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IDCM CME Issue 1-5: Updates in C Diff: Rapid Review of the 2018 IDSA Guidelines
Natasha Chida, MD, MSPH
The Current State of C. Diff in the US
Clostridium difficile (C. diff), recently reclassified as Clostridioides difficle, is an anaerobic bacteria that causes diarrhea, pseudomembranous colitis, and in severe cases, toxic megacolon and sepsis. C. diff is one of the most common healthcare-associated infections in the United States—in some locations it’s the most common.1 It is also increasingly being recognized as a community diarrheal pathogen.2 Most episodes of C. difficile infection (CDI) are precipitated by recent (prior 3 months) antibiotic use; however, in some studies 36% of patients with CDI did not report exposure to antibiotics in the 3 months preceding their infection.3 The etiology of CDI in these cases is often due to something that has disrupted the gut microbiome, such as the use of proton pump inhibitors (most relevant in community-acquired CDI), inflammatory bowel disease, the receipt of a solid organ transplant, and other causes.3,4
Since 2000 there has been an exponential rise in CDI cases and reported outbreaks. In 2011 (the most recent national data available) a half a million cases of CDI were reported in the US; of these, 83,000 patients had at least one recurrence, and 29,000 died within 30 days.5 The related annual healthcare costs of CDI are estimated to be $1.2–$5.9 billion.1,3
In 2018 the Infectious Disease Society of America (IDSA) released the first update to the C. diff guidelines since 2010, and a review of key changes follows below.
Who to Test, and How to Test
Studies have found that C. diff colonizes 3-26% of asymptomatic adult inpatients, and 5-7% of elderly patients in long-term care facilities.3 In asymptomatic adults who haven’t been exposed to healthcare facilities, the colonization rate is <2%. A positive C. diff result therefore may imply colonization, rather than infection. Given this, it is important to test patients only when there is a reasonable pretest probability of CDI. The 2018 IDSA guidelines recommend limiting C. diff testing to patients with new-onset, unexplained (e.g. no recent laxatives), and clinically significant (at least 3 unformed stools in a 24-hour period) diarrhea.
The possibility of colonization also affects the guidelines’ recommendations for testing. There are several primary tests available for C. diff: nucleic acid amplification testing (NAATs), glutamate dehydrogenase tests (GDH), and toxin enzyme immunoassay (EIA) tests. Both the NAAT and the GDH tests detect the presence of C. diff, and so positive results do not necessarily mean infection. The toxin tests evaluate for toxin production, which is a surrogate for active infection. NAATs and the GDH tests are highly sensitive but have low-moderate specificity for active CDI, while toxin tests are moderately specific for CDI but insensitive. In addition, there are multiple toxin tests available, all of which have variable performances.
The updated guidelines recommend that if an institution limits testing to patients with clinically significant and unexplained diarrhea, the pretest probability of CDI is high enough that using a NAAT alone is acceptable. Use of other recommended algorithms (GDH plus toxin; GDH plus toxin, followed by NAAT if toxin negative; or NAAT plus toxin) is also acceptable. If institutions do not have the ability to limit testing to persons with a reasonable pretest probability for CDI, it is recommended that an initial test with GDH be performed, followed by a toxin test. If that is negative, a NAAT should be done.
Treating Initial Non-severe Episodes of CDI
The most significant changes in the guidelines are the recommended regimens for initial episodes of CDI. Previously, metronidazole was the recommended first-line therapy for non-severe CDI. Now the guidelines recommend oral vancomycin OR fidaxomicin for 10 days in all non-fulminant (i.e., no hypotension, shock, ileus, or megacolon) initial episodes of CDI. This is partly driven by the results of several randomized controlled trials that showed oral vancomycin to be superior to metronidazole in curing patients with CDI.3 Two recent clinical trials compared oral vancomycin and fidaxomicin and found no difference in resolution of symptoms at the end of treatment; however, the use of fidaxomicin was associated with less recurrence at 25 days post treatment.3
Of note, the guidelines state that in some locations, both fidaxomicin and oral vancomycin are limited in supply and/or expensive, and in these situations it is reasonable to use metronidazole.
Treating Fulminant Episodes of CDI
There is no change in treatment recommendations for fulminant CDI. The recommended treatment remains administration of oral vancomycin with IV metronidazole, +/- rectal vancomycin if ileus is present. Fidaxomicin is not included in this regimen, likely due to a lack of data on its use in severe disease.
Treating recurrent episodes of CDI
For first recurrence, the prior guidelines recommended administration of the same treatment used for the first episode; therefore, if metronidazole were used during an initial episode, it would be used again. The current guidelines recommend vancomycin if metronidazole was used during the initial episode, and also offer vancomycin taper as a reasonable treatment strategy. Fidaxomicin is recommended for use if vancomycin was the drug administered during the initial episode.
For second recurrence, the prior guidelines recommended vancomycin in a pulsed/tapered regimen. The current guidelines recommend a tapered regimen of vancomycin OR vancomycin for 10 days followed by rifaximin for 20 days OR 10 days of fidaxomicin. In addition, for the first time, fecal microbiota transplantation is a recommended option for treatment of a second or subsequent recurrence.
Alternative Treatment Options
The new guidelines note there is insufficient data to recommend probiotics for primary prevention of CDI. There have been numerous studies on this topic, but the authors note that many of them examined patients on antibiotics who did not have a prior history of CDI. They also note that the incidence of CDI in some of the studies was much higher than expected in the population. Both of these issues could lead to bias.
The guidelines note there is insufficient evidence to recommend extending C. diff therapy in patients who require concomitant other antibiotics past the duration of CDI treatment. Lastly, the guidelines do not have any recommendation regarding bezlotoxumab, and monoclonal antibody therapy recently approved by the FDA. It is likely that future guidelines will examine the role of this drug further.
Bottom line: Testing strategies for C. diff infection vary according to pretest probability of infection, and vancomycin and fidaxomicin have replaced metronidazole as initial treatment for CDI.
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- Lessa FC, Mu Y, Beldavx ZG, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-34. PMID: 25714160
- Coia J. C. difficile infection - Can we do better? Clin Microbiol Infect. 2018;24(5):450-451. PMID: 29274464
- McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):987-994. PMID: 29562266
- Deshpande A, Pant C, Olyaee M, Donskey CJ. Hospital readmissions related to Clostridium difficile infection in the United States. Am J Infect Control. 2018;46(3):346-347. PMID: 29050906
- Centers for Disease Control and Prevention. Clostridium difficile infection. https://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html.