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Have you “C-een-the-DIFFerence” in the 2018 Clostridioides difficile Guidelines?

Sunday, July 15, 2018  
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Have you “C-een-the-DIFFerence” in the 2018 Clostridioides difficile Guidelines?

Brooke Barlow & Ashley Barlow, PharmD Candidates Class of 2019: Jefferson College of Pharmacy

Preceptor: Bhavik Shah, PharmD, BCPS, AAHIVP


In 2017, the IDSA-SHEA updated the guidelines for the management of Clostridioides difficile (formerly Clostridium difficileinfection (CDI), establishing a new practice changing paradigm for the treatment of this clinically significant, problematic infection.1 Amongst the several updates in the guidelines, some most relevant to clinical practice include revisions in the classification, diagnosis, and treatment of CDI which will be detailed in the following sections in this article. Other notable revisions that will not be reviewed in this article include management of CDI in pediatrics, discussion on fecal transplantation, and recommendations for pharmacological CDI prophylaxis.


The unclear algorithm for the diagnosis of CDI in the previous 2010 guidelines has resulted in an era of overdiagnosis and treatment, resulting in unnecessary antimicrobial exposure. The lack of a standard diagnostic approach sparked the update to provide specific guidance on CDI testing. According to the new recommendations, diagnostic testing should only be performed in patients with an unexplained, new onset of > 3 un-formed stools in 24 hours, in the absence of concurrent laxative therapy. The guidelines recommend that for patients who meet the aforementioned criteria, a positive nucleic acid amplification test (NAAT) alone is sufficient for the diagnosis of CDI. In centers where the NAAT is unavailable, or if testing is performed for patients on laxatives, a stool toxin can be performed in addition to either GDH (glutamate dehydrogenase antigen test) or NAAT, to confirm positive results. Overall, this updated algorithm yields a greater sensitivity and specificity to CDI detection to improve diagnostic stewardship.1


There is a noteworthy modification in the classification of CDI severity. The panel experts no longer recommend classification based on a percentage change of serum creatinine from baseline, due to the recognition that previous serum creatinine values are not readily available in many situations. The cut off values to distinguish between non-severe and severe CDI now include a leukocytosis of 15,000 cells/mm3 and a single serum creatinine value of 1.5 mg/dL. In addition, the updated classification of severe complicated CDI has changed to severe fulminant, defined in the chart below.1

Treatment of Initial Episode

One of the major practice changing updates from the 2010 guidelines is the removal of metronidazole as a first-line oral agent for non-severe initial CDI episodes. The removal of metronidazole was based on high quality evidence demonstrating the superiority of fidaxomicin and vancomycin for initial cure rates. Oral vancomycin has maintained its clinical utility in the guidelines, based off accruing evidence that demonstrate cure rates up to 97% for initial episodes. Another novel update is the implementation of fidaxomicin for initial treatment of non-severe CDI. Fidaxomicin is a unique agent, as its narrow antimicrobial spectrum of activity to gastrointestinal microflora reduces the risk of collateral damage. In addition, fidaxomicin has established evidence in reducing rates of CDI recurrence. Based on this supportive evidence, first-line recommendations for initial non-severe CDI episodes include oral vancomycin 125 mg every 6 hours or oral fidaxomicin 200 mg twice daily for a total duration 10 days. Remaining consistent with previous guidelines, intravenous metronidazole remains a useful adjunctive therapy with oral vancomycin for fulminant CDI. In the instance of drug shortages, restrictions due to drug costs or patient intolerance, the guidelines note oral metronidazole may be used as a last line agent for non-severe CDI if no other first-line agents can be utilized.1

Treatment of Recurrent Episodes

The frequency of recurrent CDI remains a significant clinical concern, occurring in approximately 25% of patients treated with vancomycin for the initial episode. The options for recurrence include vancomycin or fidaxomicin; however, no agent is preferred due to lack of comparative efficacy data. The specific treatment recommendations are as follows: if the initial episode was treated with oral vancomycin, options for recurrence include a 10 -day course of fidaxomicin or oral vancomycin as a prolonged taper or pulse regimen. Between 20-35% of patients will fail initial antibiotic treatment, where an additional 40-60% of these individuals have a secondary recurrence. In the event of a second recurrent episode, the updated guideline recommends using a multimodal approach with a tapered schedule of vancomycin followed by rifaximin. The guidelines also give a strong recommendation for the use of a fecal microbiota transplants as a viable alternative to antimicrobial therapy for patients with recurrent episodes.1

Pharmacoeconomic Considerations

With the update of these guidelines, important pharmacoeconomic and formulary decisions should be taken into consideration prior to implementation. Although the cost of fidaxomicin is ~$3,000 for a 10- day course, it may be more cost effective by virtue of reducing the rate of recurrent CDI and hospital readmissions, which are costly burdens to the healthcare system (~$34,000 per admission).2,3 The widespread use of fidaxomicin versus restricted use in patients at high risk of recurrence, remains up to the discretion of the health care providers. Factors in decision making include outweighing the upfront costs of fidaxomicin, compared to the costs of hospital readmission resulting from recurrent CDI infections.      

Due to the high cost of oral vancomycin capsules (~$500-600/course), pharmacies have implemented cost-saving initiatives by compounding the vancomycin injection for oral use. However, the restrictions on outpatient compounding and the unpalatable taste of this formulation has limited its widespread use. The recent advent of a commercially available vancomycin oral solution, FirvanqTM, for the treatment of CDI may replace the need for the compounded solution. The availability of this product as a reconstituted solution will allow for ease of access at all pharmacies and improve patient convenience. The solution is available as a powder with a palatable grape flavored diluent for reconstitution that should be refrigerated, and the final preparation discarded after 14 days. This solution costs ~$125 for a 10-day course and is easily accessible in the outpatient setting.5

Future Directions

One unanswered question in the current guidelines is the role of the newly approved bezlotoxumab (ZinplavaTM) in reducing CDI recurrence. Bezlotoxumab, a fully human monoclonal antibody that binds toxin B, was FDA approved in 2016 for the prevention of CDI recurrence in patients at least 18 years of age, receiving treatment for CDI, deemed at high risk for recurrence.6 This approval was based off the MODIFY I and MODIFY II trials that showed a significantly lower rate of recurrence in the bezlotoxumab vs. placebo (17% vs. 28%, p<0.001 and 16% vs. 26%, p<0.001 respectively).7 Bezlotoxumab is administered as a single intravenous infusion at 10mg/kg infused over 60 minutes. Although this agent addresses the significant health care burden of recurrent CDI, some considerations to take into account are the appropriate selection of high risk populations (e.g. immunocompromised, elderly, severe CDI), the cost at $4,560/vial (1000mg/vial), and the risk for exacerbating congestive heart failure.6,7 Overall the exclusion of bezlotoxumab into the updated guidelines will leave time to determine the implementation of this agent into clinical practice.


In summary, the updated guidelines provide a practice changing paradigm to the diagnosis and treatment of CDI. Overall, pharmacists should acknowledge the key elements for appropriate diagnosis and staging of CDI and the removal oral metronidazole as a first-line agent for initial non-severe CDI management. Pharmacists will “C-the-DIFFerence” in overall healthcare costs and burden of CDI in the healthcare system with the implementation of these new guidelines.


1.       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;66(7):987-994.

2.       Rodrigues R, Barber GE, Ananthakrishnan AN. A comprehensive study of costs associated with recurrent clostridium difficile infection. Infect Control Hosp Epidemiol. 2017;38(2):196-202.

3.       Fidaxomicin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at Accessed April 14, 2018.

4.       Firvanq (vancomycin hydrochloride) [prescribing information]. Wilmington, MA: CutisPharma; February 2018.

5.       Vancomycin Oral Solution (Firvanq). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at Accessed April 14, 2018.

6.       Bezlotoxumab (Zinplava). Lexi-Drugs, Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at Accessed April 21, 2018.

7.       Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317.

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