1. C. Difficile: Accurate Testing & Diagnosing New Treatments on the Horizon
October 2, 2014
For the Georgia Hospital Association(GHA)/
Georgia Advanced Practice Program (GAPP)
Bruce Kalmin, M.D.
Board Certified Gastroenterologist

2. Clostridium difficile infection (CDI)
Objectives:
Participant will be able to identify most accurate C. difficile infection testing and diagnosing recommendations
Participant will become aware of new treatments for C. difficile on the horizon including Fecal Microbial Therapy

3. What’s so important about Clostridium difficile?
Annual hospitalizations in U.S. with CDI as a diagnosis (Agency for Healthcare Research & Quality)
1993: 85,700 hospitalizations
2010: 346,800 hospitalizations
Category
# Cases
Excess Costs
Deaths
Hospital-onset
165,000
$1.3B
9,000
Community-onset, HCF-associated
50,000
$0.3B
3,000
Nursing home-onset
263,000
$2.2B
16,500
Kelly & Lamont. N Engl J Med 2008;359: Bauer et al. Clin Microbiol 2009;15: Cohen et al. Infect Control Hosp Epidemiol 2010;31:

4. What’s so important about Clostridium difficile?
Clostridium difficile-related deaths
Figure. Yearly Clostridium difficile–related mortality rates per million population, United States, 1999–2004.
Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile–related mortality rates, United States, 1999–2004. Emerg Infect Dis [serial on the Internet] Sep [date cited].Available from:

5. What is Clostridium difficile?
C. difficile is a spore-forming, gram-positive anaerobic bacillus that produces two exotoxins: toxin A and toxin B
Common cause of antibiotic-associated diarrhea (AAD)
Accounts for 15-25% of all episodes of AAD

6. What is Clostridium difficile?
First identified in 1935 (Hall and O’Toole)
60-70% of newborns colonized (Bacillus difficilis)
Possible lack of toxin receptor -> no symptoms
C. difficile identified as pathogen in 1978
(Tedesco et al. and Bartlett et al.)
Causes pseudomembranous colitis in patients receiving clindamycin
Hall EC, E OT. Intestinal flora in new-born infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935; 49: 12.
Bolton RP, Tait SK, Dear PR, Losowsky MS. Asymptomatic neonatal colonisation by Clostridium difficile. Arch Dis Child 1984; 59: 466–472. 
Bartlett JG, Chang TW, Moon N, Onderdonk AB. Antibiotic-induced lethal enterocolitis in hamsters: studies with eleven agents and evidence to support the pathogenic role of toxin-producing Clostridia. Am J Vet Res 1978; 39: 1525–1530.
Tedesco FJ, Alpers DH. Editorial: pseudomembranous colitis. West J Med 1974; 121: 499–500.
Bartlett JG, Moon N, Chang TW, Taylor N, Onderdonk AB. Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 1978; 75: 778–782.

7. Pseudomembranous Colitis

8. Colonization vs. Infection
C. difficile colonization
Patient exhibits NO clinic symptoms
Patient tests positive for C. difficile organism and/or its toxin
More common than C. difficile infection
C. difficile infection
Patient exhibits clinical symptoms

9. Can Colonization be Protective?
Gerding at al. 2013
Two different strains of non-toxigenic C. difficile provided protection against both historic and epidemic (BI/NAP1/O27) strain
Can colonization be protective against CDI?
ViraPharma is conducting Phase I/II trials
Gerding at al. Non-toxigenic Clostridium difficile vs. BI/NAP1/O27. Antimicrobial Agents and Chemotherapy, October 2013.

10. Symptoms of CDI Watery diarrhea Fever Loss of appetite Nausea
Abdominal pain/tenderness

11. At-Risk Populations Patients with: Antibiotic exposure
Proton pump inhibitors
Gastrointestinal surgery/manipulation
Long length of stay in healthcare settings
Serious underlying illness
Immunocompromising conditions
Advanced age

12. Laboratory Testing Stool culture
Most sensitive but most often associated with false-positive results due to presence of non-toxigenic strains
False positivity can be overcome by testing isolates for toxin production
Labor intensive
Slow turn-around time (48-96 hours)

13. Laboratory Testing Molecular Tests FDA-approved PCR assays
Test for gene encoding toxin B
Highly sensitive and specific
Antigen detection (latex agglutination or immunochromatographic assay)
Rapid test (<1 hour)
Non-specific but used in combination with toxin detection, PCR, or toxigenic culture

14. Laboratory Testing Toxin testing Tissue culture cytotoxicity assay
Detects toxin B only
Costly
Slow turn-around time (24-48hrs)
Historical gold standard but replaced by PCR or toxigenic culture
Enzyme immunoassay
Detects toxin A, toxin B, or toxin A and B
Concerns over A-/B+ strains causing disease
Same-day assay
Relatively insensitive
Less than tissue culture cytotoxicity and much less than PCR or toxigenic culture

15. Laboratory Testing Important Note!!!
C. difficile toxin is VERY unstable
Degrades at room temperature
May be undetectable within 2 hours after collection of a stool specimen
Specimens can be kept refrigerated

16. When can you repeat PCR Testing for C. difficile?
PCR has high sensitivity (~90%) and specificity (~90%) with high negative predictive value
Summary of literature review (8 studies: )
PCR testing is reliable; no need to repeat when initial results are negative
If C. difficile is suspected (persistent symptoms) but initial negative test, repeat from days 8-14 or after day 10

17. When can you repeat PCR Testing for C. difficile?
If initial test was positive, may remain positive. May represent asymptomatic colonization or false positives due to PCR sensitivity. If retesting is done, wait for 7 days.
Most studies look at retesting after initial negative test and not if initial test was positive.
“Test of cure” is NOT recommended.

18. CDI Prevention Use antibiotics judiciously Contact Precautions
Private rooms or (if not available) cohorted with other patients with C. difficile infection
Gloves/Gowns
Wash hands with SOAP and WATER
Alcohol-based hand rubs are not as effective
Removal of C. difficile spores is challenging, even with soap and water

19. CDI Prevention Dedicate or clean any shared equipment
Use EPA-registered disinfectant with sporicidal claim or hypochlorite (bleach)
Standard EPA-registered hospital disinfectants are NOT effective against C. difficile spores
Continue precautions until diarrhea ceases
Most institutions will routinely continue isolation for either several days beyond symptom resolution or until discharge

20. The “New” C. difficile Strain
BI/NAP1/O27
Outbreaks
Pittsburgh (2000)
Atlanta (2001-2)
Montreal (2003)
More virulent
Increased production of toxins A and B
Additional toxin: binary toxin
Resistant to fluoroquinolones
Additional info: Read Bench-to-Bedside review: Clostridium difficile colitis at

21. The “New” C. difficile Strain
Detection
Any of the current tests will detect BI/NAP1/O27
None of them differentiate between the various strains of C. difficile
Treatment
Same as standard therapy
Controversial
Metronidazole first: prevents VRE
Vancomycin first: strain may be resistant to metronidazole

22. Stratified by Disease Severity
Management of CDI
Stratified by Disease Severity
CDI Severity
Treatment
Mild to moderate
Metronidazole
500 mg 3 times per day PO days
Severe
Vancomycin
125 mg 4 times per day PO days
Severe, complicated
500 mg 4 times per day PO or by nasogastric tube or enema plus Metronidazole 500 mg q8h IV
Cohen SH, et al. Clinical Practice Guidelines, IDSA & SHEA. ICHE 2010;31(5):

23. Management of CDI
Vancomycin is more effective than metronidazole in treating severe CDI1
Severe complicated CDI (refractory/fulminant)
Early surgical consultation2
WBC >20K, creatinine >1.5 baseline, lactate >5mmol/L
In addition to vancomycin po/enema & metronidazole IV, consider
Tigecycline IV?
IVIG 400 mg/kg?
Fidaxomicin?
Colectomy vs. loop ileostomy3
93% of colon can be preserved with intraoperative colonic lavage via ileostomy and post-op antegrade vancomycin installation via ileostomy
1 Zar et al. Clin Infect Dis 2007; 45:302-7
2 Lamontagne F, et al. Ann Surg 2007; 245: Pepin J, et al. Can Med J Assoc 2004; 171: Miller MA. Clin Infect Dis 2007;45:S122-S128.
3 Neal MD, et al. Ann Surg 2001;254:

24. Management of CDI Fidaxomicin vs. Vancomycin
No significant difference in initial response
88.2% fidaxomicin vs. 85.8% vancomycin (modified ITT)
92.1% fidaxomicin vs. 89.8% vancomycin (per protocol)
Fidaxomicin is superior in preventing recurrence
15.4% fidaxomicin vs. 25.3% vancomycin (modified ITT)
P=0.005
13.3% fidaxomicin vs. 24.0% vancomycin (per protocol)
P=0.004
Louie TJ, et al. New Engl J Med 2011; 364:

25. Management of CDI Fidaxomicin (Dificid) vs. Vancomycin
Fidaxomicin superior to vancomycin for preventing a first recurrence of CDI but not long-lasting
Group
Fidaxomicin
200mg BID x10d
Vancomycin
125mg QID x10d P=
N=128 66 62
Total Recurrences
19.7% (13/66)
35.5% (22/62)
0.045
Recurrences to 14 days post therapy
7.6% (5/66)
27.4% (17/62)
0.003
Recurrences days post therapy
13.1% (8/61)
11.1% (5/45) NS
Comely, OA et al. CID 2012;55 (Suppl 2);

26. Management of CDI Taper & pulsed dosing of oral vancomycin
125mg QID x10-14d
125mg BID x7d
125mg daily x7d
125mg every 2nd day x8d
125mg every 3rd day x15d
Recurrence rates were lower
Vancomycin ≤ 1g 54.2%
Vancomycin > 1g 54.3%
Vancomycin taper 31.0% (P=0.01)
Vancomycin pulsed 14.3% (P=0.02)
Metronidazole ≤ 1g 44.6%
Metronidazole > 1g 40.0%
Tedesco et al. Am J Gastroenterol 1985;80: McFarland et al. Am J Gastroenterol 2002;97:

27. Management of CDI Rifaximin “chaser” in recurrent CDI
Standard therapy (metronidazole 82% or vancomycin 18%) PLUS placebo vs. rifaximin 400mg po TID x20d
Standard therapy + placebo = 31% recurrence within 6 months
Standard therapy + rifaximin = 15% recurrence within 6 months
Recurrence = proportion not experiencing recurrent diarrhea
Garey, et al. J Antimicrob Chemother, 2011;66:

28. Management of CDI Summary Episode of CDI Treatment First recurrence
Treat as first episode according to disease severity
Fidaxomicin?
Second recurrence
Prolonged oral vancomycin (tapering and pulse-dosed)
Third recurrence
Rifaximin “chaser”
Fecal microbial transplant (FMT aka “stool transplant”)
IVIG?
Cohen SH, et al. IDSA & SHEA Guidelines, ICHE 2010;31(5): Surawicz, et al. ACG Guidelines. Am J Gastroenterol, Kelly & LaMont. “Uptodate” accessed Apr 24, 2013.

29. Fecal Microbial Therapy
Concept originated in China millennia ago
'Yellow soup' was made of fecal matter and water, which was drunk by the patient.
The first description of FMT was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill patients with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas, which resulted in a rapid return to health.
At the Centre for Digestive Diseases in Sydney, Australia, FMT has been offered as a treatment option for more than 20 years.
Eiseman B, et al. (1958). "Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis". Surgery 44 (5): 854–859.

30. Fecal Microbial Therapy
Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile infection
First infusion of donor feces resulted in 81.3% cure rate without relapse (N=16)
Vancomycin resulted in 30.2% cure rate without relapse (N=13)
Vancomycin with bowel lavage resulted in 25.1% cure rate without relapse (N=13)
Conclusion: The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin
van Nood et al. N Engl J Med, 2013;368(5):

31. Fecal Microbial Therapy
Multiple methods of administration
From below: ~75% by colonoscopy or retention enema
From above: ~25% by nasogastric tube or upper GI endoscopy
Reported efficacy: From below >90%, from above ~80%
Bakken et al. Clin Gastroenterol & Hepatol 2001;9: Hamilton et al. Am J Gastroenterol, 2012;107: Kelly CP, N Engl J Med 2013;368:474-5.

32. Fecal Microbial Therapy
The Future of FMT
Stool banking?
“Poop pill”?
Isolation of “protective” microbes
Bacteroidetes and Firmicutes
Treatment of other disorders
Ulcerative colitis?
Crohn’s disease?

33. Summary Test early with PCR Stop all non-C. difficile antibiotics ASAP
Give oral vancomycin as first line in severe disease
For recurrent disease, consider
Fidaxomicin?
Vancomycin taper/pulse?
Rifaximin “chaser”?
FMT?

34. Questions?