Biotherapeutics for the Prevention of Clostridium difficile Infection
A product that provides a diverse array of bacteria, resembling normal intestinal microbiota is needed. Photo Credit: Biomedical Imaging Unit, Southampton General Hospital/Science Source.
Clostridium difficile exposure and acquisition are often insufficient to cause C difficile infection (CDI), particularly when intestinal microbiota is diverse and abundant. After broad-spectrum antibiotic exposure, the normal intestinal microbiota is perturbed. This dysbiosis creates an environment permissible to C difficile colonization and overgrowth and expression of toxins A and B, leading to CDI. CDI symptoms vary from mild diarrhea to fulminant, life-threatening colitis. The vast majority of patients with CDI with mild or moderate diarrhea respond to CDI antibiotic treatment, most commonly metronidazole or vancomycin. However, because these antibiotics also have a relatively broad antimicrobial spectrum, they promote persistent dysbiosis after CDI resolution. Regrowth of the original C difficile strain or reexposure to C difficile during this dysbiosis increases risk for recurrent CDI, which occurs in approximately 20% of patients.1 The intestinal microbiota can be restored through administration of live organisms through a variety of biotherapeutics strategies. We review biotherapeutics for the prevention of C difficile infection, including probiotics, fecal microbiota transplantation (FMT), and nontoxigenic C difficile.
Several commercially available probiotics have been studied for CDI prevention, but data supporting efficacy were limited until recently. No difference in CDI risk was demonstrated in elderly inpatients receiving a multistrain preparation of lactobacilli and bifidobacteria vs placebo in a large randomized controlled trial.2 However, 2 large meta-analyses3,4 each suggested efficacy of probiotics for CDI prevention, particularly when started within 2 days of initiation of CDI treatment.4 A recent smaller meta-analysis of probiotics in elderly patients did not demonstrate a difference between probiotics and placebo for CDI prevention.5
Some data support specific probiotic formulations for CDI prevention. In a pediatric meta-analysis, a modest benefit was demonstrated with Lactobacillus rhamnosus and Saccharomyces boulardii.6 A probiotic including 3 Lactobacillus species (Bio-K+) may be effective in adults.7 Although probiotics are generally safe, adverse events, such as probiotic bacteremia, can occur in patients with severe comorbidities, immunocompromise, and/or indwelling devices.6,7 Kefir is a fermented dairy probiotic product containing 12 species of bacteria. In 25 adults with recurrent CDI, 21 (84%) remained diarrhea-free for 9 months after 15-weeks of daily kefir with a staggered and tapering dosing regimen of metronidazole or vancomycin.8 These results require further investigation in a randomized controlled trial.
Despite the relative success of FMT in reducing recurrent CDI (see below), FMT logistical challenges (eg, identifying and screening donors, collecting and preparing stool for FMT, etc) and risks of invasive procedures for FMT administration are nontrivial. Thus, there is a need for a product that provides a diverse array of bacteria closely resembling normal intestinal microbiota. SER-109 is a probiotic containing bacterial spores collected from ethanol-treated stool of healthy donors (to isolate spore-forming bacteria, eliminate vegetative organisms, and eradicate potential pathogens by exposure to ethanol). The remaining spore-forming organisms are then capsulized. In a noncomparative trial, SER-109 was given orally to adults with ≥3 CDIs in the previous year. Of the 30 adults enrolled, 29 (96.7%) did not have another CDI recurrence during the 8-week follow-up period.9 Although this study reported approximately 50 species (from the Firmicutes phylum) in SER-109 by meta-genomic sequencing, many organisms were noncultivable, challenging the contribution of these noncultivable bacteria to microbiota restoration.10 However, in a follow-up phase 2 study of adults with multiply recurrent CDI (interim results were reported by the manufacturer but not yet published), CDI recurrence occurred in 26 (44%) of 59 SER-109 recipients and 16 (53%) of 30 placebo patients.11 The manufacturer believes study bias related to misdiagnosis of CDI and/or suboptimal SER-109 dosing in many study patients may have led to these disappointing results and plans to correct these limitations in a phase 3 clinical trial.12
The goal of FMT is to restore the intestinal microbiota to its normal state through the administration of stool from a healthy donor, thus promoting intestinal colonization resistance against C difficile. Until recently, efficacy and safety data were reported only in case reports and small series. An unblinded randomized controlled trial in adults with CDI compared vancomycin plus FMT (via nasoduodenal tube) with vancomycin alone. The study was terminated early when efficacy was clearly demonstrated after interim analyses; 13 (81%) of 16 FMT patients did not have a CDI recurrence compared with 4 (31%) of 13 vancomycin patients.13 Similar efficacy was seen in a randomized controlled trial in adults with CDI comparing vancomycin plus FMT via colonoscope to prolonged/tapered vancomycin.14 Of 20 FMT patients, 18 (90%) had sustained resolution of diarrhea compared with 5 (26%) of 19 vancomycin patients. Although promising, criticism of both studies includes a study design permitting multiple FMTs in experimental groups, but only single courses of antibiotics in controls.
FMT presents logistical challenges because of the need to screen donors for medical conditions and transmissible pathogens. In a randomized controlled trial of FMT (via colonoscope) in 46 adults with multiply recurrent CDI, donor stool (ie, heterologous FMT) was compared with the patient's own stool (ie, autologous FMT).15 Of the 22 (91%) heterologous FMT recipients, 20 had sustained resolution of diarrhea compared with 15/24 (63%) autologous FMT recipients, supporting the benefit of stool from a healthy donor. Commercially available FMT products are in development. One such product, RBX2660, was studied in an open-label study in adults with multiply recurrent CDI.16 Among 31 patients receiving RBX2660 via enema who completed 6-month follow-up, 16 had sustained resolution of diarrhea after 1 dose and 11 responded to a second dose; overall efficacy was 87%.
Another logistical challenge is FMT administration via an invasive procedure, conferring potential morbidity. Upper gastrointestinal bleeding, colonic perforation, and fatal aspiration pneumonia have been reported as FMT complications.1 To minimize these risks, FMT capsules frozen after encapsulation of healthy donor stool were administered by mouth to 20 adults with multiple recurrent CDI.17 Of these 20 adults, 14 (70%) responded to an initial dose of 15 capsules on 2 consecutive days, and an additional 4 of 6 nonresponders had sustained resolution of diarrhea after retreatment; overall efficacy was 90%.
Despite FMT efficacy, safety concerns remain. In addition to procedure-related adverse events described here, FMT has been associated with infectious complications (eg, norovirus, Escherichia coli bacteremia) and recrudescence of previously quiescent inflammatory bowel disease.1 Although no infectious complications were reported in a retrospective study of 80 immunocompromised patients (although 79% were healthy enough to receive FMT as an outpatient),18 larger studies are needed to assess safety in patients with severe comorbidities, particularly because of infectious complications of probiotics previously reported in such high-risk patients. Furthermore, the long-term effect of microbiome manipulation via FMT is unknown.
Nontoxigenic C difficile
As noted here, toxigenic C difficile strains cause symptoms through release of toxins A and B. Nontoxigenic C difficile strains lack genes responsible for toxin production and do not cause disease. Although probiotics and FMT likely reduce CDI through intestinal microbiota restoration, some nontoxigenic C difficile strains are thought to directly outcompete toxigenic C difficile in the intestinal tract. Strain M3 can naturally colonize hospitalized patients and reduce CDI risk,19 and was studied as a biotherapeutic for CDI prevention. In a phase 2 double-blind randomized placebo-controlled trial in 168 adults with CDI, administration of M3 spores was associated with reduced CDI recurrence.20 The promising results from this study should be confirmed in a phase 3 trial.
In summary, biotherapeutics provide a novel preventive strategy for recurrent CDI prevention that reduces dysbiosis that initially led to CDI and that persists after CDI treatment with vancomycin and metronidazole. Additional studies are needed to establish the relative safety and efficacy of the products described above, particularly in high-risk patients with significant comorbidities.
Larry K. Kociolek, MD, MSCI, is the associate medical director of infection prevention and control at the Ann & Robert H. Lurie Children's Hospital of Chicago and assistant professor of pediatrics at the Northwestern University Feinberg School of Medicine in Illinois.
Stanford T. Shulman, MD, is the medical director of Infection Prevention and Control at the Ann & Robert H. Lurie Children's Hospital of Chicago and Virginia H. Rogers Professor of Pediatric Infectious Disease at the Northwestern University Feinberg School of Medicine in Illinois.
- Kociolek LK, Gerding DN. 2016. Breakthroughs in the treatment and prevention of Clostridium difficile infections. Nat Rev Gastroenterol Hepatol. 2016;13:150-160.
- Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013;382:1249-1257.
- Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:CD006095.
- Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology. 2017;152:1889-1900.e9.
- Vernaya M, McAdam J, Hampton MD. Effectiveness of probiotics in reducing the incidence of Clostridium difficile-associated diarrhea in elderly patients: a systematic review. JBI Database System Rev Implement Rep. 2017;15:140-164.
- Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. 2015. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2015;12:CD004827.
- Goldstein EJC, Johnson SJ, Maziade PJ, et al. Probiotics and prevention of Clostridium difficile infection. Anaerobe. 2017;45:114-119.
- Bakken JS. Staggered and tapered antibiotic withdrawal with administration of kefir for recurrent Clostridium difficile infection. Clin Infect Dis. 2014;59:858-861.
- Khanna S, Pardi DS, Kelly CR, et al. A novel microbiome therapeutic increases gut microbial diversity and prevents recurrent Clostridium difficile infection. J Infect Dis. 2016;214:173-181.
- Lagier JC, Cadoret F, Raoult D. Critical microbiological view of SER-109. J Infect Dis. 2017;215:161-162.
- Seres Therapeutics announces interim results from SER-109 phase 2 ECOSPOR study in multiply recurrent Clostridium difficile infection [press release]. Cambridge, MA: Seres Therapeutics Inc. Published July 29, 2016. Accessed August 1, 2017.
- Seres Therapeutics announces key findings from SER-109 phase 2 study analyses [press release]. Cambridge, MA: Seres Therapeutics Inc. Published January 31, 2017. Accessed August 1, 2017.
- van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407-415.
- Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835-843.
- Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: A randomized trial. Ann Intern Med. 2016;165:609-616.
- Orenstein R, Dubberke E, Hardi R, et al; PUNCH CD Investigators. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: Results of the PUNCH CD study. Clin Infect Dis. 2016;62:596-602.
- Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772-1778.
- Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065-1071.
- Shim JK, Johnson S, Samore MH, Bliss DZ, Gerding DN. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet. 1998;351:633-636.
- 20. 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;313:1719-1727.