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Clostridioides (formerly Clostridium) difficile–Induced Diarrhea

(Pseudomembranous Colitis)

By

Larry M. Bush

, MD, FACP, Charles E. Schmidt College of Medicine, Florida Atlantic University;


Maria T. Vazquez-Pertejo

, MD, FACP, Wellington Regional Medical Center

Reviewed/Revised Jun 2023
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Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody, rarely progressing to toxic megacolon, colonic perforation, sepsis, and acute abdomen. Diagnosis is by identifying C. difficile toxin in stool. First-line treatment is with oral vancomycin or fidaxomicin.

C. difficile is the most common cause of antibiotic-associated colitis and is typically hospital-acquired, but community-acquired cases are increasing. C. difficile–induced diarrhea.

Risk factors for C. difficile–induced diarrhea include

  • Extremes of age

  • Prolonged hospital stay

  • Living in a nursing home

  • Severe underlying disease

  • Use of proton pump inhibitors and H2 blockers

C. difficile is carried asymptomatically in 4 to 15% of healthy adults, up to 21% of hospitalized adults, and 15 to 30% of residents in long-term care facilities (1 Reference Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ). It is common in the environment (eg, soil, water, household pets). Disease may follow overgrowth of endogenous C. difficile organisms in the intestine or infection from an external source. Health care workers are frequently the source of transmission.

A more virulent strain, BI/NAP1/027 (binary/North American pulsed-field type 1 [NAP1]/ribotype 027), has become prominent in hospital outbreaks. This strain produces substantially more toxin, causes more severe illness with greater chance of relapse, is more transmissible, and does not respond as well to antibiotic treatment.

Reference

Pathophysiology of Clostridioides difficile–Induced Diarrhea

Antibiotic-induced changes in gastrointestinal flora are the dominant predisposing factors. Although most antibiotics have been implicated, the following pose the highest risk:

  • Cephalosporins (particularly 3rd-generation)

  • Penicillins (particularly ampicillin and amoxicillin)

  • Clindamycin

  • Fluoroquinolones

C. difficile–induced colitis may also follow use of certain antineoplastic medications.

The organism secretes both an enterotoxin and a cytotoxin, typically referred to as toxins A and B. However, not all strains of C. difficile produce toxins, and some people are asymptomatic carriers of toxin-producing strains. The main effect of the toxin is on the colon, which secretes fluid and develops characteristic pseudomembranes—discrete yellow-white plaques that are easily dislodged. Plaques may coalesce in severe cases.

Toxic megacolon, which rarely develops, is somewhat more likely after use of antimotility medications. Limited tissue dissemination occurs very rarely, as do sepsis and acute abdomen. Reactive arthritis rarely has occurred after C. difficile–induced diarrhea.

Symptoms and Signs of Clostridioides difficile–Induced Diarrhea

Symptoms of C. difficile–induced diarrhea typically begin 5 to 10 days after starting antibiotics but may occur on the first day or up to 2 months later. Diarrhea may be mild and semiformed, frequent and watery, or sometimes bloody. Cramping or pain is common, but nausea and vomiting are rare. The abdomen may be slightly tender.

Patients with fulminant colitis, which is characterized by severe acute inflammation of the colon and systemic toxicity, have more pain and appear very ill, with tachycardia and abdominal distention and tenderness. If colonic perforation occurs, peritoneal signs are present.

Diagnosis of Clostridioides difficile–Induced Diarrhea

  • Stool assay for glutamate dehydrogenase (GDH) antigen and C. difficile toxin and polymerase chain reaction (PCR) test for the toxin gene

  • Sometimes sigmoidoscopy

C. difficile–induced diarrhea should be suspected in any patient who develops diarrhea within 2 months of antibiotic use or 72 hours of hospital admission.

Glutamate dehydrogenase (GDH) antigen is produced by all C. difficile strains. Enzyme-linked immunosorbent assay (ELISA) testing for the antigen is sensitive and can be done very quickly. However, a positive test indicates only presence of the organism not whether it is toxigenic (1 Diagnosis reference Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ).

Toxin assays using ELISA also can be done quickly and are very specific for active disease but are not particularly sensitive, so there is a significant number of false-negative results.

A nucleic acid amplification test Nucleic acid amplification Nucleic acid–based methods detect organism-specific DNA or RNA sequences extracted from the microorganism. Sequences may or may not be amplified in vitro. Nucleic acid–based (molecular) identification... read more (NAAT) using PCR to test for the toxin gene is very sensitive for toxigenic strains but cannot tell whether they are actively producing toxin. This test often remains positive after successful treatment, so it can be difficult to interpret in patients with known previous disease.

Because of the possibility of a carrier state, testing is usually done only on symptomatic patients (ie, those with multiple liquid stools). Because of the test characteristics, several or all of these tests are usually done, either sequentially or at once. One strategy is to first do GDH and toxin assays. If these are concordant (ie, both positive or both negative), then disease is considered confirmed or excluded. Discordant test results (ie, one positive, one negative) are resolved based on results of NAAT testing (1 Diagnosis reference Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ).

A single stool sample is usually adequate. If the first sample is negative, repeat samples should not be submitted for a minimum of 7 days unless there is a clinical change and the suspicion is high. Fecal leukocytes are often present but not specific.

Sigmoidoscopy, which can confirm the presence of pseudomembranes, should be done if patients have ileus or if toxin assays are nondiagnostic.

Abdominal x-rays, CT, or both are usually done if fulminant colitis, perforation, or megacolon is suspected.

Diagnosis reference

Treatment of Clostridioides difficile–Induced Diarrhea

  • Oral vancomycin or oral fidaxomicin

Oral vancomycin or oral fidaxomicin is recommended by the American College of Gastroenterology (1 Treatment references Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ) for the treatment of a primary episode of nonsevere C. difficile–induced diarrhea.

Fidaxomicin 200 mg orally every 12 hours for 10 days is recommended by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) as first-line therapy for C. difficile infection (2 Treatment references Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ). Fidaxomicin decreases the risk of recurrence more than vancomycin. Vancomycin 125 mg orally 4 times a day for 10 days is an alternative (2 Treatment references Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ).

Metronidazole is no longer recommended as first-line therapy for C. difficile–induced diarrhea. However, oral metronidazole can be used if vancomycin or fidaxomicin is not available.

Vancomycin 500 mg orally or by nasogastric tube 4 times a day and metronidazole 500 mg IV every 8 hours are recommended by the ISDA/SHEA for fulminant disease without ileus.

If possibly causative antibiotics are being used, they should be stopped as soon as possible, or patients should be switched to an antibiotic regimen less likely to cause C. difficile–induced diarrhea.

Cholestyramine resin, Saccharomyces boulardii yeast, and probiotics have not been proved to be beneficial but are frequently added.

Nitazoxanide appears to be comparable to oral vancomycin but is not commonly used in the United States.

A few patients require total colectomy for cure.

Treatment of recurrences

C. difficile–induced diarrhea recurs in 15 to 20% of patients, typically within a few weeks of stopping treatment. Recurrence often results from reinfection (with the same or different strain), but some cases may involve persistent spores from the initial infection. For patients with recurrent infections, the ISDA guidelines suggest fidaxomicin (standard or extended-pulsed regimen) rather than a standard course of vancomycin. Vancomycin in a tapered and pulsed regimen or as a standard course are alternatives for a first recurrence. For patients with multiple recurrences, vancomycin in a tapered and pulsed regimen, vancomycin followed by rifaximin, and fecal microbiota transplantation are options in addition to fidaxomicin (2 Treatment references Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more ).

Infusion of donor feces (fecal transplant, usually done via colonoscopy) increases the likelihood of resolution in patients who have frequent recurrences; presumably, the mechanism is restoration of normal fecal microbiota. About 200 to 300 mL of donor feces are used; donors are tested for enteric and systemic pathogens. Feces can be infused using a nasal-duodenal tube, colonoscope, or enema; the optimal method has not been determined.

Oral fecal microbiota transplant capsules and a fecal microbiota suspension for rectal administration are commercially available. They can be given a few days after antibiotic treatment of recurrent C. difficile infection to prevent recurrence.

A human monoclonal antibody, bezlotoxumab 10 mg/kg IV given once, binds to and neutralizes C. difficile toxin B; it can be used for prevention of recurrent C. difficile–induced diarrhea along with standard-of-care treatment in patients who have had a recurrence within the last 6 months.

Prevention of spread

Infection control measures are vital to reduce the spread of C. difficile among patients and health care workers.

Treatment references

  • 1. Kelly CR, Fischer M, Allegretti JR, et al: ACG Clinical Guidelines: Prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol 116(6):1124–1147, 2021. doi: 10.14309/ajg.0000000000001278. Clarification and additional information. Am J Gastroenterol 117(2):358, 2022.

  • 2. Johnson S, Lavergne V, Skinner AM, et al: Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis 73(5):e1029–e1044, 2021. doi: 10.1093/cid/ciab549

Key Points

  • Antibiotic therapy can cause intestinal overgrowth of toxin-secreting C. difficile, resulting in a pseudomembranous colitis that can be severe and difficult to cure.

  • Cephalosporins (particularly 3rd-generation), penicillins, clindamycin, and fluoroquinolones pose the highest risk.

  • Diagnose using a stool assay for C. difficile antigen and toxin and sometimes PCR testing for the toxin gene.

  • Treat with oral fidaxomicin or vancomycin.

  • Recurrence is common; re-treat with antibiotics, and consider fecal transplantation or bezlotoxumab for refractory recurrences.

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

Drugs Mentioned In This Article

Drug Name Select Trade
Principen
Amoxil, Dispermox, Moxatag, Moxilin , Sumox, Trimox
Cleocin, Cleocin Ovules, Cleocin Pediatric, Cleocin T, CLIN, Clindacin ETZ, Clindacin-P, Clinda-Derm , Clindagel, ClindaMax, ClindaReach, Clindesse, Clindets, Evoclin, PledgaClin, XACIATO
DIFICID
FIRVANQ, Vancocin, Vancocin Powder, VANCOSOL
Flagyl, Flagyl ER, Flagyl RTU, LIKMEZ, MetroCream, MetroGel, MetroGel Vaginal, MetroLotion, Noritate, NUVESSA, Nydamax, Rosadan, Rozex, Vandazole, Vitazol
Locholest , Locholest Light, Prevalite , Questran, Questran Light
Florastor, Florastor Baby, Florastor Kids, ReZyst Probiotic, ReZyst SB
Alinia
Xifaxan
REBYOTA, VOWST
ZINPLAVA
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NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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