Sections

Clostridioides (Clostridium) Difficile Colitis

Treatment

Approach Considerations

The decision to treat C difficile infection (CDI) and the type of therapy administered depend on the severity of infection, as well as the local epidemiology and type of C difficile strains present. Except for perioperative prophylaxis, it is recommended that the use of cephalosporin and clindamycin be restricted for infection prevention.^[5]No treatment is necessary for asymptomatic carriers.

Guidelines recommend administering fixaxomicin for initial and recurrent infections, with oral vancomycin as an alternative.^{[45, 46, 47, 48, 49]}Rifaximin, bezlotoxumab, and fecal microbiota transplantation (FMT) are other treatment options.

In patients with severe or complicated CDI, oral vancomycin is recommended as first-line therapy due to faster symptom resolution and fewer treatment failures than when metronidazole is used.

FMT is recommended for patients with multiple recurrences of CDI whose conditions persist despite appropriate antibiotic treatments.^{[50, 51]}A 2018 systematic review and meta-analysis comprising 7 studies with 543 patients with recurrent CDI that compared FMT to standard-of-care management found FMT to hold promise as a treatment modality in this setting relative to medical therapy alone.^[52]There was no significant difference regarding different forms (fresh vs frozen) and routes (upper vs lower) of FMT administration.

New approaches to the prevention and management of CDI continue to undergo development and investigation.^[53]See the Guidelines section for recent treatment recommendations.

CDC promotes improving inpatient antibiotic prescribing to reduce drug resistance and increase patient safety

In a CDC analysis of data regarding antibiotic prescribing in hospitalized patients, Fridkin and colleagues estimated that a 30% reduction in the use of broad-spectrum antibiotics would result in a 26% reduction in CDIs.^{[54, 55]}In addition, improvement in physician antibiotic prescribing habits from overuse and incorrect use would also help to reduce antibiotic resistance.

The authors recommended the following measures^[55]:

Promptly initiate antibiotics for a presumed infection, but first obtain any recommended cultures.
Document and specify the drug's indication, dose, and expected duration of use in the patient's medical chart.
Reassess the patient within 48 hours based on test results and patient examination; adjust the antibiotic regimen (dose, duration) and/or the agent, or end the antibiotic treatment, as needed.

Surgical intervention

A systematic review and meta-analysis of 12 observational studies with at least moderate quality that comprised 35,057 patients with inflammatory bowel disease (IBD) with CDI and 929,259 patients without CDI found that although CDI did not appear to increase the risk of colectomy in the short term in IBD patients, over the long term, it appeared to increase the colectomy risk in those with IBD overall and in those with ulcerative colitis.^[56]

Patients with fulminant colitis and toxic megacolon may require operative intervention, such as colectomy with preservation of the rectum. These patients’ serum lactate levels and peripheral leukocyte counts may aid in the decision to operate; there is a significant risk for perioperative mortality with elevated serum lactate levels (5 mmol/L) and leukocytosis (50,000 cells/µL).^[5]

Lee and colleagues evaluated clinical factors associated with mortality in emergency colectomies performed for C difficile colitis. They used the ACS-NSQIP database from 2005 to 2010 to study emergently performed open colectomies for a primary diagnosis of C difficile colitis on the International Classification of Diseases, Ninth Revision. They compared the preoperative, intraoperative, and postoperative factors between survivors and nonsurvivors. To study clinical factors that may be associated with 30-day mortality, they performed multivariate stepwise binomial logistic regression analyses. The overall mortality for this cohort was 33% (111/335) with a median time to death of 8 days. Survivors were discharged, on average, on postoperative day 24.^[57]

On multivariate analysis, those aged 80 years or older were associated with a ninefold increase in the odds of mortality. Other factors associated with increased mortality were preoperative shock, preoperative dialysis dependence, chronic obstructive pulmonary disease, and wound class III. In addition, thrombocytopenia, coagulopathy, and renal insufficiency were associated with a higher mortality. This is the largest series of colectomies performed for C difficile colitis in the literature. The investigators’ findings may be useful in selecting appropriate patients for surgical intervention and may help to define a population where surgery may not be beneficial.^[57]

For more information, see the Medscape Drugs & Diseases articles Toxic Megacolon and Pseudomembranous Colitis Surgery.

Consultations

In patients with complicated CDI, a gastroenterologic consultation may be useful for consideration of a colonoscopic evaluation. Surgical consultation is recommended in patients with suspected fulminant colitis, toxic megacolon, or peritonitis.

Pharmacologic Management

Cessation of the causative antibiotic is essential when possible, as this may affect the risk of recurrence of infection with C difficile.^[5]Avoid antidiarrheal agents (eg, diphenoxylate with atropine); they have been reported to increase the duration and severity of symptoms.

See the Guidelines section for recent treatment recommendations.

Mild to moderate infection

Discontinuing antibiotic therapy may be the only treatment necessary for those with mild antibiotic-associated diarrhea without fever, abdominal pain, or leukocytosis. This conservative approach allows for the reconstitution of the normal colonic microflora and markedly reduces the risk of relapse. If ongoing antibiotic therapy is necessary, a treatment can be chosen that is less frequently associated with CDI, such as intravenous aminoglycosides, sulfonamides, macrolides, tetracycline, or vancomycin.

Patients with mild to moderate diarrhea or colitis, as defined by the absence of leukocytosis, acute kidney injury, fever, sepsis, or megacolon, should receive antibiotic therapy with oral metronidazole or oral vancomycin (in those who are intolerant to metronidazole) for 10-14 days. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) indicate that metronidazole (500 mg PO TID for 10-14 days) is the drug of choice in these patients.^[5]

In a retrospective study of 300 patients, a low-dose regimen of oral vancomycin (< 500 mg/day) was as effective as a high-dose regimen (>500 mg/day) for the treatment of CDIs. Clinical improvement rates for the low- and high-dose regimens were 85% and 86%, respectively, at 72 hours and 93% and 96%, respectively, at the end of therapy/hospital discharge. Patients on the low vancomycin dose had lower in-hospital mortality rates (15% versus 23%) but higher C difficile –related hospital readmission rates (12% vs 5%).^[58]

Severe or severe-complicated infection

In patients with suspected severe or complicated CDI, initiate early empirical therapy while the stool tests are pending.^[5]Oral vancomycin (125 mg PO QID for 10-14 days)^[5]is recommended as first-line therapy in these cases due to faster symptom resolution and fewer treatment failures than when metronidazole is used. Vancomycin is not absorbed and acts directly at the infection site. Symptomatic improvement can be expected within 2-3 days.

Patients with inflammatory bowel disease (IBD) represent a unique population in whom treatment with vancomycin is recommended regardless of disease severity, owing to the high rate of recurrence of CDI in this population, as well as the association between CDI and adverse health outcomes, such as surgery and mortality.

In fulminant cases, combined therapy with intravenous metronidazole and vancomycin (PO or PR) is the treatment of choice.^[5]Intravenous vancomycin is ineffective and should not be used for C difficile. The SHEA and IDSA recommend intravenous metronidazole 500 mg every 8 hours with oral vancomycin 500 mg 4 times per day (and/or 500 mg PR q6h in 100 mL normal saline as a retention enema).^[5]

In several clinical trials, 200 mg of oral fidaxomicin administered every 12 hours for 10 days was found to be noninferior to 125 mg of oral vancomycin administered every 6 hours for 10 days for the treatment of C difficile in adults.^[59]There was no difference in cure rates based on C difficile disease severity. Symptomatic improvement is generally expected within 2-3 days.

The FDA approved fidaxomicin for children aged 6 months or older in January 2020 for treatment of C difficile-associated diarrhea (CDAD). Approval was based on the phase 3 SUNSHINE clinical trial that included 148 randomized patients younger than 18 years with confirmed CDI, of whom 142 received either fidaxomicin or vancomycin in a 2:1 ratio.^[60]Clinical response assessed through 2 days following 10 days of treatment was similar between the fidaxomicin and vancomycin groups (77.6% vs 70.5%), respectively). Sustained clinical response through 30 days after the end of treatment was higher for fidaxomicin than for vancomycin (68.4% vs 50.0%).^[60]

In a multicenter retrospective (2013-2014) study of CDI in 72 Spanish patients, fidaxomicin treatment was effective and well tolerated in patients with severe CDI as well as those at high risk of recurrent disease.^[61]The clinical cure rate was 90.3%, with a 16.7% recurrence rate and a 72.2% sustained cure rate. The investigators found that factors that adversely affected the sustained cure rate included the presence of cardiovascular disease, acute renal failure, and systemic antibiotic treatment, as well as the C-reactive protein level measured at the time of the diagnosis.^[61]

Relapse

Relapse is generally common, occurring in up to 20-27% of cases. Relapse typically occurs 3 days to 3 weeks after the treatment is discontinued. Possible reasons for relapse include ongoing risk factors such as antibiotic exposure, failure to eradicate the organism from the colon, and reinfection from the environment.

In October 2016, the FDA approved bezlotoxumab, a human monoclonal antibody that binds to C difficile toxin B and neutralizes its effects.^[62]It is used with standard-of-care antibiotics to reduce the recurrence of CDI in adults who have a high risk of recurrence. Approval was based on the results from the global Monocolonal Antibodies For C Difficile Therapy (MODIFY) I and MODIFY II studies, which showed a single dose of bezlotoxumab (in conjunction with antibiotics) is superior to placebo in prevention of CDI recurrence through 12 weeks (P= 0.0003 for both trials).^{[62, 63]}High risk in these studies was defined as age 65 years and older, recent CDI (within 6 months), prior recurrent CDI, compromised immunity, severe CDI (Zar score >1), or infection with a hypervirulent, binary toxin–positive strain.

In 2023, bezlotoxumab gained approval to reduce recurrence of CDI in children as young as 1 year.

In general, management of the first recurrence of CDI is the same as that for the initial episode, including stratification according to disease severity.^[5]However, although metronidazole can be used for the first recurrence of CDI (if it is not severe), the drug should not be used for subsequent recurrences or for long-term, chronic therapy (risk of cumulative neurotoxicity). Rather, a second or later recurrences should be managed with vancomycin therapy using a tapered and/or pulse regimen.^[5]

The SHEA and IDSA have made no recommendations for preventing recurrent CDI in patients with an underlying infection requiring continued antimicrobial management.^[5]

Probiotics

In adults and children on antibiotic treatment, the AGA recommends the use of S boulardii; or the 2-strain combination of i>L acidophilus CL1285 and Lactobacillus casei LBC80R; or the 3-strain combination of L acidophi ;L acidophilus, L delbrueckii subsp bulgaricus, B bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of CDI.^[46]

Probiotics are generally not recommended for the treatment of active CDI owing to limited data supporting their benefits and a potential risk for septicemia.^[5]However, a meta-analysis that evaluated 34 studies and 4138 patients supported earlier studies indicating that probiotics can prevent the diarrhea that is associated with antibiotic use.^[64]

Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) is a novel therapy that involves the transfer of stool from a healthy donor to a patient with C difficile infection (CDI) in order to reconstitute the normal colonic microbial flora.^[65]FMT has been reported to repopulate the colonic flora, with efficacy rates of greater than 90% demonstrated even in cases refractory to antibiotic therapy.^[66]Several studies have shown that FMT by colonoscopy or enema is an effective approach for patients with recurrent C difficile colitis, with clinical success rates of up to 95%.^{[67, 68]}

In November 2022, the FDA approved microbiota via rectal administration (Rebyota) for prevention of recurrence of CDI in adults following antibiotic treatment for CD recurrence. Approval was based on the PUNCH CD3 phase 3 clinical trial.^[6]Adults who had at least one CDI recurrence with a positive stool assay for C difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of microbiota or placebo. The primary endpoint was treatment success, defined as the absence of CDI diarrhea within 8 weeks of study treatment. Among 267 patients who received blinded treatment (n = 180, microbiota; n = 87, placebo), successful treatment was 70.6% versus 57.5% with microbiota and placebo, respectively. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the microbiota and the placebo groups.^[6]

A second orally administered microbiota product (Vowst) received FDA approval in April 2023. Results from the ECOSPOR III phase 3 double-blind, randomized, placebo-controlled trial showed a decreased recurrence of C difficile infection in patients treated orally with microbiota compared with placebo (12% vs 40%, respectively; P< 0.001).^[7]

Data regarding fetal microbiota transplantation (FMT) in children with recurrent C difficile colitis are limited and focus on colonoscopic administration of FMT. Kronman et al described 10 consecutive children who received FMT via nasogastric tube for the treatment of recurrent CDI. The children’s median age was 5.4 years, and 30% received simultaneous immunosuppression. Median follow-up was 44 days; 90% of patients resolved their CDI. The authors conclude that FMT via nasogastric tube appears to be safe, well tolerated, and effective in treating recurrent C difficile colitis in pediatric patients.^[69]

Long-term data from a fecal transplantation clinical trial (≥3 mo from the time of fecal transplantation) revealed that of the 77 of 98 patients who could be contacted, 91% did not have a relapse.^[70]Of the patients who did relapse, all but 1 were treated successfully with vancomycin or additional fecal transplantation.^[70]

In the first randomized, controlled trial of fecal transplantation, investigators in the Netherlands found fecal transfer to be 3 times more effective than antibiotics in curing recurrent CDI, leading to the study’s early termination.^{[71, 72]}The study compared 3 treatments: (1) standard vancomycin therapy (500 mg PO QID for 14 days), (2) standard vancomycin therapy plus bowel lavage, and (3) 4 days of vancomycin therapy (500 mg PO QID) followed by bowel lavage and infusion of donor feces through a nasoduodenal tube.^{[71, 72]}

In a retrospective study of 83 immunocompromised patients who underwent fecal transplantation for recurrent (12%), refractory (54%), or severe (34%) CDI, the cure rate after a single transplant was 79% (52 of the 66 patients with at least 12 weeks of follow-up). Seven of the 9 patients who underwent a second transplant were also cured. Mean follow-up was 12 months. Serious adverse events, including 2 deaths, occurred within 12 weeks of the transplant in 10 patients (15%).^[73]

Of the patients treated with fecal transplantation, 13 of 16 (81%) had resolution of C difficile –associated diarrhea after the first infusion, and 2 of the 3 remaining patients experienced resolution after receiving a second infusion with feces from a different donor.^{[71, 72]}By contrast, CDI resolved in only 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage.^{[71, 72]}

However, it should be noted that FMT carries the risk of infection transmission (human immunodeficiency virus [HIV], hepatitis, and retrovirus). Administration of other bacterial preparations is under investigation.

A meta-analysis of intestinal microbiota transplantation (IMT) in which intestinal microorganisms in a suspension of healthy donor stool were infused into the intestines of patients with recurrent CDI and pseudomembranous colitis found that out of 317 patients across 27 case series and reports, 92% were successfully treated with this therapy.^[74]Adverse effects were uncommon. Although further study is required, this review supports use of the IMT as a promising treatment for recurrent CDI.^[74]

See the Guidelines section for recent FMT guidelines recommendations.

Prevention

C difficile is now recognized as a major nosocomial pathogen, and universal precautions against it should be implemented. The following guidelines are recommended when dealing with patients with C difficile colitis^{[5, 29]}:

Use disposable gloves, laboratory coats, and proper washing techniques
Educate the medical and nursing staff, as well as family and visitors, regarding the disease and its epidemiology, and emphasize compliance with hand hygiene practices (such as washing with soap or antimicrobial soap and water)
Hospital transmission is likely associated with the survival of spores on inanimate objects; therefore, close attention to cleanliness and disinfective measures are important (eg, use of contact precautions for 48 hours or longer following resolution of diarrhea, disposable electronic rectal thermometers, chlorine-containing cleansers or other sporicidal agents), particularly during the patient’s diarrheal period
Isolation of patients who are infected is strongly recommended but often impractical at most hospitals; in such situations, a dedicated commode for each patient should be provided

The most important preventive measure is the judicious use of antimicrobial agents. Principal CDI prevention recommendations from the Centers for Disease Control and Prevention (CDC), as well as the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA), include improved antibiotic therapy, early and accurate CDI detection, isolation of symptomatic patients, and reduction of C difficile contamination on environmental surfaces in healthcare settings.^{[5, 29]}

CDI risk is increased 7- to 10-fold during antibiotic use and for 1 month after the drug is discontinued; the risk is approximately 3-fold during the second and third month after discontinuation.^[29]

A systematic review and meta-analyses of observational studies have shown evidence of an increased risk for recurrent CDI among patients who use gastric acid suppressants; the investigators suggest it may be reasonable for clinicians to reassess whether their patients with CDI need to take these agents.^[18]

Guidelines

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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