DR.T.V.RAO MD

Clostridium difficile

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.

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.difficle

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 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

Clostridia

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/gram400-500 speciescolonisation

resistance Transmission -

faecal/oralspores

Late log / early stationary phasetoxin production

Pathology Colonic mucosa

- raised yellow / white plaquesinitially smallenlarge and

coalesce Inflamed

mucosa

Reservoir

Infectious AgentC.difficile

Means of Transmission

Portal of entry

Susceptible Host

Chain of infection Bowel and

Contaminated environment

Contact transmission from contaminated

hands,equipment or the

environmentFaecal/Oral

>65 years History of antibiotic useRecent received healthcareUnderlying conditions Abdominal surgery Weakened immunity

Disruption of protectivecolonic flora (AB or AN)

Colonization with toxigenic C. difficileby 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:

neutrophilsinflammatory mediatorsfluid secretionaltered membrane permeabilityhaemorrhagic necrosis

Toxin B Binding site not

yet identified Depolymerisation

of filamentous actindestruction of

cell cytoskeletonrounding 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 megacolonacute dilatation of colonsystemic toxicitysigns of obstructionhigh 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

(pseudomembranous 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

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

Clostridium difficileUnique features, caveats

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.

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