1. C. difficile in the Age of Antimicrobial Stewardship
Darcy Whitlock, MS
GI Disease Product Manager

2. Top 7 Threats to the Human Race
Source adapted from Science, Vol 325, September 2009
Available at

3. Infectious Disease & Antibiotics
1970: Surgeon General William Stewart said the US was “ready to close the book on infectious disease as a major health threat”
Modern antibiotics, vaccination, and sanitation methods had done the job
1995: Infectious disease is the 3rd leading cause of death behind heart disease & cancer
2013: Infectious disease remains a critical concern as antimicrobial resistance increases

4. Inpatient Settings
One in every three patients will receive two or more antibiotics in the course of their hospital stay
Of the patients receiving antibiotics, three out of every four will receive unnecessary or redundant therapy, resulting in excessive use of antibiotics
CDC – Get Smart Campaign

5. Outpatient Settings
Each year, tens of millions of antibiotics are prescribed unnecessarily for viral upper respiratory infections
Antibiotic use in primary care is associated with antibiotic resistance at the individual patient level
The presence of antibiotic-resistant bacteria is greatest during the month following a patient’s antibiotics use and may persist for up to 1 year
CDC – Get Smart Campaign

6. Improper Antimicrobial Use
Longer duration than necessary
Noninfectious/nonbacterial syndrome
Treatment of colonization/ contamination
Unnecessary
Necessary
APUA slides / Levy presentation

7. Costs of Antibiotic Resistance
Antibiotic resistance increases the economic burden on the entire US healthcare system
Resistant infections cost more to treat and can prolong healthcare use
More than $1.1 billion is spent annually on unnecessary antibiotic prescriptions for respiratory infections in adults
In total, antibiotic resistance is responsible for:
$20 billion in excess healthcare costs
$35 billion in societal costs
8 million additional hospital days
CDC – Get Smart Campaign

8. “Every antibiotic expected by a patient, every unnecessary prescription written by a doctor, every uncompleted course of antibiotics is potentially signing a death warrant for a future patient.”
Dryden, et al. 2009

9. Why Antimicrobial Stewardship?
A balance of infection control and antibiotic management
Achieve optimal clinical outcomes
Decrease adverse drug events
C. difficile
Minimize development of antimicrobial resistance
Preserve antimicrobial resources
Reduce costs

10. Antimicrobial Stewardship Programs
Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship – 2006
Core members include:
Infectious Disease Physician
Clinical Pharmacist
Clinical Microbiologist
Infection Control Professional
Information System Specialist

11. Simple Stewardship Solutions
Treat only when necessary
Use narrow-spectrum agents whenever possible
Utilize rapid diagnostics
Consider higher doses or shorter duration

12. Rapid Diagnostics Test, Target, Treat
Know the organism, know the appropriate treatment
Reduce antibiotic overuse & unwanted side effects
Shorten time to appropriate therapy
Targeted therapy improves pharmacy savings
Reduced infection transmission increases infection control savings

13. Ideal Diagnostic Test
Affordable Sensitive (few false neg.) Specific (few false pos.) User friendly Rapid (30 min.) Equipment-free Deliverable
Mabey et al. Diagnostics for the Developing World.
Nature Rev Microbiol 2004, 2:231-40

14. Antibiotic-Associated Diarrhea: Life’s a Beach with C. difficile
Normal Gut Flora
Gut after Antibiotics
C. diff finds a nice spot
C. diff Infection
[Numbers refer to pictures, starting upper L, upper R, lower L, lower R]
Normally the large intestine is totally crowded with the normal gut flora (natural bacteria) just like this beach is crowded with people. Any C. diff spores that are passing through will not be able to find enough free space to set up shop.
When we take antibiotics they kill off most of the normal gut flora, leaving a lot of open space and a lot of available nutrition for C. diff.
If we ingest C. diff spores at this point they’ll be able to colonize (pop open their beach umbrella) and start to grow & multiply.
Once the C diff have multiplied to a high level, they get crowded, don’t have enough space or nutrition available. This is when they produce toxins that cause disease. C. diff doesn’t produce toxin all the time, it’s in response to stress. The toxins will damage our intestinal lining, and C. diff can use some of the fluids we leak out as nutrition.
© JerryD via Flickr

15. Risk Factors for C. difficile
Previous antibiotic exposure
Some cases unrelated to antibiotics
Disruption to intestinal flora
Advanced age
Hospitalization
Community acquisition becoming more common
Pregnancy

16. C. difficile Economic Impact
Several studies examine costs
$3B
$436M
Kyne, et al. Clin Infect Dis ; 34:
O’Brien et al. Infect Control Hosp Epidemiol ; 46:
Dubberke, et al. Clin Infect Dis ; 46:

17. Cycle of Antibiotics
Primary Infection
Antibiotic Treatment
C. difficile Infection
Start C. diff antibiotics
D/C primary antibiotics
Part of the difficulty in treating C. difficile is that it can impact treatments for other diseases.
If someone is in the hospital being treated for a primary infection, let’s say pneumonia, the antibiotics prescribed will make the person susceptible to a C. difficile infection
Part of the treatment for C. difficile is discontinuing any other antibiotics and starting antibiotics specific for C. difficile.
There’s a chance the original disease wasn’t fully cured when the primary antibiotics were discontinued, which means it could recur. Which puts us back at the start needing antibiotics to treat the primary infection.
Of course, the antibiotics to treat the C. diff infection also put the patient at risk of contracting a C. diff infection. So we get not only a cycle of treating the primary infection, but possibly a C. diff infection relapse cycle.
This creates huge issues for antibiotic stewardship and can lead to increasing antibiotic resistances.

18. Gastrointestinal Disease: Impossible but True
Impossible to diagnose on clinical symptoms alone, but frequently done
What’s the primary symptom of any GI disease?
100s of causes, often treated empirically with antibiotics
Primary causes: bacterial infection, viral infection, functional disorders, autoimmune disease, food allergies
Antibiotics may cure infection, may not affect disease but it runs its course and they appear to work. But can hurt the patient by increasing risk of C. diff, or worse
Test patients so we can target the cause…
Cure Infection
Hurt Patient

19. Treat the Right Patients
Lab tests are essential for proper diagnosis and to avoid empiric antibiotic treatment
What if a test:
Doesn’t actually tell if someone is sick
Takes so long for results the doctor has already treated the patient empirically

20. DNA = Cookbook; Gene = Recipe
Think about a cookbook for a minute. If you want to cook something, you can go to the cookbook and find a recipe, follow the instructions, and end up with the finished item.
That’s the same way C. diff makes something like toxin. It has a cookbook too, it’s DNA. The DNA holds all the information it needs for everything it has to make.
Just like a cookbook is broken up into recipes, so is the DNA, but we call the recipes Genes. A gene is the instructions how to make one specific thing. For instance there’s a gene for Toxin B. If C. diff needs to make toxin it will find the gene recipe and follow the instructions encoded there to make the toxin.
Now, just because we have a cookbook doesn’t mean we’re making every dish one after the other all day long. It means we have the information there if we need it.
And that’s exactly the same thing C. diff is doing. Just because it has the gene for Toxin doesn’t mean it’s turned on making toxin all the time. It means it has the information there if it needs it.
And that’s an important point to remember as we continue to talk about DNA molecular testing.
Gene
Product

21. C. difficile Toxins A&B Toxins cause the disease symptoms
Toxin results most closely correlate to disease state and clinical outcome
Not all toxin assays perform equally
Toxins produced only when needed by the bacteria
Typically in response to nutritional or environmental stress

22. Molecular Testing Nucleic Acid Amplification Tests (NAAT)
DNA test, PCR, LAMP, isothermal NAT
Detects the gene (DNA) that encodes for toxin
Great for sensitive identification,
but doesn’t always tell us what’s
happening
Doesn’t indicate if gene is turned on
producing toxin in the patient
We commonly call DNA tests a molecular test. More technically it’s called a Nucleic Acid Amplification Test.
1 – PCR is the most well known, but there are other methods like LAMP and isothermal tests available now
3 – How many of you have seen an episode of CSI where they find a drop of blood at a crime scene and rush it back to the lab for a DNA test? They identify whose blood it is – Great! Very sensitive identification. But we don’t know why the blood was there. Was that person a victim, where they the perpetrator of a crime, or an innocent bystander who tripped and fell and scraped their knee earlier in the day?
This is the same problem with DNA testing for C. diff – is the C. diff the perpetrator of disease, or an innocent bystander in a patient whose symptoms are caused by something else?

23. C. difficile GDH Antigen
Glutamate dehydrogenase (GDH) produced in large amounts by all C. difficile bacteria
GDH shows C. difficile is present & growing
Very sensitive detection of bacteria
Does not indicate if they produce toxin, need follow-up test for toxin

24. What Test is Best? There is no optimal test for C. difficile
Each method has advantages & drawbacks
Method
Advantage
Drawback
GDH
Sensitive detection, shows bacteria are present
Doesn’t say if C. difficile strain can produce toxin
Toxin A/B
Indicates active disease,
Most clinically relevant
Will not identify carriers, may not detect all positive patients
Molecular
Sensitive detection of toxigenic bacteria
Doesn’t say if toxin is present, does not differentiate active disease
[Read chart across, Advantage and disadvantage for each method]

25. Guidelines: Points All in Agreement
Toxin A/B testing should not be used as a stand-alone test
GDH screening prior to toxin testing is recommended for improved sensitivity
Repeat testing (C. diff x 3) not helpful and should be discouraged when using more sensitive testing methods (GDH or molecular)
Since there’s no easy answer for C. diff testing, several societies have set out guidelines with recommendations for testing. These include:
IDSA – Infectious Diseases Society of America
SHEA – Society for Healthcare Epidemiology of America
ASM – American Society for Microbiology
DH – UK Dept. of Health
For the most part the guidelines are all in agreement:
1 – This isn’t saying not to use a Tox A/B test, only that they shouldn’t be used stand-alone

26. Molecular Testing Disagreement
ASM: Molecular can be used stand-alone or as confirmation of rapid results
SHEA/IDSA: PCR has high sensitivity & specificity, looks promising, but not enough data yet to recommend
UK: PCR is a good screening test, but not specific for active disease
Follow up with sensitive toxin test for clinical activity

27. UK Guidelines - 2012 Largest most comprehensive study ever done
12,441 samples compared to patient clinical features & outcomes
GDH, Toxin, NAAT, Cytotoxicity, Toxigenic Culture
Testing for active toxin production is critical for determining disease state & clinical outcome
1 – This study compared to patient disease, not just other lab tests like a lot of studies do. If you think about it, this is really what all studies should do, but it’s hard to do with healthcare privacy laws and all.
3 – Cytotoxicity and Toxigenic Culture are the gold standards for lab tests that are often used for comparisons in papers
4 – When compared to patient health, the presence of active toxin is the most important aspect.
A webinar presented by the lead author of the study and UK guidelines is available online. It’s also available for PACE continuing education credits if anyone needs, and goes into detail about the study and what this new information means.
Webinar by Dr. Mark Wilcox, co-author of the UK study & Guidelines
Planche, et al. Lancet Infectious Diseases. E-pub Sept. 3, 2013.

28. C. difficile Testing Algorithm
Positive for toxigenic
C. difficile
10-15%
Reporting Results
Additional Testing
Positive GDH Antigen and Negative Toxin
10%
There is no optimal test for C. diff
Negative for toxigenic
C. difficile
NPV 99.8%
75 – 80%

29. What Does GDH + , Toxin – Mean?
C. difficile bacteria are present but toxin is not detected
Could be due to:
Colonization with a nontoxigenic strain
Patient is a carrier of a toxigenic strain
Toxin level is below the limit of detection
UK Study: GDH+, Tox- patients have similar outcomes to C. diff negative patients
1 – It’s important to know this result isn’t wrong, it’s telling us something about the patient
4 – They looked at this group as part of the big UK study, comparing their outcomes to the group with active disease that had toxin present and the group that didn’t have C. diff present at all. The patient health and clinical outcomes for GDH+/Tox- patients was similar to the group that didn’t have C. diff present, and was significantly different from the group that had active disease. So this raises questions about how best to manage patients who may be carriers.

30. Carrier Rates COMMON CARRIERS RATE Treating carriers is ineffective
Healthy Adults
1 – 3%
People with recent healthcare exposure
15 – 25%
Residents of Long Term Care Facilities %
Newborn Infants %
Treating carriers is ineffective
Contributes to antibiotic overuse
Puts individual patient at risk of contracting CDI
Identification important for infection prevention

31. Antimicrobial Stewardship Directly Impacts C. difficile Rates
AMS program instituted at VAMC Houston
Required ID Doc approval for most antibiotics
C. difficile infection rate dropped 42% solely from restricting inappropriate antibiotics
Study presented at ID Week, 2013
10% reduction in antibiotics = 17% reduction in C. diff rate
Penicillins and β-lactams had most effect
Fluoroquinolone decrease had surprisingly small effect
Nuila, et al Infection Control and Hospital Epidemiology. 29(11):

32. C. difficile Testing Companion
C. difficile toxins typically cause inflammation
Lactoferrin results can help differentiate carriers from active infections
Inflammation
Present
No Inflammation
Likely not active infection
Carrier, colonized
Likely active infection

33. Fecal WBC Smear False negatives from cell breakdown
Need intact cells for microscopic identification
WBCs break down rapidly in stool
Digestive enzymes, cytotoxins
Variation from different users, different prep techniques, number of fields examined

34. WBC Testing Options - Lactoferrin
Highly accurate marker of WBCs (neutrophils/PMNs)
Elevated lactoferrin = WBCs are present, inflammation in GI tract
Stable marker of WBCs
Unaffected by cell breakdown
Non-subjective, no variation between users

35. Infection Control Recommendations
Cohort CDI patients
C-III
Isolation
B-III
Hand Hygiene
A-II
Contact Precautions
A-I
SHEA/IDSA Guidelines for C. difficile infection in adults ICHE 31(5)

36. Importance of Daily Cleaning
Elderly relative living with you develops infectious diarrhea
Your young children have daily contact with their ill grandparent
Do you:
Wait 10 days until the illness has resolved before cleaning the bathroom & other objects the person contacts
Disinfect surfaces daily or after each use of the bathroom to prevent transmission
At end of slide say: Healthcare workers are like children…they touch everything and they don’t always wash their hands
Thanks to Dr. Curtis Donskey, Case Western Reserve University, for this example

37. Points to Remember C. difficile testing is complex
No One & Done solution
High carrier rate can complicate treatment and infection prevention decisions
Inflammation testing can aid diagnosis

38. Points to Remember Proper rapid diagnosis of C. diff disease:
Improves patient outcomes
Prevent antibiotic overuse
Protect vulnerable patients from antibiotic-related complications
Antimicrobial stewardship plays a direct role in reducing C. difficile rates

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