CLOSTRIDIUM DIFFICILE INFECTION
CLOSTRIDIUM DIFFICILE
• Obligatory Gram
positive spore-forming
anaerobic bacteria
• Discovered during the
research studies of the
normal intestinal flora in
newborns1
1. Hall & O‘Toole. Am J Dis Child
1935;49:390-402
EPIDEMIOLOGY
• Reservoir: gastrointestinal tract of humans and other
mammals
Asymptomatic carriers :
• infants (15-70%)
• healthy adults (3%)
• hospitalized patients (20%)
EPIDEMIOLOGY
C. diff. spores are found frequently in:
• hospitals
• nursing homes
• extended care facilities
• nurseries for newborn infants
Source of infection are symptomatic CDI patients
EPIDEMIOLOGY
They can be found on: • Spores are resistant to
• bedpans heat, alcohol and are most
• furniture
often spread through the
• toilet seats
hands of health care
• telephones
workers and medical
• stethoscopes
• fingernails instruments
• rings (jewelry)
• floors
• pets – zoonosis?
EPIDEMIOLOGY AND PATHOGENESIS
• Colonization of the gastrointestinal tract
by the fecal-oral route
• Acid-resistant spores in the small
intestine are converted into vegetative
forms
PATHOGENESIS
About 90% of the strains of C.diff. produces toxins
responsible for the onset of diarrhea
• Toxin A (enterotoxin)
• Toxin B (cytotoxin)
• Binary toxin more severe (necrotic enteritis)
MECHANISM OF TOXINS ACTION
RISK FACTORS
Disturbed intestinal flora:
• Antibiotics
• Laxatives
• Chemotherapeutic agents
• Antacids
• Proton pump inhibitors –PPI
RISK FACTORS
• Hospitalization (stay in a room with a patient who has
C.diff. leads to infection after 3.2 days)1
• Length of hospitalization
colonization percentage of 13% - after 2 weeks
colonization percentage of 50% - after 4 weeks
1.Gerding DN.Intern J Antimicrob Agents 2009; 33:S2-S8
RISK FACTORS
• Age > 65 years
• Chronic diseases
• Immunodeficiency conditions (AIDS, cancer)
• IBD
• Abdominal surgery
C.DIFF. ASSOCIATED DIARRHEA (CDAD)
Clinical presentation Symptoms Physical exam findings
Asymptomatic carrier - Normal
Diarrhea without colitis 10< loose stools/day Lower abdominal tenderness
Abdominal cramps, nausea
Colitis without >10 loose stools/day, mucus Lower abdominal tenderness
pseudomembrane Abdominal cramps, nausea Slight abdominal distention
Fever
Pseudomembranous colitis >10 loose stools/day, mucus Marked abdominal distention
Abdominal cramps, nausea and pain
*Fever>38.5C
*Severe *Creatinine > 1.5 x baseline
(2 or more severity markers) *WBC>15x109/l
*Hypotension
Pseudomembranous colitis >10 loose stools/day, mucus Ileus (radiological signs of
complicated Abdominal cramps, nausea bowel distension)
or Toxic megacolon
no diarrrhea (Ileus+SIRS)
Shock
TOXIC MEGACOLON
• Colon dilatation (>6cm)
• Loss of normal haustral
contours
• Thickened bowel wall
TESTING METHODS FOR C.DIFF.
Dijagnostic test Sensitivity Specificity
Toxin EIA 63-94% 80-96%
GDH antigen EIA 58-92% 80-96%
Cell cytotoxin assay 67-100% 85-100%
Culture(CCFA) 89-100% 84-99%
PCR 95% 100%
1RECOMMENDATIONS
• Only patients with diarrhea should be tested (possibility
of asymptomatic carriers of bacteria)
• EIA for toxin A and B is fast, but not sufficiently sensitive
test
• PCR is a rapid, sensitive but not routinely test for C. diff.
• The "gold standard" is toxigenic culture- culture of C.diff
followed by identification of the toxin
1.Cohen SH, et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455
PSEUDOMEMBRANOUS COLITIS
• Yellow or off-white
plaques (a few mm to 2
cm), edematous and
fragile mucosa with
superficial erosions or
linear ulcerations
PSEUDOMEMBRANOUS COLITIS
• Mucosal edema
• Inflammatory cells in lamina
propria (PMN`s, eosinophills)
• Necrosis of the superficial
crypts
• Pseudomembrane made
of PMN`s, fibrin and cellular
debris
THERAPY (SHEA/IDSA)1
• Initial episode, mild (< 4 stools/day)
rehydration, remove antibiotics
• Initial episode, non-severe
Metronidazole 500 mg tid,PO for 10-14 days
• Initial episode,severe
Vankomycin 125mg qid PO for 10-14 days
1.Cohen SH, et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455.
THERAPY
• Initial episode, complicated
Vankomycin 500 mg qid PO or by NG
tube, plus metronidazole 500 mg q8hIV
add Vankomycin PR 500 mg (ileus)
• Management of patients in intensive
care unit, adequate rehydration and
monitoring
THERAPY
• Toxic megacolon:
subtotal or total colectomy should be
considered if colon dilatation is >10 cm
or in case of perforation
THERAPY1
• 1st recurrence
Same as for initial episode
• 2nd/subsequent recurrences
Vancomycin 125mg qid PO for 10-14 days, then in
tapered and/or pulsed regimen
• Passive immunizations with human immunoglobulin
1.Cohen SH, et al. Infect Control Hosp Epidemiol 2010; 31(5):431-455
OUTCOME
• Severe, complicated colitis (3-8%)
• Toxic megacolon (64% mortality)
• Recurrence (5-50%)
• Extraintestinal manifestations-bacteremia, splenic
abscess, osteomyelitis, reactive arthritis
• Mortality approximately 3%
NEW EPIDEMIC : CLOSTRIDIUM
DIFFICILE NAP1/BI/027
• USA,Canada 2001/2002 increase in the number of
patients with CDI
• Changing epidemiology: transmission of close contact,
recurrence, younger age, blood in the stool, the absence
of previous antibiotic therapy
• TcdC gene deletion -production of large amounts of toxin
B, new gene encoding a cdtB binary toxin
• Resistance in vitro to ciprofloxsacin, mortality 16.7%
WHAT IS NEW IN CDI?
• Prevalence is increasing particularly in the elderly
• More severe colitis than usual
• Patients require surgery more frequently, and die from the
infection more frequently than before
• Increasing difficulty in treating (failure rate up to 20%)
• Resistance to metronidazole and vancomycin is on the rise
• Many patients experience multiple relapses, often
requiring prolonged antibiotic treatment
NEW THERAPEUTIC STRATEGIES
• New antimicrobial treatment (fidaxomicin, rifaximin,
teicoplanin, nitazoxanide)
• Toxin binding polymer-Tolevamer
• Toxin A/B toxoid vaccine
• Monoclonal antibodies directed against toxin A and B
• Fecal transplants
• Non-toxigenic C.diff.
FECAL TRANSPLANT
• Stool of the healthy donors is mixed with
saline (30 g of stool with 70 ml of saline)
• Homogenization with household blender
(2-4 min)
• Double filtration with coffee filter
• 25 ml of suspension is injected through
the nasogastric tube or per rectum1
1.Aas, J. et al. CID 2003; 36:580-585
