Clostridium

difficile
DR.T.V.RAO MD
 Clostridium difficile

 Clostridium difficile (
Greek kloster (κλωστήρ),
spindle, and Latin
difficile difficult), also
known as "CDF/cdf", or
"C. diff", is a species of
Gram-positive bacteria
of the genus Clostridium
that causes diarrhea and
other intestinal disease
when competing bacteria
are wiped out by
antibiotics.
 History
 1893 – first case of pseudomembraneous
colitis reported as
diphtheritic colitis.
 1935 – “Bacillus difficile” isolated.
 1970s – antibiotic-asociated colitis identified.
 1978 – C. difficile toxins identified in humans.
 1979 – therapy with vancomycin or
metronidazole
 2000 – increased incidence and virulence
 Introduction
 Clostridium difficile is a Gram-positive, spore-
forming anaerobic bacillus.

 Most common cause of nosocomial diarrhea.

 Rate and severity of C. difficile-associated

diarrhea (CDAD) increasing.

 New strain of C.difficile with increased resistance

and virulence identified.
 C.difficle

 Clostridium difficile, often

called C. difficile or "C.
diff," is a bacterium that
can cause symptoms
ranging from diarrhea to
life-threatening
inflammation of the colon.
Illness from C. difficile
most commonly affects
older adults in hospitals or
in long term care facilities
and typically occurs after
use of antibiotic
medication
C. Difficile – Environmental Epidemiology

water
 river (88%)
 lake (47%)
 sea (44%)
 swimming pool (50%)
 mains tap 1/18 (6%)
 • soil (21%)
 • raw vegetables (2%)
 • private residences (2%)
 • dogs (10%), cats (2%)
 • hospital environments
(20%)]
Clostridia
 Clostridia are anaerobic,
spore-forming rods
(bacilli). C. difficile is the
most serious cause of
antibiotic-associated
diarrhoea (AAD) and can
lead to
pseudomembraneous
colitis, a severe infection
of the colon, often
resulting from
eradication of the normal
gut flora by antibiotics
Major cause of Hospital Infection
 Antibiotic-associated (C. difficile) colitis
is an infection of the colon caused by C.
difficile that occurs primarily among
individuals who have been using
antibiotics. It is the most common
infection acquired by patients while they
are in the hospital. More than three
million C. difficile infections occur in
hospitals in the US each year
 Several Antibiotics cause
pseudomembraneous colitis
 Nearly all antibiotics
can cause antibiotic-
associated diarrhea,
colitis or
pseudomembraneous
colitis. The
antibiotics most
commonly linked to
antibiotic-associated
diarrhea :
 The antibiotics most likely to
cause diarrhea
 Cephalosporins, such as cefixime (Suprax) and
cefpodoxime (Vantin)
 Clindamycin (Cleocin)
 Erythromycin (Erythrocin, E.E.S., others)
 Penicillins, such as amoxicillin (Larotid, Moxatag,
others) and ampicillin
 Quinolones, such as ciprofloxacin (Cipro) and
levofloxacin (Levaquin)
 Tetracyclines, such as doxycycline (Vibramycin,
Periostat, others) and minocycline (Minocin,
Solodyn, others)
Uncommon in young infants
 Ampicillin, clindamycin, and
cephalosporins are the most common
antibiotics associated with this disease
in children. Pseudo membranous colitis
is rare in infants younger than 12
months old because they have
protective antibodies from the mother
and because the toxin does not cause
disease in most infants.
Traditional list of Antibiotics associated with
CDAD
MORE FREQUENT LESS FREQUENT

Cephalosporins (3rd and 4th generation) Ticarcillin-clavulanate

Ampicillin/Amoxicillin Metronidazole

Clindamycin Fluoroquinolones

Other penicillins Rifampin

Macrolides 5-Fluorouracil

Tetracyclines Methotrexate

Trimethoprim-Sulfamethoxazole Cyclophosphamide
 Other predisposing factors
 Previously experienced antibiotic-associated
diarrhea while taking an antibiotic medication
 Are age 65 or older
 Have had surgery on your intestinal tract
 Have recently stayed in a hospital or nursing
home
 Have a serious underlying illness affecting
your intestines, such as colon cancer or
inflammatory bowel disease
 Source of Infection
 C. difficile bacteria can be found
throughout the environment — in soil,
air, water, and human and animal feces.
A small number of healthy people
naturally carry the bacteria in their large
intestine. But C. difficile is most common
in hospitals and other health care
facilities, where a much higher
percentage of people carry the bacteria.
 Pathogenesis
 Disruption of
normal colonic
flora
 Colonisation with
C. difficile
 Production of toxin
A +/- B
 Mucosal injury and
inflammation
Pathogenesis 1
Pathogenesis 2
Pathogenesis 3
Pathogenesis 4
Pathogenesis 5
ENDOSCOPY PICTURE
 Pathogenesis
 Microflora of gut:
 1012 bacteria/gram
 400-500 species
 colonisation
resistance
 Transmission -
faecal/oral
 spores
 Late log / early
stationary phase
 toxin production
 Pathology
 Colonic mucosa
- raised yellow /
white plaques
initially small
enlarge and
coalesce
 Inflamed
mucosa
 Chain of infection
Infectious Agent
>65 years C.difficile
History of antibiotic use Bowel and
Recent received Contaminated
healthcare environment
Underlying conditions
Reservoir
Abdominal surgery Susceptible Host
Weakened immunity

Contact transmission
Portal of entry Means of from contaminated
Transmission hands,
equipment or the
Faecal/Oral
environment
Disruption of protective
colonic flora (AB or AN)

Colonization with toxigenic C. difficile

by fecal-oral transmission

Toxin A and B production

A/B: Cytoskeletal damage, loss of tight junctions.

A: Mucosal injury, inflammation, fluid secretion.

Colitis and Diarrhea

 Toxin production is cause of
Pathogenesis
 Toxigenic strains
produce 2 major
toxins:
toxin A
(enterotoxin)
toxin B (cytotoxin)
 Neutralised by C.
sordellii antitoxin
 Toxin A
 Binds to specific CHO receptors on
intestinal epithelium
 Toxin induced inflammatory process:
neutrophils
inflammatory mediators
fluid secretion
altered membrane permeability
haemorrhagic necrosis
 Toxin B
 Binding site not
yet identified
 Depolymerisation
of filamentous
actin
destruction of
cell cytoskeleton
rounding of cells
 Clinical Manifestations
 Asymptomatic carriage (neonates)
 Diarrhoea
5-10 days after starting antibiotics
○ maybe be 1 day after starting
○ may be up to 10 weeks after stopping
○ may be after single dose
spectrum of disease:
○ brief, self limiting
○ cholera-like - 20X/day, watery stool
 Clinical Manifestations
 Additional symptoms:
abdominal pain, fever, nausea, malaise,
anorexia, hypoalbuminaemia, colonic
bleeding, dehydration
 Acute toxic megacolon
acute dilatation of colon
systemic toxicity
signs of obstruction
high mortality (64%)
 Colonic perforation
 Symptoms
 Some people who have C. difficile never
become sick, though they can still
spread the infection. C. difficile illness
usually develops during or shortly after a
course of antibiotics. But signs and
symptoms may not appear for weeks or
even months afterward.
 Signs and symptoms
 Watery diarrhea three or more times a day for two or
more days
 Mild abdominal cramping and tenderness
 Watery diarrhea 10 to 15 times a day
 Abdominal cramping and pain, which may be severe
 Fever
 Blood or pus in the stool
 Nausea
 Dehydration
 Loss of appetite
 Weight loss
 Clinical features
 Mild disease – mild abdominal cramping pain.
- endoscopic findings of diffuse or patchy,
nonspecific colitis.

 Moderate disease – fever, dehydration, nausea,

anorexia, malaise, profuse diarrhea,
abdominal distention and cramping
pain. - moderate
leukocytosis, fecal leukocytes.
- diffuse, patchy colitis on endoscopy
 Severe disease
 – Usually profuse diarrhea, may be little
or no diarrhea. - abdominal pain
- fever - Volume depletion -
marked leukocytosis - peritoneal
signs -
Radiologic signs include ileus, colon
and edematous colonic - endoscopic
findings of adherent yellow plaques
 Dehydration
 .Severe diarrhea can lead to a
significant loss of fluids and electrolytes.
This makes it difficult for your body to
function normally and can cause blood
pressure to drop to dangerously low
levels. Kidney failure. In some cases,
dehydration can occur so quickly that
kidney function deteriorates (kidney
failure).
Complications of CDAD
 Pseudomembraneous colitis

 Toxic mega colon

 Perforation of the colon

 Sepsis

 Death
 Diagnosis of CDAD
 Endoscopy
(pseudomembranou
s colitis)
 Culture
 Cell culture cytotoxin
test
 EIA toxin test
 PCR toxin gene
detection
 Anaerobic culture
 CCFA: cycloserine, cefoxitin, fructose
agar (a selective and differential
medium)
 Very sensitive, but does not differentiate
between toxin and non-toxin strains
(must add a toxin test to increase
specificity)
 Essential for epidemiologic studies
 No longer offered routinely: cost issue
 Light Cycler PCR
 This Light
Cycler PCR
assay detects
the presence of
Clostridium
difficile and the
toxin B gene
 Light Cycler PCR
 DNA is directly extracted
from stool specimens and
C. difficile 16S DNA and
toxin B DNA are amplified
on Light cycler real-time
PCR platform. The
identity of the sequence is
confirmed by monitoring
binding of specific
fluorescent probes to
each of the amplicons and
subsequent melting-point
analysis.
 EIA toxin tests
 Can detect toxin A, toxin
B, or both
 Rapid, cheap, and
specific
 Less sensitive than
cytotoxin test
 Toxin A tests will miss
rare C. difficile isolates
that produce toxin B only
(Toxin A-negative, toxin
B-positive outbreak,
Winnipeg, 1998)
 Hand washing
 Hand washing. The
current Centres for
Disease Control and
Prevention (CDC)
guidelines recommend
that health care workers
use an alcohol-based
hand sanitizer or wash
their hands thoroughly
with soap and warm
water before and after
treating each patient.
Contact precautions
 People who are
hospitalized with
C. difficile are
cared for in a
private room.
Hospital workers
wear disposable
gloves and
gowns while in
the room.
 Thorough cleaning
 In any setting, all
surfaces and
equipment should be
carefully cleaned with
a detergent and a
hospital-grade
disinfectant or chlorine
bleach. C. difficile
spores can survive
routine household
disinfectants.
Avoiding unnecessary use of
antibiotics
 Antibiotics are often
prescribed for viral
illnesses that aren't
helped by these drugs.
Take a wait-and-see
attitude with simple
ailments. If you do need
an antibiotic, ask your
doctor to prescribe one
that has a narrow range
and that you take for the
shortest time possible.
 New strains of C.difficile
 Emergence of a new
epidemic strain of C.
difficile-associated
disease causing
hospital outbreaks in
several states was
reported by the
Centers for Disease
Control and
Prevention (CDC) at
scientific meetings.
New strains of C.difficile
 The epidemic strain
identified in 2004
appears to be more
virulent, with ability
to produce greater
quantities of toxins A
and B. In addition, it
is more resistant to
the antibiotic group
known as
fluoroquinolones.
A new strain of C. difficile (NAP-1)
 Toxinotype III

 Unsuppressed production of toxins A and B

 Associated with presence of binary toxin.

 Increased resistance to clindamycin and

fluoroquinolones.

 Potential for increased complications and

adverse outcome.
 Perform Hand Hygiene after removing
gloves.
 Because alcohol does not kill C. difficile
spores, use of soap and water is more
efficacious than alcohol-based hand
rubs. However, early experimental data
suggest that, even using soap and
water, the removal of C. diffile spores is
more challenging than the removal or
inactivation of other common pathogens
Prevention Strategies: Core

 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
Prevention Strategies: Supplemental

 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
 •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) –containing agents for
environmental cleaning
 •Implement an antimicrobial stewardship program
 In times of outbreaks
 If your institution
experiences an
outbreak, consider
using only soap and
water for hand
hygiene when caring
for patients with C.
difficile-infection.
 Safe and clean environment too
important.
 Ensure adequate cleaning and disinfection of
environmental surfaces and reusable devices,
especially items likely to be contaminated with
feces and surfaces that are touched frequently.
 Use an Environmental Protection Agency (EPA)-
registered hypochlorite-based disinfectant for
environmental surface disinfection after cleaning
in accordance with label instructions; generic
sources of hypochlorite (e.g., household
chlorine bleach) also may be appropriately
diluted and used.
 Patient care Equipment
• Dedicate equipment (e.g., thermometers,
sphygmomanometers, stethoscopes, glucometer)
for single patient use
• Use disposable equipment if possible
• Patient charts/records should not be taken into
the room

• Only take essential equipment and supplies into

the room. Do not stockpile as unused stock will
have to be discarded on cessation of Isolation
Contact Precautions.
What about the patients environment?

Daily:
• Thoroughly clean the environment and all patient care
equipment daily with a neutral detergent and disinfect with a
sporicidal disinfectant (e.g. hypochlorite solution –1000 ppm)
• Pay special attention to frequently touched sites and
equipment close to the patient.
Immediately
• Particular attention should be given to cleaning and
disinfecting immediately items likely to be faecally
contaminated e.g., the under surfaces and hand contact
surfaces of commodes.
• Environmental faecal soiling should be cleaned and
disinfected immediately.
Evidence for role of hypochlorite
to control CDi (i)
 Kaatz et al. reported an outbreak of CDI
 • ended following introduction of disinfection with
hypochlorite
 (unbuffered hypochlorite - 500 ppm available chlorine)
 • surface contamination decreased to 21% of initial
levels
 • phosphate buffered hypochlorite (1600 ppm
available
 chlorine, pH 7.6) was even more effective
 • use resulted in a 98% reduction in surface
contamination
Evidence for role of hypochlorite
to control CDi (ii)
 Mayfield et al. found that incidence of CDI in patients on a
 bone marrow transplant unit decreased significantly
following
 substitution of a quaternary ammonium solution by
 hypochlorite for environmental disinfection
 • after quaternary ammonium solution based cleaning was
 reintroduced, CDI incidence increased almost to baseline
 level
 • environmental C. difficile prevalence was not measured
 • antibiotic use altered during the study period
 • results were not reproducible for patients on other units
 Clostridium difficile
Unique features, caveats
 May be underestimated as a cause of diarrhea in
AIDS patients in the tropics because of the difficulty
in making the diagnosis. Frequent hospitalization
and exposure to antibiotics puts patients at high risk
of infection

 As in HIV-negative patients, 5-30% of patients with

C. difficile-associated diarrhea experience relapse
 Antibiotic Therapy
 Oral therapy – vancomycin, metronidazole

 Unable to tolerate oral therapy – IV metronidazole,

vancomycin via NG tube or enema.

 Vancomycin + rifampin

 Less frequently used – Bacitracin, fusidic acid

 Indications for Vancomycin
therapy
 No response to
metronidazole

 Metronidazole
intolerance

 Pregnancy and child <

10 yrs

 Severe/fulminant
CDAD
 Relation of CDAD with
Clindamycin
 Antimicrobial therapy has been identified
as the preeminent risk factor for the
development of CDAD, and restriction of
certain antibiotics has been shown to
interrupt epidemics. Various studies at
hospitals throughout the U.S. have shown
that restriction of clindamycin decreased
the incidence of CDAD associated with
clindamycin-resistant epidemic strains.
 Unproven therapies
 Tapering course of standard antimicrobials
 Yeast (Saccharomyces boulardii) with AB
 Cholestyramine
 Lactobacillus acidophilus
 Nontoxigenic C. difficile (oral)
 Bacterial enemas
 Rectal infusion of normal feces
 Synsorb Cd (toxin binding agent)
Fecal bacteriotherapy
 Known as fecal transfusion, fecal
transplant, or human probiotics
infusion (HPI), is a medical treatment
for patients with pseudomembranous
colitis (caused by Clostridium difficile),
or ulcerative colitis which involves
restoration of colon homeostasis by
reintroducing normal bacterial flora from
stool obtained from a healthy donor.
 Description of procedure
 The procedure itself
sometimes involves a 5-
to 10-day treatment with
enemas, made of
bacterial flora from feces
of a healthy donor, though
most patients recover
after just one treatment.
The best choice for donor
is a close relative who has
been tested for a wide
array of bacterial and
parasitic agent
Recurrent Infections with CDAD
 Recurrent CDAD is a problem for which
no clear consensus has emerged.
Repeating treatment courses with high-
dose vancomycin has proven
efficacious, while others employ pulsed
dosing, believing that C. difficile spores
will germinate between pulses and be
susceptible to the next dose of drug.
 Conclusion
 Increasing numbers and severity of CDAD.

 Active surveillance recommended.

 Early diagnosis and treatment are important for reducing

severe outcome.

 Judicious use of antibiotics may reduce incidence of

CDAD

 Strict infection control practices essential.

Created by Dr.T.V.Rao MD for
“e” learning for Medical
Professionals
Email
doctortvrao@gmail