To Prophylax or not to Prophylax: Preventing CDI

CDI is one of the most costly and common healthcare-associated infections in the United States with an incidence of approximately half a million cases resulting in an estimated cost of 6 billion dollars annually.^1,2 Broad spectrum antibiotics are one of the biggest risk factors for developing CDI, with third generation cephalosporins (OR 3.2) and clindamycin (OR 2.9) having the highest risk.³ Approximately 20-25% with an initial CDI episode experience recurrent CDI (rCDI) with risk of recurrence mounting with each subsequent episode.⁴ Systemic antibiotic exposure following the initial CDI episode is a primary risk factor for recurrence.⁵ The optimal approach for preventing CDI and rCDI remains unknown.⁶

CDI prophylaxis is lacking in high-quality evidence and the risk/benefit must be weighed due to disruption to the gut microbiome.⁷ There have been several studies published on the use of secondary CDI prophylaxis. Most studies were retrospective and endured significant heterogeneity, but majority demonstrated significantly lower rates of rCDI with administration of oral vancomycin therapy (OVP) in high-risk patients taking systemic antibiotics.^8,9 In a meta-analysis of 11 studies, 10 retrospective, OVP for primary and secondary prophylaxis was associated with a lower rate of CDI compared with no intervention (OR 0.13) and a subgroup analysis showed the lowest OVP dosage (125 mg once daily) was the best.¹⁰ No difference was seen between groups regarding the onset of vancomycin-resistant Enterococcus infections.^9,10 The American College of Gastroenterology (ACG) conditionally recommend OVP for secondary CDI prophylaxis in high-risk patients requiring subsequent treatment with systemic antibiotics. ACG guidelines define high-risk patients as those aged 65 years or older or with significant immunocompromised conditions or therapies who were hospitalized for severe CDI within the past 3 months. Both the ACG and IDSA/SHEA recommend vancomycin 125 mg once daily continued until 5 days after completion of systemic antibiotics, but optimal dosing and duration strategies have not been defined in prospective studies.^6,8,11 Lower doses and caution should be used when recommending OVP for CDI prevention since oral vancomycin is not C difficile specific and can cause significant dysbiosis and recurrence.^7,8

Another potential strategy for CDI prevention may be through dysbiosis prevention. Rebyota is the only FDA approved microbiome-based therapy administered as a single dose after completion of standard CDI antibiotic therapy to prevent rCDI.^12,13 SER-109 is another potential microbiome therapy administered as a single oral dose after completion of CDI therapy to prevent rCDI. In a phase 3 clinical trial, ECOSPOR III, SER-109 demonstrated superiority over placebo in reducing rCDI (12% vs. 40%, p < 0.001) and had a favorable safety profile.¹⁴ Ribaxamase (SYN-004) is a poorly absorbed, orally administered β-lactamase designed to protect the microbiota from the disruption caused by systemic β-lactam agents. In a phase 2b RCT use of ribaxamase reduced the incidence of CDI in patients receiving ceftriaxone without decreasing antibiotic efficacy.¹⁵

No effective or proven strategies are available for the primary prevention of CDI. Several promising strategies are in clinical development including microbiota-based therapies and vaccine development.¹⁶ At this time, OVP represents a reasonable strategy for secondary prophylaxis in high risk patients requiring systemic antibiotics. Further studies are ongoing on the optimal OVP schedule including dose and duration.¹⁰ Other strategies include fecal microbiota transplantation, which has proved to be a very effective treatment for patients with multiple recurrences.⁶ Bezlotoxumab, a monoclonal antibody that binds to toxin B, provides protection against rCDI, mainly in patients with primary episodes and high risk of relapse.¹⁷ Further strategies for preventing primary and secondary CDI are warranted.

References

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2.Zhang S, Palazuelos-Munoz S, Balsells EM, et al. Cost of hospital management of Clostridium difficile infection in the United States-a meta-analysis and modeling study. BMC Infect Dis. 2016 Aug 25. 16(1):447.

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6.Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021 Jun. 116(6):1124-1147.

7.Thorpe CM, Kane AV, Chang J, et al. Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile targeting antibacterial, compared to vancomycin. PLoS One. 2018; 13(8):e0199810.

8.Brown CC, Manis MM, Bohm NM, et al. Oral Vancomycin for secondary prophylaxis of Clostridium difficile infection. Ann Pharmacother. 2019 Apr. 53(4):396-401.

9.Babar S, El Kurdi B, El Iskandarani M, et al. Oral vancomycin prophylaxis for the prevention of Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2020; 41(11):1302-9.

10.Maraolo AE, Mazzitelli M, Zappulo E, et al. Oral vancomycin prophylaxis for primary and secondary prevention of Clostridioides difficile infection in patients treated with systemic antibiotic therapy: a systematic review, meta-analysis and trial sequential analysis. Antibiotics. 2022. 11:183.

11.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;66:987-994.

12.Rebyota. Prescribing Information. Parsippany, NJ: Ferring Pharmaceuticals Inc; 2022.

13.Khanna S, Assi M, Lee C, et al. Efficacy and safety of RBX2660 in PUNCH CD3, a phase III, randomized, double blind, placebo controlled trial with a Bayesian primary analysis for the prevention of recurrent Clostridioides difficile infection. Drugs. 2022;82(15):1527-1538.

14.Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med. 2022;386:220-9.

15.Kokai-Kun JF, Roberts T, Coughlin O, et al. Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial. Lancet Infect Dis. 2019;19(5):487–496.

16.Businesswire. Phase 3 CLOVER Trial for Pfizer’s investigational Clostridioides difficile vaccine indicates strong potential effect in reducing duration and severity of disease based on secondary endpoints. March 01, 2022. Phase 3 CLOVER Trial for Pfizer’s Investigational Clostridioides Difficile Vaccine Indicates Strong Potential Effect in Reducing Duration and Severity of Disease Based on Secondary Endpoints | Business Wire.

17.Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. New Engl J Med. 2017; 26;376(4):305-317.