One of the more common healthcare-associated infections, Clostridioides difficile infection (CDI), is a major public health threat. The CDC reports there are more than 223,000 cases of CDI in hospitalized patients and 12,800 deaths associated with the infection per year.1

Generally, cases of CDI occur while patients are taking antibiotics or shortly after such treatment has concluded. It is a particularly stubborn infection that often recurs. For instance, the CDC reports one in six people who contract CDI will do so again two to eight weeks following successful treatment for the earlier infection.2

However, the good news is evidence suggests newer treatments for CDI offer superior results, both in terms of treating initial infections and preventing recurrent cases. This evidence is detailed in revised guidelines for managing CDI.3

Stuart Johnson, MD, a professor of medicine at Loyola University Medical Center in Maywood, IL, served as the chair of the guidelines committee. He explains the advice represents a focused update to the last iteration of the guidelines released in early 2018. “The scope of the update includes new data for fidaxomicin and bezlotoxumab,” he notes.

Johnson adds the recommendations are restricted to the care of adults, but he says that the latest agents offer important advantages over older agents, such as vancomycin. “Unfortunately, implementation [for the newer agents] has been challenging because of costs and logistics, particularly the logistics for bezlotoxumab infusions,” he laments.

First, regarding the benefits, Johnson explains both fidaxomicin and vancomycin are administered orally and demonstrate little systemic absorption, making them both fairly safe. However, while both agents will deliver a predictable resolution of symptoms from CDI, fidaxomicin has the edge when it comes to delivering a sustained response.

“Particularly in that two- to four-week period after treatment where the risk of recurrence of CDI is significant — that is where we see the difference with fidaxomicin,” Johnson notes. “Fidaxomicin provides a better sustained response [against] recurrences than vancomycin.”

The guidelines also suggest fidaxomicin is preferred over vancomycin for a first recurrence of CDI as well two or more recurrences; however, the certainty of the evidence behind this observation was lower, according to Johnson.

The other listed in the guidelines, bezlotoxumab, is what Johnson describes as an adjunctive treatment to be used in addition to standard antibiotic therapy. “Studies show that an infusion [of bezlotoxumab] had no effect on an initial course of [CDI], but it decreased significantly the chance of recurrence [of CDI] after a standard of care antibiotic is discontinued,” he explains. “We looked at the data. Although there is evidence that some people with an initial episode of CDI, particularly those who are at high risk for a recurrence, could benefit from the infusion ... we restricted our recommendations for bezlotoxumab to patients who have already had recurrent CDI.”

In short, the evidence from two randomized clinical trials the guideline authors reviewed showed the effect of bezlotoxumab was seen only in terms of its effect on recurrence of CDI. The evidence showed the addition of bezlotoxumab to standard of care antibiotics significantly reduced recurrence at 12 weeks, Johnson notes. Further, a subanalysis of hospitalized patients showed the infusion shortened hospital admission at 30 days.

To define which patients would benefit most from bezlotoxumab infusions, the guideline authors delineated the following risk factors: patients with an episode of CDI in the previous six months, patients older than age 65 years, patients who are immunocompromised, and patients with severe CDI upon presentation.

Johnson explains the evidence showed patients with no risk factors did not benefit from bezlotoxumab infusions. However, for patients who are suitable candidates for the infusions, the guideline authors acknowledged there are logistical barriers, particularly for patients who present to the ED.

“Most hospitals do not do the infusions for patients in the ED. This is almost always arranged through a referral to an infusion center,” Johnson says. “However, you’ve got the time to do this if you are going to consider [prescribing] bezlotoxumab. [The infusion] can be given any time during the course of the antibiotic prescribed to treat CDI.”

The guideline authors considered the logistical barriers when making their recommendations. “If you look at real-world experience with bezlotoxumab ... it is almost always given in an infusion center in an outpatient setting. For practical reasons, we restricted our recommendations for bezlotoxumab to patients who had already had a CDI episode in the past,” Johnson explains.

Although the recommendations for a third treatment option, fecal transplant, have not changed with the new guidance, Johnson notes it is recommended as an option for patients who have experienced at least two recurrences of CDI and have failed to achieve a sustained response following antibiotic treatment. Still, he cautions the FDA has not approved fecal transplant, so the cost of such treatment would need to come out of the patient’s pocket.

Further, Johnson stresses any donors and donor specimens need to be screened thoroughly for transmissible infectious agents such as E. coli species as well as SARS-CoV-2.

While CDI generally is acquired in an institutional setting, the infection can be contracted in the community, leading to patients with pre-existing CDI infections who present to the ED. However, most cases occur in patients who are taking antibiotics or have recently completed an antibiotics course. Johnson says the telltale symptom for an emergency provider to consider is new-onset diarrhea. “It is usually not a grossly bloody diarrhea but it can be very voluminous, with multiple watery stools,” he says. “Abdominal cramps are frequent; not uncommonly, there is a low-grade fever.”

In C. difficile, the spores are widely disseminated in the environment, but most people are not susceptible. “Presumably, healthcare personnel are exposed quite frequently, but they don’t develop a productive infection because they are not susceptible, meaning that their colonic microbiome is diverse and able to exclude a productive infection due to Clostridioides difficile,” Johnson observes. “On the other hand, if a person has been on antibiotics, and presumably has other risk factors, and they are exposed to spores of Clostridioides difficile, they can quite easily develop a productive infection.”

The incidence of CDI is predominantly an antibiotic-associated problem. “The most effective efforts to prevent this have dealt with antibiotic stewardship intervention,” Johnson says. 


  1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019. Page last reviewed March 2, 2021.
  2. Centers for Disease Control and Prevention. What is C. diff? Page last reviewed July 20, 2021.
  3. 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 2021 Jun 24;ciab549. doi: 10.1093/cid/ciab549. [Online ahead of print].