Clostridium difficile An emerging Infection

1. Clostridium
difficile

2. 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.

3. 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

4. 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.

5.  Clostridium difficile,
C.difficle
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

6. 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%)]

7. 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

8. 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

9. 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 :

10. 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)

11. 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.

12. 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

13. 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

14. 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.

15. Pathogenesis
 Disruption of
normal colonic
flora
 Colonisation with
C. difficile
 Production of toxin
A +/- B
 Mucosal injury and
inflammation

16. Pathogenesis 1

17. Pathogenesis 2

18. Pathogenesis 3

19. Pathogenesis 4

20. Pathogenesis 5

21. ENDOSCOPY
PICTURE

22. Pathogenesis
 Microflora of gut:
 1012 bacteria/gram
 400-500 species
 colonisation
resistance
 Transmission -
faecal/oral
 spores
 Late log / early
stationary phase
 toxin production

23. Pathology
 Colonic mucosa
- raised yellow /
white plaques
 initially small
 enlarge and
coalesce
 Inflamed
mucosa

24. Chain of infection
Infectious Agent
Reservoir
C.difficile
Means of
Transmission
Susceptible Host
Portal of entry
Bowel and
Contaminated
environment
Contact
transmission from
contaminated
hands,
equipment or the
environment
>65 years
History of antibiotic use
Recent received
healthcare
Underlying conditions
Abdominal surgery
Weakened immunity
Faecal/Oral

25. 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

26. Toxin production is cause
of Pathogenesis
 Toxigenic strains
produce 2 major
toxins:
 toxin A
(enterotoxin)
 toxin B (cytotoxin)
 Neutralised by C.
sordellii antitoxin

27. Toxin A
 Binds to specific CHO receptors on
intestinal epithelium
 Toxin induced inflammatory process:
 neutrophils
 inflammatory mediators
 fluid secretion
 altered membrane permeability
 haemorrhagic necrosis

28. Toxin B
 Binding site not
yet identified
 Depolymerisation
of filamentous
actin
 destruction of
cell cytoskeleton
 rounding of cells

29. 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

30. 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

31. 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.

32. 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

33. 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

34. 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

35. 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).

36. Complications of
CDAD  Pseudomembraneous colitis
 Toxic mega colon
 Perforation of the colon
 Sepsis
 Death

37. Diagnosis of CDAD
 Endoscopy
(pseudomembranou
s colitis)
 Culture
 Cell culture cytotoxin
test
 EIA toxin test
 PCR toxin gene
detection

38. 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

39. Light Cycler PCR
 This Light
Cycler PCR
assay detects
the presence of
Clostridium
difficile and the
toxin B gene

40. 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.

41. 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)

42. 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.

43. 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.

44. 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.

45. 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.

46. 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.

47. 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.

48. 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.

49. 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

50. 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

51. 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

52. 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.

53. 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.

54. 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.

55. 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.

56. 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

57. 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

58. 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

59. 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

60. Indications for Vancomycin
therapy
 No response to
metronidazole
 Metronidazole
intolerance
 Pregnancy and child <
10 yrs
 Severe/fulminant
CDAD

61. 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.

62. 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)

63. 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.

64. 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

65. 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.

66. 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.

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