1. Antibiotic Associated Diarrhea The new and improved C diff: an emerging ‘superbug’??
Neil Stollman MD, FACP, FACG
Associate Clinical Professor of Medicine
University of California San Francisco
East Bay Center for Digestive Health
Oakland California

2. Antibiotic-Associated Diarrhea (AAD)
Estimated that 10-20% of all hospitalized patients treated with antibiotics will develop diarrhea
Most frequently implicated antibiotics include penicillin, clindamycin, and cephalosporins
Only 15-20% of AAD is due to C. difficile
Prolonged use of antibiotics alters colonic flora, especially fecal anaerobes which normally metabolize malabsorbed carbohydrates and break down primary bile acids; this can result in osmotic (carbohydrate) or secretory (bile acid) diarrhea

3. Antibiotic Associated- Diarrhea
Diarrhea predominantly mild, 3-4 four loose stools per day
Usually relieved with fasting
Fever, pain, elev WBC usually mild or absent
Fecal leukocytes and C. difficile assays usually negative
Diarrhea usually subsides with discontinuation of antibiotics

4. Can we prevent AAD? 89 hosp pts receiving Abx randomized to:
Lactobacilli-enriched yogurt vs placebo
AAD= >2 liquid stools/24h
Yogurt Placebo
AAD % %
LOS 8 days days
C diff “fewer cases” (stat sig)
Beausoleil M et al. AJG 2004;99:S234 (abstract)

5. Prevention of AAD: Probiotics
Meta-analysis of 31 RCT
RR=0.43 ( ) for AAD
Two types effective for prevention:
Saccharomyces boulardii
Lactobacullus GG
Only S boulardii prevented confirmed C diff infections
McFarland LV. Am J Gastro 2006;101:

7. Clostridium Difficile
Anaerobic, gram-positive, spore-forming bacillus, termed “difficult clostridium” because of resistance to growth in conventional medium
1935: found in fecal flora of 50% of healthy infants
1978: identified as a cause of antibiotic associated diarrhea and pseudomembranous colitis
1980’s: leading cause of nosocomial diarrhea in US

8. C Difficile: Pathophysiology
Infection requires the alteration of the normal bacterial flora, usually by antibiotics
All antibiotic have been associated with C. diff. infection, but clindamycin, PCNs most commonly in past, now flouroquinolones
75% of strains of CD produce two protein cytotoxins, A and B, which bind to colonic brush border, causing mucosal PMN infiltration, colonic secretion and shedding and necrosis, resulting in colitis and diarrhea

11. C Difficile: Transmission
Transmission of C diff is fecal-oral
Spores can survive for days outside of the body and are resistant to common hospital disinfectants
50% of rooms of C diff (+) pts have culture-positive fomites (bedpans, toilets, scales, furniture)
Hospital personnel account for the great majority of person-to-person hospital transmission
Careful hand-washing and use of vinyl gloves demonstrated to reduce spread of infection; alcohol based foams inadequate.

12. C Difficile: Epidemiology
Found in normal colonic flora of 2-5% of healthy adults and up to 70% of neonates
Approximately 20-40% of patients hospitalized for more than 2 days become colonized with C diff
Only 1/3 develop symptoms
>3 million new cases of C diff diarrhea or colitis in US hospitals each year
<20,000 infections / year acquired outside of hospital

13. C Difficile: Risk Factors
Canadian cohort study
1187 hospital pts prescribed Abx for >3d
C diff diarrhea:
Medical wards: 10.9% (OR 4.1)
Surgical wards: 2.9%
> 3 Abx: 12.1% (OR 2.1)
1-2 Abx: 5.1%
Dial S. CMAJ 2004;171:33

14. Acid Suppression: New Risk Factor?
UK case:control studies (2)
1672 cases c diff matched to 10 controls
Incidence: 1/100,000 (1994) →22/100,000 (2004)
Adjusted Rate Ratios:
Current PPI use: ( )
Current H2RA use: 2.0 ( )
Current NSAID use: 1.3 ( )
Dial S et al. JAMA 2005;294:2989

15. C diff: New epidemiology?
CDC investigation in 4 states 2005
23 community-acquired c diff cases
10 peripartum cases
4 involved transmission to close contacts
No Abx exposure in 24%
“Certain features….close-contact transmission, young age, lack of Abx exposure….reflect changing epidemiology”
MMWR 2005;54:

16. Peripartum Cases? Survey by CDC of ID clinics of CDAD in pregnancy
10 ‘severe’ cases identified
9/10 had Abx use
6/10 pre-delivery, 3/10 w/in 1 wk delivery, 1/10 w/in 4 wks
WBC 11-72K
6/10 in ICU, 6/10 toxic megacolon, 5/10 required colectomy
3/10 stillborn infants
3/10 patient died
CDC: “Severe CDAD may be increasing in peripartum women”
Rouphael NG et al. AJOG 2008; 198:

17. C diff: Epidemics?
Epidemic of C diff with increased morbidity and mortality in Quebec recently
Epidemic strain: toxinotype III (BI/NAP1) carrying binary toxin gene cdtB (negative regulator toxins A/B)
67% of those with health-care-associated disease
37% of those with community-acquired disease
Median toxin A and toxin B concentrations were 16 and 23 times higher, than isolates representing 12 different non-epidemic types
Warny, M. Lancet 2005;366:1079

18. More data from Canada… 1703 patients in Quebec (2004)
Incidence: 22/1000 admissions
84% + for binary toxin and tcdC deletion
Attributable mortality: 6.9%
Urgent colectomy: 1.9%
Mortality >90 years: 14%
Quinolone use: 52%
Loo VG. NEJM 2005;353:2442.

19. And not to be left out…. 8 US facilities (2000-2004)
187 new isolates c/w 6000 control strains
New Cases Controls
Binary Toxin (III) % %
Quinolone Resistance 100% %
McDonald LC. NEJM 2005;353:2433

20. C difficile: Diagnosis
Cytotoxin Assay
Requires >48h, and tissue culture facility
Specificity >99%, Sensitivity only 85%
Detects only toxin B
Immunoassay for toxin A or A&B
Simple, cheap, available in 4 hours
Specificity >95%, Sensitivity 75%
Culture / toxin typing
Requires 96 hours and tissue culture facility
Specificity > 98%, Sensitivity > 90%
Required for outbreak typing / analysis

21. C Difficile: Endoscopy
Sigmoidoscopy/colonoscopy are not necessary for patients with classic symptoms and a positive assay
Indicated when a rapid diagnosis needed, and no stool available due to ileus, or to rule out other confounding diseases (i.e. ischemic colitis)
Pseudomembranes virtually diagnostic of CD colitis
Colonoscopy superior to sigmoidoscopy in detecting pseudomembranes (10% right sided only)
Invasive, increased risk perforation in toxic megacolon

22. Pseudomembranous Colitis

23. C Difficile: Clinical Manifestations
Asymptomatic carriage (60-65%)
Antibiotic-associate diarrhea (without colitis)
Antibiotic-associated colitis (without pseudomembranes)
Pseudomembranous colitis
Fulminant colitis / Toxic megacolon (2-3%)
Relapsing infection (15-20%)

24. C Difficile: Asymptomatic Carriers
2/3 of infected hospital patients remain asymptomatic
Can shed toxigenic organisms and act as reservoir for continued contamination
High levels of serum IgG Abs to Toxin A appear to be protective against development of diarrhea
Treatment of asymptomatic carriers is not recommended except during epidemic hospital outbreaks

25. Diarrhea/Colitis/Pseudomembranes
More serious with systemic manifestations
Profuse, watery diarrhea 5-15/day
Abdominal pain / nausea / malaise
Fever and leukocytosis common
Treatment clearly indicated
Fulminant: acidosis, dehydration, WBC 30K+
ICU, CT scan, hydration, surgery consult, ? Abx
Monitor for perforation, megacolon
Ultimate treatment: subtotal colectomy

26. C Difficile: Treatment
Supportive measures
Correct electrolytes
Hydration
Antiperistaltic agents (narcotics, Imodium) are acceptable for mild diarrhea, but are to be avoided in patients with evidence of active colitis (bloody diarrhea, fecal leukocytes, systemic toxicity) due to risk of toxic megacolon.
If patient responding to Rx, no need to retest stool

27. C Difficile Colitis: Treatment
Stopping Abx alone is effective in 15-25% (mild dz)
Vancomycin and metronidazole are primary Abx
Prior prospective (non-blinded) trials have shown no difference in efficacy b/w them (93-97%)
Oral metronidazole mg QID or TID for 7-10 days is preferred initial treatment ($)
IV metronidazole mg TID OK if NPO
Vancomycin (125 mg QID) ($$$) for those who fail metronidazole, or severe, life-threatening disease
Intravenous vancomycin does not achieve bactericidal levels in the gut and should not be used

28. Vanco >> Flagyl? DBRCT in 150 hospitalized patients
Flagyl 250 QID vs Vanco 125 QID x 10d
Cure rates Vanco Flagyl sig?
Mild dz: 98% 90% ns
Severe dz: 97% 76% 0.02
Recurrent dz: 7% 14% ns
Zar FA et al. Clin Infect Dis 2007;45:302

29. Relapsing C Difficile Diarrhea
Approximately 15-20% of 1o infections relapse
Diarrhea usually recurs within 5 days; similar presentation, usually not progressive
After 2nd relapse, >50% recur
? Reinfection or reactivation
? Impaired host Ig immune response
Antibiotic resistance against vancomycin and metronidazole has not been described

30. Relapsing C Difficile : Treatment
First Recurrence
Confirm diagnosis
Repeat day course with metronidazole or vanco
Second Recurrence: Vancomycin Pulse / Taper
125 qid for 7 days
125 bid for 7 days
125 qd for 7 days
125 qod for 7 days
125 tiw for 7 days
Consider adjunctive S Boulardii and/or cholestyramine
McFarland LV et al. Am J Gastro 2002;97:1769

31. Relapsing C difficile: Bile Binders
Cholestyramine and colestipol have the potential to bind C diff toxins
Lancet 1978: reduced toxin titers & exposure time in C diff pts treated with bile binders
Most often used to treat recurrent CD
No new studies published in the last 25 years
Vancomycin is bound by cholestyramine so doses must be given three hours apart

32. Relapsing C Difficile: Probiotics
Saccharomyces boulardii
Live, non-pathogenic yeast (Florastor®, 250mg)
Produces serine protease which digests toxins A and B and inhibits binding of toxin A to the colonic brush border (in animal models)
Prospective RCT: 60 patients with recurrent C diff
Saccharomyces 1 gm/d or placebo (plus Abx) X 4 wks
Recurrences: 35% vs 65%
Avoid in hospitalized, immunosuppressed; reports of fungemia
McFarland LV et al. JAMA 1994;271:1913

33. Relapsing C Difficile: Probiotics
The ‘ultimate’ probiotic would be reconstitution of all fecal flora (since we don’t know which of the >400 are critical)
Stool transplantation from “healthy donors”
Can administer via NG tube, enemas or instill at colonoscopy
Reasonable uncontrolled data supports
Anecdote alert: Stollman/Surawicz 19-for-20

34. Relapsing C Difficile: Rifaxamin
Rifaxamin – rifampin derivative, approved for traveler’s diarrhea prevention. Not systemically absorbed.
400 mg BID day x 2 weeks immediately after 2 week vanco course in multiple recurrence population.
“Chaser” Rx successful in 7/8 (1/8 with resistance)
Johnson S et al. Clin Infect Dis 2007;44:846

35. Relapsing C Difficile: IVIg
Failure to mount an immunoglobulin response to CD is associated with  risk of recurrent disease
50% of population has detectable serum anti-toxin, which neutralizes toxin
9 case reports in the literature (4 adults, 5 children) successfully cured of multiple bouts of recurrent CD by immunoglobulin infusions
Dose: 400 mg/kg repeated in 21 days with a vancomycin taper
Two case reports of success with Ig infusion for severe, acute, refractory CD colitis in adults
Gut 1997;41:366-70

36. Relapsing C Difficile: MAbs?
“Treatment with Monoclonal Antibodies against Clostridium difficile Toxins”
RDBPCT in 200 patients with symptomatic Clostridium difficile infection
Treatment with single infusion of two monoclonal antibodies against C. difficile toxins A and B or placebo, in addition to metronidazole or vancomycin
Outcome: lab documented recurrence within 3 months of infusion
Lowy, I et al. N Engl J Med 2010; 362:

37. Time to Recurrence of C difficile Infection
Recurrence rates 7% vs 25%
No diff in LOS or AEs
Figure 1. Time to Recurrence of Clostridium difficile Infection (CDI). The cumulative percentages of 32 patients with laboratory-documented recurrent CDI during the 84-day study period are shown for the two study groups: 7% in the antibody group and 25% in the placebo group. Five patients had a second episode of CDI recurrence: two in the antibody group and three in the placebo group. The P value was calculated by means of the log-rank test.
Lowy I et al. N Engl J Med 2010;362:

38. C Difficile: On the horizon…
Immune Support
Hyperimmune globulin (plasmapheresis of vaccinated donors)
HuMAbs, ? Utility for severe disease, ? prophylactically
Vaccines (in Phase II trials)
Therapeutics
Tinidazole (Tindamax, available for amba, giardia, trichomoniasis)
Nitazoxanide (Alinia, available for giardia, cryptosporidium)
Rifalazil (under investigation)
Tolevamer (binding resin, under investigation)

39. C Difficile: Summary The bug is changing:
 risk in non-traditional (community, peripartum) pts
Increased morbidity, mortality, and chronicity
Epidemic strains w/  toxin production emerging
Flouroquinolone use likely important
We need to change: Increased monitoring, better infection control (gloves, isolation, handwashing) and more antibiotic restraint