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The Spectrum of Pseudomembranous Enterocolitis and Antibiotic-Associated Diarrhea
Brian W. Hurley, MD;
Cuong C. Nguyen, MD
Arch Intern Med. 2002;162:2177-2184.
ABSTRACT
Pseudomembranous (entero)colitis is primarily caused by Clostridium difficile infection. The most common predisposing factor
is prior use of antibiotics, including vancomycin and metronidazole, which
themselves are therapy for C difficile colitis. Other
risk factors have also been described. The presence of C difficile in the gastrointestinal tract leads to a spectrum of manifestations
from the asymptomatic carrier state to fulminant colitis. Successful treatment
of C difficile colitis requires prompt treatment
with appropriate antibiotics, withdrawal of the suspected predisposing antibiotics,
and, in rare cases, total colectomy. Preventive measures of adequate infection
control and judicious use of antibiotics are necessary means in attempting
to control the spread of C difficile infection. Attempts
at making an effective human vaccine are currently under way.
HISTORICAL PERSPECTIVE
Preantibiotic Era
The first reported case of pseudomembranous enterocolitis (PMC) was
reported by J. M. Finney in association with William Osler in 1893. They described
a 22-year-old woman who underwent resection of gastric tumors and developed
postoperative diarrhea. She died on the 15th postoperative day, and at autopsy,
the small bowel revealed diphtheritic membranes.1-2 In
the preantibiotic era, PMC was rare. Only about 4 cases were recognized annually
at the Mayo Clinic (Rochester, Minn).1, 3 It
was feared as a catastrophic complication of surgery because the diagnosis
was only made at autopsy.
The most common clinical setting in those cases not associated with
antibiotic therapy was colonic, pelvic, or gastric surgery. Other risk factors
include spinal fracture, intestinal obstruction, colon carcinoma, leukemia,
severe burns, shock, uremia, heavy metal poisoning, hemolytic-uremic syndrome,
ischemic cardiovascular disease, Crohn disease, shigellosis, severe infection,
ischemic colitis, and Hirschsprung disease.1 There
is no definitive explanation for how these conditions lead to PMC, but it
may be related to alterations in host defense mechanisms and enteric flora.
Several postoperative cases were related to hypotension and shock, suggesting
an ischemic origin.4
Early Antibiotic Era (1950-1969)
During the dawn of the antibiotic era, PMC became a common complication
of antibiotic use. Staphylococcus aureus, the principal
nosocomial pathogen at that time, was implicated as the agent responsible
for this condition by Gram stains and cultures of stools.1 Thus,
vancomycin became the standard treatment.
Established Antibiotic Era (1970s)
Because vancomycin therapy worked, the causative agent was not questioned
until the middle to late 1970s. The use of clindamycin had become widespread
during this period. A landmark study by Tedesco et al5 at
the Barnes-Jewish Hospital in St Louis, Mo, implicated clindamycin as a cause
of PMC. It was the first study to prospectively use en doscopy to establish
the diagnosis of PMC in the setting of antibiotic-associated diarrhea. Among
200 patients treated with clindamycin, 21% developed diarrhea and 10% developed
PMC.1 Furthermore, S aureus could not be isolated from these patients. Subsequent studies of 8
stool specimens collected and tested 5 years later in Tedesco's laboratory
showed that all contained C difficile and its cytopathic
toxins.1 Meanwhile, animal studies and subsequent
human studies isolated C difficile and its toxins
in almost all patients with endoscopic evidence of PMC.
PSEUDOMEMBRANOUS ENTEROCOLITIS
Pseudomembranous enterocolitis occurred in the preantibiotic era. There
were risk factors other than antimicrobial therapy that were important in
the development of PMC. Staphylococcus aureus was
implicated in the early antibiotic era as the causative pathogen; however,
later studies shifted the focus to C difficile. Reports
of possible S aureus–related PMC in patients
testing negative for C difficile serve as reminders
that this entity may indeed occur, albeit rarely.4 One
theory for this etiologic shift is that, with the advent of newer antibiotics,
more effective antistaphylococcal activity favored emergence of C difficile.4 Pseudomembranous enterocolitis
primarily affects the large bowel, but it can rarely affect the small bowel.
Since the 1970s, C difficile has been recognized
as the most common cause of PMC. Other causes of pseudomembrane formation
in the large and small bowel include early ischemia, verotoxin-producing organisms
such as Escherichia coli, and drug therapy with chlorpropamide,
gold, and nonsteroidal anti-inflammatory agents.
Figure 1 demonstrates the
histologic changes associated with PMC. Figure
2 illustrates the gross pathologic appearance of PMC. Figure 3 illustrates the appearance of PMC on endoscopy.
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Figure 1. Microscopic pathologic appearance
for a pseudomembrane in the colon. The pseudomembrane gives the appearance
of a "volcanic eruption." This appearance is classic for pseudomembranous
colitis. (Courtesy of James Williams, MD, Department of Pathology, Mayo Clinic
Scottsdale, Scottsdale, Ariz.)
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Figure 2. A surgical specimen of pseudomembrane
formation in the colon. The plaques were yellowish and raised and varied in
size from 2 to 10 mm. The intervening mucosa was pinkish and hyperemic. (Courtesy
of James Williams, MD, Department of Pathology, Mayo Clinic Scottsdale, Scottsdale,
Ariz.)
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Figure 3. Pseudomembranous colitis. Endoscopic
en face view of colon wall demonstrating several pseudomembranes (arrows).
(Courtesy of Jonathan Leighton, MD, Division of Gastroenterology, Mayo Clinic
Scottsdale, Scottsdale, Ariz.)
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ANTIBIOTIC-ASSOCIATED DIARRHEA
Most cases of antibiotic-associated diarrhea are categorized as nonspecific
diarrhea (Figure 4).4 These
are mild diarrhea episodes without a definitive cause. They usually resolve
with simple discontinuation of antibiotic therapy. Alteration of colonic flora
leading to impaired colonic carbohydrate metabolism may be the cause in some
cases.4 Approximately 20% of cases of antibiotic-associated
diarrhea are due to C difficile. Two percent to 3%
of cases are due to other pathogens such as Clostridium
perfringens, S aureus, and Candida albicans. Also, a few cases are categorized as antibiotic specific.
One example of this type would be the promotility adverse effect of erythromycin
causing diarrhea. Another example is the malabsorption caused by large doses
of neomycin.4
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Figure 4. Categories, causes, and relative
frequencies of antibiotic-associated diarrheas. (Reprinted from LaHatte et
al4 with permission from WB Saunders Co.)
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CLOSTRIDIUM DIFFICILE–RELATED SPECTRUM
OF DISEASE
Description of Organism and Epidemiology
Clostridium difficile is a spore-forming, gram-positive
bacillus. It was given its name because it was difficult to grow in culture
and isolate. It forms spores and thus can survive under harsh environmental
conditions and withstand antibiotic therapy.6 In
his doctoral thesis in 1974, Hafitz7 noted
that C difficile survives well in nature and is widely
distributed in the environment. The organism is frequently transmitted by
person-to-person contact. Therefore, strict hand washing and contact and enteric
precautions are imperative measures in preventing the spread of the organism.
It has been cultured from many items including toilets, bedpans, floors, telephones,
call buttons, scales, shoes of hospital personnel, fingernails, fingertips,
and the underside of rings. Clostridium difficile can
be cultured in rooms of infected individuals up to 40 days after discharge. 6
Clostridium difficile infection is primarily
a nosocomial infection. It causes approximately 3 million cases of diarrhea
and colitis annually in the United States. Only about 20 000 cases annually
are diagnosed in the outpatient setting.8 Community-acquired
disease does occur, but the epidemiologic factors in this setting are not
fully understood. In a recent study, Riley et al9 suggested
that the incidence in the community may be underestimated: this may be owing
to a lack of awareness and investigation by physicians of this organism as
a cause of community-acquired diarrhea. Table 110 demonstrates the distribution
of C difficile from the stools of various patient
populations. Clostridium difficile can be isolated
from up to 3% of healthy adults in the general population and up to 80% of
healthy newborns and infants. Infants are exposed from nosocomial infection
and not from maternal transmission. A review by Johnson and Gerding11 revealed that the rate of colonization was approximately
20% in patients who were hospitalized for more than 1 week. A minority of
these patients were colonized on admission. However, of those who were initially
negative for C difficile on admission, the risk of
acquiring the organism increased in direct proportion to the duration of the
hospital stay.11 Another study by Clabots et
al12 showed that the rate of acquisition was
13% up to 2 weeks and 50% for those hospitalized for more than 4 weeks (Figure 5). 13
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Table 1. Isolation Rates of Toxigenic Clostridium
difficile From the Stool of Various Subject Populations*
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Figure 5. Rate of Clostridium
difficile acquisition as a function of hospital stay in weeks. Only
3 (1%) of 323 patients whose hospital stays were less than 1 week acquired C difficile, whereas 10 (50%) of 20 patients hospitalized
for more than 4 weeks had positive stool cultures. (Data from Clabots et al.12)
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Pathogenesis
Development of C difficile–associated
diarrhea (CDAD) requires several factors (Figure 6).8 The first 2 factors are
treatment with antimicrobials and colonization or acquisition of C difficile. However, most patients subsequently develop asymptomatic
colonization rather than frank CDAD. Therefore, other additional factors likely
play a role in the development of CDAD. These may be related to host susceptibility
or immunity, the virulence of the particular C difficile strain, or the type and timing of antimicrobial exposure.11 However, it is clear from molecular typing studies
that even the most virulent of C difficile strains
produces asymptomatic colonization more often than CDAD, and this finding
suggests that factors in addition to virulence are necessary for CDAD to occur.11, 14 In the article by Shim et al,15 4 longitudinal studies revealed that once asymptomatic
colonization is established, these patients are at decreased risk for subsequent
development of CDAD.15
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Figure 6. The pathogenesis of C difficile colitis involves initiation of antibiotic therapy, which
alters the normal colonic flora. Note that colonization may occur before the
initiation of antibiotic therapy. The patient either develops asymptomatic
colonization or expresses C difficile–associated
diarrhea (CDAD) and/or colitis. (Modified from Kelly and LaMont8 with
permission from the Annual Review of Medicine.)
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Virtually every antibiotic has the potential to cause CDAD or colitis,
including the antibiotics used to treat the disorder itself (Table 2).16 Ampicillin, cephalosporins,
and clindamycin are the most frequently implicated antibiotics. Ampicillin
and cephalosporins are prescribed more frequently than clindamycin and therefore
cause a greater number of cases of CDAD. However, clindamycin causes a greater
percentage of cases relative to its frequency of use. Symptoms can occur at
any time during antibiotic therapy and even up to 8 weeks after discontinuation
of the antibiotic. However, most episodes of CDAD occur from days 4 through
9 of antibiotic treatment.8
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Table 2. Antibiotics Associated With Clostridium
difficile Colitis and Diarrhea*
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Clostridium difficile produces 2 toxins that
are responsible for its pathogenesis. Toxin A is a 308-kd protein and toxin
B is a 250-kd protein. Both toxins are high-molecular-weight proteins and
are heat labile. They are separated by only a small area on the C difficile chromosome. Both toxins play a role in the pathogenesis
of CDAD and colitis and share common intracellular mechanisms of action as
a result of their homology. Nontoxigenic strains lack toxins A and B.1
Toxin A is primarily an enterotoxin that causes excretion of fluid from
bowel. This fluid is profoundly inflammatory, containing neutrophils, lymphocytes,
serum proteins, erythrocytes, and mucus. Toxin B is primarily cytotoxic, causing
the disintegration of filamentous actin and leading to the collapse of the
microfilament cytoskeleton and cell rounding. Clostridium
difficile toxins also stimulate leukocyte chemotaxis in vitro and up-regulate
the production of cytokines and other inflammatory mediators. These stimulatory
effects may underlie the ability of C difficile toxins
to elicit a profound colonic inflammatory response, culminating in PMC.6 Clostridium difficile also
produces tissue degradative enzymes, which may play a minor role in the pathogenesis.
These include chondroitin 4-sulfatase, collagenase, and hyaluronidase.17
Clinical Features and Complications of C difficile Infection
Clostridium difficile infection leads to a
spectrum of disease. This spectrum includes the asymptomatic carrier state,
simple antibiotic-associated diarrhea, PMC, and fulminant colitis. The basis
for the variable expression of disease may be related to host immune factors
and virulence factors of the organism.8
The asymptomatic carrier state is the end result for most patients infected
with C difficile. These patients act as a silent
reservoir of infection and probably perpetuate contamination of the hospital
environment. Treatment of asymptomatic carriers with antibiotics does not
eradicate the carrier state and is not recommended.8
Simple antibiotic-associated diarrhea is mild. As previously stated, C difficile accounts for only 20% of all cases of antibiotic-associated
diarrhea. Obvious colitis and systemic symptoms are absent.
Colitis without pseudomembrane formation is a more serious illness than
simple antibiotic-associated diarrhea. Patients may present with malaise,
abdominal pain, nausea, anorexia, watery diarrhea, low-grade fever, and a
peripheral leukocytosis. Endoscopy reveals a nonspecific diffuse or patchy
erythematous colitis without pseudomembranes.8
Pseudomembranous enterocolitis is the characteristic manifestation of
full-blown C difficile colitis. Sigmoidoscopic examination
reveals the classic pseudomembranes—raised yellow plaques from 2 to
10 mm in diameter scattered over the colorectal mucosa.8 Patients
with PMC have a more serious illness than patients who have colitis without
pseudomembrane formation. Approximately 20% of patients have more proximal
disease not detected on routine flexible sigmoidoscopy. Pseudomembranous enterocolitis
may rarely affect the small bowel.
Fulminant colitis occurs in only 3% of patients with C difficile infection. Patients may exhibit severe abdominal pain and
diarrhea, high fevers, and a marked peripheral leukocytosis. Diarrhea may
be absent if ileus develops, and these patients are at greatest risk to develop
toxic megacolon. A protein-losing enteropathy may lead to hypoalbuminemia,
which in turn can cause ascites. Complications may include colonic perforation,
toxic megacolon, prolonged ileus, ascites, and even death. Endoscopy is usually
not prudent owing to the risk of perforation, and exploratory laparotomy and
total colectomy may become necessary interventions.8 Figure 7 is an upright abdominal plain film
that demonstrates the complication of toxic megacolon.
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Figure 7. Acute toxic megacolon in a patient
with fulminant pseudomembranous colitis. Note the thickened and edematous
bowel wall (arrow).
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Diagnosis
There are various methods and assays available for the detection of C difficile infection. Table 38 compares and contrasts various
methods used to diagnose C difficile infection. The
cytotoxin assay is considered the standard for the diagnosis of C difficile infection (Figure 8).1 It detects toxin B, which is the primary cytotoxin.
It has a sensitivity of 94% to 100% and a specificity of 97%.8 However,
it requires a tissue culture facility, which is not widely available in most
hospitals. It also takes 24 to 48 hours to perform.
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Table 3. Stool Test for Diagnosis of Clostridium
difficile Infection*
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Figure 8. Tissue culture assay for Clostridium difficile toxin. A, Normal primary human amnion
cells; B, typical actinomorphic changes after application of stool containing C difficile toxin; and C, the tissue-cultured cells with
the same specimen after neutralization with Clostridium
sordellii antitoxin. (Reprinted from Bartlett1 with
permission from WB Saunders Co.)
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The method used most widely in the clinical setting to diagnose C difficile infection is the enzyme-linked immunosorbent
assay (ELISA). It only takes 2 to 6 hours to perform. Characteristics of this
assay include a sensitivity of 85% with a specificity of 100%. The sensitivity
of ELISA may be improved by serial testing.
Another diagnostic assay is the latex agglutination assay. It does not
detect any of the toxins produced by C difficile,
but rather it detects a bacterial enzyme, glutamate dehydrogenase. This enzyme
is found in many other bacteria. Therefore, this assay has poor specificity.
It also has poor sensitivity.
Clostridium difficile can be cultured. The
culture detects both toxigenic and nontoxigenic strains. It is highly sensitive
and allows for strain typing during epidemics. Its major disadvantage is that
it takes 2 to 5 days to perform. It is also not specific for toxin-producing
bacteria. Table 41 compares
the culture method with the cytotoxin assay in patients with various manifestations
of C difficile infection.
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Table 4. Clostridium difficile and Its Cytotoxin
in Patients With Various Manifestations of C difficile Infection
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Polymerase chain reaction can be used to diagnose C difficile infection. Its sensitivity and specificity closely resemble
those of ELISA. It is not widely available in most hospitals and clinical
settings, likely because of increased costs compared with ELISA. Its use today
is primarily as a research tool. However, a group of investigators18 from Spain recently developed a rapid detection method
for toxigenic C difficile from stool samples by a
nested polymerase chain reaction of the toxin B gene. It takes only a few
hours to perform and has a sensitivity and specificity of 96% and 100%, respectively.
Thus, the clinical use of polymerase chain reaction may soon become more widespread.
Treatment
The treatment of symptomatic C difficile infection
should begin with nonspecific measures. The most important of these is the
discontinuation of the offending antibiotic, whenever possible. Discontinuation
of antibiotic therapy may not be realistic for patients who are receiving
therapy for a life-threatening illness. However, consideration of a change
to another agent that is less frequently associated with CDAD should be made.
Other nonspecific measures include supportive measures, such as correction
of fluid losses and electrolyte abnormalities. One should avoid antiperistaltic
agents and place infected patients on enteric isolation precautions.1
Oral agents used for first-line therapy include vancomycin, metronidazole,
and bacitracin. Table 51 outlines the various first-line treatment regimens.
Metronidazole given intravenously can be used to treat patients who cannot
tolerate an oral agent. Intravenous administration of vancomycin is not efficacious
in the treatment of C difficile infection.
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Table 5. Treatment of Clostridium difficile-Induced
Diarrhea and Colitis*
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A first or initial relapse should be treated with a second course of
the initial antibiotic regimen used for first-line therapy. Of patients treated
for a first episode of CDAD, 15% to 20% will have a relapse.8 There
are many different regimens used with varying degrees of success to treat
multiple relapses (Table 6). 19 A new agent, Synsorb Cd (SYNSORB Biotech Inc, Calgary,
Alberta), is currently in phase 3 clinical trials for the treatment of recurrent C difficile infection when given for 25 days in combination
therapy with metronidazole. Synsorb Cd is a synthetic oligosaccharide with
bioadsorbent properties that selectively binds toxin A.
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Table 6. Approach to Management of Recurrent Clostridium
difficile Colitis*
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There has been considerable controversy regarding whether metronidazole
or vancomycin should be used for initial therapy. Prospective randomized studies
reveal no difference in initial response rates to metronidazole and vancomycin.20 Previous exposure to vancomycin given orally and
intravenously has been proven to be a risk for the development of vancomycin-resistant Enterococcus.6 The cost
of vancomycin and metronidazole at Mayo Clinic Scottsdale's pharmacy (as of
January 2002) for a 10-day course is $215.33 and $15.97, respectively. For
these reasons, metronidazole is recommended as the drug of choice for CDAD.
Oral vancomycin treatment should be reserved for patients with metronidazole
intolerance, for patients who do not respond to metronidazole, for patients
with severe or fulminant colitis, and, perhaps, for patients who are immunocompromised.6 However, there is little clinical evidence, even in
these circumstances, that oral vancomycin is superior.
Immunity
Are there natural protective antibodies against C
difficile? Kelly21 found higher levels
of serum IgG antibody against C difficile toxins
in patients with mild, self-limiting diarrhea than in patients with more severe
diarrhea requiring specific therapy. Moreover, the appearance of neutralizing
serum antibodies correlated with resolution of the diarrhea. Two further studies
have reported low serum IgG antibody levels against toxin A in patients with
prolonged, relapsing CDAD, and one also showed that fecal IgA antitoxin levels
were reduced in this patient population.21 Thus,
there is considerable, albeit inconclusive, evidence that an inadequate humoral
response to C difficile infection predisposes to
severe or prolonged CDAD.21
Kyne et al22 found no evidence of immune
protection against colonization by C difficile. However,
after colonization, there was an association between a systemic immune response
to toxin A, as evidenced by increased serum concentrations of IgG antibody
against toxin A, and the asymptomatic carrier state.
Passive Vaccination
Kelly21 gave 5 children with recurrent
CDAD, who had low serum values of IgG antitoxin A, pooled intravenous human
gamma globulin. Their gastrointestinal tract symptoms resolved after treatment,
and there was clearance of C difficile toxin from
their stools. A case report by Kelly21 noted
successful treatment of 2 patients with the use of gamma globulin as an adjunct
to vancomycin and metronidazole for fulminant colitis. The patients were able
to avoid surgical intervention.
Animal studies demonstrated efficacy of oral anti–C difficile bovine immunoglobulin concentrate. Previous studies demonstrated
protection from other bacteria with oral administration of hyperimmune globulin.23-24 An anti-clostridium immune concentrate
has been successfully produced from cows immunized against C difficile. Clinical studies are under way to determine whether anti–C difficile bovine immunoglobulin concentrate is effective
in the prevention and treatment of C difficile infection.21, 25
Active Vaccination
Several animal studies demonstrated efficacy of parenteral immunization.26-28 Oral or mucosal immunization,
as used for cholera toxin, is an alternative approach currently under investigation.21, 29 A study in hamsters indicated that
a combination of parenteral and mucosal (intranasal) immunization appears
to provide the best protection against C difficile disease.21, 30 Formalin-inactivated culture filtrate
from toxigenic C difficile as well as purified and
inactivated toxins have been used to immunize animals with good effect.21, 25-28,31 These
studies may provide the impetus for further human investigation using similar
preparations. Although immunization against C difficile toxins may reduce symptomatic disease, there is no evidence indicating
that it will directly influence intestinal colonization rates.
Prevention
Because there is no effective commercially available human vaccine,
adequate infection control measures are absolutely necessary in controlling
the spread of C difficile infection. Table 732 outlines an effective practice
guideline for the prevention of C difficile infection.
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Table 7. Practice Guidelines for Prevention of Clostridium
difficile Diarrhea*
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SUMMARY
Pseudomembranous enterocolitis is primarily caused by C difficile infection. There are risk factors other than antibiotics
and C difficile, which have historically been associated
with the development of PMC. Most cases of antibiotic-associated diarrhea
do not have a definitive cause. Clostridium difficile accounts
for only about 20% of all cases of antibiotic-associated diarrhea. Infection
with C difficile leads to a spectrum of disease,
from the asymptomatic carrier state to fulminant colitis. Vaccination is not
yet available. Therefore, strict hand washing, enteric precautions, and judicious
use of antibiotics are imperative and remain the most effective means of preventing
the spread of the organism and disease.
AUTHOR INFORMATION
Accepted for publication February 13, 2002.
Corresponding author and reprints: Brian W. Hurley, MD, Division
of Hospital Internal Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale,
AZ 85259.
From the Division of Hospital Internal Medicine (Dr Hurley) and the
Division of Gastroenterology and Hepatology (Dr Nguyen), Mayo Clinic (Scottsdale),
Scottsdale, Ariz.
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