Clinical Updates
Focusing on Prevention, Treatment and Recurrence of
Clostridium Difficile Infection

Infections caused by Clostridioides difficile (C. difficile), a spore-forming, Gram-positive anaerobic bacillus also known as Clostridium difficile, are a major health threat in the United States. The pathogen produces two exotoxins (toxin A and toxin B) that can cause local gastrointestinal (GI) mucosal damage and systemic effects. Recurrence of C. difficile infection (CDI) is common, affecting approximately one in four or five patients. Severe fulminant colitis and potentially fatal toxic megacolon can develop. Infections caused by C. difficile affect more than 450,000 Americans and cause more than 29,000 deaths annually, with an estimated cost of $1.5 billion.

ASHP Advantage is conducting an educational initiative on the management of CDI for physicians, pharmacists, physician assistants, and nurse practitioners. Two free on-demand continuing education activities featuring the faculty team of Kevin W. Garey, Pharm.D., M.S., FASHP, and Krishna Rao, M.D., M.S., are available on the initiative website. Dr. Garey is Professor at the University of Houston College of Pharmacy and Chair of the Department of Clinical Sciences and Administration at the University of Houston College of Pharmacy in Houston. Dr. Rao is Assistant Professor of Internal Medicine at the University of Michigan in Ann Arbor.

In the first activity, Drs. Garey and Rao provide an overview of best practices for CDI management, including an update on clinical practice guidelines and stewardship strategies. They then build on that foundation during the second activity by illustrating the application of the CDI guidelines to patient cases and describing the role of new and emerging therapies for CDI.

This e-newsletter provides updates on these programs and addresses challenges in managing patients with CDI.

Initiative Faculty

Kevin W. Garey, Pharm.D., M.S., FASHP
Professor and Chair
Department of Clinical Sciences and Administration
University of Houston College of Pharmacy
Houston, Texas
View Bio

Krishna Rao, M.D., M.S.
Assistant Professor of Internal Medicine
University of Michigan
Ann Arbor, Michigan
View Bio

Managing CDI poses a challenge to clinicians because of uncertainty, unresolved controversy, and the ongoing emergence of new data about the optimal therapeutic strategy. Questions sometimes arise about which patients should be tested for CDI. Clinicians should have a high index of suspicion about the possibility of CDI in patients with certain symptoms (Table). Testing for CDI should not be performed for asymptomatic patients because colonization is common, especially among certain groups (e.g., 60% to 70% of infants, 20% to 50% of adults in long-term care facilities). Positive test results may reflect colonization without infection. Treatment is not indicated for asymptomatic patients because it typically does not affect the risk, epidemiology, or transmission of CDI.

Testing for CDI should not be performed during or immediately after treatment for the infection because the results can be misleading. Positive test results do not necessarily reflect treatment failure. Up to half of patients have positive test results 6 weeks after the completion of treatment because of the shedding of spores. Approximately 10% to 20% of patients treated for CDI become long-term carriers, and treatment of carriers is controversial because of an apparent lack of benefit. Repeat testing for cure after treatment is not recommended unless a patient is symptomatic.

Post-infectious irritable bowel syndrome (IBS) is common after treatment for and recovery from CDI. It is attributed to long-term colonization with C. difficile and can be difficult to differentiate from recurrent CDI. Post-infectious IBS usually manifests as milder illness compared with the initial CDI episode, and testing for recurrent CDI is unnecessary in patients with this presentation.

Patients with inflammatory bowel disease (IBD) have higher rates of C. difficile carriage (i.e., colonization) than the general population. Diagnosing and treating CDI in these patients pose unique challenges because CDI can mimic or trigger an IBD flare (there is overlap in symptoms). There is a lack of consensus among gastroenterologists about whether to use antibiotics alone or in combination with immunomodulators (e.g., corticosteroids) to treat CDI, flares, or both in patients with IBD and CDI. In a retrospective analysis by Ben-Horin and colleagues of hospitalized patients with IBD and CDI who were treated with antibiotics with or without immunomodulators, combination therapy was associated with worse outcomes than antibiotic therapy alone. A possible approach to managing patients with IBD who present with symptoms that suggest CDI (i.e., diarrhea) is to perform a stool test for toxigenic C. difficile and start treatment for CDI if it is present (Figure 1). Immunosuppressive therapy would be started or escalated if C. difficile is not present in the stool or if CDI symptoms do not improve after 48 hours of treatment for CDI.

Testing for CDI should be performed using only an unformed stool sample from patients with diarrhea. Various assays are available that detect or measure the organism, the toxins that it produces, and/or its genes.

The goals of treatment for CDI include correcting dysbiosis (i.e., restoring the indigenous microbiota), killing the pathogen, and if possible, modifying the adaptive immune response that causes damage to the GI mucosa and systemic effects. Metronidazole is no longer recommended for initial episodes in treatment guidelines for CDI from the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) because of its inferior clinical success and higher 30-day mortality compared with vancomycin. In current IDSA/SHEA guidelines, fidaxomicin (a narrow-spectrum, non-absorbable antibiotic) is an alternative to vancomycin because of its noninferior efficacy and the significantly lower risk of CDI recurrence compared with vancomycin. Metronidazole is reserved for use if vancomycin and fidaxomicin are not available or not tolerated.

Treating and preventing CDI recurrence can present a challenge to clinicians, especially for patients with multiple recurrences. Switching to an antibiotic that was not used to treat the initial episode is an intuitive approach that is recommended for a first recurrence. Use of a prolonged, tapered, and pulsed vancomycin regimen (125 mg orally four times daily for days 10-14, followed by two times daily for 1 week, once daily for 1 week, and once every 2 or 3 days for 2-8 weeks instead of the standard 125 mg orally four times daily for 10 days) is an option for treating first recurrences if standard vancomycin was used for treatment of the initial episode. A prolonged, tapered, and pulsed vancomycin regimen also is an option for the treatment of second and subsequent recurrences.

In theory, providing prolonged and progressively lower antibiotic exposure allows more time for clearance of C. difficile, and the antibiotic-free periods during pulsed (i.e., intermittent) administration allow replenishment of the normal microbiota. In a small study of 100 patients with recurrent CDI in whom vancomycin administration had been tapered, the use of pulsed vancomycin doses every 3 days instead of every 2 days substantially increased the clinical cure rate from 61% to 81%. This change in pulse therapy frequency increased the total duration of vancomycin therapy by nearly 50%.

The use of prolonged and pulsed fidaxomicin without a taper (200 mg orally twice daily on days 1-5 followed by once daily every other day on days 7-25) instead of the standard vancomycin regimen (125 mg orally four times daily on days 1-10) was shown to significantly reduce the rate of CDI recurrence in 356 patients 60 years of age or older with initial or recurrent CDI in the EXTEND trial. This prolonged, pulsed fidaxomicin regimen is not recommended in current IDSA/SHEA treatment guidelines.

The use of “chaser” or “follow-on” rifaximin, which is a non-absorbable rifamycin antibiotic approved by the Food and Drug Administration for the treatment of traveler’s diarrhea, for preventing CDI recurrence has been explored after resolution of CDI using primary treatment. In a study of 130 patients with resolution of CDI using vancomycin or metronidazole, a significant reduction in the rate of CDI recurrence within 12 weeks was associated with the use of rifaximin 400 mg three times a day for 2 weeks, followed by 200 mg three times a day for another 2 weeks instead of placebo (16% vs. 30%, respectively, p = 0.06). Current IDSA/SHEA treatment guidelines include the use of rifaximin 400 mg orally three times daily for 20 days as a chaser after 10 days of vancomycin 125 mg orally four times daily as an option for treating patients with a second or subsequent CDI recurrence. Resistance develops rapidly to rifaximin, so the use of fidaxomicin in place of rifaximin as chaser therapy after vancomycin has been investigated.

More Information

• Gentry CA, Giancola SE, Thind S et al. A propensity-matched analysis between standard versus tapered oral vancomycin courses for the management of recurrent Clostridium difficile infection. Open Forum Infect Dis. 2017; 4(4):ofx235. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729658/pdf/ofx235.pdf (accessed 2019 Mar 5).
• Tomas ME, Mana TSC, Wilson BM et al. Tapering courses of oral vancomycin induce persistent disruption of the microbiota that provide colonization resistance to Clostridium difficile and vancomycin-resistant enterococci in mice. Antimicrob Agents Chemother. 2018; 62:e02237-17. https://aac.asm.org/content/62/5/e02237-17 (accessed 2019 Mar 5).
• Sirbu BD, Soriano MM, Manzo C et al. Vancomycin taper and pulse regimen with careful follow-up for patients with recurrent Clostridium difficile infection. Clin Infect Dis. 2017; 65:1396-9.
• Guery B, Menichetti F, Anttila VJ et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018; 18:296-307.
• Major G, Bradshaw L, Boota N et al. Follow-on RifAximin for the Prevention of recurrence following standard treatment of Infection with Clostridium Difficile (RAPID): a randomised placebo controlled trial. Gut. 2018 Sep 25. pii: gutjnl-2018-316794. https://gut.bmj.com/content/gutjnl/early/2018/10/26/gutjnl-2018-316794.full.pdf (accessed 2019 Mar 5).

The high incidence and rate of recurrence of CDI have led to efforts to identify new modalities to prevent initial CDI episodes and prevent and treat recurrent CDI (Figure 2). New and emerging preventive strategies for CDI include probiotics to restore the normal microbiota, toxoid vaccines to elicit the production of antibodies that bind C. difficile toxins, and β-lactamase enzymes.

Ribaxamase is a novel, oral, recombinant β-lactamase enzyme that has been used in conjunction with intravenous (i.v.) β-lactam antibiotics for the prevention of CDI. Ribaxamase degrades excess β-lactam antibiotic secreted into the small intestine, thereby preventing disruption of the microbiota and CDI. Ribaxamase will not be useful for preventing CDI associated with non-β-lactam antibiotics because of its mechanism of action.

In phase 2a studies of 23 otherwise healthy patients who received ceftriaxone and had functioning ileostomies for ease of sampling of intestinal chyme, Kokai-Kun and colleagues demonstrated that ribaxamase was not absorbed after oral administration. Ceftriaxone levels in chyme were below the lower limit of quantification, and serum ceftriaxone levels were unaffected by ribaxamase. These effects were not affected by proton pump inhibitor use.

These positive outcomes were shared with the Food and Drug Administration. The agency proposed efficacy and safety criteria that could be met in a single phase 3 clinical trial that is underway in patients receiving i.v. β-lactam antibiotics who are at high risk for CDI. Multiple β-lactam antibiotics will be evaluated. Data from such a trial may be sufficient for drug approval for the prevention of antibiotic-mediated CDI.

Oral narrow-spectrum, non-absorbable antibiotics (e.g., ridinilazole, cadazolid) that provide high intraluminal concentrations, limit systemic exposure, and do not disrupt the microbiota are in clinical trials for the primary treatment of CDI. Ridinilazole has potent anti-C. difficile activity and decreases inflammatory mediators (e.g., lactoferrin, calprotectin), although its mechanism of action is not completely clear. In a phase 2 randomized, double-blind, noninferiority study of 69 patients with CDI, ridinilazole (200 mg orally every 12 hours for 10 days) was superior to vancomycin (125 mg orally every 6 hours for 10 days) for providing a sustained clinical response (67% vs. 42%, respectively, p = 0.0004), which was defined as clinical cure at the end of treatment without recurrence within 30 days. The rate of recurrence was 14% in the ridinilazole group and 35% in the vancomycin group, representing a more than 50% reduction.

Nontoxigenic C. difficile spores have been used to prevent CDI recurrence by competing with disease-producing toxigenic strains. In a randomized, placebo-controlled study of 157 patients who had successfully completed vancomycin or metronidazole treatment for a first episode or first recurrence of CDI, a significantly lower rate of CDI recurrence at 6 weeks was demonstrated from the use of the nontoxigenic C. difficile M3 strain instead of placebo. Phase 2 clinical trials of this modality are in progress.

Fecal microbiota transplantation (FMT) is recommended in IDSA/SHEA treatment guidelines after appropriate antibiotic treatments have been used for at least two CDI recurrences. Research is needed to identify the target patient populations that stand to derive the greatest benefit from FMT; demonstrate its safety in immunocompromised patients (e.g., patients with IBD) and long-term safety in these and other patient populations; and identify the optimal route, preparation, and stool characteristics for FMT.

More Information

• Kokai-Kun JF, Roberts T, Coughlin O et al. The oral β-lactamase SYN-004 (ribaxamase) degrades ceftriaxone excreted into the intestine in phase 2a clinical studies. Antimicrob Agents Chemother. 2017; 61(3):pii: e02197-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328510/pdf/e02197-16.pdf (accessed 2019 Mar 5).
• C. diff Foundation. C. diff. infection (CDI) prevention clinical studies in progress. January 2019. https://cdifffoundation.org/clinical-trials-2/ (accessed 2019 Mar 5).
• Dieterle MG, Rao K, Young VB et al. Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections. Ann N Y Acad Sci. 2019; 1435:110-38. https://nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/nyas.13958/ (accessed 2019 Mar 5).
• Vickers RJ, Tillotson GS, Nathan R et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017; 17:735-44.
• Gerding DN, Meyer T, Lee C et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA. 2015; 313:1719-27.