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__NOTOC__
__NOTOC__
{{Main|Clostridium difficile infection}}
{{CMG}}
{{CMG}}


==Overview==  
==Overview==  
''Clostridium difficile'' infection is the leading cause to nosocomial diarrhea.  Clinical presentation ranges across a broad spectrum from asymptomatic carriage, to diarrheal illness, to complicated disease hallmarked by pseudomembranous colitis, toxic megacolon, or bowel perforation.  Diagnosis is established by the presence of diarrheal symptoms coupled with positive stool tests or endoscopic findings.  Therapeutic approach and antibiotic choice should be stratified according to severity of disease and risk of recurrence.
''Clostridium difficile'' infection is the leading cause to nosocomial diarrhea.  Clinical presentation ranges across a broad spectrum from asymptomatic carriage, to [[diarrhea]]l illness, to complicated disease hallmarked by [[pseudomembranous colitis]], [[toxic megacolon]], or [[bowel perforation]].  Diagnosis is established by the presence of [[diarrhea]]l symptoms coupled with positive stool tests or endoscopic findings.  Therapeutic approach and antibiotic choice should be stratified according to severity of disease and risk of recurrence.


==Diagnostic Criteria==
==Diagnostic Criteria==


===Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)===
===Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)===
The diagnosis of ''C. difficile'' infection should be based on a combination of clinical and laboratory findings. A case definition for the usual presentation of CDI includes the following findings:<ref>{{Cite journal| doi = 10.1086/651706| issn = 1559-6834| volume = 31| issue = 5| pages = 431–455| last1 = Cohen| first1 = Stuart H.| last2 = Gerding| first2 = Dale N.| last3 = Johnson| first3 = Stuart| last4 = Kelly| first4 = Ciaran P.| last5 = Loo| first5 = Vivian G.| last6 = McDonald| first6 = L. Clifford| last7 = Pepin| first7 = Jacques| last8 = Wilcox| first8 = Mark H.| last9 = Society for Healthcare Epidemiology of America| last10 = Infectious Diseases Society of America| title = Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)| journal = Infection Control and Hospital Epidemiology| date = 2010-05| pmid = 20307191}}</ref>
The diagnosis of ''[[C. difficile]]'' infection should be based on a combination of clinical and laboratory findings. A case definition for the usual presentation includes the following findings:<ref>{{Cite journal| doi = 10.1086/651706| issn = 1559-6834| volume = 31| issue = 5| pages = 431–455| last1 = Cohen| first1 = Stuart H.| last2 = Gerding| first2 = Dale N.| last3 = Johnson| first3 = Stuart| last4 = Kelly| first4 = Ciaran P.| last5 = Loo| first5 = Vivian G.| last6 = McDonald| first6 = L. Clifford| last7 = Pepin| first7 = Jacques| last8 = Wilcox| first8 = Mark H.| last9 = Society for Healthcare Epidemiology of America| last10 = Infectious Diseases Society of America| title = Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)| journal = Infection Control and Hospital Epidemiology| date = 2010-05| pmid = 20307191}}</ref>
* The presence of diarrhea, defined as passage of 3 or more unformed stools in 24 or fewer consecutive hours {{and}}
* The presence of [[diarrhea]], defined as passage of 3 or more unformed stools in 24 or fewer consecutive hours {{and}}
* A stool test result positive for the presence of toxigenic C. difficile or its toxins {{or}} colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.
* A stool test result positive for the presence of toxigenic [[C. difficile]] or its [[toxin]]s {{or}} colonoscopic or histopathologic findings demonstrating [[pseudomembranous colitis]].


The same criteria should be used to diagnose recurrent CDI.
The same criteria should be used to diagnose recurrent ''[[C. difficile]]'' infection.


===European Society of Clinical Microbiology and Infectious Diseases (ESCMID)===
===European Society of Clinical Microbiology and Infectious Diseases (ESCMID)===
Diagnosis of ''C. difficile'' infection is based on the following criteria:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
Diagnosis of ''[[C. difficile]]'' infection is based on the following criteria:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
* A combination of signs and symptoms, confirmed by microbiological evidence of ''C. difficile'' in stools, in the absence of another cause {{or2}}
* A combination of signs and symptoms, confirmed by microbiological evidence of ''C. difficile'' in stools, in the absence of another cause {{or2}}
* Colonoscopic or histopathological findings demonstrating pseudomembranous colitis
* Colonoscopic or histopathological findings demonstrating [[pseudomembranous colitis]]


Diagnostic tests for CDI include:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
Diagnostic tests for ''[[C. difficile]]'' infection include:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
* Enzyme immunoassay (EIA): glutamate dehydrogenase (GDH), toxins A and B
* [[Enzyme immunoassay|Enzyme immunoassay (EIA)]]: [[GDH|glutamate dehydrogenase (GDH)]], [[toxins]] A and B
* Nucleic acid amplification tests (NAAT): 16S ribosomal RNA, GDH genes, toxin genes
* Nucleic acid amplification tests (NAAT): [[16S ribosomal RNA]], [[GDH]] genes, [[toxin]] genes
* Cell culture cytoxicity assay (CCA)
* Cell culture cytoxicity assay (CCA)
* Culture of toxigenic ''C. difficile''
* Culture of toxigenic ''[[C. difficile]]''


==Classification of Disease Severity==
==Classification of Disease Severity==


===Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)===
===Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)===
Initial episode of ''C. difficile'' infection may be stratified by disease severity as follows:<ref>{{Cite journal| doi = 10.1086/651706| issn = 1559-6834| volume = 31| issue = 5| pages = 431–455| last1 = Cohen| first1 = Stuart H.| last2 = Gerding| first2 = Dale N.| last3 = Johnson| first3 = Stuart| last4 = Kelly| first4 = Ciaran P.| last5 = Loo| first5 = Vivian G.| last6 = McDonald| first6 = L. Clifford| last7 = Pepin| first7 = Jacques| last8 = Wilcox| first8 = Mark H.| last9 = Society for Healthcare Epidemiology of America| last10 = Infectious Diseases Society of America| title = Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)| journal = Infection Control and Hospital Epidemiology| date = 2010-05| pmid = 20307191}}</ref>
Initial episode of ''[[C. difficile]]'' infection may be stratified by disease severity as follows:<ref>{{Cite journal| doi = 10.1086/651706| issn = 1559-6834| volume = 31| issue = 5| pages = 431–455| last1 = Cohen| first1 = Stuart H.| last2 = Gerding| first2 = Dale N.| last3 = Johnson| first3 = Stuart| last4 = Kelly| first4 = Ciaran P.| last5 = Loo| first5 = Vivian G.| last6 = McDonald| first6 = L. Clifford| last7 = Pepin| first7 = Jacques| last8 = Wilcox| first8 = Mark H.| last9 = Society for Healthcare Epidemiology of America| last10 = Infectious Diseases Society of America| title = Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)| journal = Infection Control and Hospital Epidemiology| date = 2010-05| pmid = 20307191}}</ref>
* '''Mild-to-moderate disease'''
* '''Mild-to-moderate disease'''
: Leukocytosis with WBC < 15,000 cells/mL {{and2}} serum creatinine < 1.5 times the premorbid level
: [[Leukocytosis]] with [[WBC]] < 15,000 cells/mL {{and2}} serum [[creatinine]] < 1.5 times the premorbid level


* '''Severe disease'''
* '''Severe disease'''
: Leukocytosis with WBC ≥ 15,000 cells/mL {{or}} serum creatinine ≥ 1.5 times the premorbid level
: [[Leukocytosis]] with [[WBC]] ≥ 15,000 cells/mL {{or}} serum [[creatinine]] ≥ 1.5 times the premorbid level


* '''Severe, complicated disease'''
* '''Severe, complicated disease'''
: Hypotension or shock, ileus, megacolon
: [[Hypotension]] or [[shock]], [[ileus]], [[megacolon]]


===European Society of Clinical Microbiology and Infectious Diseases (ESCMID)===
===European Society of Clinical Microbiology and Infectious Diseases (ESCMID)===
'''Severe disease''' is defined as an episode of ''C. difficile'' infection with:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
'''Severe disease''' is defined as an episode of ''[[C. difficile]]'' infection with:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
* One or more specific signs and symptoms of severe colitis {{or2}}
* One or more specific signs and symptoms of severe [[colitis]] {{or2}}
* A complicated course of disease, with significant systemic toxin effects and shock, resulting in need for ICU admission, colectomy, or death.
* A complicated course of disease, with significant systemic [[toxin]] effects and [[shock]], resulting in need for [[ICU|intensive care unit]] admission, [[colectomy]], or death.


Characteristics that correlate with severity of colitis:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
Characteristics that correlate with severity of [[colitis]]:<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
* Physical examination
* Physical examination
: Fever (core body temperature > 38.5°C)
: [[Fever]] (core body temperature > 38.5°C)
: Rigors (uncontrollable shaking and a feeling of cold followed by a rise in body temperature)
: [[Rigors]] (uncontrollable shaking and a feeling of cold followed by a rise in body temperature)
: Hemodynamic instability including signs of distributive shock
: [[Hemodynamic instability]] including signs of [[distributive shock]]
: Respiratory failure requiring mechanical ventilation
: [[Respiratory failure]] requiring [[mechanical ventilation]]
: Signs and symptoms of peritonitis
: Signs and symptoms of [[peritonitis]]
: Signs and symptoms of colonic ileus
: Signs and symptoms of colonic [[ileus]]


* Laboratory investigations
* Laboratory investigations
: Marked leukocytosis (leukocyte count > 15,000 cells/mL)
: Marked [[leukocytosis]] ([[leukocyte]] count > 15,000 cells/mL)
: Marked left shift (band neutrophils > 20% of leukocytes)
: Marked [[bandemia|left shift]] ([[band neutrophil]]s > 20% of leukocytes)
: Rise in serum creatinine (> 50% above the baseline)
: Rise in serum [[creatinine]] (> 50% above the baseline)
: Elevated serum lactate (≥ 5 mmol/L)
: Elevated serum [[lactate]] (≥ 5 mmol/L)
: Markedly reduced serum albumin (< 3 mg/dl)
: Markedly reduced serum [[albumin]] (< 3 mg/dl)
* Colonoscopy or sigmoidoscopy
* [[Colonoscopy]] or [[sigmoidoscopy]]
: Pseudomembranous colitis
: [[Pseudomembranous colitis]]


* Imaging
* Imaging
: Distention of large intestine (> 6 cm in transverse width of colon)
: Distention of [[large intestine]] (> 6 cm in transverse width of colon)
: Colonic wall thickening including low-attenuation mural thickening
: Colonic wall thickening including low-attenuation mural thickening
: Pericolonic fat stranding
: Pericolonic fat stranding
: Ascites not explained by other causes
: [[Ascites]] not explained by other causes


===American College of Gastroenterology (ACG)===
===American College of Gastroenterology (ACG)===
Classification of disease severity:<ref>{{Cite journal| doi = 10.1038/ajg.2013.4| issn = 1572-0241| volume = 108| issue = 4| pages = 478–498; quiz 499| last1 = Surawicz| first1 = Christina M.| last2 = Brandt| first2 = Lawrence J.| last3 = Binion| first3 = David G.| last4 = Ananthakrishnan| first4 = Ashwin N.| last5 = Curry| first5 = Scott R.| last6 = Gilligan| first6 = Peter H.| last7 = McFarland| first7 = Lynne V.| last8 = Mellow| first8 = Mark| last9 = Zuckerbraun| first9 = Brian S.| title = Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections| journal = The American Journal of Gastroenterology| date = 2013-04| pmid = 23439232}}</ref>
Classification of disease severity:<ref>{{Cite journal| doi = 10.1038/ajg.2013.4| issn = 1572-0241| volume = 108| issue = 4| pages = 478–498; quiz 499| last1 = Surawicz| first1 = Christina M.| last2 = Brandt| first2 = Lawrence J.| last3 = Binion| first3 = David G.| last4 = Ananthakrishnan| first4 = Ashwin N.| last5 = Curry| first5 = Scott R.| last6 = Gilligan| first6 = Peter H.| last7 = McFarland| first7 = Lynne V.| last8 = Mellow| first8 = Mark| last9 = Zuckerbraun| first9 = Brian S.| title = Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections| journal = The American Journal of Gastroenterology| date = 2013-04| pmid = 23439232}}</ref>
* '''Mild disease'''
* '''Mild disease'''
: Diarrhea as the only symptom
: [[Diarrhea]] as the only symptom


* '''Moderate disease'''
* '''Moderate disease'''
: Diarrhea but without additional symptoms/signs meeting the definition of severe or complicated disease
: [[Diarrhea]] but without additional symptoms/signs meeting the definition of severe or complicated disease


* '''Severe disease'''
* '''Severe disease'''
: Hypoalbuminemia (serum albumin < 3 g/dl) {{and}}
: [[Hypoalbuminemia]] (serum [[albumin]] < 3 g/dl) {{and}}
: WBC ≥ 15,000 cells/mL {{or}} abdominal tenderness without criteria of complicated disease
: [[WBC]] ≥ 15,000 cells/mL {{or}} [[abdominal tenderness]] without criteria of complicated disease


* '''Complicated disease'''
* '''Complicated disease'''
: Any of the following attributable to ''C. difficile'' infection:
: Any of the following attributable to ''[[C. difficile]]'' infection:
: Admission to intensive care unit
: Admission to [[intensive care unit]]
: Hypotension with or without required use of vasopressors
: [[Hypotension]] with or without required use of [[vasopressors]]
: Fever ≥ 38.5°C
: [[Fever]] ≥ 38.5°C
: Ileus (acute nausea, emesis, sudden cessation of diarrhea, significant abdominal distention, or radiological signs consistent with disturbed intestinal transit)
: [[Ileus]] (acute [[nausea]], [[emesis]], sudden cessation of [[diarrhea]], significant [[abdominal distention]], or radiological signs consistent with disturbed intestinal transit)
: Mental status changes
: [[Altered mental status|Mental status changes]]
: WBC ≥ 35,000 cells/mL or < 2,000 cells/mL
: [[WBC]] ≥ 35,000 cells/mL or < 2,000 cells/mL
: Serum lactate levels > 2.2 mmol/l
: Serum [[lactate]] levels > 2.2 mmol/l
: Any evidence of end organ failure
: Any evidence of end organ failure


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==Risk Factors==
==Risk Factors==
The most important risk factor remains antibiotic use.  Other established risk factors include:<ref>{{Cite journal| doi = 10.1016/j.mayocp.2012.07.016| issn = 1942-5546| volume = 87| issue = 11| pages = 1106–1117| last1 = Khanna| first1 = Sahil| last2 = Pardi| first2 = Darrell S.| title = Clostridium difficile infection: new insights into management| journal = Mayo Clinic Proceedings| date = 2012-11| pmid = 23127735| pmc = PMC3541870}}</ref>
The most important risk factor remains [[antibiotic|antibiotic use]].  Other established risk factors include:<ref>{{Cite journal| doi = 10.1016/j.mayocp.2012.07.016| issn = 1942-5546| volume = 87| issue = 11| pages = 1106–1117| last1 = Khanna| first1 = Sahil| last2 = Pardi| first2 = Darrell S.| title = Clostridium difficile infection: new insights into management| journal = Mayo Clinic Proceedings| date = 2012-11| pmid = 23127735| pmc = PMC3541870}}</ref>
* Advanced age
* [[Elderly|Advanced age]]
* Chemotherapy
* [[Chemotherapy]]
* Chronic kidney disease
* [[Chronic kidney disease]]
* Consumption of processed meat
* Consumption of processed meat
* Contact with active carriers
* Contact with active carriers
* Cystic fibrosis
* [[Cystic fibrosis]]
* Diabetes mellitus
* [[Diabetes mellitus]]
* Hypoalbuminemia
* [[Hypoalbuminemia]]
* Immunosuppression, immunodeficiency, or human immunodeficiency virus
* [[Immunosuppression]], [[immunodeficiency]], or [[human immunodeficiency virus]]
* Increased risk with prolonged use or multiple antibiotics
* Increased risk with prolonged use or multiple [[antibiotics]]
* Inflammatory bowel disease
* [[Inflammatory bowel disease]]
* Liver cirrhosis
* [[Liver cirrhosis]]
* Malignancy
* [[Malignancy]]
* Malnutrition
* [[Malnutrition]]
* Nursing home or long-term care facility residence
* Nursing home or long-term care facility residence
* Presence of comorbid conditions
* Presence of comorbid conditions
* Presence of gastrostomy or jejunostomy tube
* Presence of [[gastrostomy]] or [[Feeding tube#Jejunal feeding tube|jejunostomy tube]]
* Previous gastrointestinal surgery or endoscopic procedure
* Previous [[gastrointestinal]] [[surgery]] or [[endoscopic]] procedure
* Previous hospitalization and prolonged length of hospital stay
* Previous hospitalization and prolonged length of hospital stay
* Solid organ or hematopoietic stem cell transplantation
* Solid organ or [[hematopoietic stem cell transplantation]]
* Use of proton pump inhibitors
* Use of [[proton pump inhibitor]]s


Use of the following antibiotics has been associated with ''C. difficile'' infection:<ref>{{Cite journal| doi = 10.1056/NEJMra1403772| issn = 1533-4406| volume = 372| issue = 16| pages = 1539–1548| last1 = Leffler| first1 = Daniel A.| last2 = Lamont| first2 = J. Thomas| title = Clostridium difficile infection| journal = The New England Journal of Medicine| date = 2015-04-16| pmid = 25875259}}</ref>
Use of the following [[antibiotics]] has been associated with ''[[C. difficile]]'' infection:<ref>{{Cite journal| doi = 10.1056/NEJMra1403772| issn = 1533-4406| volume = 372| issue = 16| pages = 1539–1548| last1 = Leffler| first1 = Daniel A.| last2 = Lamont| first2 = J. Thomas| title = Clostridium difficile infection| journal = The New England Journal of Medicine| date = 2015-04-16| pmid = 25875259}}</ref>
* '''Very common'''
* '''Very common'''
: [[Clindamycin]]
: [[Clindamycin]]
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==''Clostridium difficile'' Infection==
==''Clostridium difficile'' Infection==
* Diarrhea (passage of 3 or more unformed stools in ≤ 24 hours) with microbiological evidence of ''C. difficile''
* [[Diarrhea]] (passage of 3 or more unformed stools in ≤ 24 hours) with microbiological evidence of ''[[C. difficile]]''
* Colonoscopic or histopathological findings demonstrating pseudomembranous colitis
* [[Colonoscopic]] or histopathological findings demonstrating pseudomembranous colitis
</div>}}
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==Focused History==
==Focused History==
* Characterize the symptoms:
* Characterize the symptoms:
:* Abdominal discomfort
:* [[Abdominal discomfort]]
:* Poor appetite
:* [[Poor appetite]]
:* Diarrhea
:* [[Diarrhea]]
:* Nausea
:* [[Nausea]]
:* Vomiting
:* [[Vomiting]]
:* Bloating
:* [[Bloating]]
:* Belching
:* [[Belching]]
:* Flatulence
:* [[Flatulence]]
:* Lack of bowel movement
:* [[Constipation]] or [[obstipation]]
* Other relevant history:
* Other relevant history:
:* [[{{PAGENAME}}#Risk Factors|Risk factors]]
:* Risk factors ([[{{PAGENAME}}#Risk Factors|details]])
:* Comorbidities
:* Comorbidities
:* Recent sick contacts
:* Recent sick contacts
:* Recent hospitalizations
:* Recent hospitalizations
:* Prior use of antibiotics
:* Prior use of [[antibiotics]]
:* Immunosuppressive state
:* [[Immunosuppressive state]]
:* Travel history
:* Travel history
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==Physical Examination==
==Physical Examination==
* Vital signs (body temperature, pulse rate, respiration rate, blood pressure)
* Vital signs ([[body temperature]], [[pulse rate]], [[respiration rate]], [[blood pressure]])
* Signs of ileus (distended and tympanic abdomen with tenderness, hypoactive bowel sounds)
* Signs of [[ileus]] ([[abdominal distention|distended and tympanic abdomen]] with [[tenderness]], [[bowel sounds|hypoactive bowel sounds]])
* Signs of peritonitis (rebound tenderness, abdominal wall rigidity, hypoactive bowel sounds)
* Signs of [[peritonitis]] ([[rebound tenderness]], [[abdominal guarding]], [[bowel sounds|hypoactive bowel sounds]])
* Signs of dehydration (delayed capillary refill, decreased skin turgor, abnormal respiratory pattern)
* Signs of [[dehydration]] ([[capillary refill|delayed capillary refill]], [[dehydration|decreased skin turgor]], abnormal respiratory pattern)
* Signs of respiratory distress (tachypnea, tachycardia, abnormal breath sounds)
* Signs of [[respiratory distress]] ([[tachypnea]], [[tachycardia]], abnormal [[breath sounds]])
* Signs of multiple organ failure (cool and clammy skin, tissue hypoperfusion)
* Signs of [[shock|multiple organ failure]] ([[cold and clammy skin]], [[shock|tissue hypoperfusion]])
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* [[Complete blood count|Complete blood count with differential]]
* [[Complete blood count|Complete blood count with differential]]
* [[Basic metabolic panel|Basic metabolic panel including urea nitrogen and creatinine]]
* [[Basic metabolic panel|Basic metabolic panel including urea nitrogen and creatinine]]
* [[AST]], [[ALT]], [[bilirubin]], [[alkaline phosphatase]], [[albumin]]
* [[AST]], [[ALT]], [[bilirubin]], [[alkaline phosphatase]], [[albumin]], [[lactate]]
* Consider abdominal CT scan or colonoscopy in severe disease or concurrent IBD
* Consider abdominal [[CT scan]] or [[colonoscopy]] in severe disease or concurrent [[inflammatory bowel disease]]
</div>}}
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{{Familytree|boxstyle=width: 700px; text-align: left; font-size: 100%; padding: 0px;| |!| | | |}}
{{Familytree|boxstyle=width: 700px; text-align: left; font-size: 100%; padding: 0px;| |!| | | |}}
{{Familytree|boxstyle=width: 700px; text-align: left; font-size: 100%; padding: 0px;| A01 | | |A01=<div style="padding: 0px 10px;">
{{Familytree|boxstyle=width: 700px; text-align: left; font-size: 100%; padding: 0px;| A01 | | |A01=<div style="padding: 0px 10px;">
==Other Investigation==
==Other Investigation==
Positive results of either EIA or NAAT should prompt treatment.
Positive results of either [[EIA]] or [[NAAT]] should prompt treatment.
* GDH (high sensitivity, low specificity): screening test
* [[GDH]] (high sensitivity, low specificity): screening test
* EIA for toxins (low sensitivity, high specificity): confirmatory test
* [[EIA]] for toxins (low sensitivity, high specificity): confirmatory test
* NAAT (high sensitivity, high specificity): standard diagnostic test
* [[NAAT]] (high sensitivity, high specificity): standard diagnostic test
</div>}}
</div>}}
{{Familytree/end}}
{{Familytree/end}}
Line 249: Line 248:
==Management==
==Management==


===Asymptomatic carrier===
* No treatment indicated


===Mild disease===
* Predisposing [[antibiotic]] cessation
* [[Hydration]]
* Monitoring of clinical status
* Administration of [[metronidazole]] (500 mg three times per day) {{or2}}
: Close outpatient monitoring without the administration of [[antibiotics]]


===Moderate disease===
* Consideration of hospitalization
* Cessation of predisposing [[antibiotics]]
* [[Hydration]]
* Monitoring of clinical status
* Administration of [[metronidazole]] (500 mg three times per day) {{or2}}
: Administration of [[vancomycin]] (125 mg orally four times per day for 14 days)


===Severe disease===
* Hospitalization
* Oral or nasogastric [[vancomycin]] (500 mg four times per day) with or without intravenous [[metronidazole]] (500 mg three times per day) {{or2}}
: Oral [[fidaxomicin]] (200 mg twice a day for 10 days) if the risk of recurrence is high


===Complicated disease===
* [[Antibiotics]] as for severe infection
* Surgical consultation for subtotal [[colectomy]] or a diverting [[ileostomy]] with [[vancomycin]] colonic lavage
* Consideration of [[fecal microbial transplantation]] or additional [[antibiotics]]
===First recurrence===
* Oral [[vancomycin]] (125 mg four times per day for 14 days) {{or2}}
: Oral [[fidaxomicin]] (200 mg twice a day for 10 days)
===Second or further recurrence===
* [[Vancomycin]] in a tapered and pulsed regimen {{or2}}
* [[Fecal microbial transplantation]] {{or2}}
* [[Fidaxomicin]] (200 mg twice a day for 10 days)<ref>{{Cite journal| doi = 10.1056/NEJMra1403772| issn = 1533-4406| volume = 372| issue = 16| pages = 1539–1548| last1 = Leffler| first1 = Daniel A.| last2 = Lamont| first2 = J. Thomas| title = Clostridium difficile infection| journal = The New England Journal of Medicine| date = 2015-04-16| pmid = 25875259}}</ref>


==Dos and Don'ts==
==Dos and Don'ts==


===Dos===
===Dos===
 
* Inform the laboratory when testing for ''[[Clostridium difficile]]'' from formed stools in a patient with [[ileus]].
 
* Initiate empiric [[antibiotics]] regardless of the laboratory results when there is a high index of suspicion for ''[[C. difficile]]'' infection.
 
* [[Vancomycin]] should be delivered via [[enema]] to treat patients in whom oral [[antibiotics]] cannot reach a segment of the colon as in [[Hartmann's operation|Hartmann's pouch]], [[ileostomy]], or [[Bowel resection|colonic diversion]].
 
* Test for ''[[C. difficile]]'' among patients with diarrhea in the context of [[malignancy]], [[chemotherapy]], [[immunosuppressive therapy]], [[organ transplantation]], [[cirrhosis]], [[inflammatory bowel disease]], or [[pregnancy]].
 


===Don'ts===
===Don'ts===
 
* Do NOT test for ''[[C. difficile]]'' in a patient without [[diarrhea]].
 
* Do NOT repeat test if the results are negative.
 
* Do NOT perform test of microbiological cure.
 
* Do NOT treat asymptomatic carriage.
 
* Do NOT administer [[peristalsis|antiperistaltic agent]]s to patients with suspected or confirmed ''[[C. difficile]]'' infection.
 


==Guidelines==
==Guidelines==
Line 291: Line 320:
===European Society of Clinical Microbiology and Infectious Diseases (ESCMID)===
===European Society of Clinical Microbiology and Infectious Diseases (ESCMID)===
* Update of the Treatment Guidance Document for ''Clostridium difficile'' Infection (2014)<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
* Update of the Treatment Guidance Document for ''Clostridium difficile'' Infection (2014)<ref>{{Cite journal| doi = 10.1111/1469-0691.12418| issn = 1469-0691| volume = 20 Suppl 2| pages = 1–26| last1 = Debast| first1 = S. B.| last2 = Bauer| first2 = M. P.| last3 = Kuijper| first3 = E. J.| last4 = European Society of Clinical Microbiology and Infectious Diseases| title = European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection| journal = Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases| date = 2014-03| pmid = 24118601}}</ref>
===American Academy of Pediatrics (AAP)===
* Policy Statement: Clostridium difficile Infection in Infants and Children (2013)<ref>{{Cite journal| doi = 10.1542/peds.2012-2992| issn = 1098-4275| volume = 131| issue = 1| pages = 196–200| last1 = Schutze| first1 = Gordon E.| last2 = Willoughby| first2 = Rodney E.| last3 = Committee on Infectious Diseases| last4 = American Academy of Pediatrics| title = Clostridium difficile infection in infants and children| journal = Pediatrics| date = 2013-01| pmid = 23277317}}</ref>


==References==
==References==
Line 297: Line 329:
[[Category:Disease]]
[[Category:Disease]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Infectious disease]]
 
[[Category:Medicine]]
[[Category:Medicine]]
[[Category:Resident survival guide]]
[[Category:Resident survival guide]]

Latest revision as of 18:41, 18 September 2017

Clostridium difficile infection

Overview

Diagnostic Criteria

Classification of Disease Severity

Risk Factors

Complete Diagnostic Approach

Management

Dos and Don'ts

Guidelines

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Clostridium difficile infection is the leading cause to nosocomial diarrhea. Clinical presentation ranges across a broad spectrum from asymptomatic carriage, to diarrheal illness, to complicated disease hallmarked by pseudomembranous colitis, toxic megacolon, or bowel perforation. Diagnosis is established by the presence of diarrheal symptoms coupled with positive stool tests or endoscopic findings. Therapeutic approach and antibiotic choice should be stratified according to severity of disease and risk of recurrence.

Diagnostic Criteria

Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

The diagnosis of C. difficile infection should be based on a combination of clinical and laboratory findings. A case definition for the usual presentation includes the following findings:[1]

  • The presence of diarrhea, defined as passage of 3 or more unformed stools in 24 or fewer consecutive hours AND
  • A stool test result positive for the presence of toxigenic C. difficile or its toxins OR colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.

The same criteria should be used to diagnose recurrent C. difficile infection.

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

Diagnosis of C. difficile infection is based on the following criteria:[2]

  • A combination of signs and symptoms, confirmed by microbiological evidence of C. difficile in stools, in the absence of another cause
    OR
  • Colonoscopic or histopathological findings demonstrating pseudomembranous colitis

Diagnostic tests for C. difficile infection include:[3]

Classification of Disease Severity

Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

Initial episode of C. difficile infection may be stratified by disease severity as follows:[4]

  • Mild-to-moderate disease
Leukocytosis with WBC < 15,000 cells/mL AND serum creatinine < 1.5 times the premorbid level
  • Severe disease
Leukocytosis with WBC ≥ 15,000 cells/mL OR serum creatinine ≥ 1.5 times the premorbid level
  • Severe, complicated disease
Hypotension or shock, ileus, megacolon

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

Severe disease is defined as an episode of C. difficile infection with:[5]

Characteristics that correlate with severity of colitis:[6]

  • Physical examination
Fever (core body temperature > 38.5°C)
Rigors (uncontrollable shaking and a feeling of cold followed by a rise in body temperature)
Hemodynamic instability including signs of distributive shock
Respiratory failure requiring mechanical ventilation
Signs and symptoms of peritonitis
Signs and symptoms of colonic ileus
  • Laboratory investigations
Marked leukocytosis (leukocyte count > 15,000 cells/mL)
Marked left shift (band neutrophils > 20% of leukocytes)
Rise in serum creatinine (> 50% above the baseline)
Elevated serum lactate (≥ 5 mmol/L)
Markedly reduced serum albumin (< 3 mg/dl)
Pseudomembranous colitis
  • Imaging
Distention of large intestine (> 6 cm in transverse width of colon)
Colonic wall thickening including low-attenuation mural thickening
Pericolonic fat stranding
Ascites not explained by other causes

American College of Gastroenterology (ACG)

Classification of disease severity:[7]

  • Mild disease
Diarrhea as the only symptom
  • Moderate disease
Diarrhea but without additional symptoms/signs meeting the definition of severe or complicated disease
  • Severe disease
Hypoalbuminemia (serum albumin < 3 g/dl) AND
WBC ≥ 15,000 cells/mL OR abdominal tenderness without criteria of complicated disease
  • Complicated disease
Any of the following attributable to C. difficile infection:
Admission to intensive care unit
Hypotension with or without required use of vasopressors
Fever ≥ 38.5°C
Ileus (acute nausea, emesis, sudden cessation of diarrhea, significant abdominal distention, or radiological signs consistent with disturbed intestinal transit)
Mental status changes
WBC ≥ 35,000 cells/mL or < 2,000 cells/mL
Serum lactate levels > 2.2 mmol/l
Any evidence of end organ failure
  • Recurrent disease
Recurrence within 8 weeks of completion of therapy

Risk Factors

The most important risk factor remains antibiotic use. Other established risk factors include:[8]

Use of the following antibiotics has been associated with C. difficile infection:[9]

  • Very common
Clindamycin
Ampicillin
Amoxicillin
Cephalosporins
Fluoroquinolones
  • Somewhat common
Penicillins
Sulfonamides
Trimethoprim
Trimethoprim-Sulfamethoxazole
Macrolides
  • Uncommon
Aminoglycosides
Bacitracin
Metronidazole
Teicoplanin
Rifampin
Chloramphenicol
Tetracyclines
Carbapenems
Daptomycin
Tigecycline

Complete Diagnostic Approach

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; DC, differential count; EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction; SMA-7, sequential multiple analysis-7.

Clostridium difficile Infection

  • Diarrhea (passage of 3 or more unformed stools in ≤ 24 hours) with microbiological evidence of C. difficile
  • Colonoscopic or histopathological findings demonstrating pseudomembranous colitis
 
 
 
 
 
 
 
 

Focused History

  • Characterize the symptoms:
  • Other relevant history:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Other Investigation

Positive results of either EIA or NAAT should prompt treatment.

  • GDH (high sensitivity, low specificity): screening test
  • EIA for toxins (low sensitivity, high specificity): confirmatory test
  • NAAT (high sensitivity, high specificity): standard diagnostic test
 
 

Management

Asymptomatic carrier

  • No treatment indicated

Mild disease

Close outpatient monitoring without the administration of antibiotics

Moderate disease

  • Consideration of hospitalization
  • Cessation of predisposing antibiotics
  • Hydration
  • Monitoring of clinical status
  • Administration of metronidazole (500 mg three times per day)
    OR
Administration of vancomycin (125 mg orally four times per day for 14 days)

Severe disease

  • Hospitalization
  • Oral or nasogastric vancomycin (500 mg four times per day) with or without intravenous metronidazole (500 mg three times per day)
    OR
Oral fidaxomicin (200 mg twice a day for 10 days) if the risk of recurrence is high

Complicated disease

First recurrence

  • Oral vancomycin (125 mg four times per day for 14 days)
    OR
Oral fidaxomicin (200 mg twice a day for 10 days)

Second or further recurrence

Dos and Don'ts

Dos

Don'ts

  • Do NOT test for C. difficile in a patient without diarrhea.
  • Do NOT repeat test if the results are negative.
  • Do NOT perform test of microbiological cure.
  • Do NOT treat asymptomatic carriage.
  • Do NOT administer antiperistaltic agents to patients with suspected or confirmed C. difficile infection.

Guidelines

Infectious Disease Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

  • Strategies to Prevent Clostridium difficile Infections in Acute Care Hospitals (2014)[11]
  • Clinical Practice Guidelines for Clostridium difficile Infection in Adults (2010)[12]

American College of Gastroenterology (ACG)

  • Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections (2013)[13]

Association for Professionals in Infection Control and Epidemiology (APIC)

  • Preventing Clostridium difficile infections (2011)[14]

Eastern Association for the Surgery of Trauma (EAST)

  • Timing and type of surgical treatment of Clostridium difficile-associated disease (2014)[15]

American Society of Colon and Rectal Surgeons (ASCRS)

  • Practice Parameters for the Management of Clostridium difficile Infection (2015)[16]

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)

  • Update of the Treatment Guidance Document for Clostridium difficile Infection (2014)[17]

American Academy of Pediatrics (AAP)

  • Policy Statement: Clostridium difficile Infection in Infants and Children (2013)[18]

References

  1. Cohen, Stuart H.; Gerding, Dale N.; Johnson, Stuart; Kelly, Ciaran P.; Loo, Vivian G.; McDonald, L. Clifford; Pepin, Jacques; Wilcox, Mark H.; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America (2010-05). "Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)". Infection Control and Hospital Epidemiology. 31 (5): 431–455. doi:10.1086/651706. ISSN 1559-6834. PMID 20307191. Check date values in: |date= (help)
  2. Debast, S. B.; Bauer, M. P.; Kuijper, E. J.; European Society of Clinical Microbiology and Infectious Diseases (2014-03). "European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection". Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 20 Suppl 2: 1–26. doi:10.1111/1469-0691.12418. ISSN 1469-0691. PMID 24118601. Check date values in: |date= (help)
  3. Debast, S. B.; Bauer, M. P.; Kuijper, E. J.; European Society of Clinical Microbiology and Infectious Diseases (2014-03). "European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection". Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 20 Suppl 2: 1–26. doi:10.1111/1469-0691.12418. ISSN 1469-0691. PMID 24118601. Check date values in: |date= (help)
  4. Cohen, Stuart H.; Gerding, Dale N.; Johnson, Stuart; Kelly, Ciaran P.; Loo, Vivian G.; McDonald, L. Clifford; Pepin, Jacques; Wilcox, Mark H.; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America (2010-05). "Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)". Infection Control and Hospital Epidemiology. 31 (5): 431–455. doi:10.1086/651706. ISSN 1559-6834. PMID 20307191. Check date values in: |date= (help)
  5. Debast, S. B.; Bauer, M. P.; Kuijper, E. J.; European Society of Clinical Microbiology and Infectious Diseases (2014-03). "European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection". Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 20 Suppl 2: 1–26. doi:10.1111/1469-0691.12418. ISSN 1469-0691. PMID 24118601. Check date values in: |date= (help)
  6. Debast, S. B.; Bauer, M. P.; Kuijper, E. J.; European Society of Clinical Microbiology and Infectious Diseases (2014-03). "European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection". Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 20 Suppl 2: 1–26. doi:10.1111/1469-0691.12418. ISSN 1469-0691. PMID 24118601. Check date values in: |date= (help)
  7. Surawicz, Christina M.; Brandt, Lawrence J.; Binion, David G.; Ananthakrishnan, Ashwin N.; Curry, Scott R.; Gilligan, Peter H.; McFarland, Lynne V.; Mellow, Mark; Zuckerbraun, Brian S. (2013-04). "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections". The American Journal of Gastroenterology. 108 (4): 478–498, quiz 499. doi:10.1038/ajg.2013.4. ISSN 1572-0241. PMID 23439232. Check date values in: |date= (help)
  8. Khanna, Sahil; Pardi, Darrell S. (2012-11). "Clostridium difficile infection: new insights into management". Mayo Clinic Proceedings. 87 (11): 1106–1117. doi:10.1016/j.mayocp.2012.07.016. ISSN 1942-5546. PMC 3541870. PMID 23127735. Check date values in: |date= (help)
  9. Leffler, Daniel A.; Lamont, J. Thomas (2015-04-16). "Clostridium difficile infection". The New England Journal of Medicine. 372 (16): 1539–1548. doi:10.1056/NEJMra1403772. ISSN 1533-4406. PMID 25875259.
  10. Leffler, Daniel A.; Lamont, J. Thomas (2015-04-16). "Clostridium difficile infection". The New England Journal of Medicine. 372 (16): 1539–1548. doi:10.1056/NEJMra1403772. ISSN 1533-4406. PMID 25875259.
  11. Dubberke, Erik R.; Carling, Philip; Carrico, Ruth; Donskey, Curtis J.; Loo, Vivian G.; McDonald, L. Clifford; Maragakis, Lisa L.; Sandora, Thomas J.; Weber, David J.; Yokoe, Deborah S.; Gerding, Dale N. (2014-09). "Strategies to prevent Clostridium difficile infections in acute care hospitals: 2014 update". Infection Control and Hospital Epidemiology. 35 Suppl 2: –48-65. ISSN 1559-6834. PMID 25376069. Check date values in: |date= (help)
  12. Cohen, Stuart H.; Gerding, Dale N.; Johnson, Stuart; Kelly, Ciaran P.; Loo, Vivian G.; McDonald, L. Clifford; Pepin, Jacques; Wilcox, Mark H.; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America (2010-05). "Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)". Infection Control and Hospital Epidemiology. 31 (5): 431–455. doi:10.1086/651706. ISSN 1559-6834. PMID 20307191. Check date values in: |date= (help)
  13. Surawicz, Christina M.; Brandt, Lawrence J.; Binion, David G.; Ananthakrishnan, Ashwin N.; Curry, Scott R.; Gilligan, Peter H.; McFarland, Lynne V.; Mellow, Mark; Zuckerbraun, Brian S. (2013-04). "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections". The American Journal of Gastroenterology. 108 (4): 478–498, quiz 499. doi:10.1038/ajg.2013.4. ISSN 1572-0241. PMID 23439232. Check date values in: |date= (help)
  14. Rebmann, Terri; Carrico, Ruth M.; Association for Professionals in Infection Control and Epidemiology, null (2011-04). "Preventing Clostridium difficile infections: an executive summary of the Association for Professionals in Infection Control and Epidemiology's elimination guide". American Journal of Infection Control. 39 (3): 239–242. doi:10.1016/j.ajic.2010.10.011. ISSN 1527-3296. PMID 21371783. Check date values in: |date= (help)
  15. Ferrada, Paula; Velopulos, Catherine G.; Sultan, Shahnaz; Haut, Elliott R.; Johnson, Emily; Praba-Egge, Anita; Enniss, Toby; Dorion, Heath; Martin, Niels D.; Bosarge, Patrick; Rushing, Amy; Duane, Therese M. (2014-06). "Timing and type of surgical treatment of Clostridium difficile-associated disease: a practice management guideline from the Eastern Association for the Surgery of Trauma". The Journal of Trauma and Acute Care Surgery. 76 (6): 1484–1493. doi:10.1097/TA.0000000000000232. ISSN 2163-0763. PMID 24854320. Check date values in: |date= (help)
  16. Steele, Scott R.; McCormick, James; Melton, Genevieve B.; Paquette, Ian; Rivadeneira, David E.; Stewart, David; Buie, W. Donald; Rafferty, Janice (2015-01). "Practice parameters for the management of Clostridium difficile infection". Diseases of the Colon and Rectum. 58 (1): 10–24. doi:10.1097/DCR.0000000000000289. ISSN 1530-0358. PMID 25489690. Check date values in: |date= (help)
  17. Debast, S. B.; Bauer, M. P.; Kuijper, E. J.; European Society of Clinical Microbiology and Infectious Diseases (2014-03). "European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection". Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 20 Suppl 2: 1–26. doi:10.1111/1469-0691.12418. ISSN 1469-0691. PMID 24118601. Check date values in: |date= (help)
  18. Schutze, Gordon E.; Willoughby, Rodney E.; Committee on Infectious Diseases; American Academy of Pediatrics (2013-01). "Clostridium difficile infection in infants and children". Pediatrics. 131 (1): 196–200. doi:10.1542/peds.2012-2992. ISSN 1098-4275. PMID 23277317. Check date values in: |date= (help)