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New C. difficile guidelines include testing, therapy changes

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February 15, 2018

Cliff McDonald
L. Clifford McDonald

Newly released practice guidelines for Clostridium difficile infection, or CDI, in both adults and children include changes in diagnostics and antibiotic therapy.

The guidelines, published in Clinical Infectious Diseases by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), also call for fecal microbiota transplantation (FMT) to fight the infection in certain cases.

“We can better control this epidemic by learning how to use new treatments and diagnostics,” L. Clifford McDonald, MD, co-chair of the guidelines panel and associate director for science at the CDC’s Division of Healthcare Quality Promotion, said in a news release. “The role of the infectious disease specialist is critical, not only in providing expert diagnosis and treatment of C. difficile infections, but also in helping set institutional policies that will lead to their prevention, including reducing the inappropriate use of antibiotics through good stewardship.”

Each year in the United States, CDI affects about 500,000 people and kills 15,000 to 30,000. The rate of CDI incidence in the U.S. reached a high in 2010 and has not decreased since then, like it has in parts of Europe.

Opinions on how best to diagnose CDI vary. However, the new guidelines recommend testing only patients with new-onset and unexplained diarrhea, defined as three or more unformed stools over 24 hours.

In addition, although most hospital labs now use molecular diagnostic testing, it is highly sensitive and can result overdiagnosis. Therefore, when an institution has no predetermined criteria limiting testing to those with significant unexplained diarrhea, the guidelines recommend a C. difficile common antigen test and stool toxin test as parts of a diagnostic process.

The guideline authors also addressed the need to avoid unnecessary antibiotic use because not everyone who has C. difficile requires treatment.

“We often find people get better on their own if they stop taking the offending antibiotic,” McDonald said.

Almost all antibiotics create a risk for CDI, but those of greater concern include fluoroquinolones, cephalosporins and clindamycin.

For cases in which antibiotics are needed, the guidelines have changed recommendations for first-line drugs. Instead of metronidazole — the previously recommended first-line therapy — the authors now suggest using vancomycin or Dificid (fidaxomicin, Merck). The latter two agents have had higher cure rates in studies, the authors concluded.

The guidelines also recommend FMT for patients with two or more recurrences of CDI and for whom traditional antibiotics have not been effective. The FDA has not approved FMT, the process of transferring bacteria from a healthy person’s stool to a patient with CDI in order to replace “good” bacteria and control the disease. But the agency has issued guidance for its use when standard CDI therapy fails. – by Joe Green

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Disclosures: McDonald reports no relevant financial disclosures. Please see the guidelines for all other authors’ relevant financial disclosures.

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Perspective

There are some important points in the newly published IDSA/SHEA CDI guidelines that stand out from the past recommendations. The first is in diagnostic testing. We have had difficulties with our tests because the more sensitive a test is at detecting the presence of C. difficile, the more likely a false positive result. A small percentage of the general population, approximately 3% to 26% of hospitalized patients and approximately 5% to 7% of elderly patients in long-term care will asymptomatically carry C. difficile. Therefore, there will always be an underlying group who will test positive for C. difficile but not have an active CDI.

The new guidelines really bring home the point that one should not test patients unless they fit the criteria for having diarrhea — at least three liquid bowel movements in a 24-hour period — and diarrhea due to C. difficile is suspected.  Furthermore, if the stool specimen presented to the laboratory is not liquid, it should not even be tested.

Those working in a resource or reference laboratory that takes all submitted specimens (ie, those not fitting the definition of diarrheal feces) and that does not have a close working relationship with the doctors who send the specimens should have in place an algorithm for C. difficile testing of stool specimens. In that way, the likelihood of a false-positive test result will be reduced. The recommended algorithm includes first screening specimens for the presence of C. difficile with a highly sensitive test (either a glutamate dehydrogenase antigen test or a nucleic acid amplification test) and, if the screening test is positive, follow-up with a specific test to determine the presence of C. difficile toxin. This is a change that was recommended in the European (ESCMID) guidelines approximately 4 years ago.

Another big change to the guidelines is the recommendation of first-line agents for CDI antimicrobial therapy. In the past, metronidazole was considered the first-line treatment for CDI.  This recommendation dates back to 1982, when infections with vancomycin-resistant Enterococcus (VRE) were increasing in hospitalized patients.  It was thought that using metronidazole would be safer for the hospital environment instead of pressuring VRE in that environment by using vancomycin.  It was hoped that by using metronidazole the rate of VRE would decrease.

Unfortunately, using metronidazole did not decrease the rates of VRE.  As well, metronidazole has been shown in several studies to be less effective than vancomycin for treating CDI.  In the newly released guidelines, for adults, metronidazole has been dropped as the recommended first-line therapy for C. difficile and only recommended for IV therapy in patients with ileus or toxic megacolon. Because there are two large randomized, placebo-controlled trials that showed improved outcomes with fidaxomicin over vancomycin in the treatment of CDI, both of these agents are now recommended as first-line therapy.  Metronidazole remains a first-line recommendation in children with an initial episode of non-severe CDI, combined with vancomycin in severe/fulminate CDI, and in first recurrence of nonsevere CDI.

The last really big change in the new guidelines is that FMT is addressed. FMT has been recommended for multiply recurrent C. difficile in other published guidelines. There are still no large randomized, double-blind, placebo-controlled studies on the use of FMT in the treatment of recurrent CDI but it has become commonplace for treatment of these difficult-to-manage patients. I believe that adding FMT to the guidelines as an option for treating patients with multiply recurrent CDI despite appropriate antibiotic therapy is something that is reasonable.  I believe that there are enough case studies, along with the small trial published by Van Nood and colleagues in The New England Journal of Medicine, to support the use of FMT. Certainly, controlled studies evaluating the efficacy of FMT compared with antimicrobial therapy are sorely needed, and the long-term effects of the introduction of a new fecal microbiome into individuals needs to be assessed.

References:

Alasmari F, et al. Clin Infect Dis. 2014;doi:10.1093/cid/ciu258.

Kagan S, et al. J Hosp Infect. 2017;doi:10.1016/j.jhin.2017.01.013.

Nissle K, et al. BMC Geriatrics. 2016;doi:10.1186/s12877-016-0358-3.

Van Nood E, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1205037.

Kathleen Mullane, DO, PharmD

University of Chicago Medicine
Section of infectious diseases and global health

Disclosure: Mullane reports receiving grants and/or personal fees from Astellas, Chimerix, ContraFect, Crestovo, Gilead Sciences, GlaxoSmithKline, Leonard Merlin Biopharm Inc., MedImmune, Merck, Nohla, Sage, Shire and Synexis.