days and re-test
2. Switch to vanco for 10 days
3. Switch to Fidaxomycin for 10 days
4. Finish metro and advise patient to call you if he
develops diarrhea

11. C diff carriage following successful Rx
Inf Control Hosp Epi Jan 2010

12. C diff Test Guidelines
• Best Bet: PCR, or screening test + PCR
• Test only unformed stools
• Do not perform a test of cure
• Correlate test results with clinical
picture
• 60-70% of healthy infants will be pos at
some time in year 1

13. Do serum antitoxins protect against C.
difficile in hospital patients receiving
Colonized by
C. difficile
84 (31%)
Hospital-acquired
28 (10%)
Hospital patients
(Acute medical ward)
LOS > 2 days
Receiving antibiotic
271 enrolled
Cases
47 (17%)
Colonized
on admission
19 (7%)
Colonized
on admission
18 (7%)
Carriers
37 (14%) Hospital-acquired
19 (7%)
antibiotics ?
540 evaluated
311 eligible
NEJM 2000;342:390

14. Serum IgG anti-toxin A levels are high
in asymptomatic carriers of C. difficile
P=0.06 P=0.002 P=0.001 P=0.005

15. C. difficile Diarrhea: Pathogenesis
Antibiotic therapy
Reduced colonic barrier flora
C. difficile ingestion & colonization
Toxins released
Effective anti-toxin
Asymptomatic Diarrhea
carriage & colitis
response
Inadequate immune
response

16. Risk of C diff with Acid Suppression
Arch Int Med 2010;170:784

17. PPIs and Susceptibility to Enteric
Infections

18. Can I ever take antibiotics again ?
A 65 yo woman had C difficile colitis after an oral
fluoroquinilone which responded well to oral
vancomycin with cessation of diarrhea after 5 days.
She took a total of 14 days of vancomycin and now
visits your office two months later. She has had no
further diarrhea and feels well. She has two questions
Can I safely take antibiotics in the future or will I get C
diff again ?
Which antibiotics are safe for me ?

19. Second episodes of C diff ?
• Second bout years later is very rare
• Antibodies acquired in infancy or after
first bout are protective
• Choice of future antibiotics should be
based on diagnosis and culture results
• Probiotic prophylaxis during antibiotic
therapy may help

20. Recurrent C diff : a major problem
• Incidence 25-30% after succesful rx of first
attack
• Recurrent diarrhea from 2 days to 6 weeks
after stopping Met ,Vanc or Fidaxo
• Results from re-infection from spores in the
environment before the barrier flora are
reconstituted
• Multiple recurrences are common
• Responds to repeat course of M,V,F

21. 90%
21
Comparative cure and recurrence rates
Cure Rates Recurrence Rates
81.3%
72.0%
30%
20%
10%
15.4%
1. Louie et al: MEJM, 2010; 2. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in
patients with Clostridium difficile-associated diarrhea (CDAD), poster K-425a, p. 212. Abstr. 47th Intersci. Conf.
Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC.
70%
Metronidazole2
Vancocin2
27.1%
23.4%
0%
Metronidazole2
Vancocin2
88.2%
Fidaxomicin1
Fidaxomicin1
85.8%
Vancocin1
80%
25.3%
Vancocin1

22. Recurrent C. difficile Diarrhea
Clostridium difficile diarrhea
(n = 63)
22 (35%)
Relapsed
19 (30%)
Died
22 (35%)
Single episode
10 / 22 (45%)
Second relapse

23. Immune Immune response response to to toxin toxin A A and and protection
protection
against against C. C. difficile difficile diarrhea and and colitis
colitis
Single episode of
C. difficile diarrhea
Asymptomatic carriers
-3 1 3 6 9 12
Days after colonization
by Clostridium difficile
Adapted Adapted from from N N Engl Engl J J Med Med 2000;2000;342:342:390 390 & & Lancet Lancet 2001;2001;357:357:Serum IgG anti-Toxin A
3
2
1
Recurrent C. difficile
diarrhea

24. The best treatment of C
diff is to allow restoration
of the normal colonic
flora
The problem :
It may take up to 12
weeks !

25. Strategies for Recurrent C. difficile
• 14 day repeat course of V or Fidaxo
• Pulse-tapered 6 week course of Vanco
• Probiotics are adjunctive not primary rx
• Fidaxo (? as primary rx) to replace V,M
• Boost Immunity with C diff antibody
• Bacteriotherapy : stool transfer
• Vaccination

26. Pulsed /tapered Vancomycin for
Recurrent C. difficile
(Tedesco, 1985)
• Tapering course over six weeks
Week 1 125 mg qid
Week 2 125 mg bid
Week 3 125 mg daily
Week 4 125 mg qod
Week 5-6 125 mg q3d
• Follow above with 4 weeks cholestyramine
or probiotic

27. Protective Effects of Lactobacillus Probiotic
Placebo
n = 84
50 X109 CFU
n = 85
100 X109
CFU
n = 86
Antibiotic
Diarrhea
44.1% 28.2%
p = 0.02
15.5%
p = 0.001
C. difficile
Diarrhea
23.8% 9.4%
p = 0.03
1.2 %
p = 0.002
Am. J. Gastro 105: 1636, 2010

28. “My C diff won’t quit”
An 83 yo MD with severe CHF is awaiting
aortic valve replacement for critical AS. He
had severe C difficile infection 18 months ago
which required hospitalization. After successful
initial rx he had three severe recurrences with
fever and dehydration , all requiring
hospitalization. His cardiac team have advised
him that he cannot have his valve replaced until
the C diff is cured. He is currently on a pulsed –
tapered vanco regimen with probiotic coverage.
He previously tried IVIG and rifaxamin. He refuses
a stool transplant.

29. Chronic low dose vancocin for
multiple relapsers
• Suitable for elderly patients with
comorbidity or limited life span
• Failure of prior attempts to wean
• Recurrences are life threatening
• Not suitable for fecal transfer
• 125 mg vanco daily or qod
• Disadvantages: cost ,VRE, no trial
data

30. Severe or Fulminant C diff
• High mortality 25-35 % esp in elderly
• C diff can start mild and worsen if rx
delayed or antidiarrheals given
• Prompt dx and rx critical here
• Evidence –based rx lacking

31. Markers of Severe Infection
• WBC > 15000; fever ; dehydration
• Colonic thickening ,megacolon , ascites
• Confluent pseudomembranes
• Hemodynamic instability
• Severe abdominal distension, pain
• Elevated creatinine level
• Decreased mental status

32. Management of Fulminant Colitis
• Oral Vancomycin 500 qid or Fidaxomicin
200 mg bid ( Dificid)
• IV Metronidazole 500 q8h
• Vanco enema 500mg in 100 ml/saline
• Sub Total Colectomy for Perforation or
Megacolon
• IVIG not recommended
• Overall Mortality : 35 %
Shea Guideline: Inf Con Hosp Epi: May 2010

33. A 42 yo man had acute C diff
infection …
..that recurred twice and finally responded to a tapered pulsed regimen
of vanco followed by a two week course of S boulardii ( Florastor ).
Two weeks after cessation of therapy he had recurrence of diarrhea
and RLQ cramps with distention and gas. A C diff assay was negative
times two. His symptoms worsened and he was started on vanco
125 qid with improvement in his symptoms. After cessation of vanco
he again developed mild diarrhea 3-4 X daily , frequent passage of clear
mucus and tenesmus.
Colonoscopy and bxs are normal. Serum tTTG antibody was negative.
What would you recommend now ?
1. Stool assay for C diff
2. EGD and bx
3. UGI and SBFT
4. Rx for IBS

34. Post-infectious IBS
• IBS : 10% relate onset to infection
• GI Infection: 3-30% followed by
IBS
• Risk Factors :
– Females, age <60
– Severe infection, antibiotics
– Preexisting IBS

35. Mimics of recurrent C diff
• Post-infectious IBS
• Collagenous or microscopic colitis
• Celiac disease triggered by infection
• IBD flare with C diff infection

36. “The vanco doesn’t work anymore"
• 71 yo female with multiple bouts of C diff now
on Vanco 125 bid. Complains of 3-4 pasty
stools per day and feeling poorly. Stool test
pos for C diff toxins.
• Diarrhea while taking vanco is not due to
bacterial resistance- it doesn’t exist !
• Clinical resistance occurs in patients with
severe or fulminant disease

37. Control Of C diff in hospitals
1. Handwashing/vinyl gloves
2. Spores rest. to ethanol
3. Limit fluoroquinolone use
4. Isolate active patients
5. Role of PPIs not yet clear

38. Stool Transfer for Recurrent
C.difficile
• Rationale: Normal flora, especially
Bacteroides spp, inhibit C.difficile
• Stool donor: Healthy relative or family
member who is stool pathogen free
• Stool suspension via NJ tube,enema or
colonoscopy
• Success in open trials : cure in 144/159 pts
Am J Gastro 2000

39. Fecal Transfer via Nasojejunal Tube for Recurrent C difficile

40. Fidaxomicin vs Vanco for acute C diff
Louie et al, NEJM 2011.
noninferior

41. Fewer relapses with Fidaxomicin vs
Vanco may relate to persistence of
Bacteroides fragilis
9
8
feces
7
gram 6
per 5
CFU 4
log10 3
2
Mean 1
0
50 mg bid
100 mg bid
200 mg bid
125 mg qid
OPT-80
OPT-80
OPT-80
Vancomycin Day 0
Day 10

42. MABs to toxins A and B prevent
recurrence ( NEJM Jan 21, 2010 )

43. Vaccination for C. difficile

44. C difficile :Take Home Points
• Incidence, severity and relapse rising
• Host immune response critical
• Vanco >Flagyl for severe disease
• Make sure its C diff
• Role of Fidaxomycin still unclear ($$$)
• Stool transfer when all else fails
• Vaccine development promising