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Changing Epidemiology and Prevention of Clostridium difficile

Changing Epidemiology and Prevention of Clostridium difficile. Carolyn Gould, MD, MS Division of Healthcare Quality Promotion Clinician Outreach and Communication Activity September 16, 2008

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Changing Epidemiology and Prevention of Clostridium difficile

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  1. Changing Epidemiologyand Prevention of Clostridium difficile Carolyn Gould, MD, MS Division of Healthcare Quality Promotion Clinician Outreach and Communication Activity September 16, 2008 The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention No Conflicts of Interest to Disclose

  2. Continuing Education Credits DISCLAIMER:In compliance with continuing education requirements, all presenters must disclose any financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters as well as any use of unlabeled product(s) or product(s) under investigational use. CDC, our planners, and the presenters for this seminar do not have financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. This presentation does not involve the unlabeled use of a product or product under investigational use.

  3. Clostridium difficile • Anaerobic spore-forming bacillus • Pseudomembranous colitis, toxic megacolon, sepsis, and death • Fecal-oral transmission through contaminated environment and hands of healthcare personnel • Antimicrobial exposure is major risk factor for disease Healthy colon Pseudo-membranous colitis

  4. Pathogenesis of C. difficile Infection (CDI) Ingestion Germination Proliferation Toxin Production Sunenshine RH, McDonald LC. Cleve Clin J Med. 2006;73:1987-1997; with permission.

  5. Antimicrobial therapy Disturbed colonic microflora Acquisition of toxigenic C. difficile Toxin A & Toxin B production Prerequisites for CDI CDI • Advanced age • Underlying illness • CDI due to recent (re)acquisition of C. difficile • Incubation period unknown • <7 days to several weeks? • Antimicrobial exposure may or may not precede acquisition • The two appear to be in proximity

  6. Changing Epidemiology of CDI • Increasing incidence and severity • Based on NNIS, national hospital discharge data, reports from healthcare systems, death certificate data • Recent outbreaks of severe disease caused by epidemic strain of C. difficile with increased virulence, antibiotic resistance • Although elderly are still most greatly affected, more disease reported in “low-risk” persons • Healthy persons in community, peripartum women

  7. National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed or Any Diagnosis Any listed Primary Discharges per 100,000 population Year From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15 and unpublished CDC data

  8. National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed or Any Diagnosis Any listed Primary Number of Discharges Year Elixhauser, A. (AHRQ), and Jhung, MA. (Centers for Disease Control and Prevention). Clostridium Difficile-Associated Disease in U.S. Hospitals, 1993–2005. HCUP Statistical Brief #50. April 2008. Agency for Healthcare Research and Quality, Rockville, MD. And unpublished data http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf

  9. Yearly Clostridium difficile–related Mortality by Listing on Death Certificates, United States, 1999–2004. Deaths per million population From Redelings MD, et al. Emerg Infect Dis. 2007;13:1417-1419.

  10. Public Reporting in Ohio, 2006Relative importance of long-term care setting • Approximately 14,100 cases • Hospital onset • ~5,000 initial cases; 7–8 per 10,000patient-days • ~1,200 recurrent cases; 1–2 per 10,000 patient-days • Long-term care facility onset • ~4,800 initial cases; 2–3 per 10,000patient-days • ~3,100 recurrent; 1–2 per 10,000 patient-days Ohio Department of Health. http://www.odh.ohio.gov/alerts/cdiff1.aspx

  11. Outcomes of CDIin Setting of Endemic Disease • Excess costs • $2,380 to $3,240 per index hospitalization • $3,797 to $7,179 inpatient costs over 180 days of follow-up • Other outcomes • 2.8 days attributable excess length of stay • 19.3% attributable readmission (180 days) • 5.7% attributable mortality (180 days) • More likely discharged to long-term care Dubberke ER, et al. Clin Infect Dis. 2008;46:497-504. Dubberke ER, et al. 17th Annual Meeting of The Society for Healthcare Epidemiology of America (SHEA), April 14-17, 2007; Baltimore, MD. Unpublished data.

  12. Current Epidemic Strain of C. difficile • BI/NAP1/027, toxinotype III • Historically uncommon, now epidemic • Current strain more resistant to fluoroquinolones • Carries extra toxin known as binary toxin • Polymorphism in toxins A and B regulatory gene (tcdC) and increased toxin productionin vitro

  13. Increased Toxin B Production In Vitro In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations. IQR=interquartile range.Adapted from Warny M, et al. Lancet. 2005;366:1079-1084; with permission.

  14. States with BI/NAP1/027 Strain ofC. difficile (N=38), November, 2007 DC HI PR AK

  15. Countries in Europe with BI/NAP1/027, November 2007

  16. CDI at an Atlanta VA Long-TermCare Facility From Gaynes R, et al. Clin Infect Dis. 2004;38:640-645.

  17. The Problem with Fluoroquinolonesis a Class Effect DDD=defined daily dose.Adapted from Biller P, et al. Infect Control Hosp Epidemiol. 2007;28:198-201.

  18. Desperate Measures for Desperate Times: Restricting all Fluoroquinolones to End an Outbreak Quinolone restriction New housekeeping company Quinolone restriction partially lifted Beginning of outbreak period Number of Cases 2004 2005 2006 2007 Month and Year Kallen, et al. 18th Annual Meeting of The Society for Healthcare Epidemiology of America (SHEA), April 6, 2008; Orlando, FL.

  19. Impact that Restricting Fluoroquinolones can Have on Reducing Unnecessary Antimicrobial Use 2500 Aminoglycosides Cephalosporins (1st gen.) Cephalosporins (2nd gen.) Cephalosporins (3rd and 4th gen.) Quinolones Vancomycin Piperacillin/Tazobactam Ampicillin/Sulbactam 2000 Azithromycin Carbapenems Aztreonam Clindamycin Quinolone Restriction Period 1500 Nimber of Defined Daily Doses 1000 500 0 Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar 2006 2007 2005 Month and Year Kallen, et al. 18th Annual Meeting of The Society for Healthcare Epidemiology of America (SHEA), April 6, 2008; Orlando, FL.

  20. Novel Risk Factors, Washington University Prevention Epicenter (n=36,086) CI=confidence interval; IV=intravenous; OR=odds ratio.Dubberke ER, et al. Clin Infect Dis. 2007;45:1543-1549.

  21. C. difficile-Associated Disease Pressure CDAD pressure =5 × days in unit CDAD pressure =1 × days in unit Unit B More patients with active CDI =higher risk of acquiring CDI Unit A Fewer patients with active CDI =lower risk of acquiring CDI

  22. How important are asymptomatic carriers in transmission? Riggs MM et al. Clin Infect Dis 2007; 45:992–8

  23. Recommendations for Hospitals • Hospitals should conduct surveillance for CDI • Track positive laboratory results • Consider measures to track outcomes • Early diagnosis and treatment important for reducing severe outcomes and reducing transmission • Strict infection control: CDC Fact Sheet* • Contact precautions for CDI patients • An environmental cleaning and disinfection strategy • Hand-washing with CDI patients in outbreak • Antimicrobial management *See CDC C. difficile Fact Sheets: http://www.cdc.gov/ncidod/dhqp/.

  24. Efficacy of Handwashing Methods for Removal of C. difficile on Hands of Experimentally Inoculated Volunteers Decrease in mean colony counts MethodLog10 CFU/mL95%CI Warm water & soap 1.76 1.47 – 2.05 Cold water & soap 1.76 1.29 – 2.23 Warm water & antibacterial soap 1.36 0.99 – 1.73 Antiseptic hand wipe 0.59 0.25 – 0.92 Alcohol hand rub -0.09 -0.58 – 0.41 Oughton MT, et al. 47th ICAAC Meeting, 2007

  25. Is alcohol gel contributing to increased CDI?... Boyce JM et al. Infect Control Hosp Epidemiol 2006; 27:479-483

  26. Probably not… Boyce JM et al. Infect Control Hosp Epidemiol 2006; 27:479-483

  27. Environmental control: Effect of hypochlorite in highly endemic ward Mayfield JL. Clin Infect Dis 2000;31:995–1000

  28. BIOQUELL RBDS Process • Hydrogen peroxide vapor (HPV) is injected into a sealed enclosure using a HPV generator • HPV is injected until a c.1micron film of H2O2, which is often invisible to the naked eye, is achieved • The perimeter of the enclosure is monitored using hand-held HPV sensors • At the end of the cycle, the HPV is catalytically converted to oxygen and water vapor by an aeration unit • Entire process complete in c. 4 hours Boyce et al. SHEA Annual Meeting, 2006, Chicago.

  29. Microbiologic Efficacy of HPV-RBD Process Before HPV-RBD After HPV-RBD # of Sponges # of Sponges (+) # of Sponges # of Sponges (+) Cultured for Cdiff Cultured for Cdiff 43 11 ( 25.6%) 37 0 Incidence of nosocomial CDI on 5 wards that underwent intensive hydrogen peroxide vapor decontamination Gray bars: pre-intervention period Black bars: intervention period Boyce et al. ICHE 2008;29:723-9.

  30. Successful control of CDI through tiered interventions Muto CA et al. Clin Infect Dis 2007; 45:1266–73

  31. Importance of controlling antimicrobial use Muto CA et al. Clin Infect Dis 2007; 45:1266–73

  32. Audit and feedback targeting broad-spectrum antibiotics Fowler et al. J Antimicrob Chemother 2007;59:990-5.

  33. Rationale to consider extending isolation beyond duration of diarrhea Bobulsky GS et al. Clin Infect Dis 2008; 46:447–50

  34. CDI in Previously Low-Risk Populations • 10 Pregnant women • 23 Generally healthy persons in the community • Cases without precedent antimicrobial use Centers for Disease Control and Prevention. MMWR Morbid Mortal Wkly Rep. 2005;54:1201-1205.

  35. Cases of SeverePregnancy-Associated CDI • 10 Cases* • Only three with prior hospitalization • One without antimicrobial exposure • Six prepartum, three of four postpartum cases within 1 week of delivery • Six required intensive care unit for toxic megacolon • Two with evidence of NAP1 • Five required colectomy • Three maternal deaths, three fetal losses Rouphael NG, et al. Am J Obstet Gynecol. 2008; 198:635.e1-e6. *Data from Ghai S, Ghai V, Sunderj S. Obstet Gynecol. 2007;109(2 Pt2):541-543; and CDC. Morbid Mortal Wkly Rep. 2005;54:1201-1205.

  36. Survey for Pregnancy-Associated CDI Emerging Infections Network of theInfectious Diseases Society of America • 419 ID clinician respondents, 2006 • 18 reported “seeing” 28 cases • 19 reporting “being aware of” 27 cases • 55 cases of pregnancy-associated CDI • 24 (43%) occurred prior to delivery • 16 (29%) occurred >1 week post delivery • 10 (18%) relapsed Rouphael NG, et al. Am J Obstet Gynecol. 2008; 198:635.e1-e6.

  37. Recommendations for Surveillanceof Clostridium difficile Infection Admission Discharge < 4 weeks 4-12 weeks > 12 weeks 48 h * HO-HCFA CO-HCFA Indeterminate CA-CDI Time HO: Hospital (Healthcare) onset CO-HA: Community Onset Healthcare-associated CA: Community Associated *Depending upon whether patient was discharged within previous 4 weeks, CO-HA vs. CA CDAD Surveillance Working Group. Infect Control Hosp Epidemiol 2007; 28:140-145

  38. Clostridium difficile Infection (CDI) cases N = 1046 Healthcare facility–onset Healthcare facility-associated (HO-HCFA) N=584 (56%) (Including 142 with onset in another HCF) Community Onset N= 462 (44%) Excluded** Community Onset Healthcare facility-associated (CO-HCFA) Unknown Community Associated (CA) Indeterminate 74 (7%) 94 (9%) 40 (4%) 46 (4%) 208 (20%) **Excluded: Prisoner: 8 Out of State:20 Bone Marrow Transplant: 17 Hemodialysis:29 Adapted from Kutty PK, et al. Infect Control Hosp Epidemiol. 2007;29:197-202.

  39. 30 25 20 No. of CDAD case-patients 15 10 5 0 0 1 2 3 4 5 6 7 8 9 24 32 33 34 35 36 37 45 46 47 48 49 50 51 52 38 39 43 44 16 17 18 19 20 21 22 23 25 26 27 28 29 30 31 40 41 42 10 11 12 13 14 15 Time (in weeks) Community Onset CDI Relative to Previous Discharge, North Carolina, 2005(N=348) // // * * 184 (48%) had a time lapse of more than one year Adapted from Kutty PK, et al. Infect Control Hosp Epidemiol. 2007;29:197-202.

  40. Estimated Incidence of Community-Associated CDI in North Carolina, 2005 • VA hospital catchments (males only) • 24 / 100,000 • Durham County • Overall 25 / 100,000 • Females 34 / 100,000 • Males 14 / 100,000 Kutty PK, et al. 44th Annual Meeting of the Infectious Diseases Society of America (IDSA), October 11-15, 2006; Toronto, Ontario, Canada.

  41. CA-CDI in North Carolina, 2005 Predisposing Factors (N=131) Kutty PK, et al. 44th Annual Meeting of the Infectious Diseases Society of America (IDSA), October 11-15, 2006; Toronto, Ontario, Canada.

  42. Enhanced Surveillance forStrains Causing CDI in Community • 10 FoodNet sites across the United States, collected over a 3-month period • C. difficile cultured from stool of patients who met community-associated criteria(CA-CDI) • C. difficile toxin–positive stool specimen collected as an outpatient or within 72 hours of admission • No hospitalization in the preceding 3 months • 92 isolates from nine states submitted to CDC for ID and typing Limbago BM, et al. Second International Clostridium difficile Symposium, June 6-9, 2007; Maribor, Slovenia.

  43. 3.3% 2.2% 4.3% Unnamed* NAP1-III 5.4% NAP4 5.4% NAP7 45.7%* NAP2 7.6% NAP3 NAP6 9.8% NAP1-IX NAP8 16.3% Recognized PFGE Patterns AmongCA-CDI Isolates, N=92 * Unnamed group is composed of 24 unique patterns PFGE=pulsed field gel electrophoresis.Limbago BM, et al. Second International Clostridium difficile Symposium, June 6-9, 2007; Maribor, Slovenia.

  44. 2% 2% 4% 1% 8% 1% 10% 52% 20% Toxinotypes Represented AmongCA-CDI Isolates, N=92 O III V VIII IX X XII XIV/XV Other Limbago BM, et al. Second International Clostridium difficile Symposium, June 6-9, 2007; Maribor, Slovenia.

  45. Potential for foodborne transmission to humans? • C. difficile is a recognized pathogen in neonatal piglets • Possible cause of enteritis in calves • Apparent increase or emergence around 2000 • Little evidence to support link to antimicrobial use • C. difficile has been isolated from retail meat products Rodriguez-Palacios et al. Emerg Infect Dis 2007;13:485-7 Slide adapted from J. Glenn Songer

  46. Epidemic Animal Strains Share Characteristics with the Human Epidemic Strain Keel K, et al. J Clin Microbiol. 2007;45:1963-1964.

  47. Tox V Isolates 10/6000 10/600 6/125 Time Prior to 2001 2001-2005 2006 ToxV (BK/NAP7-8/078) Strains;Historically Rare, Recently More Common Jhung MA, et al. Second International Clostridium difficile Symposium, June 6-9, 2007; Maribor, Slovenia. Jhung MA et al. Emerg Infect Dis 2008;14:1039-45

  48. Toxino type Binary toxin tcdC deletion Source + 39 bp Human V + 39 bp Human V + 39 bp Pig V + 39 bp Pig V + 39 bp Pig V + Human 39 bp V + Hosp Env 39 bp V + 39 bp Human V Human + V 39 bp + + Human 39 bp V Human + V 39 bp 39 bp Pig V + 39 bp + Pig 39 bp V + Pig 39 bp V Pig + V 39 bp + 39 bp Pig V Human CDAD Caused by Strains Similar to Animal Epidemic Strains, 2001–2006 Jhung MA, et al. Second International Clostridium difficile Symposium, June 6-9, 2007; Maribor, Slovenia.

  49. Summary • Rates, mortality, and costs associated withCDI continue to increase • Much of this increase may be due to emergence and spread of BI/NAP1/027 • Hospital rates can be controlled through tiered implementation of existing and enhanced recommendations • Disease becoming more notable in previously low-risk populations • Community-associated disease appears associated with variant toxinotypes • Circumstantial evidence for animal-to-human transmission of toxinotype V strains

  50. Continuing Education guidelines require that the attendance of all who participate in COCA Conference Calls be properly documented. ALL Continuing Education credits (CME, CNE, CEU and CHES) for COCA Conference Calls are issued online through the CDC Training & Continuing Education Online system http://www2a.cdc.gov/TCEOnline. Those who participate in the COCA Conference Calls and who wish to receive CE credit and will complete the online evaluation by July 31, 2008 will use the course code EC1265. Those who wish to receive CE credit and will complete the online evaluation between August 1, 2008 and July 1, 2009 will use course code WD1265. CE certificates can be printed immediately upon completion of your online evaluation. A cumulative transcript of all CDC/ATSDR CE’s obtained through the CDC Training & Continuing Education Online System will be maintained for each user.

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