ww.sciencedirect.com

t h e s u r g e on x x x ( 2 0 1 4 ) 1e7

Available online at w

ScienceDirectThe Surgeon, Journal of the Royal Colleges

of Surgeons of Edinburgh and Irelandwww.thesurgeon.net

Review

Clostridium difficile enteritis: A new role for an oldfoe

S. Killeen*, S.T. Martin, J. Hyland, P.R. O’ Connell, D.C. Winter

St. Vincent’s University Hospital, Department of Colorectal Surgery, Dublin 4, Ireland

a r t i c l e i n f o

Article history:

Received 25 October 2013

Received in revised form

16 January 2014

Accepted 16 January 2014

Available online xxx

Keywords:

Clostridium difficile

Small bowel

Pathophysiology

Risk factors

Diagnosis and management

* Corresponding author. Tel.: þ353 2214000.E-mail address: sdfkilleen@eircom.net (S

Please cite this article in press as: Killeenhttp://dx.doi.org/10.1016/j.surge.2014.01.0

1479-666X/$ e see front matter ª 2014 Publinumber SC005317) and Royal College of Surhttp://dx.doi.org/10.1016/j.surge.2014.01.008

a b s t r a c t

Background: Small bowel involvement of Clostridium difficile is increasingly encountered.

Data on many management aspects are lacking.

Aim: To synthesis existing reports and assess the frequency, pathophysiology, outcomes,

risk factors, diagnosis and management of C. difficle enteritis.

Methods: A systematic review of the literature was conducted to evaluate evidence

regarding frequency, pathophysiology, risk factors, optimal diagnosis, management and

outcomes for C. difficle enteritis. Three major databases (PubMed, MEDLINE and the

Cochrane Library) were searched. The review included original articles reporting C. difficle

enteritis from January 1950 to December 2012.

Results: C. difficle enteritis is rare but increasingly encountered. Presentation is variable and

distinct predisposing factors include emergency surgery, white race and increased age.

Diagnosis generally involves a sensitive but often non specific screening test for C. difficile

antigens. Oral metronidazole represents first line therapy and surgery may be required for

complications. Outcomes are inconsistent but may be improving.

Conclusions: A high index of clinical suspicion, early diagnosis and treatment are vital.

Further prospective studies are needed to determine the significance of asymptomatic

small bowel C. difficile infections.

ª 2014 Published by Elsevier Ltd on behalf of Royal College of Surgeons of Edinburgh

(Scottish charity number SC005317) and Royal College of Surgeons in Ireland.

Introduction

The older, immunocompromised and institutionalised patient

population undergoing surgery allied to increased practitioner

awareness has produced a significant rise in all Clostridium

difficile infections.1 Although rare, small bowel involvement of

C. difficile is increasingly identified.2e4

. Killeen).

S, et al., Clostridium dif08

shed by Elsevier Ltd on bgeons in Ireland.

Early reports of small bowel C. difficile infection suggested

significant morbidity and mortality rates.4,5 However the

enhanced recognition of small bowel colonisation post-

operatively suggests a higher than previously thought preva-

lence of a milder or even asymptomatic entity.2,6,7

Notwithstanding this a high index of suspicion is necessary

allied to early intervention to maximise optimum outcomes.

Despite these features the literature on C. difficile enteritis

is sparse comprising mainly of retrospective studies and case

ficile enteritis: A new role for an old foe, The Surgeon (2014),

ehalf of Royal College of Surgeons of Edinburgh (Scottish charity

t h e s u r g e on x x x ( 2 0 1 4 ) 1e72

series. Unlike C. difficile colitis, there are no consensus guide-

lines to assist healthcare practitioners.8

Aim

To synthesis existing reports and assess the frequency,

pathophysiology, outcomes, risk factors, diagnosis and man-

agement of C. difficle enteritis.

Fig. 1 e Diagramatic representation of presumed

pathogenesis of small bowel C. difficile infection. TcdA and

TcdB breach the intestinal barrier, bind to cellular

receptors, inhibit GTPases and trigger mucosal

inflammation and intestinal damage.

Methods

A systematic review of published work was conducted ac-

cording to the Preferred Reporting Items for Systematic Re-

view and Meta-Analysis (PRISMA) guidelines.9

The search was performed using the Cochrane library,

PubMed, MEDLINE and Embase to identify articles published

between 1980 and July 2012. The Cochrane database was

searched using a combination of the following terms with the

Boolean AND/OR operators: ‘Clostridium difficile’, “C. difficile”,

‘small bowel’, ‘enteritis’, ‘pseudomembranous’, ‘risk factors’,

‘clinical presentation’, ‘diagnosis’ and ‘treatment’. For the

MEDLINE and PubMed database searches, these same key-

words (and variants) were used as textwords and Medical

Subject Headings (MeSH terms), and were combined by using

Boolean operators as follows: (‘C. difficile*’) OR ‘Clostridium

difficile’ OR ‘small bowel’ OR ‘enteritis’ AND ‘epidemiology’ OR

‘pathogenesis’ OR ‘presentation’ OR ‘diagnosis’ OR ‘manage-

ment’ OR ‘treatment’ OR ‘surgery’ The Embase database was

searched using Combinations of the following using the

Boolean search term ‘Clostridium difficile’ ‘AND’/(Emtree

thesaurus term) ‘small bowel’/(Emtree thesaurus term), sur-

gery(Emtree thesaurus term)/Management/(Emtree thesaurus

term).

There was no restriction on the date, language or status of

publication. The search results were supplemented with hand

searching of selected reviews, expert consensus and reference

lists from included and excluded studies. After screening titles

and abstracts, studies were included if they clearly described

small bowel C. difficle infection and if pertinent correlation

could be made from colonic C. difficle infection. Full-text

publications of these articles were then reviewed. If two

separate publications included the same cohort of patients,

the larger and more complete dataset was used (see Fig. 1).

The data extracted included demographics such as age and

sex, presence of pre-existing gastrointestinal disease, risk

factors, incidence, prevalence, previous C. difficle infection,

recent antibiotic use, diagnostic techniques and medical or

surgical treatment employed.

Incidence

Historically C. difficile enteritis has been considered a rare

entity, although recent data suggest a significant increase in

prevalence and incidence.10

Until 2008, fewer than 25 cases were reported.4 Kim et al.

noted an additional 29 cases in the two years from 2008 to 2010

when they performed a pooled analysis of all published

Please cite this article in press as: Killeen S, et al., Clostridium difhttp://dx.doi.org/10.1016/j.surge.2014.01.008

cases.11 Diagnosis was based on positive C. difficile toxin in

stool or ileostomy output in patients who previously had had

colectomywith ileostomy (23 cases), positiveC. difficile toxin in

increased ileostomy output in patients with formation of

ileostomy postoperatively (3 cases) and autopsy, surgical pa-

thology, or biopsy showing histologic evidence of enteritis

with positive C. difficile toxin and/or C. difficile isolated on

culture (30 cases).11 A total of 67 cases to July 2012 were

identified in the literature. The seemingly increased popula-

tion and institutional prevalence of C. difficile, enhanced

isolation of the hypervirulent BI/NAP1/027 strain from the

small bowel allied to an older more susceptible patient cohort

may explain this proported increase.12

However accurate prevalence rate calculation is problem-

atic due to anatomically difficulty in accessing small bowel

contents, lack of awareness and underreporting of the con-

dition.13 Furthermore studies do not differentiate between

colonisation and clinically significant infection with toxin

production. Recently Tsiouris et al. suggested that ileal C.

difficile toxin can be isolated in 16% of patients after colec-

tomy1 and Testore et al. showed a 3% C. difficile jejunal colo-

nisation rate at post mortem in patients who died from

nongastrointestinal causes.13 There is undoubted selection

bias in published reports with severe cases predominating.10

Collectively this data suggests the actual incidence and

prevalence of small bowel C. difficile is probably under-

estimated and the proposed increase may also be due to

increased testing, reporting and identification of asymptom-

atic carriers. Toxin producing C. difficile is a notifiable disease

ficile enteritis: A new role for an old foe, The Surgeon (2014),

t h e s u r g e on x x x ( 2 0 1 4 ) 1e7 3

in many countries and such registries could potentially

furnish more accurate prevalence rates for small bowel C.

difficile if small bowel and colonic aetiology is differentiated

(HPA 2012).14

Pathophysiology

C. difficile is a spore-forming, anaerobic, gram-positive bacillus

that does not invade mucosa, and is the causative agent for

pseudomembranous colitis. It produces two toxins TcdA and

TcdB that breach the intestinal barrier and trigger mucosal

inflammation and intestinal damage. TcdA and TcdB bind to

cellular receptors present onmany cell types and inhibit small

GTPases such as Rho, Rac and Cdc42 that are found in

eukaryotic cells.15 TcdA and TcdB trigger inflammasome-

dependent interleukin (IL)-1beta production, which contrib-

utes to C. difficile induced inflammation and damage in vivo

(see Fig. 1).16 This may involve melanin concentrating factor

(MCH).17

The pathophysiology of small bowel C. difficile infection is

unclear. In vivo rabbit and human post mortem studies

demonstrating comparable pathological findings and the

presence of pseudomembranes suggest a similar pathogen-

esis in small bowel and colon.18

The small intestine undergoes phenotypic changes after

colectomy creating a colon like milieu with colonic-type

metaplasia and partial villous atrophy which may predispose

to C. difficile overgrowth.19 In addition resection of the ileocecal

valve facilitates small bowel colonisation.3,20 (see Fig. 1).

High levels of TcdA may be required for ileal involvement

in C. difficile infections (Testore). The BI/NAP/027 strain pro-

duces higher amounts of TcdA4 and also produces binary

toxin CDT, which is enterotoxic in an ileal loop assay.21

Adhesion of C. difficile to the intestine has been implicated

disease development22 and the BI/NAP/027 strain may colo-

nise the small intestine more easily than other strains.23 This

strain has been implicated in the increase in small bowel C.

difficile cases.4

Polymorphism in the innate immune receptor (NOD2/

CARD15) are involved in the development of C. difficile pou-

chitis24 while patients with Il-8 polymorphisms and a defec-

tive response to TcdA are more likely to acquire C. difficile

enteritis and refractory diarrhoea after colectomy.25

Given that not all cases of small bowel C. difficile occurred

post surgery, another hypothesis postulates that C. difficile is

more frequently involved in small bowel infections than

previously thought, but that limited access to the small bowel

makes anatomical diagnosis difficult.3,26 A 3% C. difficile jeju-

nal colonisation rate at autopsy in patients who died from

nongastrointestinal causes, comparable to stool carriage for C.

difficile in healthy adults suggests the small bowel may act as

reservoir.13

Risk factors

The well established risk factors for C. difficile colitis include

recent antibiotic treatment, hospitalisation, gastrointestinal

surgery, immunosuppressants, chemotherapeutic agents,

Please cite this article in press as: Killeen S, et al., Clostridium difhttp://dx.doi.org/10.1016/j.surge.2014.01.008

gastric acid suppression and inflammatory bowel disease.27 It

has been suggested that these factors also predispose to C.

difficile enteritis.11

The studies by Kim and Holmers demonstrated that over

90% of included patients had recently undergone antibiotic

therapy or in hospital treatment.11,28

In addition surgically altered intestinal continuity, specif-

ically colonic surgery definitely facilitates C. difficile infection,

with the majority of reported cases occurring after colonic

resection.10 Total abdominal colectomy or proctocolectomy is

often necessary in patients with inflammatory bowel disease,

IBD in and of itself may predispose to C. difficle enteritis. Pa-

tients with pre-existing C. difficle infection may develop C.

difficile enteritis after resection or this may be a de novo phe-

nomenon. Previous or concomitant immunosuppression may

further contribute to the development of C. difficile infection

post colonic resection in IBD patients.28,29 C. difficile enteritis

has been reported following ileopouch anal anastomosis

(IPAA) and may occur immediately after ileostomy closure as

part of a staged proctocolectomy.29e31 Cases of C. difficile en-

teritis also occur without previous colonic surgery.12 Patients

with inflammatory bowel disease are particularly susceptible

with the majority of patients appearing to contract C. difficile

as outpatients.32 Concerns have also been raised about inter

species transmission in xenografts.33 A significant number of

patients with small bowel C. difficile were on proton pump

inhibitors or chemotherapeutic agents.28

However a contemporary multivariate retrospective anal-

ysis, the largest cohort assessed to date demonstrated distinct

predisposing factors such as emergency surgery, white race

and increased age by 10 years for C. difficile infection of the

ileum after colectomy.13

Clinical presentation

Patients with clinically significant C. difficile enteritis generally

present with diarrheoa (defined as 3 or more loose stools per

day for 1e2 days), crampy abdominal pain and leukocytosis.34

Highstomaoutputcanbea featureof small bowelC. difficileand

may occur at anytime post surgery (Testore). C. difficile should

also be considered in refractory pouchitis.30 Thus C. difficile

should be sought in any patients with such symptoms. The signifi-

canceofC. difficile toxin identified fromhighoutput ileostomies

inotherwiseasymptomaticpatientspost surgery remains tobe

elucidatedwith some authors recommending treatmentwhile

others support treatment only in the presence of risk fac-

tors.35,36 C. difficile enteritis may also present with profound

sepsis and shock without the classical symptoms mentioned

above.24,35 Sometimes associated ileus prevents attainment of

suitable diagnostic specimens, in addition to the already

documented difficulty of accessing the small bowel.37

Diagnosis

The diagnosis of C. difficile enteritis can be based on toxin

identification, endoscopic, radiological or pathological find-

ings, the same modalities used to identify C. difficile in the

colon.38 The role of the laboratory is to accurately detect the

ficile enteritis: A new role for an old foe, The Surgeon (2014),

t h e s u r g e on x x x ( 2 0 1 4 ) 1e74

presence of virulent (e.g., toxigenic) C. difficile by recovering a

toxin-producing strain using culture or via detection of

toxin(s) or toxin gene(s) in small bowel contents.8

Toxin identification

Testing should only be performed on unformed (liquid) stools

or high output stoma effluent, because a positive result in a

formed stool or normal volume stoma output signifies colo-

nisation only.8 Multiple techniques for toxin identification are

available and the optimal diagnostic algorithm (for sensitivity

and cost) is controversial.39

The detection of C. difficile toxin in a cell-based cytotoxic

assay (CCA) or toxigenic culture of C. difficile obtained from

stool represent the gold standards for diagnosis.40 C. difficile is

usually cultured from stool specimens on a selectivemedium,

CCFA (Cycloserine Cefoxitin Fructose Agar).41 Both stool cul-

ture and CCA have slow turnaround times (>48 h) and CCA is

technically difficult, poorly standardised, and requires

expertise to read.42 Currently, most laboratories use a com-

bination of a sensitive, but not necessarily highly specific,

screening test followed by a more specific test on specimens

that test positive to confirm the presence of toxin.43

Enzyme ImmunoAssays (EIA) to detect C. difficile glutamate

dehydrogenase (GDH) or “common antigen” are frequently

used as screening tests since they are sensitive but not spe-

cific.44 EIA to detect TCDA and TCDB are available but are

relatively insensitive and their positive predictive value is

modest when disease prevalence is low.45 PCR-based

commercially available assays to detect conserved gene tar-

gets within the pathogenicity locus of C. difficile. including

those encoding tcdA and tcdB, and adjacent accessory gene

tcdC (for presumptive identification of PCR-ribotype 027) are

sensitive but not specific. While expensive there are now 11

FDA approved assays.42 Such assays are used within a diag-

nostic algorithm to confirm a positive result on discordant

screening modalities.42

Radiological features

Radiologically the presence of ascites with distended fluid-

filled small bowel (>2.5 cm) and bowel wall thickening

(>0.3 cm) suggests C. difficile enteritis.46 Given that C. difficile

enteritis is a mucosal disease, mesenteric or retroperitoneal

fatty stranding is a non specific sign.47

Endosocpy

Small bowel pseudomembranes, inflammation and copious

mucous at endoscopy are pathognomic C. difficile enteritis.48

However the presence of ileal pseudomembranes is

frequently not documented endoscopically and endoscopy

was only performed in 8 of the reported cases to date.4

Endoscopy may facilitate differentiation between IBD enteri-

tis, pouchitis, and C. difficile enteritis in patient post surgery.28

Pathology

C. difficile can be identified from small bowel resection speci-

mens following emergency surgery or at autopsy by

Please cite this article in press as: Killeen S, et al., Clostridium difhttp://dx.doi.org/10.1016/j.surge.2014.01.008

macroscopic evidence of pseudomembranes.11 Microscopi-

cally small bowel mucosa may show a spectrum from mild

inflammation to extensive ulceration with deposits of mucin,

fibrin and polymorphs.8 Findings need to be assessed in the

appropriate clinical scenario.

Treatment

Guidelines for treatment of C. difficile enteritis have yet to be

established and there is no evidence based concensus

regarding optimum therapy.

Ideally therapy with the inciting antimicrobial agent(s)

should be discontinued as soon as possible, as this may in-

fluence the risk of CDI recurrence.2 The significance of C.

difficile toxin in normal consistency ileal effluent and the ne-

cessity for mandatory treatment has recently been

questioned.2

The majority of reported studies utilised oral metronida-

zole as a first line antibiotic for 14 days.48 In their algorithim

Holmer et al. suggested an escalation to oral vancomycin

(given its reliable therapeutic small bowel concentrations via

the enteral route) and IV metronidazole for severe cases. This

should again be continued for 14 days in responsive cases.28

Vancomycin enemas and vancomycin via nasogastric or

nasojejunal tube could be utilise in patients who fail to

improve.50

Other than one reported case which utilised a combination

metronidazole, vancomycin and rifampicin, there is little data

on second line antibiotics such as tigecycline, fusidic acid,

Rifaximin or Tolevamer in C. difficile enteritis.10 However

Fidaxomicin is a first-in-class macrocyclic antibacterial that is

approved in several countries for the treatment of adult pa-

tients with Clostridium difficile-associated diarrhoea. A rando-

mised controlled trial including patients post colectomy was

noninferior to vancomycin treatment with regard to clinical

cure rates and was associated with statistically significantly

lower C. difficile infection recurrence rates and statistically

significantly higher global cure rates than vancomycin.51

Evidence for the use of human immunoglobulins and anti-

TcdA and TcdB antibodies is also lacking in this setting.52

Furthermore there is no data the frequency and manage-

ment of recurrent small bowel C. difficile.

These patients frequently require level 1 care and in a

recent review over 60% of patients required admission to

intensive care.11 Ultimately the patientmay require surgery to

resect involved bowel segments if complications such as

perforations arise.52 A recent study demonstrated duodenal

infusion for recurrent C. difficile colitis has promise. Although

not assessed in small bowel disease this modality may well be

applicable in C. difficile enteritis.53

Outcomes

Initially reported mortality rates for small bowel C. difficile

enteritis were high (60%e80%).54 This may be secondary to

enteric necrosis with perforation or delayed diagnosis and

treatment.53 Also small bowelmucosa has a high permeability

which favours bacterial and toxin translocation with

ficile enteritis: A new role for an old foe, The Surgeon (2014),

t h e s u r g e on x x x ( 2 0 1 4 ) 1e7 5

subsequent septicaemia.55 In addition among patients infec-

ted with the BI/NAP1/027 strain, there was a higher case-

fatality ratio after adjustment for confounding factors such

as age and the burden of chronic co-morbidities.4,23

However mortality rates depend on the numerator and

denominator (WPS).26 Thus if the prevalence of mild disease

is high, mortality rate reduce.56 C. difficile enteritis may be

more frequent than previously reported with only severe

cases (i.e. those requiring surgery or found at autopsy) being

treated and published, resulting in high reported mortality

rates.13 Indeed recent studies suggest a mortality rate of

approximately 30%11 while Tsiouris who identified C. difficile

in the stoma effluent of16% of post colectomy patients had

no reported mortality.2

Data on C. difficile enteritis associated morbidity, length of

stay, cost implications (to the patient and service provider)

and quality of life assessments is lacking. Undoubtedly C.

difficile enteritis will impact on all these variables but this

needs further investigation.

Discussion

Small bowel C. difficile involvement is increasingly identified.

This may be due to a combination of true increase in preva-

lence, enhanced awareness, more sensitive assays and

increased reporting. C. difficile enteritis shares a number of risk

factors with C. difficile colitis including antibiotic therapy,

hospitalisation, immunocompromise and old age.7,11 Howev-

er emergency surgery, white race and increased age by 10

years may be distinct risk factors for C. difficile infection of the

ileum after colectomy and clinicians need to be cognisant of

this when assessing suspected cases.2,7,13

Caregivers need to be especially coniscent of patients with

inflammatory bowel disease as they are at increased risk of

developing C. difficile infection (CDI), have worse outcomes of

CDI-including higher rates of colectomy and death. IBD pa-

tients with C. difficile tend be younger, have less prior antibi-

otic exposure, and most cases of C. difficile in these patients

represent outpatient acquired infections.

Thus a high index of suspicion is necessary allied to allow

early intervention and maximise optimum outcomes. How-

ever it may not be necessary to treat asymptomatic carriers of

C. difficile.2

Analogous to colonic infection, antibiotics such as metro-

nidazole and vancomycin are the corner stone of treatment.49

Immunoglobulins have a limited role and novel antimicro-

bials remain to be rigorously analysed in this setting.51 Ulti-

mately these patients may require operative intervention to

deal with complications such as perforation or bleeding.52

Despite these features, the literature on C. difficile enteritis

is sparse comprising mainly of retrospective studies and case

series. Unlike C. difficile colitis, there are no consensus guide-

lines to assist healthcare practitioners.

Unfortunately this review incorporated predominantly

retrospective heterogenous studies involving a spectrum of

case severities. Overall reported numbers are small and few

studies differentiate between colonisation and infection.

Diagnostic and treatment modalities vary. This collectively

limits conclusions and prohibits any formal meta-analysis.

Please cite this article in press as: Killeen S, et al., Clostridium difhttp://dx.doi.org/10.1016/j.surge.2014.01.008

However this review may provide a useful framework for

more structured recommendations.

Conclusion

A high index of clinical suspicion and early diagnosis is vital.

Patients with ileal CDI should be treated with oral metroni-

dazole. Further prospective studies are needed to determine

the significance of asymptomatic small bowel C. difficile

infections.

Author contribution

Mr S. Killeen: (Study conception and design, Acquisition of

data, Analysis and interpretation of data, Writing

manuscript).

Prof PR O Connell: (Analysis and interpretation of data,

Writing manuscript).

Prof J Hyland: (Analysis and interpretation of data, Writing

manuscript).

Prof. DC Winter: (Study conception and design, Analysis

and interpretation of data, Writing manuscript).

Mr STMartin: (Study conception and design, Acquisition of

data, Analysis and interpretation of data, Writing

manuscript).

r e f e r e n c e s

1. Lessa FC, Gould CV, McDonald LC. Current status ofClostridium difficile infection epidemiology. Clin Infect Dis2012 Aug;55(Suppl. 2):S65e70. http://dx.doi.org/10.1093/cid/cis319. Review. PubMed PMID: 22752867.

2. Tsiouris A, Neale JA, Reickert CA, Times M. Clostridiumdifficile of the ileum following total abdominal colectomy,with or without proctectomy: who is at risk? Dis Colon Rectum2012 Apr;55(4):424e8. PubMed PMID: 22426266.

3. Tsutaoka B, Hansen J, Johnson D, Holodniy M. Antibiotic-associated pseudomembranous enteritis due to Clostridiumdifficile. Clin Infect Dis 1994 Jun;18(6):982e4. PubMed PMID:8086563.

4. Lavallee C, Laufer B, Pepin J, Mitchell A, Dube S, Labbe AC.Fatal Clostridium difficile enteritis caused by the BI/NAP1/027strain: a case series of ileal C. difficile infections. Clin MicrobiolInfect 2009 Dec;15(12):1093e9 [Epub 2009 Jul 22]. Review.PubMed PMID: 19681954.

5. Vaishnavi C. Established and potential risk factors forClostridium difficile infection. Indian J Med Microbiol2009;27:289e300.

6. Gagandeep D, Ira S. Clostridium difficile enteritis 9 years aftertotal proctocolectomy: a rare case report. Am J Gastroenterol2010;105:962e3.

7. Williams RN, Hemingway D, Miller AS. Enteral Clostridiumdifficile, an emerging cause for high-output ileostomy. J ClinPathol 2009;62:951e3.

8. Cheng AC, Ferguson JK, Richards MJ, Robson JM, Gilbert GL,McGregor A, et al., Australasian Society for InfectionsDiseases. Australasian Society for Infectious Diseasesguidelines for the diagnosis and treatment of Clostridiumdifficile infection. Med J Aust 2011 Apr 4;194(7):353e8.

ficile enteritis: A new role for an old foe, The Surgeon (2014),

t h e s u r g e on x x x ( 2 0 1 4 ) 1e76

9. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group.Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med2009;151:264e9. W64.

10. Causey MW, Spencer MP, Steele SR. Clostridium difficileenteritis after colectomy. Am Surg 2009 Dec;75(12):1203e6.

11. Kim JH, Muder RR. Clostridium difficile enteritis: a review andpooledanalysis of the cases. Anaerobe 2011 Apr;17(2):52e5.http://dx.doi.org/10.1016/j.anaerobe.2011.02.002 [Epub 2011Feb 18]. Review. PubMed PMID: 21334446.

12. Wiggelinkhuizen M, Gerrits MA. Clostridium difficile-inducednecrotizingenteritis. Ned Tijdschr Geneeskd 2011;155(49):A2414.Dutch. PubMed PMID: 22166175.

13. Testore GP, Nardi F, Babudieri S, Giuliano M, Di Rosa R,Panichi G. Isolation of Clostridium difficile from humanjejunum: identification of a reservoir for disease? J Clin Pathol1986;39:861e2.

14. http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/ClostridiumDifficile/ [accessed 17.12.12].

15. Voth DE, Ballard JD. Clostridium difficile toxins: mechanismof action and role in disease. Clin Microbiol Rev 2005;18:247e63.

16. Ng J, Hirota SA, Gross O, Li Y, Ulke-Lemee A, Potentier MS,et al. Clostridium difficile toxin-induced inflammation andintestinal injury are mediated by the inflammasome.Gastroenterology 2010 Aug;139(2):542e52. 552.e1e3. [Epub 2010Apr 13]. PubMed PMID: 20398664.

17. Kokkotou E, Espinoza DO, Torres D, Karagiannides I,Kosteletos S, Savidge T, et al. Melanin-concentrating hormone(MCH)modulates Cdifficile toxinA-mediated enteritis inmice.Gut 2009 Jan;58(1):34e40 [Epub 2008 Sep 29]. PubMed PMID:18824554; PubMed Central PMCID: PMC3058236.

18. Kelly CP, Becker S, Linevsky JK, et al. Neutrophil recruitmentin Clostridium difficile toxin a enteritis in the rabbit. J ClinInvest 1994;93:1257e65.

19. Neut C, Bulois P, Desreumaux P, Membre JM, Lederman E,Gambiez L, et al. Changes in the bacterial flora of theneoterminal ileum after ileocolonic resection for crohn’sdisease. Am J Gastroenterol 2002 Apr;97(4):939e46.

20. Kralovich KA, Sacksner J, Karmy-Jones RA, Eggenberger JC.Pseudomembranous colitis with associated fulminant ileitisin the defunctionalized limb of a jejunal-ileal bypass: reportof a case. Dis Colon Rectum 1997;40:622e4.

21. Geric B, Carman RJ, Rupnik M, et al. Binary toxin-producing,large clostridial toxin-negative Clostridium difficile strainsare enterotoxic but do not cause disease in hamsters. J InfectDis 2006;193:1143e50.

22. Keel MK, Songer JG. The distribution and density ofClostridium difficile toxin receptors on the intestinal mucosaof neonatal pigs. Vet Pathol 2007;44:814e22.

23. Warny M, Pepin J, Fang A, et al. Toxin production by anemerging strain of clostridium difficile associated withoutbreaks of severe disease in North America and Europe.Lancet 2005;366:1079e84.

24. Meier CB, Hegazi RA, Aisenberg J, et al. Innate immunereceptor genetic polymorphisms in pouchitis: is CARD15 asusceptibility factor? Inflamm Bowel Dis 2005;11:965e71.

25. Jiang ZD, Garey KW, Price M, et al. Association of interleukin-8 polymorphism and immunoglobulin G anti-toxin A inpatients with Clostridium difficile-associated diarrhea. ClinGastroenterol Hepatol 2007;5:964e8.

26. Yee Jr HF, Brown Jr RS, Ostroff JW. Fatal Clostridium difficileenteritis after total abdominal colectomy. J Clin Gastroenterol1996;22:45e7.

27. Kachrimanidou M, Malisiovas N. Clostridium difficileinfection: a comprehensive review. Crit Rev Microbiol 2011Aug;37(3):178e87 [Epub 2011 May 24]. Review. PubMed PMID:21609252.

Please cite this article in press as: Killeen S, et al., Clostridium difhttp://dx.doi.org/10.1016/j.surge.2014.01.008

28. Holmer C, Zurbuchen U, Siegmund B, Reichelt U, Buhr HJ,Ritz JP. Clostridium difficile infection of the small bowel e twocase reports with a literature survey. Int J Colorectal Dis 2011Feb;26(2):245e51. http://dx.doi.org/10.1007/s00384-010-1001-y[Epub 2010 Jul 14]. PubMed PMID: 20628882.

29. Wood MJ, Hyman N, Hebert JC, Blaszyk H. CatastrophicClostridium difficile enteritis in a pelvic pouch patient: reportof a case. J Gastrointest Surg 2008 Feb;12(2):350e2 [Epub 2007Dec 11]. PubMed PMID: 18071831.

30. Shen B, Remzi FH, Fazio VW. Fulminant Clostridium difficile-associated pouchitis with a fatal outcome. Nat RevGastroenterol Hepatol 2009 Aug;6(8):492e5. http://dx.doi.org/10.1038/nrgastro.2009.105. Review. PubMed PMID: 19654602.

31. Suzuki H, Ogawa H, Shibata C, Haneda S, Watanabe K,Takahashi K, et al. The long-term clinical course of pouchitisafter total proctocolectomy and IPAA for ulcerative colitis. DisColon Rectum 2012 Mar;55(3):330e6. PubMed PMID: 22469801.

32. Issa M, Ananthakrishnan AN, Binion DG. Clostridium difficileand inflammatory bowel disease. Inflamm Bowel Dis 2008Oct;14(10):1432e42. http://dx.doi.org/10.1002/ibd.20500.Review. PubMed PMID: 18484669.

33. Bakri MM, Sutherland AD, Brown DJ, Vesely P, Crossan C,Scobie L. Assessment of the potential risk of infectionassociated with Clostridium difficile from porcine xenografts.Xenotransplantation 2009 NoveDec;16(6):472e6. PubMed PMID:20042046.

34. Hsu J, Abad C, Dinh M, Safdar N. Prevention of endemichealthcare associated Clostridium difficile infection: reviewingthe evidence. Am J Gastroenterol 2010;105:2327e39.

35. Malkan AD, Pimiento JM, Maloney SP, Palesty JA, Scholand SJ.Unusual manifestations of Clostridium difficile infection.Surg Infect (Larchmt) 2010 Jun;11(3):333e7. http://dx.doi.org/10.1089/sur.2008.099. PubMed PMID: 19795991.

36. Khan MS, Levy D, Mann S. Clostridium difficile infection inthe absence of a colon. BMJ Case Rep 2010 Oct 21;2010. http://dx.doi.org/10.1136/bcr.02.2010.2728. pii:bcr0220102728.PubMed PMID: 22791474; PubMed Central PMCID:PMC3027549.

37. Yafi FA, Selvasekar CR, Cima RR. Clostridium difficile enteritisfollowing total colectomy. Tech Coloproctol 2008Mar;12(1):73e4.

38. Shetty N, Wren MW, Coen PG. The role of glutamatedehydrogenase for the detection of Clostridium difficile infaecal samples: a meta-analysis. J Hosp Infect 2011Jan;77(1):1e6 [Epub 2010 Dec 8].

39. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG,McDonald LC, et al., Society for Healthcare Epidemiology ofAmerica, Infectious Diseases Society of America. Clinicalpractice guidelines for Clostridium difficile infection in adults:2010 update by the society for healthcare epidemiology ofAmerica (SHEA) and the infectious diseases society of America(IDSA). Infect Control Hosp Epidemiol 2010 May;31(5):431e55.http://dx.doi.org/10.1086/651706. PubMed PMID: 20307191.

40. Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ. EuropeanSociety of Clinical Microbiology and Infectious Diseases(ESCMID): data review and recommendations for diagnosingClostridium difficile infection (CDI). Clin Microbiol Infect2009;15:1053e66.

41. Jousimies-Somer H, Summanen P, Citron D, Baron E,Wexler H, Finegold S. Anaerobic bacteriology manual. StarPublishing Company; 2002.

42. Swindells J, Brenwald N, Reading N, Oppenheim B. Evaluationof diagnostic tests for Clostridium difficile infection. J ClinMicrobiol 2010;48:606e8.

43. Burnham CA, Carroll KC. Diagnosis of Clostridium difficileinfection: an ongoing conundrum for clinicians and forclinical laboratories. Clin Microbiol Rev 2013;26(3):604e30.

ficile enteritis: A new role for an old foe, The Surgeon (2014),

t h e s u r g e on x x x ( 2 0 1 4 ) 1e7 7

44. Planche T, Aghaizu A, Holliman R, et al. Diagnosis ofClostridium difficile infection by toxin detection kits: asystematic review. Lancet Infect Dis 2008;8:777e84.

45. Peterson LR, Mehta MS, Patel PA, Hacek DM, Harazin M,Nagwekar PP, et al. Laboratory testing for Clostridium difficileinfection: light at the end of the tunnel. Am J Clin Pathol 2011Sep;136(3):372e80.

46. Wee B, Poels JA, McCafferty IJ, Taniere P, Olliff J. A descriptionof CT features of Clostridium difficile infection of the smallbowel in four patients and a review of literature. Br J Radiol2009 Nov;82(983):890e5 [Epub 2009 Jul 20]. Review. PubMedPMID: 19620176.

47. Lundeen SJ, Otterson MF, Binion DG, Carman ET,Peppard WJ. Clostridium difficile enteritis: an earlypostoperative complication in inflammatory bowel diseasepatients after colectomy. J Gastrointest Surg2007;11:138e42.

48. Boland E, Thonpson JS. Fulminant Clostridium difficileenteritis after proctocolectomy and ileal pouch-analanastamosis. Gastroenterol Res Pract 2008;2008:985658. http://dx.doi.org/10.1155/2008/985658 [Epub 2009 Feb 1].

49. Follmar KE, Condron SA, Turner II, Nathan JD, Ludwig KA.Treatment ofmetronidazole-refractory Clostridium difficile

Please cite this article in press as: Killeen S, et al., Clostridium difhttp://dx.doi.org/10.1016/j.surge.2014.01.008

enteritis with vancomycin. Surg Infect (Larchmt) 2008Apr;9(2):195e200. Review.

50. Thomas K, Taylor J, Everitt L, Nelson R. Clostridium difficiledoes not only affect the colon: a case series. Colorectal Dis 2011Jun;13(6):e156e7. http://dx.doi.org/10.1111/j.1463-1318.2010.02315.x [Epub 2010 May 17].

51. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versusvancomycin for Clostridium difficile infection. N Engl J Med2011;364(5):422e31.

52. Lowy I, Molrine DC, Leav BA, et al. Treatment withmonoclonal antibodies against Clostridium difficile toxins. NEngl J Med 2010;362:197e205.

53. vanNood E,VriezeA,NieuwdorpM, Fuentes S, Zoetendal EG, deVosWM, et al. Duodenal infusion of donor feces for recurrentClostridium difficile. N Engl J Med 2013 Jan 31;368(5):407e15.

54. Hayetian FD, Read TE, Brozovich M, Garvin RP, Caushaj PF.Ileal perforation secondary to Clostridium difficile enteritis:report of 2 cases. Arch Surg 2006 Jan;141(1):97e9.

55. Vesoulis Z, Williams G, Matthews B. Pseudomembranousenteritis after proctocolectomy: report of a case. Dis ColonRectum 2000 Apr;43(4):551e4. PubMed PMID: 10789757.

56. World Population Prospect (WPS), the 2008 revision UN data.http://data.un.org/Data [accessed 18.12.12].

ficile enteritis: A new role for an old foe, The Surgeon (2014),