Alaska Regional HospitalAn HCA Facility

C.diff Reduction InitiativeJanuary 23, 2018

With Recognition To:Dr. Michael Baumann, MD, MS, Division Chief Medical Officer

Jason Braithwaite, PharmD, MS, BCPS, Division Director, Clinical Pharmacy Services

Jenny Mayo, BSc, MT-ASCP, Microbiology Supervisor, ARHLisa Tocco, MPH, CIC, Interim Infection Control, ARH, IP&MA

Rosemary Tucker, MA, RN-BC, Coordinator of Infection Control, ARH

• C. difficile cost US acute care facilities > 4.8 billion USD per year– HAI have a 9.3% mortality rate1

• Approach is not clear

• Literature on C. difficile is confounding– Example: 848 unique citations in the literature in the past

5-6 years alone. There are many variations in the study conditions, the comparator method, and therefore the results published.

– Lesson: interpret the literature carefully2

2

Introduction

1. http://www.nejm.org/doi/full/10.1056/NEJMoa1408913#t=article2. http://www.sciencedirect.com/science/article/pii/S1198743X14648473

Where did our initiative come from:

• Conversation surfaced in our division around testing algorithms and best practices– Single vs. Two-step vs. Three step testing

• Interdisciplinary collaboration within ARH– Infectious Disease, Pharmacy, Infection Control, CNO,

Quality, Lab– 2016 C.diff testing was PCR only– 2017 Goal: standardize the testing algorithm for accurate

CDI identification

3

Alaska Regional C.diff Initiative

Other Considerations:

• C.diff Case Criteria

• Sample collection

• Role of the Lab – Testing method/algorithm– Turnaround – Rejections

• Isolation Precautions

4

Alaska Regional C.diff Initiative

Sourceshttps://www.cdc.gov/hai/pdfs/toolkits/CDI-Primer-2-2016.pptxhttp://jamanetwork.com/journals/jamapediatrics/fullarticle/1659616http://apic.org/Resource_/EliminationGuideForm/59397fc6-3f90-43d1-9325-e8be75d86888/File/2013CDiffFinal.pdfhttps://gi.org/guideline/diagnosis-and-management-of-c-difficile-associated-diarrhea-and-colitis/

Action Plan:

• Standardize C.diff Case Criteria

• Standardize Sample Collection

• Develop EMR Order Screening

• Standardize Test Methodology Algorithm

• Clarify Guidelines and Expectations for Lab

• Review C.diff Infection Prevention Procedure

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Alaska Regional C.diff Initiative

• 3+ loose stools within 24 hours

• No laxative/stool softeners within 48 hours

• No +C.diff test in last 30 days

• No –C.diff test in last 7 days

• Risk factors for consideration by MD– Recent antibiotic use (10+ days) Esp: Fluoroquinolones, Clinadmycin, Cephalosporins, Penicillins

– Age (>65)– On PPI– Recent hospitalization or long term care facility

• Otherwise, C.diff test not recommended

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C.Diff Case Criteria

• Collection Container– Preservative free– No liquid medium or additives

• Collection Samples– “Loose” = #6 or #7 on Bristol Stool Chart

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Sample Collection

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EMR Order Screening

A large part of the C.diff Initiative discussion was around testing methodology

• Only strains with toxin producing genes cause C.difficile infection (CDI)– TcdA gene and TcdB gene– Sections of the pathogenicity locus (PaLoc)– NAP01-B1-027 Ribotype (indicator of a hyper-virulent strain) Note: some commercial testing methods can identify this strain

• Stains that do carry toxin producing genes are called toxigenic, or cytotoxigenic

• Strains that do NOT have toxin producing genes may be referred to as non-toxigenic, or non-cytotoxigenic. These do not cause CDI.

We want to identify true C.diff infections – what test(s) should we use?

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The Tests -- Background

• Glutamate Dehydrogenase (GDH) is a cell wall associated enzyme

• GDH is highly conserved in C.difficile– Found in both cytotoxigenic AND non-

cytotoxigenic strains– Other organisms may produce positive result

• Method of testing is EIA (Enzyme immunoassay)– Sensitivity varies in literature (76%-98%)– Examine manufacturer sensitivity claims

carefully Reported sensitivity varies with manufacturer Comparator method used in the claim is

important

• NON-SPECIFIC ASSAY: cannot be used as a stand-alone test

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The Tests -- Glutamate Dehydrogenase

• Detects Toxin A/B released from the cell to the environment– Correlation to level of toxin and severity of

disease

• Method of testing is EIA (Enzyme immunoassay)– Good specificity but very poor sensitivity

(~75%) – A positive result correlates well with disease– A negative does not indicate the absence of

cytotoxigenic C.diff Get a lot of false negatives!

• LOW SENSITIVITY ASSAY: cannot be used as a stand-alone test

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The Tests -- Toxin EIA

• NAAT stands for Nucleic Acid Amplification Test

• PCR and NAAT detect specific molecular sequences and amplify it to detect very small amounts of material– The terms are often used interchangeably

• PCR/NAAT detect a genetic sequence specific to the toxin gene in C. difficile.– Very sensitive, very specific to detecting

strains which MAY cause CDI!– The gene, while present, may not be

actively expressing – this means it is capable of producing toxins, but it might not be doing so

– Can be positive in a patient who is not symptomatic (carrier)

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The Tests -- PCR/NAAT

• Carriers are people who are host to a toxigenic strain of C. difficile but who do not have active symptoms of C. difficile disease

• Carriers may be an important reservoir of infection to other patients– “Levels of C. difficile contamination on the skin and in the

surrounding environment of carriers approached those for symptomatic patients. In optimizing diagnostic algorithms for CDI, we need to be aware of patients who may not have a laboratory diagnosis of CDI (the primary purpose of testing), but are nonetheless important as potential sources of bacterial transmission.”

• The rate of carriers varies in a population– Some nursing homes have found carrier rates up to 50%

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Emerging Topic: C.Diff Carriers

Sourceshttp://www.sciencedirect.com/science/article/pii/S1198743X14608430 http://www.uptodate.com/contents/clostridium-difficile-in-adults-epidemiology-microbiology-

andpathophysiology?source=related_link

Key Points in the Quebec Study:• Patients screened for asymptomatic C. difficile

carriage on admission (rectal swab and PCR test)• Found 4.8% rate of carriers• Instituted modified infection control measures for

these patients– They were not treated for CDI– Cohorted with other patients with carrier status– Caregivers had to wear gloves but not a gown for patient

contact or when entering the room.– Environmental cleaning was instituted to the same stringency

as CDI cases (chlorine based product for daily disinfection of room or patient area and used equipment)

• Results showed a steady 7% per month decrease of CDI in the facility over time

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C.Diff Carriers

SourcesJAMA Intern Med. 2016;176(6):796-804. doi:10.1001/jamainternmed.2016.0177

GDH+ Toxin w/NAAT

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Testing Algorithm -- Option 1

NAAT w/ Toxin

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Testing Algorithm -- Option 2

Toxigenic = toxin producing

• Sensitivity and Specificity– The lab considers the best test to be the one that has the

highest sensitivity and specificity – we want that test to be able to detect even low amounts, and we want to be confident that it’s right when it says it’s positive

• Cost– Costs are always considered. There are reagent costs, staffing

costs, equipment costs, and also the cost outside of the laboratory such as length of stay, and length of isolation.Turn Around Time

– Timely detection and isolation is critical to reducing C. difficile

• Staffing and Workflow– Consider how many staff must be trained to run the

test and how often the tests will be run. In general, multi-step, reflex tests involving multiple decisions and actions take longer, particularly on night shift if staff are covering multiple departments.

• Potential Errors– The lab is always considering the potential error sources

in any assay

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Considerations

Analytical Sensitivity is reported as:

# positive results obtained (new test)# true positives (reference method)

• Sensitivity = what percent of the time will this test detect a true positive

• Example: 90% sensitive sounds good but it means you miss 21 positive patients out of every 201 positive patients!

Analytical specificity is reported as:

# negatives results obtained (new test) # true negatives (reference method) + false positives

• Specificity = how well the assay does at detecting ONLY the substance of interest

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Considerations: Sensitivity + Specificity

Sourceshttps://www.accessdata.fda.gov/cdrh_docs/reviews/K082499.pdf

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Comparing Sensitivities

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Consideration: Cost/Tech Time

2016 Medicare reimbursement in Alaska is $16.33 for GDH/toxin and $47.80 for NAAT ($31.47 more)

The cost of ONE missed CDI case is estimated at $13,845

Assay (Time) Tech Time

# Technical Steps

Estimated Reagent Cost

GDH + toxin EIA (15min) 4-5 min 11* $

GDH + toxin + PCR (43-85 min)

8-10 min 15-18 $$$

NAAT/PCR (28-70 min) 4-5 min 4-7 $$

PCR + toxin (19-20 min)

8-10 min 15-18 $$$

• Limit of detection – how many bacteria have to be present for the assay to get a positive result?

• PCR limit of detection is superior to EIA• “The misperception of GDH tests rested on their

evaluation in terms of cytotoxin assay. “A relatively insensitive assay compared to a relatively insensitive assay looks good,” says Lance R. Peterson, MD, director of microbiology and infectious diseases research, Department of Pathology and Laboratory Medicine, Evanston (Ill.) Hospital, and associate epidemiologist, NorthShore University HealthSystem. “Compared to CTA,” he adds, “GDH is 90 percent sensitive, but both are only 55 percent to 85 percent sensitive compared to toxigenic culture.”

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Consideration: Limit of Detection

Assay Limit of Detection (CFU/mL)Real-time PCR 2,047Loop-mediated Amplification 32,750GDH EIA 100,000

When reviewing algorithm options:

• Type of facility

• Bed allocation

• Patient population

• Equipment availability

• Staffing/staff workflow

• Cost

• Risk Assessment

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Other Considerations

• Favored using the most sensitive and specificassay, which is NAAT/PCR

• Recognized benefit of adding a toxin assay to positive NAAT/PCR result is to guide better recognition of carrier state (vs CDI) and lead to better antimicrobial stewardship

• Recognized the workflow challenges associated with toxin EIA but due to the clinical significance of C. difficile we will prioritize testing and perform toxin EIA immediately after a positive PCR result is generated

• Thus, decided to follow NAAT w/ Toxin algorithm

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Testing -- Final Thoughts

• Testing criteria– Type 6 or 7 liquid stools only Note: unless prior consultation has been arranged to test a patient

with an ileus diagnosis– Only stools received in sterile container without liquid

preservative

• Rejection criteria– Do not test non-liquid stool in non-sterile container– Do not repeat PCR test within 7 days of a negative test– Do not repeat PCR test within 30 days of a positive test– Do not test samples on patients <12 months of age without

prior consultation

• Immediate PCR and toxin testing– Samples must be refrigerated (toxin is labile in as little as 2

hours)– Inpatient samples >2 hours old must be recollected– Outpatient samples >2 hours old will receive PCR testing only

• Support staff who may have questions on methodology, interpretations, or test restrictions

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Guidelines and Expectations for Lab

1. Identify patient meeting C.diff criteria

2. Place Enteric precautions

3. Collect appropriate sample

4. Interpret lab resultsa. Treatmentb. Isolationc. Room cleaning

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C.diff Infection Prevention Procedure

• Treatment will depends on severity of disease

• *Clinical correlation with symptoms is required, as patients in the early stage of symptoms may not yet have toxin produced at a detectable level

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Interpretation Table

Lab Result Interpretation Isolation Needs Treatment of CDICleaning of Patient

Rooms

PCR- /

No Toxin needed

Negative

DNA for strain of C. difficile that produces toxin is not detected.

No isolation No treatment of C. difficile recommended

No extra cleaning precautions needed

PCR+ / Toxin- Possible Carrier

Clinical interpretation required

Full isolation -Remove/reduce broad spectrum antibiotics -If other clinical causes likely caused diarrhea – no C. difficile treatment is needed*

-Daily cleaning with bleach required-Terminal clean at discharge with ATP quality test

PCR+ / Toxin+ Positive

Both DNA and C. difficile toxin are detected in the stool.

Full isolation -Remove/reduce broad spectrum antibiotics -Oral vanco or IV/Oral metronidazole

-Daily cleaning with bleach required-Terminal clean at discharge with ATP quality test

1. Identify patient meeting C.diff criteria

2. Place Enteric precautions

3. Collect appropriate sample

4. Interpret lab resultsa. Treatmentb. Isolationc. Room cleaning

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C.diff Infection Prevention Procedure

*Proposed Addendum*5. Downgrade precautions

a. PCR+ patient has had formed stools for 72 hoursb. Move patient into new roomc. Terminal clean old roomd. Initiate “Modified” Enteric Precautions

Key Points in the Quebec Study:

• Instituted modified infection control measures for these patients– They were not treated for CDI– Cohorted with other patients with carrier status– Caregivers had to wear gloves but not a gown for patient

contact or when entering the room– Environmental cleaning was instituted to the same

stringency as CDI cases (chlorine based product for daily disinfection of room or patient area and used equipment)

• Results showed a steady 7% per month decrease of CDI in the facility over time

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C.diff Infection Prevention Procedure

SourceJAMA Intern Med. 2016;176(6):796-804. doi:10.1001/jamainternmed.2016.0177

• Conclusions: “patients under contact precautions were more likely to perceive problems with their care, especially poor coordination of care and a lack of respect for patient preferences”

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C.diff Infection Prevention Procedure

Sourcehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070370/

• APIC 2013 recommendation:– “It is currently recommended that Contact Precautions may be discontinued when

the patient no longer has diarrhea. Because of continued environmental contamination and patient skin colonization, some experts recommend continuing Contact Precautions for 2 days after diarrhea stops. In addition, if the rates of CDI remain high, Contact Precautions may be continued until hospital discharge.”

• Quebec Study– “Current infection control recommendations focus mainly on patients with

CDI.9,10However, C difficile asymptomatic carriers may also have a role in spore dissemination11for several reasons: they outnumber patients with CDI,12- 14 they can contaminate the environment and caregivers’ hands,12,15 and they are not detected and thus are not placed under isolation precautions.16”

– Detecting and isolating asymptomatic carriers was associated with a significant decrease in the HA-CDI incidence rate

• Our approach– Modified precautions for all PCR+ patients no longer symptomatic (regardless of

EIA result)30

C.diff Infection Prevention Procedure

Enteric Precautions “Modified” Enteric Precautions

Required:GownsGlovesBleachSoap/Water

Required:GlovesBleachSoap/Water

Not Required:Gowns

• Before 2017: reported any PCR+ CDI LabIDs• 2018: anticipate our facility having more “carriers” and

fewer CDI, thus fewer CDI LabIDs reported to NHSN– True cases

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New: Testing Impact on HA-CDI LabID

Sourcehttps://www.cdc.gov/nhsn/pdfs/newsletters/nhsn-nl-dec-2017-508.pdf

After the initial spike in apparent CDI with implementation of NAAT, CDI rates are seen to drop below

the pre-implementation rate.Case Study: John Hopkins Hospital, 2010-2012

In 2010, the laboratory switched completely to a NAAT that was implemented twice daily 5 days per week and

offered once per day on weekends. In the period immediately after implementation, C. difficile transmission rates appeared to increase from 11.5 cases/10,000 patient days to close to 15 cases/10,000 patient days for calendar year 2010 (Lisa Maragakis, JHH, personal communication).

Rapid test availability allowed for improved isolation. Additionally, the apparent increase in transmission was

used to campaign for better hand hygiene and compliance with infection control practices, such as enhanced

environmental cleaning. By the second quarter of 2012, the transmission rates were among the lowest seen since 2007:

9 cases/100,000 population (Lisa Maragakis, JHH, personal communication).

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The NAAT Reporting Phenomenon

Sourcehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719497/

• Starting out– Multiple Coaching Calls – CMOs, CNOs, Labs, ICPS, EVS, Quality, Leadership

collaboration– Requested feedback

• Obstacles encountered– IT: Incorporating the screening questions into the EMR– Lab: Re-prioritize poop, and expect questions from clinicians – Nursing: interpreting results and isolation precautions– Infection Control: controversy over “modified” contact

precautions

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Where We Started…

• Testing well received– Clinical outcomes are reviewed and appropriate– More colonizations in community than expected (PCR+/Toxin-) Outpatient especially

– No NAP01 strains

• Rejections at all time low

• Identified fewer HA-LabIDs in 2017 than 2016

• “Modified” Enteric Precaution protocol pending

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Where We Are Now…

• Review the literature

• Infectious Disease, Infection Prevention, Lab, Quality, Nursing, and Educators need convey same message and support each other

• Educate staff properly

• Remember: the goal is to appropriately test and treat patients while controlling the spread of the organism to others

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Final Thoughts