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Clostridium difficile

I SHA BHATT
DEPARTMENT OF EPI DEMI OLOGY AND BI OSTATISTICS
DREXEL UNI VERSI TY SCHOOL OF PUBLI C HEALTH
MAY, 2014
Overview
Clinical context and terminology
Microbiology
Pathogenesis and reservoirs
Disease definition, syndromes , outcomes
Diagnosis and treatment
Surveillance and prevention strategies
Impact

History :
First cases of C.diff infections reported as far back as 1890s
First isolated in the stools of infants and described by Hall and
OToole in 1935 as Bacillus difficile.
In 1978, Bartlett et al, demonstrated a link between C.diff toxins and
cases of pseudomembranous colitis after antibiotic use.
The years 2003 2005 saw several outbreaks in Canada and United
Kingdom
2004 First International Clostridium difficile symposium(FICDS)
Microbiolo
gy
Gram positive
Motile ,obligate
anaerobe
Spore and Toxin
producing
Normal gut flora
especially in
infants and
elderly
Multiple strains
Also known as
C.diff
Source: http://www.bioquell.com/technology/microbiology/clostridium-difficile/
Culture : Isolation Media
CCFA: first proposed
BA with lysed horse blood:
Opaque grey-white colonies
TCCFA: Enhances sporulation

CDMN Selective Agar: C.
difficile grows better
Buchanens broth




Terminology:
Antibiotic-associated diarrhea : C.diff is only one of the etiologic
factors (10%-25%). Others include MRSA, Klebsiella, E.coli infections
Clostridium difficile infections (CDI) : diarrhea associated with
positive stool culture and toxin assays
Clostridium difficile associated diarrhea (CDAD): used
interchangeably with CDI.
Pseudomembranous colitis: fulminant CDI, severe and often fatal.
Confirmed endoscopically
Toxic megacolon: also diagnosed by CT and endoscopy. May lead to
perforation and death
Reservoir :

~2% normal adult gut flora
10 70% colonization in newborns and infants (50%)
Exogenous reservoir : animals feces
Spores : highly resistant to destruction and disinfection
Most acquired disease causing strains are in hospital settings and
through HCW hands
Increased colonization rates in hospitalized patients or those in long-
term care facilities after antibiotic exposure (10- 25 %)




Risk Factors :
Patients in hospitals and long-term care facilities
Exposure to antibiotics
Elderly
Children >1 year
Peripartum women
History of Inflammatory bowel diseases
Antibiotics implicated :
High Frequency Medium frequency Low Frequency
Ampicillin Erythromycin Chloramphenicol
Amoxicillin Other macrolides Metronidazole
Clindamycin Sulphonamides Rifampin
Fluoroquinolones Tetracyclines
Cephalosporins Vancomycin
Transmission:
Primary mode of transmission:
Fecal-Oral route
Direct contact: Hands of health
care workers
Patient to patient transmission
Family and/or visitor introduction
Asymptomatic carriers
Indirect transmission via fomites
Procedural transmission:
through improperly sterilized
rectal thermometers and
endoscopic tubes and intubation

CDI : Symptoms
CDI have a wide range of clinical presentation
Ingestion of C.diff may lead to excretion or asymptomatic
colonization of healthy individuals
Manifested disease may be mild, moderate to severe with
life-threatening consequences
Relapses are not uncommon in healthcare settings

Mild to Moderate cases Severe cases
Fever Pain, fever, diarrhea, increased WBCs
Abdominal pain Blood in stool
Diarrhea (>10 bowel movements
per day)
Electrolyte imbalance
Increased WBCs Paralytic ileus
Dehydration Toxic megacolon
Pseudomembranous colitis
Perforation
Death
Pathogenesis:
Disruption of normal protective gut flora
Ingestion of spores and colonization of C.diff
Toxin production A and B
Damage to the cytoskeletal structures, loss of tight
junctions leading to mucosal injury , inflammation,
increased fluid secretion
Colitis and diarrhea

Onset and Progression :
Source: http://www.cdc.gov/HAI/pdfs/cdiff/Cohen-IDSA-SHEA-CDI-guidelines-2010.pdf
Course :
Onset usually >3 days - ~7 days
Latent period difficult to determine due to
asymptomatic carriers
Acute infection lasts for more than 10 days and
continues depending on severity and extent of
mucosal damage
Infection may progress to complete resolution ,
recurrence or in severe cases coma or death
Case definition: Incident

Presence of symptoms (usually diarrhea i.e >10 bowl
movements per day)
AND
Either Stool test result positive for C. difcile toxins or toxigenic
C. difcile
OR
or colonoscopic evidence of pseudomembranous colitis.

Source : http://www.cdc.gov/HAI/pdfs/cdiff/Cohen-IDSA-SHEA-CDI-guidelines-2010.pdf
Probable case: prompt to isolate
and test
Consider presumptive isolation for patients with > 3 unformed stools
within 24 hours
Send specimen for testing and presumptively isolate patient pending
results
Positive predictive value of testing will also be optimized if focused on
patients with >3 unformed stools within 24 hours
Exception: patient with possible recurrent CDI (isolate and test following
first unformed stool)

Source : CDC SHEA Guildelines, 2012

Diagnosis : Laboratory
Testing
Tissue Culture Cytotoxin Assay : Gold standard to identify toxin in fecal
samples in Vero cells
Toxigenic Culture
4-6 isolates to CMC
24 hr. filtrate for toxin detection ( fast )
Enzyme Immunoassay for toxin detection ( Toxin A and B )
Glutamate dehydrogenase detection : characteristic enzyme produced
by C.diff
PCR toxin gene detection, greater sensitivity and specificity

Limitations to Laboratory
testing:
Cytotoxin assays have low sensitivity and specificity
Stool culture time-consuming
GDH : risk of cross reaction
Recommendation for best predictive outcome :
-Screening for GDH
-Followed by culture for C.diff or EIA toxin assay

Radiologic testing : CT
Accordion Sign
evidence of
Pseudomembranous
colitis
Endoscopic Testing :
Colonoscopy

Evidence suggestive
of PMC
Treatment :
Discontinue the offending agent stop the antimicrobial
treatment !!
Start supportive treatment simultaneously : Fluid and
symptomatic treatment
If not resolved with conservative therapy Start oral
metronidazole for 10 days or Vancomycin
When both vancomycin and metronidazole fail : antibiotic
combination therapy

Newer treatment modalities
:

Probiotics efficacy undetermined
Fecal micro biota transplant : risk of transplanting
other pathogens
IV immunoglobulins passive immunization
especially for Immunocompromised
Surgical approach : in severe fulminant cases
resection of necrotic colon to prevent sepsis
New Antibiotic: Fidaxomycin
Prevention: Core
strategies
Judicious use of high potency antibiotics
Contact Precautions for duration of diarrhea
Hand hygiene in compliance with CDC/WHO
Cleaning and disinfection of equipment and environment
Laboratory-based alert system for immediate notification
of positive test results
Educate about CDI: HCP, housekeeping, administration,
patients, families
Source: http://www.cdc.gov/ncidod/dhqp/id_CdiffFAQ_HCP.html
Dubberke et al. Infect Control Hosp Epidemiol 2008;29:S81-92
Prevention: Supplemental
strategies
Extend use of Contact Precautions beyond duration of diarrhea (e.g.,
48 hours)
Presumptive isolation for symptomatic patients pending
confirmation of CDI
Evaluate and optimize testing for CDI : for faster and accurate
diagnosis
Implement soap and water for hand hygiene before exiting room of a
patient with CDI
Implement universal glove use on units with high CDI rates
Use sodium hypochlorite (bleach) for spores

CDI : Incidence and Epidemiology
(US)
Increased incidence (2.7 cases per
1,000 discharges in 1997 to 6.8 cases
per 1,000 discharges in 2001)
Increased severity (0.15 to 0.60 cases
per 1,000 discharges) of CDI
23% annual increase in CDI-related
hospitalizations between 2000 and
2005, associated with an increased
age-adjusted, annual case-fatality rate
of 0.2% over the study period

Changing trends and
causes:
The proportion of children with toxin-positive stool tests
increased from 46% in 2001 to 64% in 2006.
Prior to 1990, predominant strain was toxinotype
0/ribotype 001
Now: ribotype 027 (BI/NAP1/027) is associated with
increased virulence, mortality and morbidity
Increase incidence in previously considered non-high risk
groups

Surveillance :
To layout case definitions for Healthcare facility
acquired CDI and community acquired CDI
Use these as universal guidelines to survey the
disease in populations across the country and the
world
Devise prevention strategies to curb the epidemic

Surveillance and
reporting :
EIP : Emerging Infections program - surveillance
representative of the whole country.
NHSN : National Healthcare Safety Network data
entered from hospitals
HHS Action Plan : targets towards reducing HAIs
including CDI

Impact on Health care :
CDI may have resulted in $4.8 billion in
excess costs in US acute-care facilities
Per person cost increases by $2000- $7000
due to prolonged hospital stay and
additional testing
Increased risk of recurrence

Global impact
New MRSA
Similar increase in CDI worldwide across North America,
Europe and Asia
New strain in Asia O17 in addition to O27
Globally difficult surveillance : no universal case
definitions, diagnostic gold standards, inadequate data
reporting ad collection
Ongoing research and cumulative efforts to combat CDI

References :
Bartlett, J. G., & Gerding, D. N. (2008). Clinical recognition and diagnosis of clostridium difficile
infection. Clinical Infectious Diseases, 46(Supplement 1), S12-S18. doi:10.1086/521863
Centers for Disease Control and Prevention (CDC). (2012). Vital signs: Preventing clostridium difficile
infections.MMWR.Morbidity and Mortality Weekly Report, 61(9), 157-162. doi:mm6109a3 [pii]
Cohen, S. H., Gerding, D. N., Johnson, S., Kelly, C. P., Loo, V. G., L Clifford McDonald, M., . . . Wilcox, M.
H. (2010). Clinical practice guidelines for clostridium difficile infection in adults: 2010 update by the
society for healthcare epidemiology of america (SHEA) and the infectious diseases society of america
(IDSA).Infection Control and Hospital Epidemiology, 31(5), 431-455.
HALL, I. C., & O'TOOLE, E. (1935). Intestinal flora in new-born infantswith a description of a new
pathogenic anaerobe, bacillus difficilis. American Journal of Diseases of Children,49(2), 390-402.
Kelly, C. P., & LaMont, J. T. (2008). Clostridium difficilemore difficult than ever. New England Journal
of Medicine, 359(18), 1932-1940.
L Clifford McDonald, M., Coignard, B., Dubberke, E., Song, X., Horan, T., Kutty, P. K., & Ad Hoc
Clostridium difficile Surveillance Working Group. (2007). Recommendations for surveillance of
clostridium difficileassociated disease.Infection Control and Hospital Epidemiology, 28(2), 140-145.
Lessa, F. C., Gould, C. V., & McDonald, L. C. (2012). Current status of clostridium difficile infection
epidemiology. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of
America, 55 Suppl 2, S65-70. doi:10.1093/cid/cis319 [doi]

Thank you