Small intestinal Clostridium difficile seems to be increasing in incidence. The spectrum of Clostridium difficile infection (CDI) has definitely expanded with small bowel involvement. They are more frequently reported in patients with inflammatory bowel disease (IBD) who have undergone total colectomy or patients with Ileal anal pouch anastomosis. The most common presentation is increased ileostomy output with associated dehydration. High clinical suspicion, early recognition and appropriate treatment are the keys to successful resolution. The increase in the number of these patients may actually reflect an increase in the rising incidence of CDI in general or increasing virulence of the organism. Heightened public awareness and initiation of prompt preventive measures are the keystones to control of this infection. This disease is no longer limited to the colon and physicians should be educated to think beyond the colon in patients with CDI

Giannella, Ralph A

Navaneethan, Udayakumar

Gut Pathogens

English

PubMed

Springer - Publisher Connector

BioMed CentralGut Pathogens
ssOpen AcceReview
Thinking beyond the colon-small bowel Involvement in clostridium 
difficile infection
Udayakumar Navaneethan and Ralph A Giannella*
Address: Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Email: Udayakumar Navaneethan - navaneur@ucmail.uc.edu; Ralph A Giannella* - ralph.giannella@uc.edu
* Corresponding author    
Abstract
Small intestinal Clostridium difficile seems to be increasing in incidence. The spectrum of Clostridium
difficile infection (CDI) has definitely expanded with small bowel involvement. They are more
frequently reported in patients with inflammatory bowel disease (IBD) who have undergone total
colectomy or patients with Ileal anal pouch anastomosis. The most common presentation is
increased ileostomy output with associated dehydration. High clinical suspicion, early recognition
and appropriate treatment are the keys to successful resolution. The increase in the number of
these patients may actually reflect an increase in the rising incidence of CDI in general or increasing
virulence of the organism. Heightened public awareness and initiation of prompt preventive
measures are the keystones to control of this infection. This disease is no longer limited to the
colon and physicians should be educated to think beyond the colon in patients with CDI.
Review
Clostridium difficile infection (CDI) is traditionally
thought off, as a disease of the colon frequently with pseu-
domembrane formation. We have recently encountered
three cases of CDI involving the small intestine; a clinical
situation which we believe is poorly appreciated. The fol-
lowing brief case report highlights an increasingly com-
mon clinical scenario.
A 38-year-old woman with history of Crohn's disease
(CD) presented with nausea, vomiting, and abdominal
pain. Her past medical history was significant for CD with
colonic and small bowel involvement with history of total
colectomy with end ileostomy 4 years prior for medically
refractory disease. The patient also reported that she had
been changing her ileostomy bag every 6 h for 4–5 days
prior to presentation. Her labs were significant for acute
renal failure with a blood urea nitrogen and serum creati-
nine of 56 and 2.94 at admission and leukocytosis. Stool
studies were sent from the ileostomy fluid and the studies
reported positive for Cl. difficile toxin A and B by enzyme
immunoassay. Patient was diagnosed with small bowel
CDI and was started on oral vancomycin (125 mg q.i.d.),
which resulted in resolution of the symptoms (within 48
h) and decrease in the ileostomy output and her repeat
stool studies for CDI became negative. Patient subse-
quently completed 10 days of vancomycin treatment and
has been asymptomatic in the ensuing two months.
This clinical situation epitomizes the expanding clinical
spectrum of CDI which in spite of several recent reports of
small bowel involvement is poorly appreciated. Although
colonization of the small bowel by Cl. difficile was
reported almost three decades before and the organism
Published: 19 March 2009
Gut Pathogens 2009, 1:7 doi:10.1186/1757-4749-1-7
Received: 21 January 2009
Accepted: 19 March 2009
This article is available from: http://www.gutpathogens.com/content/1/1/7
© 2009 Navaneethan and Giannella; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
Gut Pathogens 2009, 1:7 http://www.gutpathogens.com/content/1/1/7was isolated from the jejunal segments in autopsy and
from the jejunal aspirate of patients with chronic diarrhea
[1,2], reports of small bowel CDI were rare until recently.
Thus the small intestine may serve as a reservoir and cer-
tain factors could precipitate disease and infection. 34
patients with Cl. difficile enteritis are reported thus far in
the literature. [3-20] It is surprising that only 14 case
reports were reported from 1980 to 2006 and the remain-
ing reported over the past two years. With the expanding
spectrum of CDI, physicians need to be aware and suspect
and treat this infection.
Pathogenesis
The risk of CDI involving the colon increases with antibi-
otic use, intensive care unit or prolonged hospital stay,
increasing age, a defective immune system and contact
with infected patients. Studies from nationwide inpatient
databases also demonstrate an increase in incidence and
severity of CDI of the colon in patients with inflammatory
bowel disease (IBD) [21-23].
In patients with small bowel CDI, the risk factors seem to
be slightly different. Antibiotic use and IBD predispose to
small bowel CDI similar to CDI of the colon. 31/34
patients received antibiotics before the development of
small bowel CDI [3-20]. Prior surgeries of the colon/
colectomy, and host factors including advanced age,
immunocompromised state are proposed as additional
risk factors for small bowel CDI [16]. More than 90% of
patients (31/34) reported in the literature had gastrointes-
tinal surgery of the colon.
The reason for the predisposition of patients who undergo
colonic surgery to small bowel CDI is not clear although
multiple hypotheses can be offered. Firstly, after colec-
tomy changes occur in the small-bowel bacterial flora
such that the neoterminal ileum is colonized by colonic-
type bacterial flora [24], which may make it susceptible to
overgrowth with Cl. difficile, particularly with concomi-
tant antibiotic use [10]. Similarly, changes occur in the ile-
ostomy flora which comes to resemble the fecal flora [25].
The fecal stream also changes the mucosa of the small
bowel to undergo metaplastic changes. This occurs in
patients with Ileal anal pouch anastomosis (IPAA) in
which the epithelium of pelvic ileoanal pouches undergo
morphologic changes including mild villus atrophy,
paneth cell hyperplasia, and a partial transition to colonic
mucin phenotype without complete metaplasia, all of
which facilitate fecal flora establishment [26,27]. Similar
changes may occur in patients with end ileostomy and the
long latent period between the surgery and CDI supports
this as 11 of the 31 patients had surgeries performed
between 1 and 52 years before developing enteritis [3-20].
In patients who develop infection in the immediate post
operative period, many had CDI of the colon prior to sur-
gery which suggests the hypothesis that in those patients
CDI of the small bowel may be secondary to migration of
the Cl. difficile into the small bowel after surgery.
The pathogenesis of CDI of the colon is toxin mediated
through colonic receptors for Cl. difficile toxin. The nature
of the interaction of Cl. difficile toxin(s) with the small
bowel epithelium is unclear although the sucrase-isoma-
ltase complex, a small intestinal brush border enzyme,
has been proposed to contain a receptor for Cl. difficile
toxin (s) [28]. Toxin interaction with this glycoprotein
complex could mediate diarrhea in the immediate post
operative period [29]. Secondly, colonization of the small
bowel occurs because the protective mechanisms are com-
promised by colonic resection surgeries [8]. The mechan-
ical action of the ileocecal valve may be lost because of
surgery. Surgeries involving only the left side of the colon
with preservation of the ileocecal valve do not seem to
increase the risk of CDI of the small bowel highlighting
the importance of the ileocecal valve in preventing coloni-
zation.
Clinical presentation
Increasing ileostomy output seems to be the most com-
mon clinical presentation of small bowel CDI. Increased
ileostomy output was the presenting manifestation in 16/
17 patients in two large case series [16,17]. Increased ile-
ostomy output is severe enough in some patients to result
in acute renal failure and in fact in the largest series to
date, 8/11 presented with acute renal failure [17].
Also it is interesting to note that more than 50% of
patients (19/34) with small bowel CDI had IBD. 18
patients had end ileostomy and one had IPAA following
ulcerative colitis (UC). 13 of these patients with ileosto-
mies had UC and the other five patients had CD. The ris-
ing incidence of CDI should raise suspicion of Cl. difficile
when IBD patients develop profuse diarrhea, particularly
in patients who underwent recent surgical intervention.
The susceptibility of IBD patients to CDI both of the colon
and small bowel is intriguing. Although IBD patients are
at risk because of antibiotic use, hospitalizations, the dra-
matic risk of infection cannot be fully explained by the
above risk factors and raises the question whether abnor-
malities in mucosal immune response in IBD might play
a role in CDI.
Treatment and prognosis
Initial reports highlighted that infection of the small
bowel with Cl. difficile was associated with increased mor-
tality [3-15]. The increased permeability of the small
intestinal mucosa was hypothesized to be due to result in
profound sepsis [8]. Also the presence of several comor-
bidities could have increased the risk of complications
associated with infection. However recent reports arePage 2 of 4
(page number not for citation purposes)
Gut Pathogens 2009, 1:7 http://www.gutpathogens.com/content/1/1/7associated with good prognosis; in fact, two large recent
case series reported no mortality [16,17]. This may be sec-
ondary to earlier diagnosis and detection of the problem
and early initiation of treatment.
The optimal treatment of small bowel CDI is unclear and
stratification of the disease severity as CDI of the colon
could be used to initiate an appropriate management
plan. In a series of 11 patients, more than 50% responded
to metronidazole alone [17]. In another series, all the six
patients were treated with a combination of metronida-
zole and vancomycin [16]. Thus similar to colonic CDI,
vancomycin may be the first line treatment for severe CDI,
while in mild to moderate disease, metronidazole may be
used; however switching to vancomycin in patients who
do not improve within 72 hours of initiation of treatment
with metronidazole would seem appropriate.
Conclusion
Small intestinal Cl. difficile seems to be increasing in inci-
dence. The spectrum of CDI has definitely expanded with
small bowel involvement. They are more frequently
reported in patients with IBD who have undergone total
colectomy or patients with IPAA. The most common pres-
entation is increased ileostomy output with associated
dehydration. High clinical suspicion, early recognition
and appropriate treatment are the keys to successful reso-
lution. The increase in the number of these patients may
actually reflect an increase in the rising incidence of CDI
in general or increasing virulence of the organism. Height-
ened public awareness and initiation of prompt preven-
tive measures are the keystones to control of this
infection. This disease is no longer limited to the colon
and physicians should be educated to think beyond the
colon in patients with CDI.
Abbreviations
CD: Crohn's disease; CDI: Clostridium difficile infection;
IBD: Inflammatory bowel disease; IPAA: Ileal anal pouch
anastomosis; UC: Ulcerative colitis.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
UN drafted the manuscript. RG conceived of the topic,
and participated in manuscript editing and revisions. All
authors read and approved the final manuscript.
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Thinking beyond the colon-small bowel Involvement in clostridium difficile infection

Udayakumar Navaneethan

Ralph A Giannella

Crossref

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Ostroff JW: Fatal Clostridium difficile enteritis after total abdominal colectomy.

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Pseudomembranous enteritis after proctocolectomy: report of a case. Dis Colon Rectum

Pseudomembranous enteritis associated with Clostridium difficile.

RW: Perforation complicating rifampin-associated pseudomembranous enteritis. Arch Surg

SR: A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients.

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Trnka YM: Therapeutic implications of Clostridium difficile toxin during relapse of chronic inflammatory bowel disease. Lancet

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