C. difficile in the Age of Antimicrobial Stewardship

Darcy Whitlock, MSGI Disease Product Manager

Top 7 Threats to the Human Race

2Source adapted from Science, Vol 325, September 2009Available at http://www.sciencemag.org/content/325/5948.cover-expansion

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

CDC – Get Smart Campaign 4

Outpatient Settings

CDC – Get Smart Campaign 5

Improper Antimicrobial Use

• Longer duration than necessary• Noninfectious/nonbacterial

syndrome• Treatment of colonization/

contamination

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Unnecessary

Necessary

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 7

“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. 20098

Why Antimicrobial Stewardship?

• A balance of infection control and antibiotic management

Achieve optimal clinical outcomesDecrease adverse drug events• C. difficile

Minimize development of antimicrobial resistancePreserve antimicrobial resourcesReduce costs

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Antimicrobial Stewardship Programs

• Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship – 2006http://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

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Mabey et al. Diagnostics for the Developing World. Nature Rev Microbiol 2004, 2:231-40

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

14© JerryD via Flickr

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

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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.

Cycle of Antibiotics

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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

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Gene Product

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 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)

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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

27Planche, et al. Lancet Infectious Diseases. E-pub Sept. 3, 2013.

C. difficile Testing Algorithm

Positive for toxigenic C. difficile

Positive GDH Antigen and Negative Toxin

Negative for toxigenic C. difficile

•Reporting Results •Additional

Testing

75 – 80%

10%

10-15%

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NPV 99.8%

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 RATEHealthy Adults 1 – 3%People with recent healthcare exposure 15 – 25%Residents of Long Term Care Facilities 20 - 51%Newborn Infants 50 - 70%

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• Treating carriers is ineffective – Contributes to antibiotic overuse– Puts individual patient at risk of contracting CDI

• Identification important for infection prevention

Antimicrobial Stewardship Directly Impacts C. difficile Rates

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• 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. 2008. Infection Control and Hospital Epidemiology. 29(11): 1096-97

C. difficile Testing Companion

Likely active infection Likely not active infection– Carrier, colonized

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• C. difficile toxins typically cause inflammation• Lactoferrin results can help differentiate carriers

from active infections

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

SHEA/IDSA Guidelines for C. difficile infection in adults. 2010 ICHE 31(5) 35

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 contacts2. Disinfect surfaces daily or after each use of the bathroom

to prevent transmission

36Thanks to Dr. Curtis Donskey, Case Western Reserve University, for this example

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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