PUBLIC HEALTH DIVISION

Acute and Communicable Disease Prevention Section

Clostridium difficile: An Overview

CDI Webinar

July 11, 2017

Outline

• Background

– Microbiology

– Burden

– Pathogenesis

• Diagnostic testing

• Treatment

• Prevention

– Antimicrobial stewardship

– Practical approach to CDI prevention

• How is your facility dealing with CDI?

Background:

Microbiology,

Burden,

Pathogenesis

C. difficile: Microbiology

• Gram-positive spore-forming

obligate anaerobic rod-shaped

bacterium

• 1935: part of flora of healthy

infants; Bacillus difficilis

– 1-3% of heatlhy adults

– 70% of children < 12 months

• 1970s: C. difficile CDAD

(CDI preferred)

• Toxins-producing strains cause

C. difficile infection (CDI)

Smits Nat Rev Dis Primers. 2016 Apr 7; 2:16020. doi: 10.1038/nrdp.2016.20

Time line for surveillance definitions of CDI

Admission Discharge

< 4 weeks 4-12 weeks

HO CO-

HCFA

Indeterminate CA-CDI

Time

2 d > 12 weeks

*

HO: Hospital (Healthcare)-Onset

CO-HCFA: Community-Onset , Healthcare Facility-

Associated

CA: Community-Associated

* Depending upon whether patient was discharged within previous 12 weeks

Onset defined in NHSN by specimen collection date

Day 1 Day 4

C. difficile: Impact

• 453,000 CDI cases1

• 293,000 healthcare-associated

• 107,000 hospital-onset

• 104,000 nursing home-onset

• 81,000 community-onset, healthcare-facility associated

• 160,000 community-associated

• 82% associated with outpatient healthcare exposure

Overall, 94% of CDI cases related to healthcare

• 29,000 deaths

• $4.8 billion in excess healthcare costs2

1. Lessa et al. N Engl J Med 2015; 372(9):825-834. 2. Dubberke et al. Clin Infect Dis 2012; 55:S88-92.

Estimated U.S. Burden of CDI, According to the Location of Stool Collection and Inpatient Health Care Exposure, 2011.

CO-HCA: Community onset healthcare-associatedNHO: Nursing home onsetHO: Hospital onset

1. Magill et al. N Engl J Med 2014; 370:1198-1208. 2. Steiner et al. HCUP Projections Report 2014-01.

C. difficile: Impact

• C. difficile most commonly reported pathogen in 2011 multistate

prevalence survey of healthcare-associated infections (HAI)1

• 12.1% of 452 HAIs caused by CDI

• Rates of CDI per 1,000 discharges have risen through 20132

Oregon C. difficile standardized infection

ratios (SIR): 2012-2015

• Fecal-oral route

– Contaminated hands of healthcare workers

– Contaminated environmental surfaces.

• Reservoir

– Human: colonized or infected persons

– Contaminated environment

• C. difficile spores can survive for up to 5 months on environmental

surfaces.

C. difficile : Transmission

CDI: Pathogenesis Step 1-

Ingestion

of spores

transmitted

from

reservoirs

Step 2- Germination

into growing

(vegetative) form

Step 3 - Altered lower

intestine flora (due to

antimicrobial use)

allows proliferation of

C. difficile in colon

Step 4 - Toxin B & A

production leads to colon

damage +/- pseudomembrane

CDI Pathogenesis

Admitted to

healthcare facility

Antimicrobials

C Diff exposure &

acquisition

Colonized

no

symptoms

Infected

Symptomatic

CDI: Host risk factorsAdvanced age

• Incidence higher among females, whites, and persons > 65 years1

• Death more common in persons > 65 years (5x greater risk)2

Underlying illness and medical history

• 79% of 7421 patients with CDI had a comorbid condition2

• 38% of 585 patients with NAP1 strain had ED visit in previous 12 weeks2

• Tube feeds3

Immunosuppression

• Inflammatory bowel disease2

• Immune-suppressive treatment2

• Hematological malignancy/stem cell transplant (15-25x greater risk)4

1. Lessa et al. N Engl J Med 2015; 372(9):825-834.

2. See et al. Clin Infect Dis 2014; 58(10):1394-1400.

3. Bliss et al. Ann Intern Med 1998; 129:1012-1019.

4. Kombuj et al. Infect Control Hosp Epidemiol 2016; 37:8-15.

CDI: Modifiable risk factors

Exposure to antibiotics

High Risk:

• Fluoroquinolones 1

• 3rd and 4th generation cephalosporins, clindamycin, carbapenems2

Exposure to C. difficile spores

• Spores can remain viable for months3

• Contamination is increased in rooms of patients with active CDI 4,5

• Hands of patients and personnel are easily contaminated5

Gastric acid suppression

• Data, though inconsistent, implicate proton pump inhibitor (PPI) use1,4,6,7

• More study is needed to link restriction of PPI use with decreased CDI incidence8

1. Pepin. Clin Infect Dis 2005; 2. Hensgens. J Antimicrob Chemother 2012; 3. Weber.

Infect Control Hosp Epidemiol 2011; 4. Dubberke. Am J Infect Control 2007.

5. Shaugnessy. Infect Control Hosp Epidemiol 2011; 6. Linney. Can J Hosp Pharm 2010;

7. Buendgens. J Crit Care 2014; 8. Dubberke. Infect Control Hosp Epidemiol 2014.

• Illness caused by toxin-producing strains of

C. difficile ranges from

– Asymptomatic carriers = Colonized

– Mild or moderate diarrhea

– Pseudo membranous colitis that can be fatal

• A median time between exposure to onset of

CDI symptoms is of 2–3 days

• Risk of developing CDI after exposure ranges

between 5-10 days to 10 weeks

Clinical manifestations

• Watery diarrhea ( > 3 unformed stools in 24 or fewer consecutive

hours)

• Loss of appetite

• Fever

• Nausea

• Abdominal pain and cramping

CDI: Symptoms

Epidemiology: Epidemic Strain

• BI/NAP1/027, toxinotype III

• First emerged in 2000 (Eastern Canada)1

• Associated with healthcare2

• More resistant to fluoroquinolones3

• Greater virulence

• Associated with more severe disease and mortality4

• Increased toxin A and B production4,5

• Polymorphisms in binding domain of toxin B5

• Oregon: 16% (11 of 68) strains with PFGE performed

1. McDonald et al. N Engl J Med 2005; 353(23):2433-2441.

2. See et al. Clin Infect Dis 2014; 58(10):1394-1400.

3. Pepin et al. Clin Infect Dis 2005; 41(9):1254–1260.

4. Stabler et al. J Med Micro 2008; 57(6):771-775.

5. Warny et al. Lancet 2005; 366(9491):1079-1084.

Diagnostic testing

• Testing should be performed only on diarrheal

stool

• Testing asymptomatic patients is not indicated

• Testing for cure is not recommended

Best Strategy for C. difficile Testing

2. Dubberke et al. Infect Control Hosp Epidemiol 2014; 35 (6):628-645

Diagnostic tests for toxigenic C. difficileTests by Type & Method Target(s) Characteristics

Gold

standards

Toxigenic

culture

Toxigenic C. difficile Reference standard

Difficult to perform

Time consuming (24-48 h)

Cell

cytotoxic

assay

Toxins A or B Reference standard

Highly sensitive for toxin vs. EIA

Difficult to perform

Time consuming (24-48 h)

Rapid

diagnostic

tests

EIA Glutamate

dehydrogenase

EIA Toxins A or B

NAAT

RT-PCR tcdB or tcdC genes

LAMP tcdA or tcdB genes

References

Diagnostic tests for toxigenic C. difficileTests by Type & Method Target(s) Characteristics

Gold

standards

Toxigenic

culture

Toxigenic C.

difficile

Cell

cytotoxic

assay

Toxins A or B

Rapid

diagnostic

tests

EIA Glutamate

dehydrogenase

Must be paired with a test of toxin

Variable sensitivity & specificity

EIA Toxins A or B Variable sensitivity & specificity

NAAT More expensive than EIA

Highly sensitive & specific for toxigenic C. difficile

May increase detection of colonization

RT-PCR tcdB or tcdC

genes

tcdA-negative/tcdB-positive strains can cause

disease

LAMP tcdA or tcdB

genes

tcdA-positive/tcdB-negative strains not well described

in human disease

Caution required in interpreting negative results

based on tcdA testing alone by LAMP

References

Guidance from the American

Society for Microbiology

• Toxin A/B enzyme immunoassays have low sensitivity and should not be used as stand alone tests.1

• Highly sensitive screening tests like glutamate dehydrogenase antigen assays (GDH) should have positive results confirmed.

• Nucleic acid amplification that detects C. difficile toxin genes may be used as a stand alone test.

1. Am Soc Microbiol, 2010.

Sample multistep algorithm for rapid

diagnosis of C. difficile infection

JAMA. 2015;313(4):398-408. doi:10.1001/jama.2014.17103

Studies examining

performance

characteristics of

multistep

algorithms for

rapid diagnosis of

C. difficile

infection

NAAT-containing algorithms

perform better

Bagdasarian JAMA. 2015;313(4)398-408. doi:10.1001/jama.2014.17103

Treatment

Treatment options for CDI

Smits Nat Rev Dis Primers. 2016 Apr 7; 2:16020. doi: 10.1038/nrdp.2016.20

Fecal microbiota transplant

Prevention

Overview

Basic Practices Special Approaches

Appropriate use of antimicrobials Antimicrobial stewardship program

Hand hygiene per CDC/WHO recommendations

Measure healthcare personnel adherence

Hand hygiene with soap and water after glove removal

following care of CDI patients

Intensify measurement of adherence

Contact Precautions for CDI patients

Measure healthcare personnel adherence

Presumptive Contact Precautions while laboratory

results are pending

Prolonged duration of Contact Precautions

Intensify measurement of adherence

Cleaning and disinfection of equipment and

environment

Use of EPA-approved sporicidal disinfectant

Assess adequacy of room cleaning

Laboratory-based alert system for immediate

notification to IP and clinical personnel of newly

diagnosed CDI patients

CDI surveillance, analysis, and reporting

Educate healthcare personnel, patients, and families

• Basic practices are prevention measures that should be in place at all times.

• Facilities should consider adopting some or all of the special approaches whenever ongoing

opportunities for improvement are identified or as indicated by risk assessment.

Dubberke et al. Infect Control Hosp Epidemiol 2014; 35(6):628-645.

Antimicrobial Stewardship

Exposure to any antimicrobial is the single most important risk

factor for C. difficile infection (CDI).

• Antibiotic exposure has lasting impact on the

microbiome.

• Risk of CDI is elevated (7-10 fold) during and in the 3 months

following antimicrobial therapy1,2

• 85-90% of CDI occurs within 30 days of antimicrobial exposure1

• Target high risk antibiotics for CDI prevention

• Fluoroquinolones3

• 3rd/4th generation cephalosporins, carbapenems2

1. Chang et al. Infect Control Hosp Epidemiol 2007; 28(8):926–931.

2. Hensgens et al. J Antimicrob Chemother 2012; 67(3):742-748.

1. Hsu et al. Am J Gastroenterol 2010; 105(11):2327–2339.

Currently 39% (1,642/4,184) of U.S. hospitals have an antibiotic stewardship

program with all 7 core elements.

The national goal is 100% of hospitals by 2020.

http://www.cdc.gov/getsmart/healthcare/evidence.html

Seven Core Elements of

Antimicrobial Stewardship

1. Leadership CommitmentDedicating necessary human, financial, technological resources

2. AccountabilityAppointing a single leader (physician or pharmacist) responsible for program outcomes

3. Drug Expertise A single dedicated pharmacist with responsibility to improve antibiotic use

4. TrackingMonitoring antibiotic prescribing and resistance patterns

5. ReportingFeedback of information on antibiotic use and resistance to frontline providers

6. EducationOngoing education of clinicians about resistance and optimal prescribing

7. Action Implementing at least one recommended action

http://www.cdc.gov/getsmart/healthcare/implementation/core-elements.html

Stewardship Approach: Feedback

Non-restrictive feedback resulted in statistically significant

reductions in incident CDI.

Valiquette et al. Clin Infect Dis 2007; 45:S112-121.

Tertiary Hospital in Quebec, 2003-2006

Reductions in CDI attained through antimicrobial stewardship surpassed those attained through infection control measures.

Fig. 1 Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile and extended-spectrum β-lactamase (ESBL)-producing coliform rates following a restrictive antibiotic policy in a district general hospital over 2 years. pt/occ.bds, patient-occupied bed-days; DDDs, defined daily doses.

Dancer et al. Intl J Antimicrob Agents 2013; 41(2):137-142.

District general hospital; Glasgow, UK, 2007-2009

Stewardship Approach: Restriction

Formal restriction implemented

Restricting the use of ceftriaxone was associated with reduced

rates of CDI.

A practical approach

to CDI prevention

Targeted Assessment for

Prevention (TAP) Strategy

www.cdc.gov/hai/prevent/tap.html

CDI TAP reports available in NHSN

Work ongoing to use CO-CDI and other data sources to identify CDI cases from nursing homes and other community sources

Targetfacilities/units

Assess gaps in infection

prevention in targeted areas

Preventinfections by implementing

interventions to address the gaps

CDI Risk Assessment

• Conduct a risk assessment annually and whenever CDI goals

are not met1

• Use CDC’s Targeted Assessment for Prevention (TAP) Strategy

• Pairing the results of a CDI facility assessment with the CDI

Implementation Tool allows facilities to implement infection

prevention strategies that most directly meet their needs.

Dubberke et al. Infect Control Hosp Epidemiol 2014; 35(6):628-645. www.cdc.gov/hai/prevent/tap.html

CDI Case Review

• Review each CDI case (e.g., root cause analysis)

• Examine temporal and spatial relationships between

cases to determine units at risk for transmission due to

community-onset or hospital-onset CDI cases.

The CDI Implementation Tool includes a template for CDI Case Review

Dubberke et al. Infect Control Hosp Epidemiol 2014; 35(6):628-645. www.cdc.gov/hai/prevent/tap.html

A Coordinated Response

Partners in Prevention:

The state and local

health department and

other state partners

can assist and provide

opportunities to

extend efforts across

the continuum of care

1. Slayton et al. MMWR 2015; 64(30): 826-831.

Figure from CDC Vitals Signs: http://www.cdc.gov/vitalsigns/stop-spread/index.html

A coordinated response is more effective than independent

efforts1

Communication During Patient Transfer of

Multidrug-Resistant Organisms (MDROs)

• Effective Jan 2014, OAR 333-019-0052 requires

facilities to notify in writing receiving institution

that patient is infected or colonized with MDRO

requiring transmission-based precaution in

addition to standard precautions

• Examples: CRE, MRSA, C. diff

• Typically require additional precautions such as

wearing mask, gown and gloves with patient

contact, in some cases, patient isolation

Template form

IFT rule implementation

• OR hospitals and SNFs surveyed in 2015 & 2016

# of facilities surveyed: 60 55 140 134

IFT rule implementation“We notify receiving facilities

of MDROs at discharge”

“Transferring facilities notify

us of MDROs”

What is your facility

doing?

48