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