Transcript Parasitology

C. difficile in the Age of Antimicrobial
Stewardship
Darcy Whitlock, MS
GI Disease Product Manager
Top 7 Threats to the Human Race
Source adapted from Science, Vol 325, September 2009
Available at http://www.sciencemag.org/content/325/5948.cover-expansion
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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
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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
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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
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Improper Antimicrobial Use
Unnecessary
Necessary
• Longer duration than necessary
• Noninfectious/nonbacterial
syndrome
• Treatment of colonization/
contamination
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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
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“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
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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
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Antimicrobial Stewardship Programs
• Guidelines for Developing an Institutional Program
to Enhance Antimicrobial Stewardship – 2006
http://www.idsociety.org
• Core members include:
–
–
–
–
–
Infectious Disease Physician
Clinical Pharmacist
Clinical Microbiologist
Infection Control Professional
Information System Specialist
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Simple Stewardship Solutions
•
•
•
•
Treat only when necessary
Use narrow-spectrum agents whenever possible
Utilize rapid diagnostics
Consider higher doses or shorter duration
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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
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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
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Antibiotic-Associated Diarrhea:
Life’s a Beach with C. difficile
Normal Gut Flora
C. diff finds a nice spot
Gut after Antibiotics
C. diff Infection
© JerryD via Flickr 14
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
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C. difficile Economic Impact
• Several studies examine costs
Kyne, et al. Clin Infect Dis. 2002; 34: 346-353.
O’Brien et al. Infect Control Hosp Epidemiol. 2008; 46: 497-504.
Dubberke, et al. Clin Infect Dis. 2008; 46: 497-504.
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Cycle of Antibiotics
Primary
Infection
D/C primary
antibiotics
Antibiotic
Treatment
Start C. diff
antibiotics
C. difficile
Infection
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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
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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
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DNA = Cookbook; Gene = Recipe
Gene
Product
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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
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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
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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
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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
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Guidelines: Points All in Agreement
• Toxin A/B testing should not be used as a standalone 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)
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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
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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
Webinar by Dr. Mark Wilcox, co-author of the UK study &
Guidelines available @ http://www.whitehatcom.com/alere
Planche, et al. Lancet Infectious Diseases. E-pub Sept. 3, 2013.
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C. difficile Testing Algorithm
Positive for toxigenic
C. difficile
10-15%
Positive GDH Antigen and
Negative Toxin
10%
Negative for toxigenic
C. difficile
•Reporting
Results
•Additional
Testing
NPV 99.8%
75 – 80%
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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
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Carrier Rates
COMMON CARRIERS
RATE
Healthy Adults
People with recent healthcare exposure
Residents of Long Term Care Facilities
Newborn Infants
1 – 3%
15 – 25%
20 - 51%
50 - 70%
• Treating carriers is ineffective
– Contributes to antibiotic overuse
– Puts individual patient at risk of contracting CDI
• Identification important for infection prevention
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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
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Nuila, et al. 2008. Infection Control and Hospital Epidemiology. 29(11): 1096-97
C. difficile Testing Companion
• C. difficile toxins typically cause inflammation
• Lactoferrin results can help differentiate carriers
from active infections
Likely active infection
Likely not active infection
– Carrier, colonized
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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
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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
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Infection Control Recommendations
Hand
Hygiene
Isolation
A-II
Contact
Precautions
A-I
B-III
Cohort CDI
patients
C-III
SHEA/IDSA Guidelines for C. difficile infection in adults. 2010 ICHE 31(5)
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Importance of Daily Cleaning
• Elderly relative living with you develops infectious
diarrhea
• Your young children have daily contact with their ill
grandparent
• Do you:
1. Wait 10 days until the illness has resolved before cleaning
the bathroom & other objects the person contacts
2. Disinfect surfaces daily or after each use of the bathroom
to prevent transmission
Thanks to Dr. Curtis Donskey, Case Western Reserve University, for this example
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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
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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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