Clostridium Difficile : Epidemiology and Clinical Spectrum

1. Clostridium Difficile: Epidemiology and Clinical Spectrum Cassandra D Salgado, MD, MS Associate Professor of Medicine Hospital Epidemiologist, MUSC March 15, 2012

2. I have no Disclosures to report relevant to the content of this presentation. Cassandra D Salgado, MD, MS Associate Professor of Medicine Hospital Epidemiologist, MUSC March 15, 2012

3. Case Presentation • 50 year old female was admitted for COPD exacerbation. She was treated with steroids, inhalers, and antibiotics. • On hospital day 6 she develops fever of 102°F hypotension, diarrhea, and increased WBC count with profound bandemia (WBC= 48,000 with 30% bands). • Septic workup was done…

4. Case Presentation • Patient continued to decompensate with continued fevers and hypotension requiring vasopressors and transfer to MICU • Bowel movements ceased on hospital day 8 and patient was evaluated for toxic megacolon…

5. Case Presentation: X-ray Profoundly dilated bowel with wall thickening

6. Case Presentation • The patient was taken to surgery…

7. Case Presentation • Colectomy was performed • Patient died on hospital day 9: autopsy revealed severe disease and pseudomembranous colitis

8. Clostridium difficile (C. diff) • C. diff is a spore forming gram-positive anaerobic bacillus that produces at least two exotoxins (A and B) and a binary toxin • The ability to produce spores allows C. diff to be acquired from outside the host

9. C. difficile: Epidemiology • “difficult” to isolate in laboratory • 1978: cause of pseudomembranous colitis • Most commonly recognized microbial cause of hospital-acquired diarrhea • 3-5% of healthy adults are colonized • 20-40% of hospitalized patients are colonized • Asymptomatic carriers outnumber patients with disease by several fold Bartlett JG. NEJM 1978;298:531. Viscidi R. Gastroenterol 1981;81:5. McFarland LV. NEJM 1989;320:204.

10. Clostridium Difficile: Risk Factors • Exposure to antibiotics the preeminent risk factor for developing disease • More than 90% of healthcare-associated CDI occur while on antibiotics • Agents active against anaerobic organisms are considered to present the greatest risk (clindamycin) • Most cases are associated with β-lactam therapy • Growing number of reports of associations with fluoroquinolone therapy • Duration of antecedent therapy may be brief (surgical prophylaxis)

11. C. Diff and Antibiotic Use • Broad-spectrum agents with a greater effect on the normal intestinal flora have been associated with CDAD • Meta-analysis: 49 studies Bignardi GE. J Hops Infect 1998;40:1.

12. Clostridium Difficile: Risk Factors • Cancer with or without chemotherapy • GI surgery and other types of GI manipulation • Older age • Severity of illness • Immunocompromising conditions • Longer duration of stay in hospital • ICU stay • Exposure to an infected roommate • Anti-ulcer medications Bignardi GE. J Hops Infect 1998;40:1.

13. C. diff: Special Populations • Most cases of CDI occur in healthcare • Among hospitalized patients • Medical patients are at increased risk compared to surgical patients • C. diff is the most common cause of acute diarrheal illness in LTCF • Population is older, receive more medications known to increase risk of C. diff • Neonates may also be colonized with C. diff • Up to 70% • Neonates colonized with toxogenic strains less likely than adults to develop symptomatic disease • Neonates may lack receptors for toxin A in their immature enterocytes Sunenshine R. Clev Clinic J Med 2006;73:187.

14. Clostridium difficile: Clinical Disease C. Diff exposure (fecal-oral) and colonization Antibiotic therapy Disruption of colonic microflora Release of toxin A (enterotoxin) and toxin B (cytotoxin) Mucosal injury and inflammation… Can cause diarrhea, severe GI disease, and sometimes death

15. Clostridium difficile: Clinical Disease • Watery diarrhea (10-15 times per day) • Lower abdominal cramping • Low grade fever • Leukocytosis (WBC>15,000) • Symptoms generally occur during antibiotic therapy • Sometimes 5-10 days after completion • Rarely weeks after completion • Physical exam: abdominal tenderness

16. CDI vs. AAD

17. C. diff: Clinical DiseaseEffect of Toxin

18. C. diff: Clinical Disease • Pseudomembranous colitis: toxin induced shallow ulcerations which release proteins, mucus, and inflammatory cells • Type 1- mildest changes confined to superficial layers • Type 2- more severe with marked secretions • Type 3- intense necrosis and full intestinal thickness involvement produces a confluent membrane

19. C. diff: Clinical Disease • Fulminant colitis (rare) • Severe abdominal pain, abdominal distention, diarrhea, fever, hypovolemia, lactic acidosis. Marked leukocytosis (WBC>40,000) • Toxic Megacolon (rare) • Severe abdominal pain, abdominal distention, scant to no diarrhea, fever, shock, marked leokocytosis

20. Clostridium difficile: Clinical Disease • X-ray: distended bowel and colonic wall thickening • CT scan: colonic wall thickening and/or pericolonic stranding

24. Clostridium Difficile: At What Cost? • Estimated 3,000,000 new cases of C. diff diarrhea and colitis in US hospitals annually • Affects as many as 10% of patients hospitalized for more than 2 days • Relapsing disease occurs in 20-25% of adequately treated patients • Further relapses occur in 65% of patients who have suffered more than one relapse

25. Clostridium Difficile: At What Cost? *Australian dollars

26. Clostridium Difficile • Spore forming toxin producing bacillus responsible for most nosocomial diarrhea. Risks for CDI include antibiotic exposure, other drugs, older age, and co-morbidities. CDI has been associated with notable morbidity, but traditionally low rates of severe disease and mortality.

27. C. diff: New Epidemiologic Issues • C. diff rates are increasing • More severe disease with higher mortality and higher rates of colectomy • A common epidemic strain has been found in North America and Europe • Fluoroquinolone use may be driving its emergence

28. CDI is Increasing • Average rate of CDI among NNIS hospitals from 1987-1998 • 12.2 cases per 10,000 pt-days • Teaching hospitals: 13.0 per 10,000 pt days • Non-teaching hospitals: 11.4 per 10,000 pt days • CDC reports that hospitalizations with a discharge diagnosis of CDI • Was 31 per 100,000 in 1996 • Was 61 per 100,000 in 2003 www.CDC.gov

29. CDI is Increasing

30. CDI is Increasing

31. C. diff-Associated Infection Recent data: Incidence of healthcare-associated C. diff colonization and infection are 29.5 and 28.1 cases per 10,000 pt days, respectively. Incidence of CDI per 10,000 patient days NNIS 1987-2001 Archibald et al JID 2004;189:1585

32. C. diff: Increased Morbidity and Mortality • A hospital in Pittsburgh reports 253 nosocomial CDI cases in 2 years with an increase from 2.7 to 6.8 cases per 1,000 discharges (p<0.001)1 • 26 (10%) colectomies • 18 (7%) mortality • A Chicago hospital reports increased severity of CDI and increased mortality in MICU and oncology patients2 • high rates of shock • 37% mortality 1Muto et al. ICHE 2005;26:273., 2Patel et al. 2005 SHEA Annual Meeting #285.

33. C. diff: Increased Morbidity and Mortality • Prospective study of 1719 CDI episodes in 12 Quebec hospitals • Determine incidence of CDI and complications • 22.5 per 1,000 admissions • Incidence increased with age • 30-day attributable mortality was 6.9% • Attributable mortality increased with age • 110 (6.5%) required ICU care • 33 (1.9%) required colectomies Loo VG et al. NEJM 2005;353(23):2442.

34. C. diff: Pathogenicity • In general, C. diff strains either possess the entire genetic element (PaLoc) responsible for producing toxin (toxigenic strains) or lack this genetic element and thus, do not cause disease (non-toxigenic strains)

35. C. diff: Pathogenicity • Mutation(s) in the tcd C gene can cause the C. diff strain to produce increased amounts of toxin causing more severe disease. • 16 x more toxin A and 23 x more toxin B • A binary toxin may also contribute, but clinical significance is not yet known. • This “epidemic strain” is PCR ribotype 027, PFGE type NAP1, and restriction endonuclease type B1.

36. States with BI/NAP1/027 strain of C. difficile Recent data: among patients colonized or infected with C. diff, 36% and 63% have the NAP1 strain, respectively DC HI PR AK

37. CDI: Risk Factors • Pittsburgh hospital outbreak (MVA) *Levofloxacin use significantly increased over the preceding months leading up to the outbreak Muto et al. ICHE 2005;26:273.

38. CDI: Risk Factors • Quebec hospitals Outbreak • Fluoroquinolone receipt OR 3.9 (2.3-6.6) • All fluoroquinolones studies were independently associated with CDI • Cephalosporin receipt OR 3.8 (2.2-6.6) • All cephalosporins studies were independently associated with CDI • PPI, H2 blockers, or chemotherapy were not significantly associated with CDI • All isolates with tcdC gene mutations also had the binary toxin gene • Severe CDI was observed in 22 of 132 patients with both genetic elements • Severe CDI was not observed in any pt that did not have these genetic elements (p=0.03) Loo VG et al. NEJM 2005;353(23):2442.

39. CDI: An Antibiotic-Resistance Issue? • Pittsburgh hospital outbreak • No isolates R to metronidazole or vancomycin • 85.7% R to clindamycin • Clindamycin was a significant risk • 94.5% R to levofloxacin • Levofloxacin was a significant risk • Quebec hospitals Outbreak • No isolates R to metronidazole, vancomycin or clindamycin • Clindamycin was not a significant risk • 100% of predominate type isolates R to ciprofloxacin, moxifloxacin, gatifloxacin, and levofloxacin • All FQ were associated with increased risk Muto et al. ICHE 2005;26:273., Loo VG et al. NEJM 2005;353(23):2442.

40. CDI and Fluoroquinolones • Characterization of 187 C. diff isolates from 8 healthcare facilities from 2001-2003 and comparison to historic isolates • An epidemic strain was identified and was responsible for 50% or more of the isolates from most facilities (binary toxin and tcdC deletions in all) • This epidemic strain was in existence since 1984 • Compared to similar historic strains where no R to FQ was detected, all recent strains were R to gatifloxacin and moxifloxacin • Conclusion: A previously uncommon strain of C. diff with variation in toxin genes has become more R to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of CDI McDonald LC et al. NEJM 2005;353(23):2433.

41. C. diff: Community Setting • 31 yo woman 14 weeks pregnant with twins developed 3 weeks of intermittent diarrhea- stool specimens positive for C. diff • Only ABX exposure was TMP-SXT 3 mo prior • Treated but ultimately developed severe disease hospitalized for 18 days • Had recurrent disease 4 days after discharge, spontaneously aborted her fetuses, developed sepsis and died • CDC and Philadelphia Department of Public Health launched investigation

42. C. diff: Community Setting • 33 cases of CA-CDI were reported from NH, PA, NJ, OH, all but 1 occurring in 2004-2005 • 15 (46%) required hospitalization or an ED visit • 13 (39%) had a relapse requiring treatment • 8 (24%) reported no ABX exposure in prior 3 months • 3 of these cases had exposure to patient with “diarrheal illness” (2 confirmed C. diff) • Of those who had received ABX (25 patients) • 3 had received <3 doses, 2 had received only 1 dose • 10 reported exposure to clindamycin • 10 among peripartum women • Transmission to close contacts evident for 4 patients • 23 among non-peripartum individuals • Ages 6 mo to 72 years (mean 26 years)

43. C. diff: Community Setting • The estimated minimum annual incidence of CA-CDI in Philadelphia and its surrounding four counties • 7.6 per 100,000 population • One case for every 5,549 outpatient ABX prescriptions • Twice as high as the <1 case per 10,000 cited in earlier studies

44. C. diff: Community Setting • Conclusions • These cases of severe CDI among individuals previously thought to be at low risk might reflect changing epidemiology • Certain features of CDI that have been uncommon in the past might be changing • Close-contact transmission • High recurrence rate • Younger age patients • Lack of ABX exposure • Because reporting was voluntary, the true incidence of CDI is likely higher

45. Clostridium Difficile • Emerging issues related to CDI include an increase in overall disease incidence associated with an epidemic strain that contains a mutation for increased toxin production and thus more severe disease with higher risk of death. This strain has an increased rate of resistance to certain antimicrobials, particularly fluoroquinolones, which may be driving the rates. Additionally, the epidemiology of CDI in the community, previously thought to be low risk, may be changing.

46. CDI: Treatment • Stop the inciting antibiotic • Up to 25% will recover without further therapy • Metronidazole vs. Vancomycin • Several older retrospective studies comparing oral metronidazole to oral vancomycin • Metronidazole just as effective • Response rates >95% • Less expensive ($2 day vs. $70 day) • Less risk for VRE emergence and spread • A recent prospective observational study • Response rate to metronidazole was only 78% • Due to recent emergence of newer strain?

47. CDI: Treatment • Metronidazole vs. Vancomycin • Both drugs have good in vitro activity • Median MICs <1.0 • Both drugs promote VRE overgrowth in the stool during treatment • Relapse rates after treatment are about the same for both drugs • Controversy regarding gut levels of metronidazole • Only present with active disease? Wafa N. AAC 2008;52(7):2403-2406.

48. CDI: Treatment • Metronidazole vs. Vancomycin Zar FA. CID 2007;45:302-307.

49. CDI: Treatment • Metronidazole vs. Vancomycin Louie T. ICAAC 2007. Abstract K-4259.

50. CDI: Treatment • Metronidazole vs. Vancomycin Lahue B. ECCMID 2007. Abstract 1732.