Changing Epidemiology and Prevention of Clostridium difficile

1
Changing Epidemiology and 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 DISCLAIMERIn
  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.
2006731987-1997 with permission.
5
Prerequisites for CDI
CDI

• Advanced age
• Underlying illness

• CDI due to recent (re)acquisition of C.
  difficile
• Incubation period unknown
• lt7 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.
200612(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,
19932005. 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/sb5
0.pdf
9
Yearly Clostridium difficilerelated Mortality by
Listing on Death Certificates, United States,
19992004.
Deaths per million population
From Redelings MD, et al. Emerg Infect Dis.
2007131417-1419.
10
Public Reporting in Ohio, 2006Relative
importance of long-term care setting

• Approximately 14,100 cases
• Hospital onset
• 5,000 initial cases 78 per 10,000patient-days
• 1,200 recurrent cases 12 per 10,000
  patient-days
• Long-term care facility onset
• 4,800 initial cases 23 per 10,000patient-days
• 3,100 recurrent 12 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.
200846497-504. 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.
IQRinterquartile range.Adapted from Warny M, et
al. Lancet. 20053661079-1084 with permission.
14
States with BI/NAP1/027 Strain ofC. difficile
(N38), 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.
200438640-645.
17
The Problem with Fluoroquinolonesis a Class
Effect
DDDdefined daily dose.Adapted from Biller P, et
al. Infect Control Hosp Epidemiol.
200728198-201.
18
Desperate Measures for Desperate Times
Restricting all Fluoroquinolones to End an
Outbreak
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 (n36,086)
CIconfidence interval IVintravenous ORodds
ratio.Dubberke ER, et al. Clin Infect Dis.
2007451543-1549.
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 459928
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
• Method Log10 CFU/mL 95CI
• 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 27479-483
26
Probably not
Boyce JM et al. Infect Control Hosp Epidemiol
2006 27479-483
27
Environmental control Effect of hypochlorite in
highly endemic ward
Mayfield JL. Clin Infect Dis 2000319951000
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 200829723-9.
30
Successful control of CDI through tiered
interventions
Muto CA et al. Clin Infect Dis 2007 45126673
31
Importance of controlling antimicrobial use
Muto CA et al. Clin Infect Dis 2007 45126673
32
Audit and feedback targeting broad-spectrum
antibiotics
Fowler et al. J Antimicrob Chemother
200759990-5.
33
Rationale to consider extending isolation beyond
duration of diarrhea
Bobulsky GS et al. Clin Infect Dis 2008
4644750
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. 2005541201-1205.
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
198635.e1-e6. Data from Ghai S, Ghai V, Sunderj
S. Obstet Gynecol. 2007109(2 Pt2)541-543 and
CDC. Morbid Mortal Wkly Rep. 2005541201-1205.
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 gt1 week post delivery
• 10 (18) relapsed

Rouphael NG, et al. Am J Obstet Gynecol. 2008
198635.e1-e6.
37
Recommendations for Surveillanceof Clostridium
difficile Infection
Admission
Discharge
lt 4 weeks
4-12 weeks
gt 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 28140-145
38
Clostridium difficile Infection (CDI) cases N
1046
Healthcare facilityonset Healthcare
facility-associated (HO-HCFA) N584
(56) (Including 142 with onset in another HCF)
Community Onset
N 462 (44)
Excluded
Community Onset Healthcare facility-associated (CO
-HCFA )
Community Associated (CA)
Unknown
Indeterminate
74 (7)
40 (4)
94 (9)
208 (20)
46 (4)
Excluded Prisoner 8 Out of
State20 Bone Marrow Transplant 17
Hemodialysis29
Adapted from Kutty PK, et al. Infect Control Hosp
Epidemiol. 200729197-202.
39
Community Onset CDI Relative to Previous
Discharge, North Carolina, 2005(N348)
//
//

184 (48) had a time lapse of more than one year
Adapted from Kutty PK, et al. Infect Control Hosp
Epidemiol. 200729197-202.
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 (N131)
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 for Strains 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 toxinpositive 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
Recognized PFGE Patterns AmongCA-CDI Isolates,
N92
Unnamed group is composed of 24 unique patterns
PFGEpulsed field gel electrophoresis.Limbago
BM, et al. Second International Clostridium
difficile Symposium, June 6-9, 2007 Maribor,
Slovenia.
44
Toxinotypes Represented AmongCA-CDI Isolates,
N92
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
200713485-7
Slide adapted from J. Glenn Songer
46
Epidemic Animal Strains Share Characteristics
with the Human Epidemic Strain
Keel K, et al. J Clin Microbiol.
2007451963-1964.
47
ToxV (BK/NAP7-8/078) StrainsHistorically Rare,
Recently More Common

• Tox V Isolates
• 10/6000
• 10/600
• 6/125

• Time
• Prior to 2001
• 2001-2005
• 2006

Jhung MA, et al. Second International Clostridium
difficile Symposium, June 6-9, 2007 Maribor,
Slovenia. Jhung MA et al. Emerg Infect Dis
2008141039-45
48
Human CDAD Caused by Strains Similar to Animal
Epidemic Strains, 20012006
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 CEs obtained through the CDC
  Training Continuing Education Online System
  will be maintained for each user.

51

• CME CDC is accredited by the Accreditation
  Council for Continuing Medical Education (ACCME)
  to provide continuing medical education for
  physicians. CDC designates this educational
  activity for a maximum of 1 Category 1 credit
  toward the AMA Physician's Recognition Award.
  Physicians should only claim credit commensurate
  with the extent of their participation in the
  activity.
• CNE This activity for 1.0 contact hours is
  provided by CDC, which is accredited as a
  provider of continuing education in nursing by
  the American Nurses Credentialing Center's
  Commission on Accreditations.
• CEU CDC has been reviewed and approved as an
  authorized provider by the International
  Association for Continuing Education and Training
  (IACET), 8405 Greensboro Drive, Suite 800,
  McLean, VA 22102. CDC has awarded 0.1 CEU to
  participants who successfully complete this
  program.
• CHEC CDC is a designated provider of continuing
  education contact hours (CECH) in health
  education by the National Commission for Health
  Education Credentialing, Inc. This program is a
  designated event for the CHES to receive 1
  Category I Contact Hour(s) in health education.
  CDC provider number GA0082.