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Clostridium Difficile Update

Transmission, Prevention, Treatment Maggie Hagan, M.D.

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C. Diff Colitis

• History – Described in 1935 by Hall and O Toole – Named the Difficult Clostridium – Found to colonize healthy newborns – Found to be toxigenic – 1978 C diff. Toxin found in the stool of patients

with antibiotic associated diarrhea

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Heron et al. Natl Vital Stat Rep 2009;57(14). Available at http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf

Background: Impact Age-Adjusted Death Rate* for

Enterocolitis Due to C. difficile, 1999–2006

*Per 100,000 US standard population

0

0.5

1.0

1.5

2.0

2.5

1999 2003

Rate

2000 2004 2001 2005 2002 2006 Year

Male Female White Black Entire US population

Heron et al. Natl Vital Stat Rep 2009;57(14). Available at http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf

Background: ImpactAge-Adjusted Death Rate* for

Enterocolitis Due to C. difficile, 1999–2006

*Per 100,000 US standard population

0

0.5

1.0

1.5

2.0

2.5

1999 2003

Rate

2000 20042001 20052002 2006Year

MaleFemaleWhiteBlackEntire US population

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Epidemiology of C diff

• Prevalence of asymptomatic colonization 7-50% of adult inpatients in acute care

• 5-7% among adults in long term care • Risk of colonization increases during

hospitalization

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Clostridium Difficile Treatment and Transmission Margaret Hagan, MD

Family Medicine Winter Symposium December 5, 2014

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Changing Epidemiology of C diff

• Estimated 500,000 cases of C diff/year in US • Estimated 15,000-20,000 deaths/year • Community C diff 7.6 cases/100,000 person

years • 35% have had no antibiotics within 42 days

Nature. 2009:7;526-36

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Changing Epidemiology of C diff

• Beginning in 2001 there was an abrupt increase in hospital discharges listing C diff as a diagnosis

• 5 fold increase in patients >65 • Strain termed NAP1/BI/027 • Increase in cases in healthy people/outpatients

Critical Care 2008, 12:203

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Pathogenesis of C diff

• A “two hit”phenomenon – Colonization with C diff – Alteration of gut flora with antibiotics

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• Oral ingestion of C diff spores • Spores germinate into vegetative form in small

intestine • Disruption of commensal flora of intestine

allows C diff to flourish • C diff produces two exotoxins: Toxin A and

Toxin B Critical Care 2008, 12:203

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C diff Outbreaks

Three Factors Implicated – Increased production of Toxins A and B – Floroquinolone resistance – Production of a binary toxin

N Engl J Med. 2008: 359;18

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Toxin Production in Epidemic Strains of C diff

N Engl J Med. 2008: 359;18 10


Nature. 2009:7;526-36 11


Nature. 2009:7;526-36 12



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Risk Factors for C diff

• Advanced age • Duration of hospitalization • Exposure to antibiotics • Chemotherapy • HIV • GI surgery • Acid suppression

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Clinical Manifestations of C diff

• Range from asymptomatic to fulminant disease

• Diarrhea • Fever • Abdominal pain • Leukocytosis • May have abdominal pain/distention without

diarrhea in advanced disease

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Clinical Manifestations of C diff

• Incubation period from acquisition of C diff to CDI is short (median2-3 days)

• Patients may remain at risk for C diff for 3 months or longer after they have stopped antibiotics

MMWR Morb Mortal Wkly Rep 2012;61:157-162. 15

Diagnosis of C difficile Infection

• Testing should be performed only on diarrheal stool, unless ileus due to C diff is suspected

• Only a single specimen needed for testing • PCR testing is rapid, sensitive and specific • EIA testing for C diff toxin A and B is rapid but less

sensitive • Repeat testing during the same episode of

diarrhea is discouraged • No “test of cure”

Infect Control Hosp Epidemiol 2010; 31,431-55. 16



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Transmission of C diff

CID 2010:50:1458-61 17

Factors Associated with Increased Shedding of C diff

• Diarrhea • Fecal incontinence • High concentrations of organisms in the stool • “super shedders”

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Environment as a Source of Transmission of C difficile

• C diff is commonly isolated from the hands of health care providers

• The frequency of positive hand cultures is strongly correlated to the level of environmental contamination

• Hands 0% when Environment 0-25% • Hands 8% when Environment 26-50% • Hands 36% when Environment >50%

Am J Infect Control 2010;38:S25-33. 19

Environment as a Source of Transmission of C difficile

• Acquisition of spores on gloved hands occurred as frequently after contact with environmental surfaces as after contact with skin sites (50% vs 50%)

• Prior room occupant with C diff is a significant risk factor for C diff acquisition (11% vs 5%)

1). Guerrero DM, et al. Am J Infect Control 2011 2). Shaughnessy MK, et al. Infect Control Hosp Epidemiol 2010;32:210-6

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Environmental Sources of C difficile

• Electronic thermometers • Blood pressure cuffs • Bedside commodes • Stethoscopes

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What Makes C diff Different From Other Bacteria?

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Infection Control Measures for C diff Infection

• Gowns and gloves for contact with patients • Wash hands with soap and water • Private room or cohort patients with private

commode • Chlorine containing cleaning agents, terminal

cleaning of rooms • Antibiotic restraint

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Special Approach to Prevent C diff Transmission

• Expedite identification and isolation of patients

• Prolong duration of contact precautions • Improve bathing to reduce the burden of

spores on skin • Daily disinfection of high-touch surfaces

during C diff treatment • Use more sensitive diagnostic tests

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Cleaning of High Touch Surfaces Daily

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Environmental Cleaning to Control C diff

CDC, SHEA, IDSA all recommend use of a 1:10 dilution of sodium hypochlorite for environmental disinfection in outbreak settings of C diff

Am J Infect Control 2010;38:S25-33.

27 28



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29 30

UV Light and C diff

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Use of UV Light to Control C diff

• Numerous retrospective studies funded by industry

• Recent prospective study looking at environmental cultures

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Use of UV Light to Control C diff

Infect Control Hosp Epidemiol. May 2013; 34(5): 466–471. 33

Hand Hygiene for C diff

• C diff in its spore form is highly resistant to killing by alcohol

• Spores can be physically removed by soap and water

• Several studies have documented reduction in C diff rates by improvement in hand washing compliance

Infect Control Hosp Epidemiol. 2009 Oct;30(10):939-44.

Infect Control Hosp Epidemiol 2010;31:565–570.

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C diff on Hands of HCWs • Compared hand contamination

• 66 HCW caring for patients with CDI • 44 HCW controls • Monitored for 8 weeks

• Results • C diff spores on 24% of samples of hands from HCWs

caring for CDI patients • No spores on hands of control HCWs

• Nursing assistants had highest rates • Most of HCWs used gloves for patient contact

Infect Cont and Hosp Epidemiol. January 2014;35 (1): 10-15 35

Summary of Prevention Measures

• Contact Precautions for duration of illness

• Hand hygiene in compliance with CDC/WHO

• Cleaning and disinfection of equipment and environment

• Laboratory-based alert system

• CDI surveillance • Education

• Prolonged duration of Contact Precautions*

• Presumptive isolation • Evaluate and optimize

testing • Soap and water for HH upon

exiting CDI room • Universal glove use on units

with high CDI rates* • Bleach for environmental

disinfection • Antimicrobial stewardship

program

Core Measures Supplemental Measures

* Not included in CDC/HICPAC 2007 Guideline for Isolation Precautions 36



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Measures to Improve C diff Rates

• Analyze rates • Form a multidisciplinary performance

improvement team – Environmental cleaning – Proper PPE – Hand washing – Antibiotic stewardship

37 38

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Treatment of C diff Infection

• Metronidazole • Vancomycin • Fidaxomicin • Probiotics • Immunoglobulin • Fecal Transplant

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• Metronidazole is the drug of choice – 500mg tid for 10-14 days

• Vancomycin drug of choice for severe infection – 125-500mg qid for 10-14 days – Tapering schedule for recurrent infections

• Severe/Complicated C diff Vancomycin 500mg po q 6 hours and Metronidazole 500mg IV q 8 hours

Infection Control and Hospital Epidemiology, Vol. 31, No. 5 (May 2010), pp. 431-455 41

Metronidazole vs Vancomycin

N Engl J Med. 2008: 359;18 42

Fidaxomicin vs Vancomycin

• A multicenter, prospective, randomized, placebo controlled trial

• 629 patients enrolled at 52 sites • No difference in cure rates • Treatment with Fidaxomicin associated with

lower rate of recurrence (15.4 vs 25.3%) • Cost issues

N Engl J Med 2011; 364:422-431 43


• Vancomycin enema • Fecal transplant • Colectomy

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Fecal Transplantation

• Treating Clostridium difficile Infection With Fecal Microbiota Transplantation

• Obtain donor stool from a relative • Screen donor for C diff • Mix donor stool with tap water to make an solution • Instill as an enema to the patient

• Via Christi has a protocol for FMT • Requires specific consent form

Clin Gastro and Hepatol. , December 2011.9(12) 1044-1049

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Probiotics in the Treatment of C diff

• Current C diff guidelines do not recommend use of probiotics

• Cochrane review 2008 reviewed 4 studies and found a statistically significant benefit in only one small study

• More recent studies of multi-strain probiotics show promise

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Role of Immunotherapy in the Treatment of C diff

• Inability to mount an immune response appears to make patient susceptible to recurrent infections

• Favorable outcomes with use of IgG for recurrent infections

• No randomized controlled trials • Vaccine for C diff is being studied

49 Nature. 2009:7;526-36 Nature. 2009:7;526-36 50

Immune Response to C diff

N Engl J Med. 2008: 359;18 51

Treatment of C diff

• Check IgG level on patients with severe or recurrent C diff

• Give a one-time dose of IVIG to patients with low IgG

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Role of Antibiotic Stewardship in Controlling C diff

• Use of antibiotics is associated with increase in C diff rates

• Certain antibiotics are associated with higher C diff rates (floroquinolones)

• Several studies have shown reductions in C diff rates with effective antimicrobial management programs

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