Finding an optimal diagnostic algorithm for C. difficile

Balancing sensitivity, specificity and cost

Valerie Midgley, Ph.D.December 8, 2017

National Pathology Forum

Clostridium difficile

• C. difficile is a gram positive, spore-forming bacillus that can be a normal part of the intestinal microbiota

• C. difficile infection (CDI) is a toxin-mediated intestinal disease (C. diff toxin A and toxin B)

• Clinical symptoms of CDI include watery diarrhea, fever, loss of appetite, nausea and abdominal pain

• Infection is spread by bacterial spores found within feces – Any surface, device, or material (e.g. commodes, bathing tubs, and electronic rectal thermometers) that

becomes contaminated with feces may serve as a reservoir for the Clostridium difficile spores

• CDI is the most commonly recognized cause of diarrhea in hospitalized patients and in patients in long term care facilities – Clostridium difficile spores are transferred to patients mainly via the hands of healthcare personnel who

have touched a contaminated surface or item.

Epidemiology

• Incidence of CDI has been rising steadily over the past two decades with subsequent increases in mortality, prolonged hospital stays, and a substantial rise in healthcare costs

(Stephen M Vindigni and Christina M Surawicz, NATURE 2015)

– CDI makes up about 15-25% of cases of antibiotic-associated diarrhea (AAD)

– It has replaced methicillin-resistant Staphylococcus aureus as the most common hospital-acquired infection overall

• Several subpopulations are disproportionately affected by C. difficile and have higher associated morbidity and mortality (e.g. elderly, immunocompromised individuals)

Citation: Clinical and Translational Gastroenterology (2015) 6, e99; doi:10.1038/ctg.2015.24 C. difficile Infection: Changing Epidemiology and Management Paradigms

Rates of Clostridium difficile infection among hospitalized patients aged ≥65 years, by age group

From the National Hospital Discharge Survey, United States, 1996–2009 (from Centers for Disease Control and Prevention. Morb Mortal Wkly Rep (MMWR) 2011;60(34):1171.

Continuous Evolution of C.Diff

• CDI is no longer thought to be limited to populations with prior antimicrobial exposure – Rates continue to rise and it is thought that up to 40% of CDI cases can be attributed to community

acquisition diagnosed in outpatient care settings– Overall the reported incidence of CDI has changed dramatically over the last decade

• New strains of C. diff are emerging– Hyper virulent, toxigenic strain, BI/NAP1/O27 caused an international epidemic between 2002-2006– PCR ribotypes 001, 018, 078, and 106 also caused outbreaks– These new and distinct clonal lineages that appear more transmissible and cause more severe

infection

• C. difficile appears to have evolved over the past 20 years, responding to a range of selective pressures created by human activity and practices in healthcare settings (Cairns, M.D. et al. Future Microbiol. 2012;7(8):945-957.)

Diagnosing C.Diff• There are a number of new laboratory tests and algorithms that can be used to diagnose CDI

– New molecular tests allow for earlier detection and more rapid treatment

• However there is a lack of consensus for the best diagnostic algorithm due to disagreement between diagnostic tests– Depending on the test, a positive result may only reflect colonization rather than an incubating infection – Inclusion of a Toxin A/B test is generally recommended since CDI is a toxin-mediated disease

• Reliance on any test for C. difficile without relevant clinical information is likely to lead to either over or under diagnosis of CDI– Only symptomatic patients should be tested

• There is also a lack of agreement on what is the most accurate reference method for C. difficile infection – cytotoxigenic culture or cytotoxin assay (Planche and Wilcox J. Clin Pathol 2011:64:1-5)

– These issues combined with variations in selection of patients and samples to test, has created inconsistent and inequitable practices (Lancet)

C. Diff Diagnostic Assays

BENEFITS LIMITATIONS

Stool cultureHigh sensitivityCheap

Long TAT (3-5 days)Confirmation of toxigenicity required

Toxin A/B Rapid

CheapEasy to use

Low sensitivityLow PPV so cannot be used as a screening assay

GDH Rapid

High sensitivityHigh NPVCheapEasyCan be used an a first-line screen

Confirmation of toxigenicity required

Molecular (PCR or LAMP)

High sensitivityHigh specificityShort TAT

More expensiveSome methods are laboriousOnly confirms the presence of a toxin-producing C. difficile organism

No single test for the

detection of CDI is 100%

sensitive and specific

Studies on Testing Algorithms

3 Step AlgorithmScreen by GDH(+) Toxin A/B(-) Molecular

2 Step AlgorithmScreen by GDH(+) Molecular

Other studies: The Lancet Infectious Diseases (2013) Timothy Planche and colleagues More than 12,000 samples from four centers were included in the study, and the results confirm that a two-step algorithm comprising a sensitive glutamate dehydrogenase (or molecular) assay, with positive results confirmed by a specific enzyme immunoassay, is the best performing method currently available (sensitivity 82·9%, 95% CI 80·0–85·6%).

2 Step AlgorithmScreen by GDH or Molecular(+) Toxin A/B

(-) Molecular(if GDH was performed as 1st step)

• Factors that enter into the choice of test include:

1. Rapid turnaround2. Specificity3. Sensitivity4. Cost

TAT & Material Cost Comparison

GDH EIA

TOXIN A/B EIA

Molecular

RESULT

+

-

30 min

30 min

+ 1hr

GDH EIA

+

RESULT

< 1hr

Molecular

RESULT

< 1hr30 min

• Assume cost of goods:GDH: $9/testToxin A/B: $12/testCombo: $14/testMolecular: $20/test

• Assume CDI positivity rate of 20%

2-Step3-Step 1-Step

Approx. Cost = $12,000(n = 1,000)

Approx. Cost = $20,000(n = 1,000)

Approx. Cost = $11,400(n = 1,000)

Combo GDH & A/B

Molecular

-

RESULT

< 1hr

30 min

2-Step

Approx. Cost = $14,400(n = 1,000)

+

*Algorithm used where positivity rate is high @ 40%

TOXIN A/B EIA

Problems with Unreliable C.Diff Diagnosis

Planche and Wilcox J. Clin Pathol 2011:64:1-5

False negatives

• Fail to diagnose and treat patient appropriately

• Fail to isolate infected patients with potential for disease spread

False positives

• Inappropriate cessation of antimicrobials

• Unnecessary initiation of CDI therapy (expensive)

• Not investigating patients for other causes of infection

• Cohorting non-infected with infected patients

Clinicians should be aware of and understand their own laboratories’ testing practices, including the limitations

Meridian’s Suite of C.Diff Diagnostics

Current Australian Customers

Clinical Labs (1-step molecular)AdelaideBendigoClaytonThe Northern Hospital

Pathology North (1-step molecular)TamworthCoffs HarborLismoreJohn HunterGosfordTweed Heads

Sonic (1-step molecular)Capital Pathology (ACT)

Sonic (3-step)Clinpath SAHobart Pathology

Clinical Labs (2-step)Bella Vista, NSW

SEALS PathologyPrince of Wales (GHD cards)

Peter MacCallum Cancer Centre (2-step)Victoria

Victorian Health (1-step)Eastern Health Box Hill

Meridian Bioscience at a Glance

35+ Years History | 650 Employees | $200M+ in Sales | 13 Worldwide Locations 70+ Global Markets | Nasdaq: VIVO

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