1. Epidemiology and Prevention of Clostridium difficile
W.I.P.E. Out Those Bugs
May 2, 2014
Kavita K. Trivedi, MD
Principal, Trivedi Consults, LLC
Adjunct Clinical Professor of Medicine, Stanford University School of Medicine

2. Objectives
Describe the changing epidemiology of Clostridium difficile infections (CDI) in the United States
Review recent research on prevention of CDI
Discuss how to apply accepted infection prevention practices for CDI in healthcare settings

3. Background Gram positive, spore forming rod Obligate anaerobe
Toxin A and Toxin B
Required to cause disease
Clostridium difficile infection (CDI, formerly CDAD)
Most common cause of healthcare- associated diarrhea
Fecal-oral transmission
Can be community-associated
Key Points:
Can produce at least 2 enterotoxins: Toxin A and Toxin B
Toxin B is particularly toxic and causes disease
Antibiotic exposure can trigger expression of the toxins

4. Background: Adults
2-5% of healthy adults have C. difficile colonization of the colon
20-40% of hospitalized adults are colonized with C. difficile

5. Background: Children
Colonization rates of up to 70% have been reported in children < 1 year
By 2 years the ‘normal’ colonic flora is established and colonization decreases to the rate of healthy adults

6. Epidemiology Range from mild to severe
Starting in 2002, changes in C. difficile noted, first in Quebec
Increased incidence (1991/19922003)
36/100,0000156/100,000
65 and older: from 102/100,000 to 866/100,000
Increased complications
Complicated disease: 7.1%18.2%
Death within 30 days: 4.7%13.8%
Comparing 1991/19922003
Lisa Winston, MD; Pepin et al., CMAJ 2004;171:466-72

8. C. Difficile Infection (CDI)
Incidence and severity have increased with dissemination of BI/NAP1 isolates
Historically uncommon – epidemic since 2000
Increased virulence
Increased toxin A and B production
Polymorphisms in binding domain of toxin B
Increased sporulation
Increased resistance to fluoroquinolones
Higher MICs compared to historic strains and current non-BI/NAP1 strains
Early diagnosis and treatment are required to reduce morbidity/mortality
McDonald et al. N Engl J Med. 2005;353: ; Warny et al. Lancet. 2005;366:
Stabler et al. J Med Micro. 2008;57:771–5; Akerlund et al. J Clin Microbiol. 2008;46:1530–3

10. Clostridium difficile Incidence and Mortality Are Increasing
No. of CDI Cases per 10,000 Discharges
Annual CD-related Mortality Rate per Million Population
Elixhauser A, et al. Healthcare Cost and Utilization Project: Statistical Brief #50. April Available at: Accessed March 10, 2010.
Redelings MD, et al. Emerg Infect Dis. 2007;13:

11. Cost of CDI in US CDI accounts for 336,000 hospitalizations annually
Aggregate hospital costs exceed $8.2 billion annually
Patients with principal CDI diagnosis remain hospitalized for 6.9 days at a cost of $10,100/stay
Patients with secondary CDI diagnosis remain hospitalized for 16.0 days at a cost of $31,500/stay.
CDI disproportionately affects the elderly
CMS pays for 68% of CDI hospital stays
Lucado J, Gould C, Elixhauser A. Clostridium difficile infections (CDI) in hospital stays, HCUP Statistical Brief124. January Rockville, MD: Agency for Healthcare Research and Quality. Accessed December 27, 2011.

12. Pathogenesis of CDI Key steps Acquisition of C. difficile
Alteration of colonic flora
Growth of C. difficile and elaboration of toxins
Poorly understood additional factor (s?)
Key Points:
Data is challenging our previous understanding of C.diff pathogenesis
Previous conception: Colonized with C. Diff, get antibiotics, get C. diff infection
But, it’s not that simple. It is a multi-step process: acquire C. diff (often in the hospital), then bowel flora is altered through antibiotic use, conditions promote C. diff growth and tissue damage
There are still factors that we don’t understand
Gerding D N , Johnson S. CID 2010;51:

13. CDI Risk Factors Antimicrobial exposure Acquisition of C. difficile
Advanced age
Underlying illness
Immunosuppression
Tube feeds
? Gastric acid suppression
Instructor Notes: Acknowledge C. Gould – CDC
Key Points:
These risk factors are similar to the risk factors for MDRO gram negatives.
The impact of tube feeding and gastric acid suppression are both pathogenically and programmatically limited. Neither one imparts the independent high risk of a patient developing CDI. While they may impact development of CDI in an individual patient, neither is particularly amenable to programmatic intervention.

14. Risk Factors Antimicrobial exposure Acquisition of C. difficile
Advanced age
Underlying illness
Immunosuppression
Tube feeds
? Gastric acid suppression
Major modifiable risk
factors

15. C. difficile Hospital Epidemiology
Use of antibiotics is frequent
Environmental contamination by C. difficile is common
Spores are difficult to eradicate
Personnel carry C. difficile on their hands
Asymptomatic patients carry C. difficile

16. Major Modifiable Risk Factors
Instructor Note:
This slide leads into topics introduced in the next two slides.
Key Point:
Other approaches to modifying risk factors include:
block transmission of C. diff with barrier precautions and environmental cleaning
preventing unnecessary/inappropriate antibiotic use
Gerding D N , Johnson S. CID 2010;51:

17. Major Modifiable Risk Factors
Antibiotic Exposure
Antibiotic Stewardship
Acquisition of C. difficile
Key Points:
How do we use antibiotic exposure interventions to reduce C. diff infections?
Optimizing Environmental Cleaning and Hand Hygiene

18. Antimicrobial Stewardship

19. Antibiotic misuse adversely impacts patients - Clostridium difficile
Antibiotic exposure is the single most important risk factor for the development of Clostridium difficile associated disease (CDAD)
Up to 85% of patients with CDAD have antibiotic exposure in the 28 days before infection
Chang HT et al. Infect Control Hosp Epidemiol 2007; 28:926–931.

20. Antimicrobials Predisposing to CDI
Very Commonly Related
Less Commonly Related
Uncommonly Related
Clindamycin
Ampicillin
Amoxicillin
Cephalosporins
Fluoroquinolones
Other penicillins
Sulfonamides
Trimethoprim
Cotrimoxazole
Macrolides
Carbapenems
Aminoglycosides
Bacitracin
Metronidazole
Teicoplanin
Rifampin
Chloramphenicol
Tetracyclines
Daptomycin
Tigecycline
Instructor Notes:
Acknowledge E. Dubberke, Wash U
Key Points:
antimicrobials predispose people to CDI through the alteration of their colonic flora
CDI is classically linked to Clindamycin, but we’ve learned that nearly any antibiotic can alter flora sufficiently to allow C. diff growth
The antibiotics commonly related to CDI are just a list of the commonly used antibiotics!
Uncommonly associated antibiotics have no or very little anaerobic activity. This may be significant since disruption of the normal anaerobic bowel flora appears to be a key element in C. diff pathogenesis.
Bouza E, et al. Med Clin North Am. 2006;90:
Loo VG, et al. N Engl J Med. 2005;353:

21. Impact of Fluoroquinolone Optimization on Rates of Hospital-Onset CDI
HO-CDAD cases/1,000 pd
2005
2006
2007
Month and Year
Infect Control Hosp Epidemiol Mar;30(3):

22. 66 Studies had meaningful data analysis
16 Studies evaluated microbiologic outcomes
4 Studies – Favorable
8 Studies +/-
4 Studies—no effect
Key Points:
Group out of UK did a systematic review of antimicrobial policies and correlated them with the impact on C. diff infections
Only 16/309 represented carefully designed studies that could objectively asses whether or not an antibiotic management program could impact a clinical condition such as CDI
Of the 16 studies evaluated, 4 had compelling and supporting data that stewardship effectively reduced the rate of CDI, 8 had some other favorable effect, and 4 had no effect.
In sum, of the 16 studies evaluated, 12 of them showed that antimicrobial policies had a positive effect.

23. Antimicrobial Stewardship Impact on C. difficile Disease
Key Points:
This is another slide illustrating the relative impact of antimicrobial stewardship on CDIs
The graph shows 4 different potential outcomes: Sudden increase in CDI, Sudden decrease in CDI, Sustained decreased effect on CDI, Sustained increase effect on CDI
X axis: The immediate effect of antimicrobial stewardship on CDI. The further to the left of the y-axis, the more impact it had. 4 papers showed a sudden decrease in CDI.
Y axis: The sustained impact of antimicrobial stewardship on CDI. 4 papers showed a sustained positive effect on CDI.
The dotted line shoes 95% confidence intervals. The study by Calli was limited to an ICU setting whereas the studies by Cimino and Carling represented highly effective hospital wide stewardship programs that might not be generalizable.
This shows that antimicrobial stewardship programs can have both an immediate and a sustained impact on C. diff infections.
Instructor Note:
The modeling used in the study is extremely sophisticated and transportable. Recommend that participants in this program interested in analyzing multisite interventions study the methods used in this paper. Mark Wilcox, the senior author, is widely recognized in Great Britain for his work related to epidemiology and pathogenesis of CDI and other HAPs.

24. ASP Make a Difference with Hospital-Associated CDI
Tertiary Care Hospital; Québec, Canada ( )
This particular study looks at implementing enhanced infection control for C. diff and having a minimal impact (Editor’s note: In reading the study, there may have been some limitations in the approaches that were taken with respect to hand hygiene and environmental services cleaning). But then, when combined with a second intervention in antibiotic optimization and stewardship, you can see that they were able to decrease the targeted antibiotics (2nd and 3rd gen cephs, macrolides, cipro, clinda) in this study, as directed by the yellow-orange line, and, at the same time, had a decrease in their C. diff prevalence or incidence in the hospital. Interesting to note that levoflox/moxi use was stable or increased but important to note that total usage decreased. There was a clear sustained, statistically significant decrease in CDI over time with a sustained decrease in abx utilization.
Valiquette, et al. Clin Infect Dis 2007;45:S112.

25. ASP Community Hospital Example
Team: ID pharmacists, ID physicians
Target: 8 target antimicrobials
Interventions: Prospective audit of new antimicrobial starts and weekly use
Measure: Significant reductions in Clostridium difficile rates, antimicrobial utilization and pharmacy costs
Malani, AN et al. Clinical and economic outcomes from a community hospital's antimicrobial stewardship program. American Journal of Infection Control 2012 May 9.

26. Environmental Cleaning

27. C. difficile and the Environment
Level of contamination may be high
Spores survive > 5 months
Key Points:
C. diff can reside on inanimate objects as a spore for months Contamination of the environment with C. diff spores contributes to transmission
What is interesting is that data shows that hospital surfaces have diffuse spread of C. diff spores but a low level contamination. High levels of contamination of C. diff spores are not needed to cause infection, though (acquisition dose is 10 or less spores).
Infective dose < 10 spores

28. C. Difficile and the Environment
Key Points:
This graph shows the % of skin contamination stratified by patients that have C. diff infection, are colonized with C. diff but have no symptoms, or are not even carriers of C. diff, but who are in hospital beds.
The bars are color coded according to different parts of the body with skin contaminated by C. diff: Skin (anywhere), groin, chest/abdomen
Overall, this study shows that C. diff spores are almost as common on the skin of carriers as they are in symptomatic patients. How many undiagnosed carriers are there in the average hospital? Remember, we only test symptomatic patients.
It’s also important to remembers that many patients recovering from acute CDI excrete C. diff for months after becoming asymptomatic.
Sethi et al. 2010

29. C. Difficile and the Environment
Key Points:
Similarly, this same study showed that a) environmental contamination associated with asymptomatic patients is almost as great as with symptomatic patients; b) 30% of surfaces around non carriers were also culture positive.
What does the latter mean? (Ask the audience)
Answer: these spores most probably came from prior room occupants in the setting of suboptimal disinfection cleaning.
Sethi et al. 2010

30. C. Difficile and the Environment
Key Points:
This quantitative study classified different surfaces as near or distant from patients with acute CDI.
It was discovered that both near and distant surface contamination associated with symptomatic patients was only 50% less than the ill patients’ hands.
Also of note is the fact that C. diff could be found on near and distant environmental surfaces on wards that had not had a recognized patient with CDI in at least six months.
While it certainly is possible that these C. diff spores had been sitting alive and well on these surfaces for six or more months, it is also possible that recently admitted asymptomatic carriers contaminated the surrounding environment which was not, in either case, being effectively cleaned.

31. Is the environment important in C. difficile transmission?
Key: Environmental colonization is important, widespread, and must not be ignored.

32. Persistence of spores
Key Points:
This study was presented at ICAAC in 2008 and published in ICHE January, 2011
Looks at the incidence of CDI in patients with respect to whether they were in a room previously occupied by a patient with C. diff
If a patient was in a room previously occupied by a C. dif f positive patient, that new patient has >110% higher risk of developing CDI.
This does not show causation, but perhaps it is supporting evidence that the environment is involved with transmission
In multivariate analysis, OR for prior room occupant with CDI = 2.4 ( )
Adjusted for age, APACHE score, PPI, abx use… but not for length of stay
Shaugnessy et al. Infect Control Hosp Epidemiol Mar;32(3):201-6.

33. Can disinfection cleaning decrease environmental contamination?
Key Point:
Answer: Yes

34. Studies reporting a favorable impact of enhanced environmental hygiene during a CDI outbreak
Key Point:
Over the years researchers reporting quasi-experimental studies have repeatedly reported that more thorough environmental cleaning had a favorable impact on C. difficile outbreak setting transmission.
While this phenomenon might merely be a reflection of an otherwise independent epidemic curve, the large number of studies, taken together, provide substantial support for the likelihood that improving environmental hygiene and disinfection cleaning can favorably impact CDI incidence.

35. Culture based evaluation - Pre-intervention
- after routine terminal cleaning
- after terminal cleaning by the research staff
- following education of the ES staff and administrative interventions
Key Points:
This landmark study carefully evaluated the impact of routine and subsequently more thorough environmental cleaning on C. diff environmental surface contamination.

36. Percentage of C. difficile-positive cultures n=9 rooms80 70 60 50 40 30 20 10
Percent positive
Before cleaning
After
housekeeping
cleaning
disinfection by
research team*
Bedrail
Bedside table
Phone
Call button
Toilet
Door handle
Key Points:
Even when you are using bleach, as was done in this study, usual cleaning of hospital rooms is not particularly effective at reducing C. diff contamination
Contamination of the bedrail, toilet, went down but contamination of the phone, call button, and bedside table barely changed after routine cleaning
But then look what happened when the same rooms were thoroughly cleaned by a “research team” (the investigators). Only one culture was positive. Subsequently similar results were found after carefully educating the environmental services workers.
Unfortunately, these results were not sustained and contamination rates rapidly returned to the “after housekeeping levels” due to lack of feedback or long-term programmatic intervention (personal communication, Curtis Donskey, senior author).
*Similar results found after ES cleaning following interventions
Eckstein et al, BMC Infect Dis Jun 21;7:61.

37. Can improved disinfection/cleaning lead to decreased CDI?
Answer: Yes

38. Greater New York CDI Collaborative
40 Hospitals – New York area,
Pre-intervention rate – 8.1/ 10,000 PtD
Similar education, check sheet and self reporting of thoroughness of terminal cleaning. Glitterbug lotion used for some teaching (not monitoring).
70% of Hospitals saw an average decrease of 26% in HO CDI (Mean for the system = 15%)
Key Points:
This very important study is hopefully moving towards publication.
It’s the only large multi-site study of the impact of improved environmental hygiene on endemic CDI rates and clearly showed the short term impact a focal programmatic effort to improve environmental hygiene had on CDI rates in many participating hospitals.
Source: Barbra Smith, RN CIC and Brian Koll, M.D. project Coordinators. APIC presentation.

39. Prevention Strategies

40. CDC Prevention Strategies
Supplemental Strategies
Core Strategies
High levels of scientific evidence
Demonstrated feasibility
Some scientific evidence
Variable levels of feasibility
There are two approaches to controlling C. diff described in CDC recommendations. There are core strategies that are better supported by the scientific literature and less well proven supplemental strategies.

41. Environmental Cleaning
Core
Supplemental
Cleaning and disinfection of equipment and environment
Consider sodium hypochlorite in outbreak or hyper endemic settings
Routinely assess adherence to protocols and adequacy of cleaning
Reassess adequacy of room cleaning and address issues
Use sodium hypochlorite (bleach) – containing agents
Key Points:
C. diff is very hardy. You need to use bleach because it isn’t susceptible to the usual agents used
(although bleach is not strongly recommended, it is the standard for known c. diff in many hospitals)
The rigor of cleaning needs to be assessed. You can’t just go by how it looks
Dubberke et al. Infect Control Hosp Epidemiol 2008;29:S81-92
Cohen et al. Infect Control Hosp Epidemiol 2010;31

42. Contact Precautions Core Supplemental Gloves/gowns on room entry
Private room (preferred) or cohort with dedicated commodes
Dedicated equipment
Maintain for duration of diarrhea
Measure compliance
Extend use of Contact Precautions beyond duration of diarrhea (hospitalization)
Presumptive isolation
Universal glove use on units with high CDI rates
Intensify assessment of compliance
Key Points:
Contact Precautions are recommended for C. diff
There has been a suggestion that Isolation leads to worse patient satisfaction and patient outcomes (anxiety, depression, worse healthcare) but these are not sufficiently explored to have an impact on the recommendation to use Contact Precautions.

43. Hand Hygiene Supplemental Core
Soap and water for hand hygiene before exiting room of a patient with CDI
Intensify assessment of compliance
Core
Hand hygiene based on CDC or WHO guidelines
Soap and water preferentially in outbreak or hyper endemic settings
Measure compliance
Key Points:
There are guidelines that explain how to monitor hand hygiene
Since you can’t use bleach on your hands, patients and HCWs need to use soap and water when interacting with patients that have CDI

44. Diagnostic Testing Core Supplemental
Laboratory-based alert system for immediate notification of positive test results
Evaluate and optimize testing for CDI

45. Evaluate and Optimize Testing for CDI
Toxin A/B enzyme immunoassays have low sensitivities (60-80%)
Despite high specificity, poor test ordering practices (i.e. testing formed stool) may lead to false positives
Consider more sensitive diagnostic paradigms but apply judiciously
Restrict testing to unformed stool only
Focus testing on patients with > 3 unformed stools within 24 hours
Repeat testing no more than every 5-7 days if negative
Require expert consultation for repeat testing within 5 days
Test of cure is not recommended
Key Points:
This slide expands on the complexities of testing for CDI
There needs to be uniform and consistent testing strategies
VERY IMPORTANT: Patients should only be tested if they have loose stools
Most hospitals are using the 2 step testing method now
Peterson et al. Ann Intern Med 2009;15:176-9.
Cohen et al. Infect Control Hosp Epi 2010; 31 (5):

48. Two-Step Testing Utility related to Promoted to enhance sensitivity
Sensitivity of initial screen
Sensitivity of GDH EIA screen 76% to 100%
Cost of confirmatory test alone versus screen plus confirmatory test
Cost of false positive test (not quantified)
Promoted to enhance sensitivity
Actually enhances positive predictive value of confirmatory test
Increased prevalence of disease
Instructor Notes: Acknowledge E. Dubberke, Wash U
Key Points:
Note again a growing consensus around using GDH plus/minus EIA for screening and PICR for confirmation if GDH is positive and EIA is negative when using a combined testing system.
This approach needs to be standardized and promoted if we are to move ahead with understanding epidemiology and impact of preventive measures related to CDI.
So, if each of these tests are flawed, maybe the solution is to use more than one to diagnose C. diff.
This method will improve the positive predictive value, but will increase the cost.

49. Conclusions CDI is the most serious, frequent and costly HAI
Decreased antibiotic exposure and stewardship optimization are important in preventing CDI
Optimizing environmental hygiene is becoming recognized as central to controlling CDI
All hospitals should be in compliance with CDC Core Recommendations 49

50. CDI and Infection control
Gloves + gowns for duration of diarrhea
Wash with soap and water (epidemic setting)
Private rooms
Dedicated commode
Bleach cleaning
Antimicrobial stewardship
Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31:

51. Conclusions
Gerding D N , Johnson S. CID 2010;51: