Clostridium difficile and Inflammatory Bowel Disease:
What are the risks?
David G. Binion, M.D.!Co-Director, Inflammatory Bowel Disease Center!
Director, Translational Inflammatory Bowel Disease Research!Division of Gastroenterology, Hepatology and Nutrition
UPMC Presbyterian Hospital Visiting Professor of Medicine
University of Pittsburgh School of Medicine Pittsburgh,PA!
I. Background – Gut microflora and intestinal immune health!
II. !Impact of C. difficile on IBD!
III. !Diagnostic considerations C. difficile!
IV. !Treatment considerations!
>100 trillion bacteria
1-2 kg of body weight
Up to 1 trillion/gm
1/3 of the dry weight of stool
2-4 million genes
10-20% culturable
Normal GI mucosa
Crohn’s disease
Surface area with external environment Largest immune organ in body
Physiologic inflammation
“You are only 10% human”
Destructive chronic inflammation
No “autoimmune target” identified in body
Oral tolerance
Impaired tolerance to enteric flora?
Stomach 0-102 Lactobacillus Candida Streptococcus Helicobacter pylori Peptostreptococcus
Colon 1011 Bacteroides Bifidobacterium Clostridium coccoides Clostridium lepium/fusobacterium
Distal Ileum 107-108 Clostridium Bacteroides sp Coliforms
Duodenum 102 Streptococcus Lactobacillus
Jejunum 102 Streptococcus Lactobacillus
Proximal Ileum 103 Streptococcus Lactobacillus
1930’s - Bacillus difficillis first described as part of the normal flora of neonates. Difficult to culture.
1974 - C. difficile recognized as complication of Clindamycin use.
1978 - C. difficile identified as the cause of antibiotic-associated pseudomembranous colitis in humans.
Clinical syndrome may range from watery diarrhea, abdominal pain, pseudo-membranous colitis, toxic megacolon, sepsis, colonic perforation and death
* Hall, I. and E. O'Toole. Am J Dis Child, 1935. 48: p. 390-402. ‡Tedesco, F.J et al. Ann Intern Med, 1974. 81(4): p. 429-33.
I. Clostridium difficile – the “difficult” bacteria
In the past: C. difficile linked to antibiotic use. Most cases treated successfully with metronidazole
Doubling of C. difficile associated disease between 1996 - 2003.
Diminished therapeutic response to metronidazole (50% failure rate with initial course of treatment).
* McDonald LC et al. Emerg Infect Dis 2006;12:409-415. ‡ Musher DM et al. Clin Infect Dis 2005;40:1586-1590.
C. difficile: Changing spectrum of clinical disease
700 C. difficile related deaths in Quebec, Canada in one year (2003-4)
400 C. difficile related deaths annually in Quebec at the present time
Regional outbreaks - Pittsburgh, PA, Quebec, Canada and the mid-Atlantic and southeastern U.S.
C. difficile in low risk populations – young individuals, peripartum women, community dwelling and in individuals with no exposure to antibiotics.
Muto, C.A., et al., Infect Control Hosp Epidemiol, 2005. 26(3): p. 273-80. McDonald, L.C., et al.,N Engl J Med, 2005. 353(23): p. 2433-41. 2005. MMWR Morb Mortal Wkly Rep, 2005. 54(47): p. 1201-5.
BI/NAP1 Epidemic strain C. difficile
PR AK
HI
Centers for Disease Control and Prevention. Data & Statistics about Clostridium difficile infections. www.cdc.gov/ncidod/dhqp/id_cdiff_data.html
DC
PR AK
HI
BI/NAP1 C. difficile in U.S. Nov. 2007 (n = 38)
BI/NAP1 C. difficile in U.S. Oct. 2008 IDSA Meetings
C. difficile Epidemic in U.S.
October 2008 – BI/NAP1 has been isolated in all 50 states (IDSA).
Total number of C. difficile cases annually in U.S. is >500,000.
Total number of C. difficile related deaths annually in the U.S. is >15,000.
Epidemic is predicted to worsen.
Cause?
Current burden of C. difficile in U.S.
Where does the majority of antibiotic use occur in the U.S.?
Poultry industry – antibiotic use to prevent diarrheal illness
Corn fed beef require antibiotics to prevent bacterial overgrowth
Antibiotic use in food animal industry
Colonization and carriage with the epidemic strain C. difficile (B1 NAP1 strain) reported in cows.
C. difficile has been isolated from retail ground meat purchased in Canada.
Songer, J.G. and M.A. Anderson, Clostridium difficile: an important pathogen of food animals. Anaerobe, 2006. 12(1): p. 1-4. Rodriguez-Palacios, A., et al., Clostridium difficile in retail ground meat, Canada. Emerg Infect Dis, 2007. 13(3): p. 485-7.
BI/NAP1 Epidemic strain C. difficile and food animals
Poutanen SM et al. CMAJ. July 6,2004;171(1).
C. difficile infectious inoculum is 10 spores
C. difficile spores may be resistant to cooking. Source of bacterial food poisoning?
1) Antibiotic destroys normal bacterial flora
3) Toxins inflame and ulcerate mucosa
2) C. difficile grows and secretes toxins
Colonic Mucosa
Normal flora C. difficile
Toxin
PMN
Gut Lumen
4) Damaged mucosa secretes fluid causing diarrhea
Antibiotic
Poutanen SM et al. CMAJ. July 6,2004;171(1).
C. difficile: Pathogenic mechanisms
Fluid secretion
Clostridium difficile
C. difficile and IBD present in identical fashion ranging from mild diarrhea to fulminant colitis.
Early studies performed 2 decades ago indicated little overlap between C. difficile and IBD, concluding “No need for routine screening for C. difficile in IBD population”.
Recent studies: Increasing incidence and severity of C. difficile in IBD population
C. difficile recently identified to have a significant negative impact on IBD morbidity.
Kochlar R et al. J Clin Gastroenterol 1993;16:26-30. Bolton RP et al. Lancet 1980;1:383-384 Trnka Y et al. Gastroenterology 1981;80:693-696.
Issa, M., et al. Clin Gastroenterol Hepatol, 2007. 5(3): p. 345-51. Rodemann, J.F., et al.Clin Gastroenterol Hepatol, 2007. 5(3): p. 339-44. Ananthakrishnan, et al. Gut, 2008. 57(2): p. 205-10.
Clostridium difficile and IBD
Increasing impact of C difficile on IBD
Rodemann JF et al. Clin Gastroenterol Hepatol. 2007;5: 339-44. Meyer AM et al. J Clin Gastroenterol. 2004;38(9): 772-5
Rodemann JF et al.
Increasing Impact of Clostridium difficile on IBD
P≤.01
0
10
20
30
40
50
1998 1999 2000 2001 2002 2003 2004 2005
Num
ber o
f Pat
ient
s
Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.
Increasing Proportion of Clostridium difficile Patients With IBD
P≤.01
Num
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f Pat
ient
s
0
50
100
150
200
250
300
350
2000 2001 2002 2003 2004 2005
Total C. diff patients
IBD patients with C. diff 4%
7%
16%
p=<0.01
Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.
Complications: Clostridium difficile Infected Patients With IBD*
36%
15%
Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.
Endoscopic appearance of C. diff in control patients
Endoscopic Appearance of C. difficile
Endoscopic appearance of C. diff in patients with IBD
Ulcerative Colitis Crohn’s Disease
Issa M, et al. Clin Gastroenterol Hepatol. 2007;5: 345-51. Bossuyt P, et al. J Crohns Colitis 2009;3:4-7.
91% Colonic IBD
61% Recent antibiotic exposure
Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.
IBD patients with C. difficile compared with IBD alone: Longer hospital stay Increased hospitalization costs Higher colectomy rates Increased mortality rate – 118 IBD C.diff deaths in NIS 2004 (>500 IBD C.diff deaths in U.S. 2004) UC C diff operative mortality 25%
0.5% IBD alone
3.7% C. difficile alone
4.2% IBD pts with C. difficile
Ananthakrishnan AN, et al. Gut, 2008. 57(2): p. 205-10.
Clostridium difficile in IBD: Morbidity and Mortality
0
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60
1998 2004 2007
Pro
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C d
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cile
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100
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Year
IBD
Crohn's
UC
All patients
Clostridium difficile in IBD: Increasing U.S. hospitalizations 2004 - 2007
Ananthakrishnan AN et al. Med Clin N Am. 2009.
Clostridium difficile and host immune status Increased asymptomatic carriage of C difficile in IBD
– 8% IgG immune response to toxin A seen in 50% of
patients. Immune response correlates with asymptomatic
carriage. Inability to mount immune response may result in
infection and chronic, relapsing clinical course.
Clayton EM et al. Am J Gastroenterol. 2009;104: 1162-9.
C. difficile in IBD: Asymptomatic carriage
Clostridium difficile and IBD treatment Patients with most severe colitis with worse
outcomes Maintenance immunosuppression correlated with
infection (purine analogs, methotrexate) No association of anti-TNF therapy with C difficile. Corticosteroids associated with 3 fold increase in
developing C difficile – inhibition of humoral immune response to toxin A?
Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51. Ben-Horin S. et al. Clin Gastroenterol Hepatol. 2009; 9: 981-7. Schneeweis S, et al. Aliment Pharmacol Ther. 2010; 30: 253-64.
C. difficile in IBD: Impact of immunosuppression
Clostridium difficile and IBD Patients with colitis are at increased risk Maintenance immunosuppression correlated with
infection (purine analogs, methotrexate) 10% of cases were new IBD presentations Contributes to flare in setting of new and
longstanding disease in remission Recommend multiple stool samples for ELISA toxin
A, B analysis. 54% of patients detected on first stool sample.
No prompt response to metronidazole, consider vancomycin p.o.
Issa M et al. Clin Gastroenterol Hepatol. 2007;5: 345-51.
Laboratory - Leukocytosis - Hypoalbuminemia Radiographic
Endoscopy - Pseudomembranes in 50% of patients with CDAD – rare in IBD patients.
Leukocytosis, hypoalbuminemia, pseudomembranes are markers of severity
III. Diagnostic considerations: C. difficile in IBD
Cell culture toxin assay (cytotoxicity) is the gold standard. Excellent sensitivity. Requires 24 – 48 hrs; labor intensive and expensive.
Performed in 15 hospitals in U.S. (total of 6,000 hospitals). ELISA for toxin A and/or B. More rapid , less expensive and requires less expertise.
Sensitivity varies from 79% to 97%. Performed in >90% of US hospitals at this time.
PCR analysis of stool samples. Sensitivity in IBD population?
Stool culture. Important for strain identification. Too slow for routine clinical use.
Diagnosis of Clostridium difficile
(A) Negative cell culture cytotoxicity assay. Human fibroblasts remain spindle-shaped and in contact with each other
(B) Positive cell culture cytotoxicity assay revealing cytopathic effects of C difficile toxin B causing cell rounding and separation. (Courtesy of Ray Hariri, PhD)
Issa M et al. Clin Gastro Hep. 2007 Mar;5(3):345-51.
Stool ELISA testing in IBD patients for C. Difficile toxins A and B
C. d
iffic
ile c
onfir
med
Stool ELISA sample
0 10 20 30 40 50 60 70 80 90
100
1st 2nd 3rd 4th
Positive C. difficile ELISA
4 stool samples to reach 90% detection with ELISA
C. difficile in ileo-anal Pouchitis
C. difficile in segments of diverted bowel
Chronic refractory pouchitis
Unresponsive to broad spectrum antibiotics
C. difficile developed while patients were on metronidazole therapy
19% of pouch patients with C. difficile
One case report of C. difficile in UC pt following subtotal colectomy with end-ileostomy.
Treated successfully with 10 day course of metronidazole suppositories.
Mann, S.D., et al. Dis Colon Rectum, 2003. 46(2): p. 267-70. Shen, B., et al. Dig Dis Sci, 2006. 51(12): p. 2361-4. Shen B, et. al. Clin Gastroenterol Hepatol 2008;6:782-8
Tsironi, E., et al. Dis Colon Rectum, 2006. 49(7): p. 1074-7.
Special IBD scenarios with C. difficile
Rare but associated with significant morbidity with mortality rates ranging from 60-83%
MCW institutional series of six patients (2004-2006). C. difficile manifested in high volume watery ileostomy output, ileus and fever with leukocytosis. No mortality with prompt diagnosis and therapy.
Miller, D.L et al. Arch Surg, 1989. 124(9): p. 1082. Jacobs, A., et al. review of the literature. Medicine (Baltimore), 2001. 80(2): p. 88-101. Hayetian, F.D., et al. Arch Surg, 2006. 141(1): p. 97-9. Lundeen et al. J Gastroentest Surg (2007) 11:138-142
C. difficile enteritis: An early complication in IBD patients following colectomy
IV. Therapeutic considerations: C. difficile in IBD
C. difficile isolation and contact precautions. Daily stool testing for C. difficile (until positive
sample). Possibility for in-hospital acquisition. Empiric oral vancomycin from day 1, alone or in
combination with metronidazole (IV or po). Maintain oral diet! Decrease corticosteroid dosing – steroids blunt
humoral immunity and IgG response to toxin A is necessary to resolve CDAD.
Approach for hospitalized IBD patients with Suspected/confirmed C. difficile
FDA-approved
Colonic levels
Effectivity Mild Severe
Promotion of VRE
Failure rate
Relapse rate
Side effects
Response(median time)
Cost Zar, F.A., et al.. Clin Infect Dis, 2007. 45(3): p. 302-7. Lucas GM et al. Clin Infect Dis. 1998 May ;26 (5):1127-339 Aslam et al. Lancet Infect Dis 2005;5:549-557. Wilcox, M.H. and R. Howe, J Antimicrob Chemother, 1995. 36(4): p. 673-9.
Oral vancomycin vs metronidazole for C. difficile
Only FDA approved drug for the treatment of C. difficile Tablets of vancomycin – shortages in past, high cost Patent for vancomycin tablets will expire at the end of 2010 Parenteral (intravenous formulation) vancomycin for oral use Decreased cost – involves hospital pharmacy formulation Palatability can be improved
mouthwash “chaser” Apple juice “chaser”
Parenteral vancomycin for enema formulation
Oral vancomycin for C. difficile
Decreasing colectomy rate among hospitalized IBD patients with C. difficile
0
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1999 2000 2001 2002 2003 2004 2005 2006
Num
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ases
Issa M et al. Clin Gastro Hep. 2007 Mar;5(3):345-51.
Number of infections and rate of hospitalization remained constant, but Significant decrease in colectomy rate. - High index of suspicion
- Use of oral vancomycin - Decreased corticosteroid dosing
Prophylaxis - Limit exposure to antibiotics - MacFarland et al. Probiotics (Saccharomyces boulardii,
Lactobacillus rhamnosus GG, and probiotic mixtures) effective for the prevention of CDAD (OR 0.59). Data was strongest with S. boulardii
- Environmental decontamination requires 10% sodium hypochlorite solutions.
- Alcohol based hand gels are in-effective against spore-forming organisms. Soap and water dislodges spores from skin.
McFarland, L.V. Am J Gastroenterol, 2006. 101(4): p. 812-22. Mayfield, J.L., et al. Clin Infect Dis, 2000. 31(4): p. 995-1000. Wilcox, M.H., et al.J Hosp Infect, 2003. 54(2): p. 109-14. Leischner, J., et al., American Society for Microbiology, 2005. ((abstract # LB 29)).
Preventive strategies - C. difficile
Refractory C. difficile: - Intravenous immunoglobulin was used in a series of 14 patients (200 mg/kg).
64% responded. One patient required 2nd dose. - Consideration for hypogammaglobulinemia associated IBD.
Recurrent C. difficile: - 59% of IBD patients (27 out of 46) had a recurrence.
Of the recurring patients, one-quarter required colectomy. C. difficile treatment regimens used: 1- Prolonged courses of vancomycin with or without pulse dosing (2 months)
2- Initial course of vancomycin followed by rifaximin maintenance course.
McPherson, S., et al. Dis Colon Rectum, 2006. 49(5): p. 640-5. Issa, M., et al. Am J Gastro, 2006. 101(9): p. S469. Johnson, S., et al. Clin Infect Dis, 2007. 44(6): p. 846-8.
Refractory and recurrent C. difficile - I
Stool transplantation: - Following vancomycin course, PEG colonic prep, blended and filtered donor stool is
introduced via nasal-duodenal tube or via colonoscopy.
Loop ileostomy – vancomycin flush (UPMC Protocol): - Loop ileostomy is created in severely ill patients facing colectomy and vancomycin is
perfused into the efferent limb.
Monoclonal antibodies against C. difficile toxin A and B: - 200 non-IBD patients randomized to receive either monoclonal antibody against CDA1
and CDA2 or placebo. Recurrence rates of C. difficile were 7% vs 25% (p<0.001).
C. difficile toxin vaccine: - Inactivated C difficile toxoids A and B were administered to 3 patients with recurrent
disease, with no relapse.
Aas J., et al.Clin Infect Dis, 2003. 36: p.580-585. Lowy I., et al. N Engl J Med, 2010. 362: 197-205. Sougioultzis S, et al. Gastroenterology 2005. 128; 764-70.
C. difficile Experimental Therapies
C. difficile has doubled in North American Medical Centers in the past 5 years.
IBD colitis patients have been affected at highest rate. C. difficile in IBD is associated with high rates of
hospitalization and colectomy and increased mortality. Antibiotic use may not be required to precipitate infection. Endoscopic and Histologic appearance is frequently not
classical – pseudomembranes not always present. Multiple stool ELISA samples for toxin analysis are
required to make a diagnosis.
Metronidazole failure rate is 50%; Oral vancomycin may be superior in hospitalized patients.
C. difficile enteritis may occur in post-colectomy patients and patients with ileoanal reconstruction.
C. difficile recurrence rates are high. Early surgical consultation for patients
developing severe disease (>10 BM/day, WBC>20K, severe abdominal pain, ileus).
Hand washing with soap and water is essential to prevent nosocomial transmission.
