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Clostridium difficile–Associated Disease (CDAD)

Prepared byHassan Mohammed Abdel Rahman

M.B.BCH.MSc

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Clostridium difficle

(Greek clostr ; spindle and Latin difficile;

difficult), is a species of Gram-positive spore-

forming anaerobic bacillus bacteria of the genus

Clostridium that causes diarrhea and other

intestinal diseases when competing bacteria are

wiped out by antibiotics.

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Background

• The first case of pseudomembranous colitis was reported in 1893 as “diphtheritic colitis,” and the Clostridium difficile organism was described in 1935.

• It was not until the 1970s that C difficile was implicated as a causative factor in pseudomembranous colitis.

• Although C difficile–associated disease was described before antibiotics were introduced, most current cases are associated with antibiotic use.

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Several Antibiotics cause pseudomembraneous colitis

• Nearly all antibiotics can cause antibiotic-associated diarrhea, colitis or pseudomembraneous colitis.

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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)

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• Other conditions that can predispose persons to C difficile–associated disease include:

Bowel ischemia. Surgery. Malnutrition. Chemotherapy. & Critical illness.

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• The spectrum of disease associated with C. difficile includes :

Asymptomatic carrier state. Diarrhea without colitis. Various degrees of colitis +/-

pseudomembranes.

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Epidemiology

• Since the late 1980s, there has been an increase in the occurrence rate and a more modest clinical spectrum of C difficile–associated disease, trends thought to be due to increased use of antibiotics, more aggressive testing, and early intervention.

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• Clostridium difficileis more common in hospitalized adults and in patients receiving antibiotic therapy.

• Recently, however, there has been an increase in the number of cases of C difficile–associated diarrhea in the absence of prior antibiotic exposure.

• Up to 50% of infants and children carry the bacterium, but pseudomembranous colitis is rare in this age group.

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The incidence of antibiotic-associated diarrhea:

varies from 5% to 39%,depending on the antibiotic used, and most cases are due to the antibiotic and not to infection with C difficile, particularly in outpatients.

Pseudomembranous colitis occurs in only 10% of cases of antibiotic-associated diarrhea.

In contrast to antibiotic-associated diarrhea, most cases of pseudomembranous colitis are due to C.difficile.

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• Risk factors for C difficile–associated disease may include:

older age (>70 years), uremia, burns, abdominal surgery, cancer, inflammatory bowel disease, use of gastric acid–suppressive medication, and hospitalization in an intensive care unit.

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Risk factors for CDI...

• C. difficile-associated disease occurs when the normal intestinal flora is altered, allowing C. difficile to flourish in the intestinal tract and produce a toxin that causes a watery diarrhea.

• Antibiotic use• Proton-pump inhibitors (antacids)• Repeated enemas• Prolonged nasogastric tube• Gastrointestinal tract surgery• Cross contamination from

environment• Food sources

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Proton Pump Inhibitors

• Reduction of gastric acid secretion may allow C difficile to be ingested and survive a "first wall of host defense" -- the acidic gastric pool.

• Reduced gastric acid facilitates survival of C.difficile in the upper gastrointestinal tract, leading to disease-associated sequelae

• C difficile spores are resistant to gastric acid

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Other Risk Factors

• Anticonvulsant therapy• Antiplatelet agents• Osteoporosis medication• Angiotensin II receptor antagonists• Asthma medications• Systemic corticosteroids• Antidiabetic agents• Antidepressant medications• Age• Length of admission• The highest identified risk was actually with use of

antidepressants (OR 2.99, 95% CI 2.16-4.15). By logistic regression, the number of days of PPI use was a significant predictor of C difficile infection (OR 1.01/day, 95% CI 1.00-1.02)

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Source of Infection

• C. difficle 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. difficle is most common in hospitals and other health care facilities, where a much higher percentage of people carry the bacteria.

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Reservoir

Infectious AgentC.difficile

Means of Transmission

Portal of entry

Susceptible Host

Chain of infection Bowel and

Contaminated environment

Faecal/Oral

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

Contact transmission from contaminated

hands,equipment or the

environment

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Case Presentation

• A 75-year-old man sought care for a 2-day history of crampy lower abdominal pain, non bloody diarrhea, tenesmus, and fever.

• He recently completed a course of antibiotic therapy for pneumonia.

• On physical examination, he appeared ill, with a temperature of 38.3°C, normal blood pressure, and a pulse rate of 98 beats per minute.

• The abdomen was mildly distended and tender without guarding or rebound.

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• Laboratory studies showed leukocytosis of

13,400/µL, with 15% band forms. Stool analysis showed many leukocytes, and C difficile toxin was detected.

• Abdominal radiography showed mild ileus but no dilatation of the colon.

• Treatment with metronidazole, 500 mg 3 times daily by mouth, promptly improved the symptoms.

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Clinical Presentation

• The time between the initiation of antibiotic therapy and the appearance of clinical symptoms varies from 1 day to 6 weeks,most commonly 3 to 9 days.

• However, symptoms may occur after a single dose of antibiotics (including topical antibiotics), or they may not begin until several weeks after antibiotic therapy has been discontinued.

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• Presentation may range from only loose stools to toxic megacolon (nausea, vomiting, high-grade fever, and ileus) and colonic perforation.

• Typically, the disease manifests with watery or mucoid diarrhea, abdominal pain, and low-grade fever.

• Stools may contain small amounts of blood.

• Extraintestinal manifestations, such as arthritis, are rare.

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• Diarrhea may cause dehydration and electrolyte depletion.

• The overall mortality rate is low (2%-3%), although it is higher among elderly or debilitated patients (10%-20%) and patients with fulminant colitis or toxic megacolon (30%-80%).

• In some patients (5%-19%), disease is localized to the proximal colon; these patients may present with an acute abdomen and localized rebound tenderness, but no diarrhea, and normal findings on sigmoidoscopy.

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• Despite successful treatment, 10% to 25% of patients have disease relapse regardless of the therapeutic agent used.

• Disease relapse usually responds well to re-treatment with metronidazole or vancomycin, but the risk of additional recurrences is high.

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Complications of CDAD

• Pseudomembranous colitis

Toxic mega colon

Perforation of the colon

Sepsis

Death

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Differential Diagnosis

• Staphylococcal enterocolitis can occur in patients receiving chemotherapy, and these patients can have a presentation similar to that of patients who have C difficile–associated disease.

• Exacerbation of Crohn disease and Ulcerative colitis can simulate C difficile–associated disease, and, importantly, C difficile infection can cause a symptom flare in patients with inflammatory bowel disease.

• Chemical colitis (chemotherapy or gold), Ischemic colitis, and other infections (from Campylobacter, Salmonella, Shigella, E coli, Entamoeba, Listeria, and cytomegalovirus).

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Pathophysiology

• The development of C difficile–associated disease requires:

• An alteration in the normal gut flora or mucosal immunity, the acquisition and germination of spores, an overgrowth of C difficile, and the production of toxin.

Toxin A binds to mucosal receptors and causes cytotoxicity by disruptin cytoplasmic microfilaments and inducing apoptosis.

Toxin B can then enter the damaged mucosa and cause further cytotoxicity, resulting in hemorrhage, inflammation, and cellular necrosis.

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• The toxins also interfere with protein synthesis, stimulate granulocyte chemotaxis, increase capillary permeability, and promote peristalsis.

• In severe cases, inflammation and necrosis may involve deeper layers of the colon and result in toxic dilatation or perforation.

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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.

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A new hypervirulent strain of C difficile (NAP1/BI/027) has been linked with selected outbreaks of severe disease in recent years.

• An epidemic strain of NAP1/BI/027 is known to produce a binary toxin not produced by other C difficilestrains.

• The epidemic strain also produces larger quantities of toxins A and B in vitro and is resistant to fluoroquinolones in vitro.

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• NAP1 - a mutated version that produces roughly 20 times the toxins responsible for illnesses ranging from simple diarrhea to blood poisoning — and death.

• The NAP1 strain has been found in other sites and populations in recent years, infecting young adults and pregnant women with no history of antibiotic use, according to federal sources.

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Pathogenesis

• Microflora of gut:– 1012 bacteria/gram– 400-500 species

– colonisation resistance

• Transmission - faecal/oral

– spores

• Late log / early stationary phase

– toxin production

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Pathogenesis

• Disruption of normal colonic flora

• Colonization with C. difficle

• Production of toxin A +/- B

• Mucosal injury and inflammation

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Diagnostic Testing

• Endoscopy (pseudomembranous colitis)

• Culture

• Cell culture cytotoxin test

• EIA toxin test

• PCR toxin gene detection

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• Diagnostic Testing: based on a combination of clinical findings, laboratory test results, and occasionally endoscopy.

• Leukocytosis and hypoalbuminemia are not uncommon.

• Fecal leukocytes can be seen, but their absence does not exclude colitis.

• Stool culture for C difficileis relatively demanding and has low predictive value

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• Cytotoxicity assays : • This test is performed by culturing fibroblasts in

the presence of stool supernateare considered positive when cultured cells(fibroblasts) show cytopathic changes on exposure to stool filtrates.

• The result is then confirmed by neutralizing these effects with specific antitoxins.

• This is considered the standard diagnostic method because of its high sensitivity and specificity (95-99%). However, cytotoxicity assays are expensive and time consuming.

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• ELISA for the detection of toxin A or B is less expensive and faster than tissue culture and, thus, is preferred at many centers.Sensitivity is lower (75%-85%) than for cytotoxic assays.

• A newer ELISA to detect the presence of either toxin (TOX A/B test; Techlab, Inc) has excellent specificity and improved sensitivity compared with testing for either toxin alone, because some strains of C difficilemay produce only 1 toxin or the other.

• initially utilizing an EIA for glutamte dehydrogenase (GDH) an enzyme produced by C deff. followed by EIA for toxin in GDH +ve stools.

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• In July 2009, a PCR assay based on the stool toxin assay was introduced, with a sensitivity of approximately 95% with use of a single stool sample.

• This PCR-based assay has now become the diagnostic test of choice in many centers because of its greater sensitivity.

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• Although endoscopic findings may be normal in patients with mild C difficile–associated disease, most patients have abnormal mucosa.

• Flexible sigmoidoscopy is diagnostic in most patients, but colonoscopy may be required in about 10% of patients when disease is localized above the splenic flexure.

• Endoscopy may be the fastest means of suggesting the diagnosis, but in patients with severe disease, it is hazardous and should be avoided.

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Colitis may range from minimal erythema or edema to ulceration, often with nodular exudates that may coalesce to form yellow “pseudomembranes” consisting of mucus and fibrin filled with dead leukocytes and mucosal cells

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ENDOSCOPY PICTURE

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Histopathological view

• Colonic mucosa - raised yellow / white plaques

– initially small– enlarge and

coalesce

• Inflamed mucosa

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Treatment of Primary Infection

For mild disease:• supportive therapy alone (without antibiotic

treatment) may be sufficient, including rehydration and discontinuation of treatment with the offending antibiotic.

• Antidiarrheal agents and narcotics should be avoided because they may prolong exposure to toxins and result in more severe colitis.

• Specific antibiotic therapy should be prescribed if supportive therapy fails, if treatment with the offending antibiotic cannot be discontinued, or if symptoms are severe

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For severe disease:

• Hospitalization for antibiotic therapy and intravenous hydration may be necessary. When C difficile–associated disease is suspected in elderly and severely ill patients, empirical antibiotic therapy should be started before test results are known.

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• Metronidazole is inexpensive and effective and has response and relapse rates comparable to those of vancomycin.The usual oral dose is 500 mg 3 times daily for 14 days.

• Because of concerns about cost and resistance with vancomycin, metronidazole is the preferred first-line therapy for patients with mild disease (white blood cell count <15,000/µL and normal serum creatinine).

• For patients presenting with more severe disease (white blood cell count >15,000/µL and elevated serum creatinine), vancomycin is recommended at a dose of 125 mg 4 times daily for 14 days.

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• Metronidazole has more adverse effects and is not recommended for children or pregnant women.

• If the patient’s condition does not improve promptly (2-3 days), the situation should be reassessed and, if the diagnosis is secure, vancomycin should be substituted for metronidazole.

• Vancomycin is a reliable but more expensive treatment, with response rates of 90% to 100%, and is the preferred agent for severely ill patients.

• Because oral vancomycin is poorly absorbed,a high stool concentration can be achieved without systemic adverse effects.

• A higher dose (250-500 mg 4 times daily) can be given to severely ill patients

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Indications for Vancomycin therapy

• No response to metronidazole

• Metronidazole intolerance

• Pregnancy and child < 10 yrs.

• Severe/fulminant CDAD

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• Parenteral therapy is less effective than oral therapy: Intravenous metronidazole (500-750 mg 3 or 4 times daily) is recommended but when necessary (eg, paralytic ileus).

• Vancomycin (500 mg 4 times daily) through a nasogastric tube or by enema.

• Anion exchange resins work by binding toxin. Cholestyramine (4 g 4 times daily) can help decrease symptoms in mild disease.

• Because cholestyramine binds vancomycin, they should not be given simultaneously

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Treatment of Recurrent Infection

• Recurrent disease usually responds well to re-treatment with metronidazole or vancomycin at standard doses.

• For multiple or refractory recurrences, several therapeutic options are available:

I. One is a prolonged course of vancomycin therapy, followed by gradual tapering (eg, 125 mg 4 times daily for 4-6 weeks, 125 mg twice daily for 1 week, 125 mg daily for 1 week, and 125 mg every other day for 1 week, followed by 125 mg every 72 hours for 2 weeks).

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II. An alternative to prolonged antibiotic tapering is vancomycin 500 mg 4 times daily for 10 to 14 days, followed by rifaximin 400 mg twice daily for 14 days.

III. Another option is fidaxomicin 200 mg twice daily for 10 days. This has been shown to be as effective as vancomycin for clearing C difficileinitially and is associated with a lower likelihood of recurrent disease (recurrence rate: 25% with vancomycin, 15% with fidaxomicin)

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IV. 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)

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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.

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Fecal microbiota transplantation is showing tremendous promise in difficult-to-treat cases of recurrent C difficile infection.

• The fecal material is administered into the proximal colon at colonoscopy.

• This therapy has led to cure rates of approximately 90% in cases of medically refractory disease and is an area of considerable research and growth.

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Fecal microbiota transplantation

• Alteration of intestinal flora-The GIT is colonized by a complex balance of diverse microorganisms. Administration of antibiotics disrupts this balance and is a key factor in the pathogenesis of C. difficile colonization and disease.

• Most probiotics colonize the gut temporarily, producing bactericidal acids and peptides and promoting "competition" among microbes by competing for nutrients and epithelial adhesion. These effects appear to reduce the favorability of the environment for C. difficile

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Fecal microbiota transplantation

• Antimicrobial activity- Bacteria in probiotic preparations produce acids that lower the pH of the local gut environment as well as toxins that inhibit the growth of other bacteria.

• Intestinal barrier protection -The initial site of interaction between commensal and pathogenic bacteria in the human host is the gut epithelium. Probiotics may be capable of interfering with the binding of C. difficile toxins A and B to intestinal epithelial cells

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Fecal microbiota transplantation• Immunomodulation - Probiotics modulate both

the innate and adaptive immune systems by stimulating toll like receptors (TLRs) and upregulating cytokine expression in dendritic cells and peripheral blood monocytes

• Ingestion of Lactobacilli has been associated with enhanced phagocytic activity. In addition, several strains of Lactobacillus , Bifidobacterium, and Sacchromyces have been associated with increased IgA secretion in both stool and serum.

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• 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

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Surgical Treatment

• Surgical treatment usually is not necessary for C. difficile–associated disease.

• Diverting ileostomy or colectomy is performed for severe refractory disease or for complications such as perforation or megacolon.

• Because the risk of complications increases markedly after several days of ineffective therapy, some advocate surgery for severe disease that does not respond after 2 to 7 days of treatment

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Prevention

• The spores of C difficilecan survive for up to 5 months in the environment, and a primary mode of infection is the hands of hospital personnel or contaminated objects.

• Therefore, prevention has a crucial role in disease management and can be facilitated by :

The prudent use of antibiotics. Routine hand washing. Disinfection of potentially contaminated objects. & Isolation of infected patients, with the use of gloves for

patient contact.

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• Hand washing: The (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.

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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.

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Treatment of asymptomatic carriers is not recommended because it may prolong the carrier state, which usually resolves spontaneously.

Restricting the use of broad-spectrum antibiotics has decreased the rate of C difficile–associated disease at some institutions.

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Summary Clostridium diffiile is a spore-forming toxigenic Clostridium diffiile is a spore-forming toxigenic

bacterium that causes diarrhea and colitis, typically bacterium that causes diarrhea and colitis, typically

after antibiotic therapy. after antibiotic therapy.

The clinical presentation ranges from self-limited The clinical presentation ranges from self-limited

diarrhea to fulminant colitis and toxic megacolon.diarrhea to fulminant colitis and toxic megacolon.

Although in most cases the disease is mild and Although in most cases the disease is mild and

responds quickly to treatment, C diffiile colitis may be responds quickly to treatment, C diffiile colitis may be

severe, especially if diagnosis and treatment are severe, especially if diagnosis and treatment are

delayed.delayed.

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Summary

Prevention is achieved best by limiting the use of Prevention is achieved best by limiting the use of

broad-spectrum antibiotics and by following good broad-spectrum antibiotics and by following good

hygienic techniques and universal precautions to hygienic techniques and universal precautions to

limit the transmission of the bacteria. limit the transmission of the bacteria.

A high degree of awareness results in early A high degree of awareness results in early

diagnosis and treatment and potentially decreases diagnosis and treatment and potentially decreases

the incidence of complications.the incidence of complications.

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• Thank you very muchThank you very much