1. Clostridium difficile: An overview
CDI Webinar
July 11, 2017
PUBLIC HEALTH DIVISION Acute and Communicable Disease Prevention Section

2. Outline Background Diagnostic testing Treatment Prevention
Microbiology
Burden
Pathogenesis
Diagnostic testing
Treatment
Prevention
Antimicrobial stewardship
Practical approach to CDI prevention
How is your facility dealing with CDI?

3. Background: Microbiology, Burden, Pathogenesis

4. C. difficile: Microbiology
Gram-positive spore-forming obligate anaerobic rod-shaped bacterium
1935: part of flora of healthy infants; Bacillus difficilis
1-3% of heatlhy adults
70% of children < 12 months
1970s: C. difficile  CDAD (CDI preferred)
Toxins-producing strains cause C. difficile infection (CDI)
Smits Nat Rev Dis Primers Apr 7; 2: doi: /nrdp

5. Time line for surveillance definitions of CDI
Admission
Discharge
< 4 weeks
2 d
4-12 weeks
> 12 weeks HO
CO-HCFA
Indeterminate
CA-CDI *
Day 1
Day 4
Time
HO: Hospital (Healthcare)-Onset
CO-HCFA: Community-Onset , Healthcare Facility-Associated
CA: Community-Associated
* Depending upon whether patient was discharged within previous 12 weeks
Onset defined in NHSN by specimen collection date

6. C. difficile: Impact 453,000 CDI cases1 29,000 deaths
293,000 healthcare-associated
107,000 hospital-onset
104,000 nursing home-onset
81,000 community-onset, healthcare-facility associated
160,000 community-associated
82% associated with outpatient healthcare exposure
Overall, 94% of CDI cases related to healthcare
29,000 deaths
$4.8 billion in excess healthcare costs2
Estimated U.S. Burden of CDI, According to the Location of Stool Collection and Inpatient Health Care Exposure, 2011.
CO-HCA: Community onset healthcare-associated
NHO: Nursing home onset
HO: Hospital onset
Lessa et al. N Engl J Med 2015; 372(9):
Dubberke et al. Clin Infect Dis 2012; 55:S88-92.

7. C. difficile: Impact
C. difficile most commonly reported pathogen in 2011 multistate prevalence survey of healthcare-associated infections (HAI)1
12.1% of 452 HAIs caused by CDI
Rates of CDI per 1,000 discharges have risen through 20132
Magill et al. N Engl J Med 2014; 370:
Steiner et al. HCUP Projections Report

8. Oregon C. difficile standardized infection ratios (SIR): 2012-2015

9. C. difficile : Transmission
Fecal-oral route
Contaminated hands of healthcare workers
Contaminated environmental surfaces.
Reservoir
Human: colonized or infected persons
Contaminated environment
C. difficile spores can survive for up to 5 months on environmental surfaces.

10. CDI: Pathogenesis Step 1- Ingestion of spores transmitted
from reservoirs
Step 2- Germination into growing (vegetative) form
Step 4 - Toxin B & A production leads to colon damage +/- pseudomembrane
Step 3 - Altered lower intestine flora (due to antimicrobial use) allows proliferation of C. difficile in colon

11. CDI Pathogenesis Colonized no symptoms Antimicrobials
C Diff exposure & acquisition
Admitted to healthcare facility
Infected
Symptomatic

12. CDI: Host risk factors Underlying illness and medical history
Advanced age
Incidence higher among females, whites, and persons > 65 years1
Death more common in persons > 65 years (5x greater risk)2
Underlying illness and medical history
79% of 7421 patients with CDI had a comorbid condition2
38% of 585 patients with NAP1 strain had ED visit in previous 12 weeks2
Tube feeds3
Immunosuppression
Inflammatory bowel disease2
Immune-suppressive treatment2
Hematological malignancy/stem cell transplant (15-25x greater risk)4
1. Lessa et al. N Engl J Med 2015; 372(9):
2. See et al. Clin Infect Dis 2014; 58(10):
3. Bliss et al. Ann Intern Med 1998; 129:
4. Kombuj et al. Infect Control Hosp Epidemiol 2016; 37:8-15.

13. CDI: Modifiable risk factors
Exposure to antibiotics High Risk:
Fluoroquinolones 1
3rd and 4th generation cephalosporins, clindamycin, carbapenems2
Exposure to C. difficile spores
Spores can remain viable for months3
Contamination is increased in rooms of patients with active CDI 4,5
Hands of patients and personnel are easily contaminated5
Gastric acid suppression
Data, though inconsistent, implicate proton pump inhibitor (PPI) use1,4,6,7
More study is needed to link restriction of PPI use with decreased CDI incidence8
1. Pepin. Clin Infect Dis 2005; 2. Hensgens. J Antimicrob Chemother 2012; 3. Weber. Infect Control Hosp Epidemiol 2011; 4. Dubberke. Am J Infect Control 2007.
5. Shaugnessy. Infect Control Hosp Epidemiol 2011; 6. Linney. Can J Hosp Pharm 2010; 7. Buendgens. J Crit Care 2014; 8. Dubberke. Infect Control Hosp Epidemiol 2014.

14. Clinical manifestations
Illness caused by toxin-producing strains of C. difficile ranges from
Asymptomatic carriers = Colonized
Mild or moderate diarrhea
Pseudo membranous colitis that can be fatal
A median time between exposure to onset of CDI symptoms is of 2–3 days
Risk of developing CDI after exposure ranges between days to 10 weeks

15. CDI: Symptoms
Watery diarrhea ( > 3 unformed stools in 24 or fewer consecutive hours)
Loss of appetite
Fever
Nausea
Abdominal pain and cramping

16. Epidemiology: Epidemic Strain
BI/NAP1/027, toxinotype III
First emerged in 2000 (Eastern Canada)1
Associated with healthcare2
More resistant to fluoroquinolones3
Greater virulence
Associated with more severe disease and mortality4
Increased toxin A and B production4,5
Polymorphisms in binding domain of toxin B5
Oregon: 16% (11 of 68) strains with PFGE performed
1. McDonald et al. N Engl J Med 2005; 353(23):
2. See et al. Clin Infect Dis 2014; 58(10):
3. Pepin et al. Clin Infect Dis 2005; 41(9):1254–1260.
4. Stabler et al. J Med Micro 2008; 57(6):
5. Warny et al. Lancet 2005; 366(9491):

17. Diagnostic testing

18. Best Strategy for C. difficile Testing
Testing should be performed only on diarrheal stool
Testing asymptomatic patients is not indicated
Testing for cure is not recommended
2. Dubberke et al. Infect Control Hosp Epidemiol 2014; 35 (6):

19. Diagnostic tests for toxigenic C. difficile
Tests by Type & Method
Target(s)
Characteristics
Gold standards
Toxigenic culture
Toxigenic C. difficile
Reference standard
Difficult to perform
Time consuming (24-48 h)
Cell cytotoxic assay
Toxins A or B
Highly sensitive for toxin vs. EIA
Rapid diagnostic tests
EIA
Glutamate dehydrogenase
NAAT
RT-PCR
tcdB or tcdC genes
LAMP
tcdA or tcdB genes
References

20. Diagnostic tests for toxigenic C. difficile
Tests by Type & Method
Target(s)
Characteristics
Gold standards
Toxigenic culture
Toxigenic C. difficile
Cell cytotoxic assay
Toxins A or B
Rapid diagnostic tests
EIA
Glutamate dehydrogenase
Must be paired with a test of toxin
Variable sensitivity & specificity
NAAT
More expensive than EIA
Highly sensitive & specific for toxigenic C. difficile
May increase detection of colonization
RT-PCR
tcdB or tcdC genes
tcdA-negative/tcdB-positive strains can cause disease
LAMP
tcdA or tcdB genes
tcdA-positive/tcdB-negative strains not well described in human disease
Caution required in interpreting negative results based on tcdA testing alone by LAMP
References

21. Guidance from the American Society for Microbiology
Toxin A/B enzyme immunoassays have low sensitivity and should not be used as stand alone tests.1
Highly sensitive screening tests like glutamate dehydrogenase antigen assays (GDH) should have positive results confirmed.
Nucleic acid amplification that detects C. difficile toxin genes may be used as a stand alone test.
1. Am Soc Microbiol, 2010.

22. Sample multistep algorithm for rapid diagnosis of C
Sample multistep algorithm for rapid diagnosis of C. difficile infection
JAMA. 2015;313(4): doi: /jama

23. Studies examining performance characteristics of multistep algorithms for rapid diagnosis of C. difficile infection  NAAT-containing algorithms perform better
Bagdasarian JAMA. 2015;313(4) doi: /jama

24. Treatment

25. Treatment options for CDI
Smits Nat Rev Dis Primers Apr 7; 2: doi: /nrdp

26. Fecal microbiota transplant

27. Prevention

28. Overview
Basic practices are prevention measures that should be in place at all times.
Facilities should consider adopting some or all of the special approaches whenever ongoing opportunities for improvement are identified or as indicated by risk assessment.
Basic Practices
Special Approaches
Appropriate use of antimicrobials
Antimicrobial stewardship program
Hand hygiene per CDC/WHO recommendations
Measure healthcare personnel adherence
Hand hygiene with soap and water after glove removal following care of CDI patients
Intensify measurement of adherence
Contact Precautions for CDI patients
Presumptive Contact Precautions while laboratory results are pending
Prolonged duration of Contact Precautions
Cleaning and disinfection of equipment and environment
Use of EPA-approved sporicidal disinfectant
Assess adequacy of room cleaning
Laboratory-based alert system for immediate notification to IP and clinical personnel of newly diagnosed CDI patients
CDI surveillance, analysis, and reporting
Educate healthcare personnel, patients, and families
Dubberke et al. Infect Control Hosp Epidemiol 2014; 35(6):

29. Antimicrobial Stewardship
Exposure to any antimicrobial is the single most important risk factor for C. difficile infection (CDI).
Antibiotic exposure has lasting impact on the microbiome.
Risk of CDI is elevated (7-10 fold) during and in the 3 months following antimicrobial therapy1,2
85-90% of CDI occurs within 30 days of antimicrobial exposure1
Target high risk antibiotics for CDI prevention
Fluoroquinolones3
3rd/4th generation cephalosporins, carbapenems2
Chang et al. Infect Control Hosp Epidemiol 2007; 28(8):926–931.
Hsu et al. Am J Gastroenterol 2010; 105(11):2327–2339.
Hensgens et al. J Antimicrob Chemother 2012; 67(3):

30. The national goal is 100% of hospitals by 2020.
Currently 39% (1,642/4,184) of U.S. hospitals have an antibiotic stewardship program with all 7 core elements.
The national goal is 100% of hospitals by 2020.

31. Seven Core Elements of Antimicrobial Stewardship
1. Leadership Commitment
Dedicating necessary human, financial, technological resources
2. Accountability
Appointing a single leader (physician or pharmacist) responsible for program outcomes
3. Drug Expertise
A single dedicated pharmacist with responsibility to improve antibiotic use
4. Tracking
Monitoring antibiotic prescribing and resistance patterns
5. Reporting
Feedback of information on antibiotic use and resistance to frontline providers
6. Education
Ongoing education of clinicians about resistance and optimal prescribing
7. Action
Implementing at least one recommended action

32. Stewardship Approach: Feedback
Non-restrictive feedback resulted in statistically significant reductions in incident CDI.
Reductions in CDI attained through antimicrobial stewardship surpassed those attained through infection control measures.
Tertiary Hospital in Quebec,
Valiquette et al. Clin Infect Dis 2007; 45:S

33. Stewardship Approach: Restriction
Restricting the use of ceftriaxone was associated with reduced rates of CDI.
Formal restriction implemented
District general hospital; Glasgow, UK,
Fig. 1 Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile and extended-spectrum β-lactamase (ESBL)-producing coliform rates following a restrictive antibiotic policy in a district general hospital over 2 years.
pt/occ.bds, patient-occupied bed-days; DDDs, defined daily doses.
Dancer et al. Intl J Antimicrob Agents 2013; 41(2):

34. A practical approach to CDI prevention

35. Targeted Assessment for Prevention (TAP) Strategy
Target facilities/units
Assess gaps in infection prevention in targeted areas
Prevent infections by implementing interventions to address the gaps
CDI TAP reports available in NHSN
Work ongoing to use CO-CDI and other data sources to identify CDI cases from nursing homes and other community sources

36. CDI Risk Assessment
Conduct a risk assessment annually and whenever CDI goals are not met1
Use CDC’s Targeted Assessment for Prevention (TAP) Strategy
Pairing the results of a CDI facility assessment with the CDI Implementation Tool allows facilities to implement infection prevention strategies that most directly meet their needs.
Dubberke et al. Infect Control Hosp Epidemiol 2014; 35(6):

37. The CDI Implementation Tool includes a template for CDI Case Review
Review each CDI case (e.g., root cause analysis)
Examine temporal and spatial relationships between cases to determine units at risk for transmission due to community-onset or hospital-onset CDI cases.
The CDI Implementation Tool includes a template for CDI Case Review
Dubberke et al. Infect Control Hosp Epidemiol 2014; 35(6):

38. A Coordinated Response
A coordinated response is more effective than independent efforts1
Partners in Prevention:
The state and local health department and other state partners can assist and provide opportunities to extend efforts across the continuum of care
Figure from CDC Vitals Signs:
Slayton et al. MMWR 2015; 64(30):

39. Communication During Patient Transfer of Multidrug-Resistant Organisms (MDROs)
Effective Jan 2014, OAR requires facilities to notify in writing receiving institution that patient is infected or colonized with MDRO requiring transmission-based precaution in addition to standard precautions
Examples: CRE, MRSA, C. diff
Typically require additional precautions such as wearing mask, gown and gloves with patient contact, in some cases, patient isolation

40. Template form

41. IFT rule implementation
OR hospitals and SNFs surveyed in 2015 & 2016
# of facilities surveyed:

42. IFT rule implementation
“We notify receiving facilities of MDROs at discharge”
“Transferring facilities notify us of MDROs”

43. What is your facility doing?