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November
2007: VOLUME
1, NUMBER 5
Diagnosis and Management of Clostridium difficile
Infections
In this Issue...
Clostridium
difficile (C. difficile) is clearly the most
important and most common bacterial infection of the
GI tract in the U.S. Although this pathogen has been
known and studied for nearly 30 years, there now appears
to be an epidemic of a new and problematic strain, designated
North American pulsed-field gel electrophoresis type
1 (NAP1).
In this issue, we discuss the history of C. difficile-associated
diarrhea, and review the current literature describing
antibiotic treatment strategies, diagnostic testing
options, the challenges posed by recurrent infection,
and the impact of emergency colectomy on the survival
of patients infected by the hypervirulent NAP1strain. |
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Course
Directors
John
G. Bartlett, MD
Professor of Medicine
Department of Medicine
The Johns Hopkins University
School of Medicine
Baltimore, MD
Paul
G. Auwaerter, MD
Associate Professor of Medicine
Clinical Director
Division of Infectious Diseases
The Johns Hopkins University
School of Medicine
Baltimore, MD
Sara
E. Cosgrove, MD, MS
Assistant Professor of Medicine
Division of Infectious Diseases
Director
Antibiotic Management Program
Associate Hospital Epidemiologist
The Johns Hopkins University
School of Medicine
Baltimore, MD |
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GUEST
AUTHOR OF THE MONTH |
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Commentary
& Reviews: |
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John
G. Bartlett, MD
Professor of Medicine
Department of Medicine
The Johns Hopkins University
School of Medicine
Baltimore, MD |
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Guest
Faculty Disclosures
John
G. Bartlett, MD has disclosed that he serves
on the HIV Advisory Board for GlaxoSmithKline,
Abbott, Bristol-Myers Squibb, Pfizer, and Tibotec.
He is also on the Policy Board for Johnson & Johnson.
Unlabeled/Unapproved Uses
The author has indicated that his discussion includes
reference to unlabeled / unapproved uses of metronidazole.
Program
Directors' Disclosures |
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the conclusion of this activity, participants
should be able to: |
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Describe
the contemporary standards for diagnosing and
managing C. difficile-associated diarrhea |
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Explain
the important changes in disease management that
accompany the epidemic of the C. difficile
NAP1 strain |
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Discuss
the role of oral vancomycin and oral metronidazole
in C. difficile-associated diarrhea |
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COMPLETE
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Complete the post-test and course evaluation.
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eInfections
Review is proud to continue its accredited
PODCASTS for 2007. Listen
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In
this audio interview Dr. John Bartlett discusses additional
topics related to Clostridium difficile.
Participants can now receive 0.5 credits per podcast
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To learn more about podcasting and how to access this
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The
history of antibiotic-associated colitis goes back to
the beginning of the antibiotic era, with the accounts
of Staphylococcus aureus enterocolitis reported
primarily by surgeons in the 1950s through 1970. In
1974, Tedesco et al1
reported on 200 consecutive patients who received clindamycin
at Barnes Hospital in St. Louis; of these, 42 developed
diarrhea and 20 had pseudomembranous colitis (PMC) detected
with endoscopy. However, unlike the reports of enterocolitis
attributed to S. aureus, this organism could
not be recovered in stool, leading to a search for alternative
pathogens that eventuated in the detection of C.
difficile. Over the next several years this new
disease, "clindamycin colitis", was extensively studied.
Among the key findings:
-
The disease was caused by a toxin or toxins designated
Toxin A and Toxin B, produced by C. difficile.
- The diagnostic test of choice was a cytotoxin
assay, which proved to be extremely sensitive and
specific for this diagnosis. However, studies in
the 1980s showed an enzyme immunoassay (EIA) to
be faster, easier, and cheaper, and it was adopted
as the standard test by at least 95% of laboratories
in the U.S.
- Despite the original appellation of "clindamycin
colitis", it was learned that all antibiotics with
an antibacterial spectrum of activity could cause
this complication. However, there was a hierarchical
order, with the dominant agents found to be clindamycin
and broad-spectrum betalactams, especially third
generation cephalosporins.
- The pathophysiology of the disease appeared to
be a reflection of suppression of normal flora by
the antibiotics in patients who were colonized by
or who acquired C. difficile. In the colon
this organism usually remained dormant as a spore,
but in the presence of suppressed competing flora,
it reverted to the vegetative form with toxin production.
These toxins, A and B, were noted to be highly potent
in causing a severe inflammation in experimental
animals.
- The risk factors for C. difficile were
identified as antibiotic exposure, elderly age,
and hospitalization or residence in a chronic care
facility. The latter risk presumably reflects clustering
of patients who are vulnerable due to advanced age
and high rates of antibiotic exposure, in an environment
where C. difficile is commonly found on
the walls, beds, and other surfaces, as well as
on the hands of the healthcare workers who care
for these patients.
- The clinical features of C. difficile
were diarrhea in almost all cases, and evidence
of inflammation with colitis in most. The signs
of inflammation included cramps, fecal leukocytes,
fever, leukocytosis, and colitis demonstrated by
computerized tomography or endoscopy.
- Oral vancomycin was the first agent used to treat
C. difficile; its use had substantial precedent
in the treatment of S. aureus enterocolitis.
This drug also made theoretical sense: all strains
were sensitive and continued to be highly sensitive
in vitro, and the drug is not absorbed
when taken orally, so that levels in the colon (where
the putative agent colonizes) reach levels that
are commonly 100-1000 times the minimum inhibitory
concentration (MIC). However, metronidazole was
also uniformly active against C. difficile.
Although the pharmacology of this drug was not particularly
good for reaching the colon lumen, therapeutic trials
supported its use, and it became a favored drug
because of low price and concerns about oral vancomycin
promoting colonization with vancomycin-resistant
Enterococcus (VRE).
- While most of the studies showed that the great
majority of patients responded to either of these
drugs, there were two important problems. First,
some patients had ileus, making it very difficult
to get vancomycin by mouth to the colonic lumen.
The second problem was relapse: about 20% of patients
who were treated with either agent did well, but
then had recurrent disease when the treatment was
discontinued. Some of these patients had multiple
relapses.
This summary represents the state-of-the-art for C.
difficile knowledge until about five years ago.
Since then, there has been a substantial increase in
interest and concern about C. difficile. Issues
include morbidity and mortality attributed to this organism,
the adequacy of the current diagnostic testing, the
problems associated with standard management, and the
impression that there is more frequent disease occurrence,
more severe disease, and more disease that is refractory
to the standard treatment. Some or most of this may
now be attributed to a newly recognized "hypervirulent
strain" of C. difficile.
The NAP1 Strain
The increasing problem of C. difficile was
first recognized by Jacques Pepin et al, who reported
that the rates of this complication in Sherbrooke, Quebec
had increased more than ten fold in persons who were
over the age of 65 years.2
This increase, initially noted in 2002, showed that
the disease was not only more frequent, but also was
more severe, with an attributable mortality of 6-17%;
further, it was more refractory to therapy and more
prone to relapse. There was initial skepticism that
these findings were, in fact, real. However, the observations
of Pepin et al were also observed at McGill University
(also in Quebec), in at least 24 states in the U.S.,
and in several countries in Europe. The presumed explanation
was the appearance of the NAP1 strain, as summarized
by Blossom and McDonald from the CDC (reviewed herein).
This "hypervirulent strain" appears now to be an important
cause of this disease in most states of the U.S., and
has also been reported from several countries in Europe.
This strain is relatively new, and as noted in the review
from the CDC, may cause more disease as a result of
extensive use of fluoroquinolones, with more serious
disease possibly the result of an increase in toxin
production. With regard to the U.S., the number of reported
cases is noted to have increased more than two-fold
during the past decade, and the anecdotal experience
is that many of these cases are now apparently more
serious than those seen previously.
The diagnostic testing for C. difficile in
the U.S. is done by the EIA test, which has become the
standard for more than 95% of laboratories. There have
been extensive studies showing reduced sensitivity of
this assay, which was reported in the CDC review as
60-95%. However, at Johns Hopkins Hospital, the sensitivity
was only 40%, necessitating a shift to an alternative
diagnostic testing strategy.3
Nevertheless, there appear to be substantial differences
in this experience. Musher et al (reviewed herein) have
reviewed a series from Houston that appears to show
that the EIA from multiple suppliers provides an excellent
correlation with the "gold standard" cytotoxin assay.
The explanation for the difference between this and
prior reports remains unclear. The current recommendation
is for physicians to simply use caution when depending
on the EIA, until there are better data on the relative
sensitivity of this test.
With regard to treatment, there has always been the
problem of the occasional case that is treated late
in the course when there is ileus or toxic megacolon,
which preclude getting an orally administered drug to
the site of the infection (the colonic lumen). This
concern is now elevated because of the more severe consequences
of the NAP1 strain. The review by Lamontagne et al (summarized
herein) provides important information about the risks
for severe disease, which include a leukemoid reaction
and advanced age. The leukemoid reaction is of particular
interest, since it is a property of C. difficile
that is shared with C. sordellii, another Clostridia
species that produces toxin antigenically related to
C. difficile. Both have the property of causing
a leukemoid reaction despite very different clinical
expression. Colectomy is also discussed in the Lamontagne
article: although this is rarely required with C.
difficile infection, the authors report the procedure
seems to show substantial benefits in patients who have
very advanced disease. Some caution is advised here,
since there may be substantial selection bias, as surgeons
may simply have refused to operate on patients with
the most advanced disease. Nevertheless, it may be important
to get surgery consultations in patients who are critically
ill, and to use Lamontagne's paper to get surgeons to
more seriously consider this intervention if other therapeutic
modalities fail.
References
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COMPARISON
OF TREATMENT AGENTS |
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Zar
FA, Bakkanagari K, Moorthi KM, Davis MB.
A comparison of vancomycin and metronidazole
for the treatment of Clostridium difficile-associated
diarrhea, stratified by disease severity.
Clin Infect Dis. 2007;45:302-7.
(For non-journal subscribers, an additional
fee may apply for full text articles.)
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The
authors performed a prospective, randomized, double
blind trial to determine the relative merits of
metronidazole versus vancomycin. The eligibility
criteria included antibiotic-associated diarrhea
with a positive toxin assay for toxin A or endoscopic
evidence of PMC. One hundred fifty participants
were stratified by severity of disease. Severe
disease was classified as having endoscopic evidence
of PMC, admission to the intensive care unit,
or two of the following: age >60 years, temperature
>38.3ºC, albumin <2.5 mg/dL, or WBC >15,000/mm3
(n=69). Mild disease was defined simply as lacking
the criteria for severe disease (n=81). Participants
were randomized to metronidazole 250 mg qid (n=79)
or oral vancomycin 125 mg qid (n=71) for 10 days.
The outcome was classified as cured if there was
resolution of diarrhea by day 6 and a negative
stool for toxin A at days 6 and 10. Failure was
defined as the inability to achieve the criteria
for cure, or death after at least 5 days of treatment,
or the requirement for a colectomy or relapse
by day 21 post-treatment.
The results of the study showed those classified
with severe disease had a higher cure rate with
vancomycin (97% vs. 76%, respectively; p=0.02).
For the 81 patients classified as mild disease,
the response rates were 98% vs. 90% for vancomycin
and metronidazole, respectively a difference that
is not statistically significant (Table 1). The
frequency of relapse was 14/137 (10%); while somewhat
more frequent with severe disease, there was no
difference for relapse rates based on randomization
to vancomycin or metronidazole. These results
are summarized in the following table:
Although it is unconventional to use the toxin
assay as a test-of-cure, only two patients were
deemed failures only because of a positive toxin
assay without persistent diarrhea or other evidence
of clinical failure. The authors conclude that
metronidazole and vancomycin are therapeutically
equivalent for patients with C. difficile
infection that is considered mild, but that vancomycin
is superior in those with severe disease as described
by this protocol. |
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COMPARISON
OF DIAGNOSTIC TESTING ASSAYS |
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Musher
DM, Manhas A, Jain P, et al. Detection
of Clostridium difficile toxin: comparison
of enzyme immunoassay results with results obtained
by cytotoxicity assay. J Clin Microbiol.
2007;45:2737-9.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Musher
et al performed a two-stage test to investigate the
relative merits of the enzyme immunoassay for C.
difficile toxin A and toxin B versus the "gold
standard" cytotoxin assay.
The first stage compared outcomes using the cytotoxin
assay versus one commercially available EIA test for
toxin A/B (EIAPREM™, Meridian Bioscience, Cincinnati
OH). The results were based on 446 consecutive stool
samples submitted to the clinical microbiology laboratory.
Seventy-six showed positive results by cytotoxin assay,
while the EIA test showed 75 positives; of the 370 samples
that were negative by cytotoxin assay, 10 showed positive
in the EIA test. Thus, the EIA test showed a sensitivity
of 98.7% and a specificity of 97.3%, with a positive
predictive value of 75/85 (88.2%) and a negative predictive
value of 360/361 (99.7%). The conclusion of this first
stage was that the correlation between these two tests
was really quite good, particularly for the sensitivity
of the EIA when compared to the cytotoxin assay.
These initial results led to the second phase of the
study, in which 131 fresh fecal samples were tested
by the cytotoxin assay versus three EIA tests from different
reagent suppliers. The purpose was to determine the
relative merits of the different commercially available
immunoassays. Of the 131 samples selected, the cytotoxin
assay was positive in 54 and negative in 77.
The following table summarizes the results with the
different EIA kits from the three suppliers. While all
three showed some minor variations, each of the EIA
tests performed well compared to the cytotoxin assay
in terms of sensitivity.
The authors conclude that the commercially available
EIA tests showed good sensitivity and specificity compared
to the cytotoxin assay - which, while considered the
"gold standard", is more labor intensive and costly,
and delays reported results. |
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Blossom
DB, McDonald LC. The challenges posed
by reemerging Clostridium difficile infection.
Clin Infect Dis. 2007;45:222-7.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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The
report from the CDC emphasizes the changing epidemiology
of C. difficile and discusses the appearance
of a new "hypervirulent strain" in North America and
Europe. The following is a bulleted summary of this
contemporary problem with C. difficile as viewed
by experts from the CDC:
-
Increased Rates of C. difficile
Infection: The diagnosis of C. difficile
by IDC-9 listings from short stay hospitals in the
U.S. have shown relatively stable rates for the
age category 15-64 years (<50/100,000 population),
but a significant increase in persons >64 years,
from approximately 170/100,000 population in the
year 2000 to about 340/100,000 population in 2003.1
- The NAP1 Strain: Much of this
increase is attributed to a unique strain that was
uncommon in prior reports of C. difficile,
but then emerged with multiple near-simultaneous
outbreaks in hospitals in the U.S., Quebec and several
countries in Europe.2,3
This strain was identified by pulsed field electrophoresis
as the NAP1 strain, by restriction enzyme analysis
as the BI strain, by PCR as ribotype O27, and by
toxin analysis of regulatory genes as toxinotype
III. Although oversimplifying, the appellation of
this new strain is referred by the method used to
identify it: therefore, this is the "NAP1/BI/O27/toxinotype
III" strain. While all of these terms are used interchangeably,
many refer to it simply as the "NAP1" strain.
- Virulence: The virulence of this
new epidemic strain is largely attributed to the
production of substantial amounts of toxin according
to in vitro assays, and this may reflect
the deletion of tcdC which is a negative
regulator of toxins A and B.2,4,5
This strain of C. difficile also produces
a "binary toxin" which is related to the iota-toxin
of C. perfringens. While this "binary toxin"
seems to be a relatively good marker of the NAP1
strain, it is unclear if it represents any contribution
to pathology, since it does not produce disease
when inoculated into intestinal loops of experimental
animals.
- New Risk Factors: The most important
new observation is the high frequency of fluoroquinolones
as inducing agents. The presumed explanation is
the fact that the majority of NAP1 strains are highly
resistant to this antibiotic, whereas the historic
strains were almost uniformly sensitive. Another
relatively new risk factor is agents that suppress
gastric acid, especially proton pump inhibitors
(PPIs), although the data on these are inconsistent.6
- Diagnostic Challenges: The majority
of laboratories in the U.S. use EIAs, which are
relatively easy to perform and give rapid results;
however, EIAs show sensitivity rates of only 6-95%
compared to cytotoxin assays. The authors note that
many European laboratories offer culture followed
by a test for toxogenic potential by the recovered
strain, which may be the most sensitive test available.7
- Treatment Concerns: Failure rates
with metronidazole in more recent reports have generally
been 16-38%,8,9
and vancomycin is preferred for the more seriously
ill patients. A second treatment problem is relapse.
The previously reported rate was relatively consistent
at 20%; now, with the emergence of the NAP1 strain,
it is now reported as high as 50-65%.10
There are no clear guidelines for management, although
human stool transplants "have shown some promise"
and "few data support the use of probiotics".11
- Prevention Challenges: Contact
precautions are standard: patients should be in
a single room with exclusive use of a bathroom (or
patient cohorting), hand washing should be done
with soap and water rather than alcohol-based sanitizers,
and environmental cleaning should be done with a
sporicidal such as a 1:10 dilution of household
bleach. Antibiotic control is also important, especially
in epidemics, where restricted use of clindamycin
has proven successful.12
Under current conditions, prevention may also require
control of fluoroquinolones; the authors conclude
that the restriction or reduced use should apply
to all fluoroquinolones rather than specifically
selected agents within the class.
References
| 1. |
McDonald
LC, Owings M, Jernigan DB. Clostridium
difficile infection in patients discharged
from U.S. short-stay hospitals, 1996-2003.
Emerg Infect Dis. 2006;12:409-15. |
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| 2. |
McDonald
LC, Killgore GE, Thompson A, Owens RC Jr et al.
An
epidemic, toxin gene-variant of Clostridium
difficile. N Engl J Med. 2005;353:2433-41. |
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| 3. |
McDonald
LC, Coignard B, Dubberke E, Song x et al. Recommendations
for surveillance of Clostridium difficile-associated
disease. Infect Control Hosp Epidemiol.
2007;28:140-5. |
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| 4. |
Warny
M, Pepin J, Fang A, Killgore G, Thompson A et
al. Toxin
production by an emerging strain of Clostridium
difficile associated with outbreaks of severe
disease in North America and Europe. Lancet.
2005;366:1079-84. |
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| 5. |
Bartlett
JG. Narrative
review: the new epidemic of Clostridium difficile-associated
enteric disease. Ann Intern Med.
2006;145:758-64. |
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| 6. |
Dial
S, Delaney JA, Schneider V, Suissa S. Proton
pump inhibitor use and risk of community-acquired
Clostridium difficile-associated disease
defined by prescription for oral vancomycin therapy.
CMAJ. 2006;175:745-8. |
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| 7. |
Delmee,
M, Van Broeck J, Simon A, Janssens M, Avesani
V. Laboratory
diagnosis of Clostridium difficile-associated
diarrhoea: a plea for culture. J Med Microbiol.
2005;54:187-91. |
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| 8. |
Musher
DM, Logan N, Mehendiratta V, Melgarejo NA. Clostridium
difficile colitis that fails conventional
metronidazole therapy: response to nitazoxanide.
J Antimicrob Chemother. 2007;59:705-10. |
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| 9. |
Pépin
J, Alary ME, Valiquette L, Raiche E et al. Increasing
risk of relapse after treatment of Clostridium
difficile colitis in Quebec, Canada.
Clin Infect Dis. 2005;40:1591-7. |
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| 10. |
McNulty C, Logan M, Donald IP, Ennis D et al.
Successful
control of Clostridium difficile infection
in an elderly care unit through use of a restrictive
antibiotic policy. J Antimicrob Chemother.
1997;40:707-11. |
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| 11. |
Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic
therapy for the prevention and treatment of Clostridium
difficile-associated diarrhea: a systematic
review. CMAJ. 2005;173:167-70. |
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| 12. |
Johnson
S, Samore MH, Farrow KA, Killgore GE et al. Epidemics
of diarrhea caused by a clindamycin-resistant
strain of Clostridium difficile in four
hospitals. N Engl J Med. 1999;341:1645-51. |
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IMPACT
OF EMERGENCY COLECTOMY |
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Lamontagne
F, Labbe AC, Haeck O, Lesur O, Lalancette M, et
al. Impact of emergency colectomy on survival
of patients with fulminant Clostridium difficile
colitis during an epidemic caused by a hypervirulent
strain. Ann Surg. 2007;245:267-72.
(For non-journal subscribers, an additional
fee may apply for full text articles.) |
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Lamontagne's
group performed a retrospective analysis of patients
who were seriously ill with C. difficile-associated
diarrhea to determine factors that correlated with a
lethal outcome. The only criterion for inclusion was
transfer or direct admission to the ICU due to the severity
of this complication. The study was done at the University
of Sherbrooke in Quebec, Canada, which has been the
source of much of the information about the NAP1 strain.
The study included 165 patients with diarrhea or colitis
who had confirmed infections with C. difficile
that were sufficiently severe to require hospitalization
in the intensive care unit. Of these, 87 (53%) had an
ultimately lethal outcome. Factors that correlated with
the lethal outcome included the leukemoid reaction,
elderly age, lactic acidosis and immunosuppression.
Of particular note was the fact that patients who underwent
a colectomy had a risk ratio of 0.2, indicating an 80%
reduction in mortality. These observations are summarized
in Table 3.
The authors conclude that emergency colectomy substantially
reduces the mortality associated with fulminant C.
difficile infection. |
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At
the conclusion of this activity, participants
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Describe
the contemporary standards for diagnosing
and managing C. difficile-associated
diarrhea |
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Explain
the important changes in disease management
that accompany the epidemic of the C.
difficile NAP1 strain |
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Discuss
the role of oral vancomycin and oral metronidazole
in C. difficile-associated diarrhea |
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John
G. Bartlett, MD has disclosed that
he has served on the HIV Advisory Board
for GlaxoSmithKline, Abbott, Bristol-Myers
Squibb, Pfizer and Tibotec. He is also on
the Policy Board for Johnson & Johnson.
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Paul
G. Auwaerter, MD has disclosed
that he has served as a consultant for Novartis,
Pfizer, Ortho-McNeil, Schering-Plough, and
Genzyme. He is on the Speakers' Bureau for
Schering-Plough and has also disclosed that
he is a Stock Shareholder for Johnson &
Johnson. |
|
|
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Sara
E. Cosgrove, MD, MS has disclosed
that she has received grants or research
support from Merck and served on the Advisory
Boards for Ortho-McNeil, Cadence Pharmaceuticals,
and Theravance/Astellas. |
Guest
Author Disclosures |
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opinions and recommendations expressed by faculty
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program are their own. Use of The Johns Hopkins
University School of Medicine name implies review
of educational format design and approach. Please
review the complete prescribing information of
specific drugs or combination of drugs, including
indications, contraindications, warnings and adverse
effects before administering pharmacologic therapy
to patients. |
|
©
2007 JHUSOM and eInfections Review
Created by
DKBmed. |
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