Clostridioides difficile, also known as Clostridium difficile, C difficile, or C diff, is a gram-positive spore-producing bacterium that causes diarrhea, defined as 3 or more unformed stools passed within the past 24 consecutive hours. As of 2017, C difficile was the most common cause of healthcare-associated diarrhea and an important cause of community-associated illness, with almost 500,000 cases in the United States.^{1, 2} The C difficile spores spread via the fecal-oral route, hand-to-hand contact, and airborne environmental dispersal, especially in hospitals.³

The bacterium disturbs the normal bacterial flora by colonizing the colon and releasing toxins that cause inflammation and damage to the mucosa.⁴ Advanced age, underlying chronic medical conditions, immunocompromised states, hospitalization, prior infections with C difficile, and treatment with antibiotics are the most common risk factors to developing C difficile infection (CDI). There has been some evidence to suggest that treatment with acid-suppressing medications may also put patients at risk; however, there are often concurrent factors which may be increasing the diarrhea in those patients. Therefore, this needs further study.¹

The recurrence rate of CDI has been shown to be 15% to 35% in patients who have had one previous episode and 33% to 65% in patients who have had two or more previous episodes.⁵

Infection with C difficile is diagnosed by having the symptoms, of which the most common is diarrhea, but which also can include fever, abdominal tenderness or pain, anorexia, and nausea, and a positive result by one of the diagnostic testing modalities. The optimal testing modality to use is controversial, as there is no one test that is highly specific, highly sensitive, and also rapid and cost-effective.⁶ Therefore, the test chosen is partially dependent on where and in what patient population a test is being performed. Most commonly, this is done by testing for the C difficile toxins A and B via enzyme immunoassay (EIA). Other diagnostic methods used are either measuring glutamate dehydrogenase (GDH), the enzyme produced by C difficile, by EIA, or nucleic acid amplification test (NAAT), both of which should be coupled with a test detecting toxin.

Culture is the most sensitive and specific test, but takes longer and, therefore, is not practical when used alone.⁴ A polymerase chain reaction test that detects C difficile as part of a panel of enteric pathogens is another option for testing. As some tests will pick up colonization with C difficile, rather than infection, testing should only be performed on unformed stool obtained from a patient with diarrhea. The exception to this is stool from a patient with suspected CDI who has an ileus or toxic megacolon, as they may be passing stool infrequently.⁶

If a patient is more seriously ill, they may need to undergo a colonoscopy and biopsy, revealing gross or histopathologic evidence of pseudomembranous colitis.¹ Assessing the degree of illness in these patients is also generally done with complete blood count, electrolyte levels, albumin (for hypoalbuminemia), and lactate (elevated with severe disease).⁴

Once diagnosed, proper treatment is key to recovery. Discontinuing the antibiotics that may be leading to CDI is the first step. Then, starting empiric therapy for C difficile if there will be a delay in diagnosis or if a patient is extremely ill is recommended.¹ Metronidazole had been the first-line therapy in the past and is still recommended in certain situations, but vancomycin or fidaxomicin are the current recommended antibiotic therapies (Table 1). Studies both in 2014 and 2016 have shown these medications to be superior to metronidazole for treatment of CDI. If they are not available, it is the first episode of CDI, and the illness is not severe, metronidazole can be used.

For fulminant CDI, which would include disease with hypotension, shock, ileus, or megacolon, treatment should be with oral and rectal vancomycin plus intravenous metronidazole if there is an ileus.¹ Recurrent CDI is also treated with oral vancomycin, but in pulsed tapering dosing rather than the usual 10-day course, or alternatively, with oral fidaxomicin. If the first episode had been treated with metronidazole, the recurrent episode should be treated with the standard 10-day course of oral vancomycin. If there are more recurrences, the treatment is either a tapered and pulsed dosing regimen with oral vancomycin, or oral vancomycin followed by rifaximin, or fidaxomicin.¹

Table 1. Antibiotic treatment for CDI in adults¹

* If 1^st-line and alternative antibiotics are not available, it is the first episode of CDI, and the illness is not severe.

** If the first episode had been treated with metronidazole

Fecal microbiota transplantation (FMT), which transfers fecal microbiota from a healthy individual to a patient with a CDI to restore a healthy intestinal bacterial environment, is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments.¹ The donated stool is usually obtained from a donor stool bank. FMT is performed via several methods, nasogastric tube (NGT), colonoscopy, frozen capsules, or enemas.⁷

The recommended treatment for pediatric patients with C difficile is largely based on adult studies in addition to anecdotal experience with good results, as few randomized controlled studies have included children. Either oral vancomycin or metronidazole are recommended for treatment of an initial uncomplicated episode or a first recurrence of C difficile in a pediatric patient. Oral vancomycin is recommended for treatment of an initial severe episode and for second or more recurrences.¹ Fidaxomicin was recently approved by the Food and Drug Administration (FDA) for use in patients from age 6 months and up and is now available as a suspension; until then it did not have FDA approval for use under the age of 12.^8–10 However, it has not been formally recommended by infectious disease specialists at this time. There is limited evidence and experience with using FMT in children for recurrence and failed antibiotic therapy; it has been successful in some,⁷ but there are risks associated with FMT, such as the procedure-related risks of using an NGT or colonoscopy, the potential for transmitting resistant organisms and blood-borne pathogens, and possible development of metabolic or immune-based disorders.¹ The most recent, multicenter retrospective study revealed effective and safe use in children and young adults. There are ongoing studies at several institutions to further investigate the risks and benefits.⁷ At one children’s hospital, there is an ongoing successful FMT program, where the procedure is largely performed via NGT as an outpatient procedure, with an 83% success rate.¹¹

A newer treatment recommended is bezlotoxumab, which is a monoclonal antibody [Mab] directed against toxin B produced by C difficile. This antibody has been approved as adjunctive therapy for patients who are receiving antibiotic treatment for CDI and who are at high risk for recurrence.^1,12 There have also been successful Phase I and Phase II trials with actoxumab (MAb against C difficile toxin A) plus bezlotoxumab.¹³

Just as important as treatment, prevention of infection is key to decreasing the morbidity and mortality associated with C difficile. Antibiotic stewardship, limiting use of broad-spectrum antibiotics in particular, especially fluoroquinolones, clindamycin, and cephalosporins, is associated with decreased C difficile infection, based on a systematic review that included one randomized controlled trial and five interrupted time series studies.^1,14 These antibiotics disrupt the normal bacteria in the intestines, which allows overgrowth of C difficile. Other preventative strategies which have been investigated, but only have low evidence of success, are FMT and probiotics.¹⁵ Another crucial aspect to prevention is preventing the transmission to others. Strict handwashing campaigns have been found to be moderately effective. In a hospital, it is important to keep a patient with CDI isolated, in a private room, if possible, or if not possible, cohorted with others with the same infection. Any incontinent patients, especially, should have their own toilet. Contact precautions (gloves and gowns) for healthcare workers should be used when caring for or entering the room of a patient with CDI. This also includes proper hand hygiene. These precautions should begin once CDI is suspected and continued if testing is positive and until diarrhea has been resolved for 48 hours.¹

C difficile is an important pathogen in both community and hospital acquired diarrheal illness. New testing modalities and treatments have been developed; there is ongoing research into how accurate these tests are and how successful these treatments are in modulating and eradicating this virulent bacterium.

References

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2. C. diff guidelines and prevention resources. Centers for Disease Control and Prevention. Updated March 27, 2020. Accessed April 27, 2020. https://www.cdc.gov/cdiff/clinicians/resources.html
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9. FDA approves Merck’s Dificid (fidaxomicin) to treat Clostridioides difficile in children aged six months and older. Merck. January 27, 2020. Accessed April 30, 2020. https://www.mrknewsroom.com/news-release/prescription-medicine-news/fda-approves-mercks-dificid-fidaxomicin-treat-clostridioides
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