clostridium difficle

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Dr.T.V.Rao MD : 

Dr.T.V.Rao MD Clostridium difficile

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 : 

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 : 

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.difficle

C. Difficile – Environmental Epidemiology : 

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 Clostridia

Major cause of Hospital Infection : 

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 : 

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 : 

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 : 

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 : 

Traditional list of Antibiotics associated with CDAD

Other predisposing factors : 

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 : 

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 : 

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

Pathogenesis 1 : 

Pathogenesis 1

Pathogenesis 2 : 

Pathogenesis 2

Pathogenesis 3 : 

Pathogenesis 3

Pathogenesis 4 : 

Pathogenesis 4

Pathogenesis 5 : 

Pathogenesis 5



Pathogenesis : 

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

Pathology : 

Pathology Colonic mucosa - raised yellow / white plaques initially small enlarge and coalesce Inflamed mucosa

Slide 24: 

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

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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 : 

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 : 

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 : 

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

Clinical Manifestations : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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 : 

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

Diagnosis of CDAD : 

Diagnosis of CDAD Endoscopy (pseudomembranous colitis) Culture Cell culture cytotoxin test EIA toxin test PCR toxin gene detection

Anaerobic culture : 

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 : 

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

Light Cycler PCR : 

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 : 

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 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 : 

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 : 

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 : 

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 : 

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 : 

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) : 

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. : 

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 : 

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 : 

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 : 

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. : 

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 : 

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? : 

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 hypochloriteto control CDi (i) : 

Evidence for role of hypochloriteto 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 hypochloriteto control CDi (ii) : 

Evidence for role of hypochloriteto 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

Slide 58: 

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 : 

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 : 

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

Relation of CDAD with Clindamycin : 

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 : 

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 : 

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 : 

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 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 : 

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.

Slide 67: 

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

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