eMedicine Specialties > Infectious Diseases > Gastrointestinal Tract and Intra-abdominal Infections

Pseudomembranous Colitis

Jennifer A Curry, MD, MPH, Staff Physician, Infectious Disease Clinic, Naval Medical Center Portsmouth
Braden R Hale, MD, MPH, Assistant Clinical Professor, Department of Internal Medicine, University of California at San Diego; Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Naval Medical Center at San Diego; Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences; Joseph Lee, MD, Staff Physician, Department of Medicine, Walter Reed Army Medical Center

Updated: Aug 25, 2009

Introduction

Background

Clostridium difficile is a gram-positive spore-forming organism responsible for an infectious colitis that affects 1 of every 200 patients who are admitted to the hospital.Increasingly implicated as a significant cause of morbidity and mortality among hospitalized patients, C difficile colitis should also be recognized among outpatient populations. Prior antibiotic exposure remains the most significant risk factor for development of disease.

Several synonymous terms are used to refer to the spectrum of disease attributable to C difficile; these terms include C difficile –associated diarrhea (CDAD), antibiotic-associated colitis, C difficile colitis, and pseudomembranous colitis (PMC). Pseudomembranous colitis specifically describes the formation of a membranous exudate in the colon, which occurs in approximately 50% of cases of CDAD. However, because endoscopy is now used less frequently to demonstrate pseudomembranes in the evaluation of CDAD, most recent journal articles reference this entity under the umbrella term of CDAD. The underlying management of the disease does not change based on classification. Although CDAD is inherently an antibiotic-associated diarrhea, the latter term is usually reserved for milder disease that is not caused by C difficile or its toxins.  

In 1893, Finney first reported pseudomembranous colitis in a patient who died after developing severe diarrhea after gastric surgery. Later, in the 1950s, both Staphylococcus aureus and Candida albicans were considered etiologic sources after isolation from the stools of affected patients. In 1977, C difficile and its toxins were established as the cause of antibiotic-associated colitis.  

Any antibiotic can increase the risk of C difficile disease, including metronidazole and vancomycin, which are used in the treatment of CDAD. Disease has been reported following as little as one dose of antibiotic. Although the attributable relative risk has varied among studies, fluoroquinolones, macrolides, clindamycin, beta-lactam/beta-lactamase inhibitors, and all 3 generations of cephalosporins have consistently been shown to pose a significant risk for the development of CDAD.

Recently, an increasing number of C difficile infections have been reported, and the proportion of cases complicated by severe outcomes has increased. This may be due to the spread of a particularly virulent clonal strain. In 2003, an outbreak in Quebec and 8 US states received significant media attention. More than 80% of the isolates tested were of the same strain, designated as pulsed-field gel electrophoresis NAP1, or polymerase chain reaction (PCR)–ribotype 027. This strain is notable for the presence of binary toxin and an 18–base pair (bp) deletion in the regulatory gene tcdC, which ordinarily downgrades toxin production.^1,2,3

Pathophysiology

C difficile is an anaerobic, toxigenic, spore-forming, gram-positive rod. The spores can survive for months on hospital environmental surfaces, and patients can remain asymptomatic carriers. The risk of colonization increases with length of hospital stay; nearly 20% of hospitalized patients have asymptomatic fecal colonization, as opposed to the 1-3% rate in healthy community residents.  

The use of antibiotics alters the normal bowel flora, predisposing to the overgrowth of C difficile and the production of its toxins. Antineoplastic agents such as 5-fluorouracil, methotrexate, cisplatin, and cyclophosphamide have also been associated with CDAD.

CDAD results from the inflammatory reaction of the bowel wall to luminal toxins produced by C difficile. Continuation of inflammatory process can lead to formation of pseudomembranes, a mixture of inflammatory cells, fibrin, and bacterial and cellular components, which exudes from the bowel mucosa. Not all strains of C difficile are toxigenic.

Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.

C difficile produces two similar large molecular weight toxins, which are unique among bacterial enterotoxins. Both disrupt the barrier function of the colonic mucosa.

• Toxin A is an enterotoxin that binds to known receptors in the bowel wall. This process leads to activation of the inflammatory cascade, cytoskeletal derangements, and disruption of the intercellular tight junctions, causing fluid secretion, mucosal injury, edema, and inflammation.
• Toxin B is a cytotoxin for which a receptor has not been found in the human bowel mucosa; however, this cytotoxin also appears to act as a cytoskeletal disruptor, leading to further mucosal injury. Toxin B may play a role in activating the inflammatory cascade.

Frequency

United States

The number of hospital admissions complicated by C difficile –associated disease has increased steadily over the last decade, increasing from 0.27% of all hospital admissions in the United States prior to 2000 to 0.51% of all hospital admissions in 2003.⁴

In elderly patients, the increased incidence is more pronounced; the most recent estimate of incidence in patients older than 65 years was 228 per 100,000 person-years.⁴  

The outpatient incidence of CDAD is significantly lower than the inpatient rate. The most recent estimates are 0.5-1 hospital admissions per 100,000 person-years; however, these rates may have also recently increased.

International

Canada and Europe have historically reported similar rates of CDAD as those noted in the United States. However, Canada has reported increased rates over the past decade. A 2004 report from a large university center in Canada noted an increase in incidence from 35.6 per 100,000 in 1991 to 156.3 per 100,000 in 2003; among patients aged 65 years or older, the rate increased from 102 to 866.5 per 100,000.

Mortality/Morbidity

CDAD causes a significant burden on the health care system. The costs associated with each hospitalized case of CDAD were $3,699 in excess health care costs and 3.6 extra days of hospitalization, according to a report of short-stay hospitals in 2002.

Infection with toxigenic C difficile is a potentially life-threatening disease process. Patients who are not treated or in whom treatment is delayed may develop complications including fulminant toxic megacolon. The mortality rate in patients who develop complications is as high as 30%.

Sex

Women are at higher risk for developing recurrent disease than men.

Age

Elderly persons are at higher risk for developing CDAD and recurrent disease than younger persons.

Clinical

History

The clinical course prior to development of C difficile –associated diarrhea (CDAD) typically contains a history of antibiotic exposure, risk factors for colonization, and alterations in host physiology.  

• History of antibiotic exposure
  • CDAD symptoms typically develop 5-10 days after initiation of antibiotic therapy. However, they can develop after a single day of antibiotic use or can occur as late as 10 weeks after cessation. 
  • Some patients may develop CDAD without a clearly identified antibiotic exposure. 
  • Importantly, not all diarrhea cases following antibiotic use are due to C difficile. In fact, 70-80% of diarrhea following antibiotic use is due to changes in the osmotic pressure in the lumen after alteration of the bowel flora decreases the use and absorption of carbohydrates.
• Colonization with C difficile
  • Generally, colonization occurs following ingestion of acid-resistant spores. 
  • In the hospital environment, the spores are common contaminants from patients who harbor C difficile. The organism can be transmitted via fomites or the hands of health care providers. 
  • Hospitalized patients and residents of long-term care facilities are at higher risk of colonization with C difficile. 
  • Although less common, colonization can occur in the outpatient setting.
• Host factors that increase susceptibility to C difficile –associated diarrhea
  • Chronic debilitation critical illness 
  • Alteration in gut motility
    • Agents that affect the bowel, including enemas, stool softeners, and opioids, are identified as risk factors for disease development. 
    • Patients who have undergone abdominal surgery with subsequent ileus are also at increased risk.
  • Receipt of enteral tube feeds 
  • Use of proton pump inhibitors (These may increase the rate of successful colonization after oral ingestion; clinical studies have shown mixed results.)
  • Impaired humoral immunity (especially of the IgG subclasses) (This may increase the susceptibility to relapsing disease.) 
  • A common single nucleotide polymorphism (SNP) of the interleukin (IL)–8 gene promotor⁵

The clinical presentation of C difficile –associated disease can range from mild self-limited diarrhea to severe colitis with pseudomembrane formation complicated by development of toxic megacolon or colonic perforation. The classic presentation is cramping abdominal pain with profuse, mucoid, greenish, malodorous watery stools.

• Clinical signs
  • Diarrhea: This is usually fairly mild, with 2-6 stools per day. However, persons with severe cases may have more than 20 stools per day.
  • Leukocytosis: Leukocytosis is found in 50-60% of patients. A WBC count of 12,000-20,000 10³/μL with associated with minimal diarrhea and a lack of other presenting signs is a common hospital presentation. However, 30% of patients have a WBC count of more than 30,000 10³/μL.
  • Fever: This affects 30-50% of patients.
  • Abdominal pain or cramping: This affects 20-33% of patients and may have various presentations. Sometimes generalized, diffuse, and cramping, it can also manifest as focal pain that mimics acute abdomen. Evidence of peritoneal signs should immediately raise suspicion for fulminant colitis and toxic megacolon.
  • Constipation with or without dyspepsia: This can be an atypical presentation.
  • Colitis can be present without accompanying diarrhea, particularly in patients with right-sided colonic involvement.
  • Toxic megacolon can complicate severe infection and can lead to bowel perforation.
  • Extraintestinal manifestations are rare and include the following:
    • Bacteremia, generally polymicrobial
    • Splenic abscess
    • Osteomyelitis
    • Reactive arthritis or tenosynovitis
  • Other findings include the following:
    • Nausea
    • Malaise
    • Anorexia
    • Hypoalbuminemia
    • Anasarca
    • Electrolyte disturbances
    • Occult colonic bleeding
    • Orthostatic due to dehydration

Physical

The diagnosis of CDAD relies primarily on an appropriate suggestive history. Physical examination findings may include fever, abdominal tenderness, and diarrhea. In cases of severe diarrhea, physical signs suggestive of dehydration (eg, dry mucous membranes, decreased skin turgor, orthostasis) may also be present.

Causes

C difficile –associated disease results from the action of toxins formed by the organism. Rarely, pseudomembranous colitis can be caused by other etiologies, such as Staphylococcus species or enterotoxigenic C perfringens, Campylobacter species, Listeria species, and Salmonella species.

Differential Diagnoses

Other Problems to Be Considered

Amebic dysentery
Bacterial dysentery
Ischemic colitis
Adverse reaction to medications or antibiotics
Intra-abdominal sepsis
Typhilitis

Workup

Laboratory Studies

Evaluation of C difficile –associated diarrhea (CDAD) or antibiotic-associated colitis primarily focuses on the detection of C difficile or its toxins in stool. Testing methods available vary among laboratories. 

• In general, repeated testing (ie, 3 samples) increases the sensitivity of the most commonly used toxin assays into acceptable ranges. 
  • Cytotoxic assays are highly sensitive (67-100%) and specific (85-100%); however, they are costly, require 48 hours to complete, and lack standardization. Stool filtrate is mixed with mammalian tissue-culture cell lines and observed for cytopathic effect. Stool filtrate mixed with antitoxin to C difficile toxin B usually serves as a negative control.
  • Enzyme-linked immunosorbent assay (ELISA) techniques are used to detect the presence of toxin A and/or B. A wide variety of these tests are available. Reported sensitivities range from 63-99%, with specificities of 75-100%. These tests are less expensive than cytotoxic assays and yield quicker results. Assays that detect both toxin A and B are preferred because some circulating strains express only toxin B.
  • Stool samples should be refrigerated or frozen (depending on laboratory requirements) after collection if a delay in further processing is expected. The toxin may degrade to undetectable levels within 4 hours after collection if stored at room temperature
• Direct culture of C difficile from the stool provides the most sensitive diagnostic measure. This study is not commonly performed because it often costs more and does not differentiate between nontoxigenic and toxigenic C difficile.
• Latex agglutination studies focus on detecting glutamate dehydrogenase. This test has been shown to lack specificity and sensitivity and is not recommended.
• PCR technology can be used to detect the presence of toxins A or B; this test is sensitive and specific and has recently become commercially available. However, cost issues may preclude widespread use at present. The technology required for this technique is generally limited to research centers.
• Other items to consider in the laboratory analysis include fecal leukocytes and fecal lactoferrin assays upon evidence of colonic inflammation. These test lack specificity and have limited roles.

Imaging Studies

• Imaging studies do not aid in confirming the diagnosis of early or mild colitis.
• In patients with severe disease, radiographic studies can aid in detecting complications (eg, toxic dilation, perforation). These studies may also be indicated to investigate other possible diagnoses.
• CT scanning of the abdomen can be helpful by revealing the presence of bowel wall edema (>4 mm) and inflammation, particularly in cases involving the right colon; however, these findings are nonspecific. 
• Barium enema has no role in the diagnosis of early colitis and can be catastrophic in the setting of dilatation due to toxic megacolon or perforation.
• Toxic megacolon is characterized radiographically by dilation of the transverse colon to greater than 6 cm and lossof colonic haustrations (possible “thumbprinting”)

Procedures

• Sigmoidoscopic examination
• Pseudomembranes can be visualized in up to 50% of patients with CDAD via endoscopic examination. Flexible sigmoidoscopy is sufficient in 90% of cases; few may require full colonoscopy. 
• In mild cases, pseudomembranes may not be grossly present, and diagnosis must be confirmed with biopsy.  
• The classic appearance of 2- to 10-mm raised yellow nodules is pathognomonic. These lesions are usually discrete but may become confluent plaques in more advanced cases. The pseudomembranes can be easily removed during endoscopy, revealing an erythematous inflamed mucosa.  
• Sigmoidoscopy is not routinely used in the diagnosis of CDAD because its invasiveness. Indications for endoscopy, according to the AmericanCollege of Gastroenterology guidelines, include the following: 
• Need for rapid diagnosis 
• Patient with ileus or who cannot produce stool 
• As part of workup for other colonic diseases

Histologic Findings

Macroscopically, pseudomembranes are appreciated as patchy flecks of tan-to-black nodules, loosely adherent to the erythematous bowel wall with superficial erosions, punctate in mild forms, and more confluent in advanced disease.

Microscopically, the earliest sign is focal necrosis of surface epithelial cells in the glandular crypts, with neutrophilic infiltration and fibrin plugging of capillaries in the lamina propria and mucus hypersecretion in adjacent crypts. This leads to the formation of crypt abscesses. As the disease progresses, necrosis and denudation of the mucosa occurs with thrombosis of submucosal venules. The bowel wall inflammation tends to remain superficial; however, exposure of unprotected submucosa to the fecal stream can lead to global dysfunction of the colonic musculature and subsequent dilatation.

Treatment

Medical Care

• Stop the offending agent if possible. In about 20% of patients, C difficile– associated disease resolves within 2-3 days of discontinuing the antibiotic to which the patient was previously exposed.
• Given the potential morbidity of C difficile –associated diarrhea (CDAD), treatment should be initiated immediately rather than waiting for potential resolution of symptoms. In mild cases that are brought to clinical attention and are diagnosed after the resolution of symptoms, withholding antibiotics may be reasonable.
• Provide supportive care for the diarrhea, including repletion of fluid and electrolyte losses.
  • Antiperistaltic agents and opiates should be avoided, as slowing of fecal transit time is thought to result in extended toxin-associated damage.
  • Test confirmation of C difficile involvement is indicated prior to treatment, provided the patient is not critically ill.
  • Empiric treatment prior to confirmation of diagnosis is reasonable in critically ill patients; but stool samples for analysis should be obtained with 48 hours of therapy initiation.
• Implement contact isolation precautions to reduce the spread of C difficile to other hospitalized patients.
• Patients generally respond to 7-10 days of metronidazole or vancomycin therapy (see Medication); however, patients with severe colitis or underlying GI conditions (eg, irritable bowel syndrome, lactose intolerance) may require prolonged courses of therapy.
• Treatment of completely asymptomatic carriers remains controversial.

Surgical Care

Surgical intervention is usually indicated for patients whose conditions are complicated by toxic megacolon with subsequent risk for perforation or existing perforation. The frequency of surgical intervention is low, reported at 0.39-3.6% of cases of C difficile –associated colitis. Various approaches can be used, including diverting ostomy of the affected segment or subtotal colectomy. The overall mortality rate for patients requiring surgery is reportedly as high as 30-35%. Several recent studies have emphasized the importance of early surgical intervention if indicated (eg, prior to end organ failure or lactate >4).

Consultations

• Gastroenterologist for endoscopy, if indicated
• General surgeon if toxic megacolon or perforation is present or possible
• Infectious disease specialist or gastroenterologist for recurrent disease

Diet

Recommendations should be based on the severity of the symptoms. For moderate-to-severe cases, a clear liquid diet is recommended until the patient’s diarrhea resolves.

Activity

Activity is as tolerated, depending on degree of symptoms.

Medication

Oral metronidazole and oral vancomycinhave similar efficacy in the treatment of C difficile –associated diarrhea (CDAD). However, metronidazole is the empiric treatment of choice because of cost and the risk of selection for vancomycin-resistant enterococci in the stool with oral vancomycin. 

• Metronidazole: In adults, oral metronidazole is administered at 500 mg tid or 250 mg qid for 10 days. 
• Vancomycin 
• Oral vancomycin is administered at 125-250 mg qid for 10 days in the following situations: 
• When metronidazole fails to elicit a response after 3-4 days of treatment 
• When organisms resistant to metronidazole are present (Metronidazole resistance remains uncommon in the United States. The NAP1 strain responsible for multiple outbreaks in the United States and Canada has been uniformly susceptible to metronidazole. However, surveillance reports from China, France, and Spain have noted resistance rates as high as 14%.6
• Patients who cannot tolerate metronidazole
• Patients who are pregnant or younger than 10 years
• Patients who are critically ill secondary to C difficile infection (toxic megacolon, colonic perforations)
• Doses of 250-500 mg qid may be required in severe disease or in the setting of ileus.

Despite the lack of conclusive clinical trials, intravenous metronidazole, 500 mg q6h, is generally recognized as adequate therapy for patients who cannot tolerate oral therapy⁸ (although failures have been documented). Intravenous vancomycin therapy is not adequate because no significant delivery of vancomycin to the bowel lumen occurs. 

Rectal vancomycin by colonic infusion via a catheter has been anecdotally reported.⁹ This treatment has usually been limited to adjunctive therapy with intravenous metronidazole. 10,11,12  

• Anion-exchange resin agents (eg, cholestyramine): These provide a 63% clearance rate as a single therapy; however, they bind antibiotic agents, limiting their clinical usefulness in more severe disease. 
• Oral bacitracin was used in the 1980s but is no longer readily available. 
• Teicoplanin¹³ has an efficacy that is similar to that of vancomycin but is not available in the United States. 
• Fusidic acid¹² has poor tolerability due to gastrointestinal adverse effects when compared to vancomycin and is not available in the United States. 
• Tolevamer is administered at 3-9 g/day in divided doses for 14 days. It is a high molecular weight anionic polymer that covalently binds C difficile toxins A and B. Such nonantibiotic treatments may lead to decreased recurrence rates. A 2006 randomized controlled trial showed that tolevamer 6 g/d was not inferior to oral vancomycin.¹⁴  
• Nitazoxanide is administered at 500 mg bid for 10 days.¹⁵ Nitazoxanide is a nitrothiazolide with broad activity against intestinal parasites and enteric pathogens. In a 2006 prospective, randomized, double-blind study, the efficacy of nitazoxanide was at least as effective as metronidazole in treating C difficile colitis. Several phase III trials are underway for further study. Early data suggest that it may have minimal interaction with warfarin (Coumadin). 
• Rifaximin is administered at 200 mg tid for 10 days. Rifaximin is a poorly absorbed rifamycin that has been FDA approved for traveler's diarrhea. It was successfully used in conjunction with oral vancomycin in a case series of patients with multiple recurrences of CDAD. The patients underwent a 2-week course of rifaximin after completing treatment with vancomycin.¹⁶ A phase III trial is underway.
• 17
• 18  
• PAR 101 (OPT-80, tiacumicin B) - Novel nonabsorbed macrocycle with minimal activity against enteric organisms other than C difficile¹⁹  
• Hyperimmune bovine gammaglobulin 
• Immunization with C difficile toxoid (toxins A and B)^20,21
• Monoclonal antibodies²²  

• Recurrent disease is an increasingly prevalent problem.^23,24,25  Estimates of reoccurrence (within 90 days) average around 30%. True treatment failures (persistent symptoms after 10 d of therapy) have been reported in up to 15% of cases. 
• Note that recurrence of disease is not commonly associated with resistance and should thus be treated similarly to the initial occurrence. 
• No randomized controlled trials are available to guide therapy of recurrent disease. A retrospective review showed that metronidazole and vancomycin had equivalent efficacy in the treatment of a first recurrence; furthermore, treatment of the first recurrence with the same or a different agent did not affect the outcome. 
• The first or second recurrence should be treated with a repeat treatment course of oral vancomycin or metronidazole.  
• With further recurrences, use of tapered or pulsed vancomycin should be considered.²⁶
• Other nonantibiotic therapies that have been used successfully as adjuncts in severe relapsing disease include stool transplant,²⁷ IVIG,^28,29 and tolevamer (a high molecular weight anionic polymer that binds C difficile toxins). 

Antibiotics

Effective therapy against C difficile colitis should be used.

Metronidazole (Flagyl)

First-line agent. Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. If unable to tolerate PO, may administer IV as second-line therapy.

Dosing

Adult

500 mg PO tid or 500 mg IV q6h

Pediatric

<10 years: Not recommended
>10 years: 35-50 mg/kg/d PO in 3 divided doses

Interactions

May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity of metronidazole; disulfiram reaction may occur with orally ingested ethanol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy

Vancomycin (Vancocin)

Potent antibiotic directed against gram-positive organisms and active against C difficile and Enterococcus species.
Minimal systemic absorption with PO form.

Dosing

Adult

125 mg PO qid for 7-10 d
250-500 mg PO qid for 7-10 days in setting of ileus

Pediatric

40 mg/kg/d IV divided tid/qid 7-10 d

Interactions

Erythema and histaminelike flushing may occur; thrombocytopenia, anaphylactic reactions, and Stevens-Johnson syndrome/toxic epidermal necrolysis are rare reactions

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal failure, neutropenia; red man syndrome is caused by too-rapid IV infusion (dose given over a few minutes) but rarely happens when dose given IV over 2 h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Follow-up

Further Inpatient Care

• Further inpatient care is required only if the patient continues to have significant diarrhea, related fluid losses, or other medical issues; otherwise, outpatient therapy may be appropriate.

Further Outpatient Care

• Follow-up care is not generally required.  
• The return of diarrhea may indicate the need for retreatment for recurrent disease.
• After treatment, repeat C difficile testing is not recommended if the patient’s symptoms have resolved, as patients may remain colonized.

Inpatient & Outpatient Medications

• Optimal treatments are discussed in Treatment and include antibiotics with activity against C difficile.
• The use of antidiarrheals such as loperamide is not recommended in the treatment of acute C difficile –associated diarrhea (CDAD).

Deterrence/Prevention

• Proper stewardship of antibiotics may limit the risk of CDAD.
• Avoidance of unnecessary antibiotics, especially within the first few months after treatment for CDAD, may limit the risk of recurrent disease. 
• Implementation of infection control procedures is imperative to control spread. 
• C difficile is shed in feces. Any surface or material that becomes contaminated with feces may serve as a reservoir for the C difficile spores.
• Use contact isolation for infected patients, particularly those with bowel incontinence. Infected patients can be isolated in private rooms (preferred) or through cohorting of patients with C difficile infection. Some advocate empiric isolation of patients with incontinence who have diarrhea C difficile infection is suspected while confirmatory testing is pending. Contact isolation should be continued until the treatment course for CDAD is complete and the patient regains continence.
• Gloves and gowns should be used during all patient contact. (Some advocate the use of gowns only soiling clothes is a risk).
• Dedicate equipment when possible.
• Hands should be washed with soap and water. Alcohol-based hand solutions may not be as effective against spore-forming bacteria.
• Hospital rooms must be appropriately cleaned to ensure sterilization of spores. Hypochlorite-based disinfectants (eg, chlorine bleach) have been used with some success.
• Probiotics may help minimize the risk of CDAD after antibiotic use.³⁰  
• Saccharomyces boulardii yeast
• S boulardii rapidly colonizes the bowel without significantly altering the remaining bowel flora, and it is cleared from the bowel after cessation of therapy.
• Some data suggest that S boulardii produces a protease capable of destroying the receptor site for C difficile toxins A and B.
• Safety concerns exist regarding fungemia with use in immunocompromised patients.
• It is available as the dietary supplement Florastor in the United States.
• Lactobacillus
• Lactobacillus is available as a "natural" product with limited quality control.
• In 2004, a small randomized controlled trial showed a 50% reduction in the incidence of CDAD when used as prophylaxis initiated at the time of antibiotic therapy.³¹

Complications

• Major complications of acute disease include development of toxic megacolon, transverse volvulus, or colon perforation. These complications can be avoided with early detection and treatment, avoidance of antimotility agents in patients with nosocomial diarrhea (until etiology is known), and early surgical consultation.
• Recurrent colitis and diarrhea occur in approximately 20% of patients (depending on populations studied), typically 2 weeks to 2 months after successful therapy completion; occasionally, more than 6 episodes may occur. The etiology is unclear; however, it is thought to be related to the persistence of spores that are not killed by the antibiotic courses. Relapses are treated in the same manner as the initial episode, with oral metronidazole. Recurrent colitis does not necessarily represent the development of metronidazole-resistant organisms; hence, administration of vancomycin should still be limited to the exceptions listed above (see Medication).

Prognosis

• When properly treated, CDAD is a limited disease process with a good prognosis; however, recurrent disease is not unusual, often requiring repeat courses of treatment.

Patient Education

• Education is critical for health care providers and should include proper contact isolation procedures for infected patients (ie, use of gloves, hand washing, disposable thermometers).
• Patient education should include instruction about the link of the disease with antibiotic use and the need to return for retreatment if symptoms return.
• Patient education regarding the adverse effects of metronidazole, including metallic taste and adverse reaction to alcohol-containing fluids, should be provided.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose or delay in therapy, which can result in abdominal perforation due to toxic megacolon
• Use of antiperistaltic agents in confirmed or suspected cases of C difficile –associated diarrhea (CDAD), as these may halt clearance of formed toxins 
• Failure to institute appropriate infection control guidelines to prevent transmission of the disease

Special Concerns

• Because of the lack of safety data, metronidazole is not recommended for use in children younger than 10 years; instead, vancomycin is used.
• Strains of metronidazole- and vancomycin-resistant C difficile have been reported. However, routine susceptibility testing for C difficile is not recommended. In the setting of severe recurrent disease, consultation with an infectious disease specialist should be considered. 

Multimedia

Media file 1: Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.

References

1. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. Dec 8 2005;353(23):2442-9. [Medline].

2. McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. Dec 8 2005;353(23):2433-41. [Medline].

3. Stabler RA, Gerding DN, Songer JG, Drudy D, Brazier JS, Trinh HT. Comparative phylogenomics of Clostridium difficile reveals clade specificity and microevolution of hypervirulent strains. J Bacteriol. Oct 2006;188(20):7297-305. [Medline].

4. McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis. Mar 2006;12(3):409-15. [Medline].

5. Jiang ZD, DuPont HL, Garey K, Price M, Graham G, Okhuysen P. A common polymorphism in the interleukin 8 gene promoter is associated with Clostridium difficile diarrhea. Am J Gastroenterol. May 2006;101(5):1112-6. [Medline].

6. Johnson S, Sanchez JL, Gerding DN. Metronidazole resistance in Clostridium difficile. Clin Infect Dis. Aug 2000;31(2):625-6. [Medline].

7. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults [database online]. Cochrane Database Syst Rev; 2005 Jan 25.

8. Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut. Oct 1986;27(10):1169-72. [Medline].

9. Apisarnthanarak A, Razavi B, Mundy LM. Adjunctive intracolonic vancomycin for severe Clostridium difficile colitis: case series and review of the literature. Clin Infect Dis. Sep 15 2002;35(6):690-6. [Medline].

10. Aslam S, Musher DM. An update on diagnosis, treatment, and prevention of Clostridium difficile-associated disease. Gastroenterol Clin North Am. Jun 2006;35(2):315-35. [Medline].

11. Surowiec D, Kuyumjian AG, Wynd MA, Cicogna CE. Past, present, and future therapies for Clostridium difficile-associated disease. Ann Pharmacother. Dec 2006;40(12):2155-63. [Medline].

12. Wenisch C, Parschalk B, Hasenhündl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. May 1996;22(5):813-8. [Medline].

13. de Lalla F, Privitera G, Rinaldi E, Ortisi G, Santoro D, Rizzardini G. Treatment of Clostridium difficile-associated disease with teicoplanin. Antimicrob Agents Chemother. Jul 1989;33(7):1125-7. [Medline].

14. Louie TJ, Peppe J, Watt CK, Johnson D, Mohammed R, Dow G. Tolevamer, a novel nonantibiotic polymer, compared with vancomycin in the treatment of mild to moderately severe Clostridium difficile-associated diarrhea. Clin Infect Dis. Aug 15 2006;43(4):411-20. [Medline].

15. Musher DM, Logan N, Hamill RJ, Dupont HL, Lentnek A, Gupta A. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. Aug 15 2006;43(4):421-7. [Medline].

16. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. Mar 15 2007;44(6):846-8. [Medline].

17. Fung HB, Doan TL. Tinidazole: a nitroimidazole antiprotozoal agent. Clin Ther. Dec 2005;27(12):1859-84. [Medline].

18. Pullman J, Prieto J, Leach TS. Ramoplanin vs. Vancomycin in the treatment of Clostridium difficile diarrhea: A Phase 2 Study, poster presented at the 44th ICAAC, an annual meeting of the American Society for Microbiology, October 2004. Available at http://www.oscient.com/products/pdf/Ramo_PII_C_AD_ICAAC_2004.pdf.

19. Credito KL, Appelbaum PC. Activity of OPT-80, a novel macrocycle, compared with those of eight other agents against selected anaerobic species. Antimicrob Agents Chemother. Nov 2004;48(11):4430-4. [Medline].

20. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet. Jan 20 2001;357(9251):189-93. [Medline].

21. Aboudola S, Kotloff KL, Kyne L, Warny M, Kelly EC, Sougioultzis S. Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A. Infect Immun. Mar 2003;71(3):1608-10. [Medline].

22. Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatright N. Human monoclonal antibodies directed against toxins A and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun. Nov 2006;74(11):6339-47. [Medline].

23. Musher DM, Aslam S, Logan N, Nallacheru S, Bhaila I, Borchert F. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. Jun 1 2005;40(11):1586-90. [Medline].

24. Pepin J, Alary ME, Valiquette L, Raiche E, Ruel J, Fulop K. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. Jun 1 2005;40(11):1591-7. [Medline].

25. Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Lancet Infect Dis. Sep 2005;5(9):549-57. [Medline].

26. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. Jul 2002;97(7):1769-75. [Medline].

27. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. Mar 1 2003;36(5):580-5. [Medline].

28. Wilcox MH. Descriptive study of intravenous immunoglobulin for the treatment of recurrent Clostridium difficile diarrhoea. J Antimicrob Chemother. May 2004;53(5):882-4. [Medline].

29. McPherson S, Rees CJ, Ellis R, Soo S, Panter SJ. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum. May 2006;49(5):640-5. [Medline].

30. D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ. Jun 8 2002;324(7350):1361. [Medline].

31. Plummer S, Weaver MA, Harris JC, Dee P, Hunter J. Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhoea. Int Microbiol. Mar 2004;7(1):59-62. [Medline].

32. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. Jan 31 2002;346(5):334-9. [Medline].

33. Bartlett JG. Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis. May 1994;18 Suppl 4:S265-72. [Medline].

34. Cotran RS, Kumar V, Robbins S. Robbins Pathologic Basis of Disease. WB Saunders Co; 1989:360-1.

35. [Guideline] Dubberke ER, Gerding DN, Classen D, Arias KM, Podgorny K, Anderson DJ, et al. Strategies to prevent clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol. Oct 2008;29 Suppl 1:S81-92. [Medline].

36. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. May 1997;92(5):739-50. [Medline].

37. Friedenberg F, Fernandez A, Kaul V, et al. Intravenous metronidazole for the treatment of Clostridium difficile colitis. Dis Colon Rectum. Aug 2001;44(8):1176-80. [Medline].

38. Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. Aug 1995;16(8):459-77. [Medline].

39. Jodlowski TZ, Oehler R, Kam LW, Melnychuk I. Emerging therapies in the treatment of Clostridium difficile-associated disease. Ann Pharmacother. Dec 2006;40(12):2164-9. [Medline].

40. Johnson S, Gerding DN. Clostridium difficile--associated diarrhea. Clin Infect Dis. May 1998;26(5):1027-34; quiz 1035-6. [Medline].

41. Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med. Aug 15 1992;117(4):297-302. [Medline].

42. Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. N Engl J Med. Oct 30 2008;359(18):1932-40. [Medline].

43. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med. Jan 27 1994;330(4):257-62. [Medline].

44. Kim J, Smathers SA, Prasad P, Leckerman KH, Coffin S, Zaoutis T. Epidemiological features of Clostridium difficile-associated disease among inpatients at children's hospitals in the United States, 2001-2006. Pediatrics. Dec 2008;122(6):1266-70. [Medline].

45. Leffler DA, Lamont JT. Treatment of Clostridium difficile-associated disease. Gastroenterology. May 2009;136(6):1899-912. [Medline].

46. Monaghan T, Boswell T, Mahida YR. Recent advances in Clostridium difficile-associated disease. Gut. Jun 2008;57(6):850-60. [Medline].

47. Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficile--Associated diarrhea: A review. Arch Intern Med. Feb 26 2001;161(4):525-33. [Medline].

48. Noblett SE, Welfare M, Seymour K. The role of surgery in Clostridium difficile colitis. BMJ. May 6 2009;338:b1563. [Medline].

49. O'Connor JR, Johnson S, Gerding DN. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology. May 2009;136(6):1913-24. [Medline].

50. Pépin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. Nov 1 2005;41(9):1254-60. [Medline].

51. Theilman NM, Wilson KH. Antibiotic associated colitis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6^th ed. Churchill Livingstone; 2005:1249-62.

Keywords

pseudomembranous colitis, PMC, antibiotic-associated colitis, antibiotic-associated diarrhea, Clostridium difficile colitis, C difficile colitis, C difficile diarrhea, Clostridium difficile diarrhea, Clostridium difficile –associated diarrhea, –associated diarrhea, CDAD, C difficile infection, pseudomembranes, antibiotic therapy, enterotoxin, cytotoxin, fulminant toxic megacolon, colonic perforation, transverse volvulus, binary toxin

Contributor Information and Disclosures

Author

Jennifer A Curry, MD, MPH, Staff Physician, Infectious Disease Clinic, Naval Medical Center Portsmouth
Jennifer A Curry, MD, MPH is a member of the following medical societies: American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Braden R Hale, MD, MPH, Assistant Clinical Professor, Department of Internal Medicine, University of California at San Diego; Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Naval Medical Center at San Diego
Braden R Hale, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, Armed Forces Infectious Diseases Society, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Duane R Hospenthal, MD, PhD, Chief, Infectious Disease Service, San Antonio Military Medical Center, Brooke Army Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences
Duane R Hospenthal, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Society for Infectious Diseases, International Society of Travel Medicine, and Medical Mycology Society of the Americas
Disclosure: Nothing to disclose.

Joseph Lee, MD, Staff Physician, Department of Medicine, Walter Reed Army Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Gary L Gorby, MD, Program Director of Adult Infectious Diseases Fellowship, Associate Professor, Department of Internal Medicine, Division of Infectious Disease, St Joseph Medical Center, Creighton University School of Medicine
Gary L Gorby, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Joseph F John Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: BioMerieux Honoraria Review panel membership; Cubist Honoraria Review panel membership; Pfizer Honoraria Speaking and teaching; Merck Stock dividends stock holdings

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Aslam S, Musher DM. An update on diagnosis, treatment, and prevention of Clostridium difficile –associated disease. Gastroenterol Clin North Am. Jun 2006;35(2):315-35.

Clinical trials

Vancomycin Vs. Nitazoxanide to Treat Recurrent C. Difficile Colitis

Association Between Response to Treatment of C. Diff Colitis and Anti-C.Diff Toxin Antibody

Response of Clostridium Difficile Infection to Metronidazole Therapy

Compassionate Use of Nitazoxanide for the Treatment of Clostridium Difficile Infection

Fecal Bacterial Flora in Clostridium Difficile-Associated Diarrhea

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