Sections

Clostridioides (Clostridium) Difficile Colitis

Guidelines

2021 ASCRS Guidelines on Management of CDI

Guidelines for the management of Clostridioides difficile infection (CDI) were published in June 2021 by the American Society of Colon and Rectal Surgeons (ASCRS) in Diseases of the Colon and Rectum.^[47]

Evaluation

When Clostridioides difficile infection (CDI) is suspected, perform a disease-specific history emphasizing risk factors, symptoms, comorbidities, and signs of severe or fulminant disease.

Evaluate patients to determine severity of CDI and presence of peritonitis or multisystem organ failure.

Diagnosis of CDI should include two-step laboratory stool testing to increase accuracy.

Routine endoscopic evaluation to diagnose or determine the extent of CDI is not recommended.

Management

Oral vancomycin or fidaxomicin is first-line treatment for an initial CDI.

Metronidazole alone is no longer considered appropriate first-line treatment for CDI.

Surgery

Reserve surgery for C difficile colitis for patients with colonic perforation or severe colitis who do not improve with medical therapy.

Subtotal colectomy with end ileostomy is recommended for severe-complicated or fulminant C difficile colitis.

A diverting loop ileostomy with antegrade colonic lavage may be an alternative to subtotal colectomy for the treatment of severe-complicated or fulminant CDI.

Recurrent and Refractory CDI

A prolonged course of vancomycin, adding bezlotoxumab or using fidaxomicin, is an acceptable therapy for recurrent or refractory CDI in stable patients.

Patients with recurrent or refractory CDI should be considered for fecal bacteriotherapy if conventional measures have failed.

2021 Updated ISDA/SHEA guidelines

The following selected updated recommendations on Clostridium difficile infection (CDI) were released in September 2021 by the Infectious Diseases Society of America (ISDA) and Society for Healthcare Epidemiology of America (SHEA).^[48]

In patients with a first CDI episode, fidaxomicin is recommended instead of a standard course of vancomycin.

In those with recurrent CDI episodes, fidaxomicin (standard or extended-pulsed regimen), rather than a standard course of vancomycin, is recommended.

In patients who experience a recurrent CDI episode within the last 6 months, use bezlotoxumab as a co-intervention in combination with standard-of-care (SOC) antibiotics rather than SOC antibiotics only.

2018 Updated ISDA/SHEA guidelines

The following ISDA/SHEA guidelines were released in February 2018.^{[50, 51]}

Diagnosis (adults)

Patients with unexplained and new-onset ≥3 unformed stools in 24 hours are the preferred target population for testing for CDI.

Use a stool toxin test as part of a multistep algorithm (ie, glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated by nucleic acid amplification test [NAAT]; or NAAT plus toxin) rather than NAAT alone for all specimens when there are no preagreed institutional criteria for patient stool submission.

Use NAAT alone or a multistep algorithm for testing (ie, GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) rather than a toxin test alone when there are preagreed institutional criteria for patient stool submission.

Do not perform repeat testing (within 7 days) during the same episode of diarrhea and do not test stool from asymptomatic patients, except for epidemiologic studies.

Diagnosis (pediatric)

Because of the high prevalence of asymptomatic carriage of toxigenic C difficile in infants, testing for CDI should never be routinely recommended for neonates or infants ≤12 months of age with diarrhea.

C difficile testing should not be routinely performed in children with diarrhea who are 1-2 years of age unless other infectious or noninfectious causes have been excluded.

In children ≥2 years of age, C difficile testing is recommended for patients with prolonged or worsening diarrhea and risk factors (eg, underlying inflammatory bowel disease or immunocompromising conditions) or relevant exposures (eg, contact with the healthcare system or recent antibiotics).

Treatment (adults)

Discontinue therapy with the inciting antibiotic agent(s) as soon as possible, as this may influence the risk of CDI recurrence.

Antibiotic therapy for CDI should be started empirically for situations where a substantial delay in laboratory confirmation is expected, or for fulminant CDI.

Either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI. The dosage is vancomycin 125 mg orally 4 times per day or fidaxomicin 200 mg twice daily for 10 days.

In settings where access to vancomycin or fidaxomicin is limited, metronidazole is suggested for an initial episode of nonsevere CDI only. The suggested dosage is metronidazole 500 mg orally 3 times per day for 10 days. Avoid repeated or prolonged courses due to the risk of cumulative and potentially irreversible neurotoxicity.

For fulminant CDI, vancomycin administered orally is the regimen of choice. If ileus is present, vancomycin can also be administered per rectum. The vancomycin dosage is 500 mg orally 4 times per day and 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema. Intravenously administered metronidazole should be administered together with oral or rectal vancomycin, particularly if ileus is present. The metronidazole dosage is 500 mg intravenously every 8 hours.

If surgical management is necessary for severely ill patients, perform subtotal colectomy with preservation of the rectum. Diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes is an alternative approach that may lead to improved outcomes.

Treat a first recurrence of CDI with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin; OR treat a first recurrence of CDI with a 10-day course of fidaxomicin rather than a standard 10-day course of vancomycin; OR treat a first recurrence of CDI with a standard 10-day course of vancomycin rather than a second course of metronidazole if metronidazole was used for the primary episode.

Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI whose conditions have failed appropriate antibiotic treatments.

Treatment (pediatric)

Either metronidazole or vancomycin is recommended for the treatment of children with an initial episode or first recurrence of nonsevere CDI.

For children with an initial episode of severe CDI or with a second or greater episode of recurrent CDI, oral vancomycin is recommended over metronidazole.

Prevention

In 2018, The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) released strategies on the prevention of Clostridium difficile infection (CDI) in acute care settings (outbreak and endemic).^[75] Select strong recommendations are outlined below.

Diagnostic approach

Use a two-stage test (glutamate dehydrogenase [GDH] or nucleic acid amplification test [NAAT]) for toxin genes, followed by a highly sensitive toxin test or GDH in combination with a toxin test. If the toxin test is negative, clinicians can perform NAAT (if not already part of the first diagnostic step) or toxigenic culture on the basis of clinical assessment or local prevention requirements.

Surveillance

In an outbreak setting, perform CDI surveillance with timely feedback of infection rates on the hospital and the ward level.

In an endemic setting, surveilla CDI surveillance with timely feedback of infection rates.

Screening

In outbreak and endemic settings, ESCMID does not recommend healthcare workers be screened for C difficile gut colonization as a means of routine control measure for CDI.

Hand hygiene

ESCMID does not have specific recommendations about the most effective techique/product for removing C difficile spores.

Personal protective equipment (PPE)

In the outbreak setting, ESCMID strongly recommends use of PPE (gloves, gowns/disposable aprons) for reducing the transmission of C difficile or the incidence of CDI.

Contact precautions

In outbreak and endemic settings, ESCMID strongly recommends use of contact precautions for reducing both the transmission of C difficile and the incidence of CDI.

Environmental cleaning and disinfection

In the outbreak setting, institute daily environmental and terminal sporicidal disinfection of rooms of patients with CDI to reduce the transmission of CDI.

Antibiotic stewardship

In outbreak and endemic settings, restricting the use of antibiotic agents/classes is effective in lowering the rates of CDI. In addition, shortening the duration of antibiotic therapy is effective in lowering rates of CDI.

Treatment

In 2021, the ESCMID updated their 2014 guidelines for the treatment of CDI, which included antibiotic treatment for all but very mild cases.^[49]Suggested treatment recommendations are outlined below.

In nonsevere CDI, discontinue antibiotic therapy with the inciting antibiotic if possible. Closely monitor the patient for 48 hours.

Standard of care

First-line treatment: For the initial CDI, administer fidaxomicin 200 mg twice daily (BID) for 10 days. For a first recurrence, administer the standard of care plus bezlotoxumab. For two and more recurrences, administer fecal microbiota transplantation (FMT).

Second-line treatment: For the initial CDI, administer vancomycin 125 mg four times daily (QID) for 10 days. For a first recurrence, administer fidaxomicin 200 mg BID for 10 days. For two and more recurrences, administer either FMT or the standard of care plus bezlotoxumab.

High recurrence risk

First-line treatment: For the initial CDI, administer fidaxomicin 200 mg BID for 10 days.

Second-line treatment: For the initial CDI, administer the standard of care plus bezlotoxumab.

When the preferred option is not available

For the initial CDI, administer metronidazole 500 mg three times daily (TID) for 10 days. With the first and more recurrences, consider use of a vancomycin tapering and pulse strategy (125 mg QID for 2 weeks, followed by 125 mg BID for 1 week, then 125 mg daily for 1 week, then 125 mg every 48 hours for 1 week, and finally 125 mg every 72 hours for 1 week).

Severe CDI

For the initial CDI and first and more recurrences, administer vancomycin or fidaomicin. If oral administration is not possible, use local delivery (rectal or nasoduodenal delivery) with or without adjunctive intravenous (IV) metronidazole or IV tigecycline.

Severe-complicated CDI and refractory severe CDI

For the initial CDI and first and more recurrences, administer vancomycin or fidaomicin. Use a multidisciplinary approach and surgical consultation. In a setting of refractory severe CDI, consider administering IV tigecycline and FMT.

The 2014 ESCMID recommendations included the following^{[76, 77]}:

For patients with nonepidemic, nonsevere CDI clearly induced by antibiotic use, with no signs of severe colitis, it may be acceptable to stop antibiotic treatment and observe the clinical response for 48 hours.
Antibiotic treatment is recommended for all except very mild cases actually triggered by antibiotic use; suitable treatments include metronidazole, vancomycin, and fidaxomicin.
For mild/moderate disease, oral metronidazole (500 mg 3 times daily for 10 days) is recommended as the initial treatment.
In patients for whom oral treatment is inappropriate, fidaxomicin may be used; specific indications include first-line treatment in patients with recurrence or at risk for recurrence.
For patients with severe CDI, suitable antibiotic regimens include vancomycin (125 mg 4 times daily for 10 days; may be increased to 500 mg 4 times daily) or fidaxomicin (200 mg twice daily for 10 days).
Use of fidaxomicin is not supported in life-threatening CDI.
Use of oral metronidazole in severe or life-threatening CDI is discouraged.
Fecal transplantation is recommended for multiple recurrent CDI.
For patients with colonic perforation and/or systemic inflammation and deteriorating clinical condition despite antibiotic treatment, total abdominal colectomy or diverting loop ileostomy combined with colonic lavage is recommended.
Additional management measures include discontinuing unnecessary antimicrobial therapy, adequate replacement of fluids and electrolytes, avoiding antimotility medications, and reviewing the use of proton pump inhibitors.

2019 WSES Guidelines on CDI

The World Society of Emergency Surgery (WSES) released guidelines on diagnosis and treatment of Clostridioides (Clostridium) difficile infection (CDI) in surgical patients in February 2019.^[78]

Diagnosis

Diagnosis of CDI should be based on clinical signs and symptoms in combination with laboratory tests. Stool testing should only be performed on diarrheal stools from at-risk patients with clinically significant diarrhea (≥3 loose stools in 24 hours) with no obvious alternative explanation.

For patients with ileus who may be unable to produce stool specimens, polymerase chain reaction (PCR) testing of perirectal swabs is an acceptable alternative to stool specimen analysis.

Nucleic acid amplification testing (NAAT) for C difficile toxin genes appears to be sensitive and specific and may be used as a standard diagnostic test for CDI. NAAT may be performed as a single-step algorithm or included in a two-step algorithm starting with toxin enzyme immunoassay (EIA).

Glutamate dehydrogenase (GDH) testing is sensitive but does not differentiate between toxigenic and nontoxigenic strains. It may be used in association with toxin A/B EIA testing. Algorithms including screening with EIA for GDH followed by toxin assay may be suggested.

EIA for toxin A/B is fast, inexpensive, and highly specific but is relatively insensitive and is not recommended alone.

C difficile culture is relatively slow but sensitive and is rarely performed as a routine diagnostic test. It is recommended for subsequent epidemiologic typing and characterization of strains.

Repeat testing after a first negative sample during the same diarrheal episode may be useful only in selected cases with (a) ongoing clinical suspicion during an epidemic situation or (b) high clinical suspicion during endemic situations.

Computed tomography (CT) is suggested for patients with clinical manifestations of severe-to-complicated C difficile colitis; however, it is not sensitive enough for screening.

Ultrasonography (US) may be useful in critically ill patients suspected of having pseudomembranous colitis who cannot be transported to the CT suite.

Flexible sigmoidoscopy may be helpful in diagnosing C difficile colitis when there is a high level of clinical suspicion for CDI.

Antibiotic therapy

Unnecessary antibiotics should be discontinued if CDI is suspected. Unnecessary proton pump inhibitors (PPIs) should be discontinued in patients at high risk for CDI.

Empirical antibiotic therapy should be avoided unless CDI is strongly suspected. In such cases, empirical therapy for CDI should be considered while test results are awaited.

Oral metronidazole should be limited to treatment of an initial episode of mild-to-moderate CDI. Oral vancomycin is recommended for treatment of mild-to-moderate disease unresponsive to metronidazole. Repeated or prolonged courses of metronidazole should be avoided. Oral vancomycin and fidaxomicin are both recommended for treatment of severe CDI.

When oral antibiotics cannot reach the colon, vancomycin may be administered as a retention enema via a large rectal tube or catheter.

Fidaxomicin may be used to treat CDI, especially in patients at higher risk for recurrence (eg, elderly patients or those receiving concomitant antibiotics).

Surgical management

Patients with severe CDI who progress to systemic toxicity should undergo early surgical consultation and should be evaluated for potential surgical intervention.

For patients with fulminant colitis, total colectomy should be considered. However, diverting loop ileostomy with colonic lavage is a useful alternative.

Fulminant colitis should be treated with high-dose vancomycin (500 mg q6hr), orally or via enema or both, in combination with intravenous (IV) metronidazole (500 mg q8hr).

Supportive care

Early detection of shock and aggressive management of organ dysfunction are essential for improved outcomes in fulminant colitis. Supportive measures (eg, IV fluid resuscitation, albumin supplementation, and electrolyte replacement) should be provided to all patients with severe CDI.

Recurrent CDI

The first recurrence of CDI may be treated with vancomycin (particularly if metronidazole was used for the initial episode) or fidaxomicin. Antibiotic options for further recurrences include oral vancomycin in a tapered and pulsed regimen.

Probiotics

Limited direct evidence supports the use of probiotics in managing a first episode of CDI as an adjunct to antibiotics for immunocompetent patients.

Prophylactic probiotics may be considered for inpatients receiving antibiotics during a high-risk period before the disease develops. Probiotics should be not used in immunocompromised patients.

Probiotics for prevention of recurrent CDI may be an effective adjunct to standard antibiotic treatment (vancomycin) in patients with at least one prior episode of CDI.

Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) may be an effective option for patients with multiple recurrences of CDI in whom appropriate antibiotic treatments have failed.

Monoclonal antibodies

Coadjuvant monoclonal antibody (bezlotoxumab) therapy may prevent CDI recurrences, particularly in patients who have CDI due to the 027 epidemic strain, are immunocompromised, or have severe CDI.

Intravenous immunoglobulin

IV immunoglobulin (IVIG) should be used only as adjunctive therapy in patients with multiple recurrences or fulminant CDI.

Enteral nutrition

Tube feeding patients should be clinically assessed due to their risk for developing CDI.

Antimotility agents

The use of antiperistaltic agents to treat CDI is discouraged. If such agents are used to control persistent symptoms, they must always be accompanied by medical therapy.

2018 ESCMID Guidance for Prevention of CDI in Acute Healthcare Settings

^[75]

2018 BSG and HIS Guidelines on FMT

In September 2018, the British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) released guidelines on best practices of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection (CDI) and for potential non-CDI indications in adults.^[79]

FMT should be offered to patients with CDI who have had at least 2 recurrences and to patients who have had one recurrence and also have risk factors for additional recurrences.

Consider FMT in cases of refractory CDI.

Do not administer FMT as the initial treatment for CDI.

Recommend that FMT be considered for recurrent CDI only after recurrence following resolution of an episode of CDI treated with appropriate antimicrobials for at least 10 days.

Recommend considering extended/pulsed vancomycin and/or fidaxomicin before FMT is considered for recurrent CDI.

In cases of severe or complicated CDI, before offering FMT, recommend considering treatment with medications such as fidaxomicin and bezlotoxumab, which are associated with reduced risk of recurrence.

Recommend that FMT be offered after initial failure of FMT.

Clinicians should follow-up FMT recipients for at least 8 weeks in total.

Recommend that patients be warned about short-term adverse effects of FMT, particularly possible self-limiting GI symptoms, and be advised that serious adverse effects are rare.

Recommend that, after enteral tube administration, the tube be removed and oral water given following 30 minutes after tube administration.

Recommend that FMT be avoided in patients who have anaphylactic food allergy.

Suggest that FMT be offered with caution to patients who have CDI and decompensated chronic liver disease.

Recommend that FMT be offered with caution to immunosuppressed patients, in whom FMT appears to be efficacious without significant additional adverse effects.

Recommend that patients who are immunosuppressed and at risk of severe infection if exposed to Epstein–Barr virus (EBV) or cytomegalovirus (CMV) receive FMT only from donors who are negative for Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

Suggest that people be considered as potential FMT donors only if they are 18 to 60 years of age and have a body mass index of 18 to 30 kg/m².

Medication

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Media Gallery

Clostridioides (Clostridium) Difficile Colitis. Endoscopic visualization of pseudomembranous colitis, a characteristic manifestation of full-blown <i>C difficile</i> colitis. Classic pseudomembranes are visible as raised, yellow plaques ranging from 2 to 10 mm in diameter and scattered over the colorectal mucosa. Courtesy of Gregory Ginsberg, MD, University of Pennsylvania.
Clostridioides (Clostridium) Difficile Colitis. Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M Osgard, MD.
Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis revealing the characteristic yellowish plaques.
Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis, again demonstrating the characteristic yellowish plaques.
Clostridioides (Clostridium) Difficile Colitis. Frontal abdominal radiograph in a patient with proven pseudomembranous colitis. Note the nodular haustral thickening, most pronounced in the transverse colon.
Clostridioides (Clostridium) Difficile Colitis. Barium enema demonstrating the typical serrated appearance of the barium column (resulting from trapped barium between the edematous mucosal folds and the plaquelike membranes of pseudomembranous colitis).
Clostridioides (Clostridium) Difficile Colitis. Axial computed tomography scan of pseudomembranous colitis.
Clostridioides (Clostridium) Difficile Colitis. Computed tomography scan depicting pseudomembranous colitis.
Clostridioides (Clostridium) Difficile Colitis. Ultrasonographic image of pseudomembranous colitis.

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Author

Faten N Aberra, MD, MSCE Assistant Professor of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine

Faten N Aberra, MD, MSCE is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, Crohn's and Colitis Foundation of America, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Jennifer A Curry, MD, MPH Attending Physician, Infectious Disease Clinic, Naval Medical Center Portsmouth; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences

Jennifer A Curry, MD, MPH is a member of the following medical societies: American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

Acknowledgments

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US government.

LCDR Jennifer Curry is a military service member. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties.

Additional Contributors

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America