Abstract
The beneficial effect of colonization of the gastrointestinal tract by non-toxigenic Clostridioides difficile (NTCD) strains as a preventive of toxigenic C. difficile infection (CDI) has been known since the early 1980s. Investigators in both the USA and United Kingdom demonstrated that prior colonization by randomly selected NTCD strains provided prevention against infection by toxigenic C. difficile in hamsters, albeit with limited durability. In the 1980s two patients with multiply recurrent CDI in the UK were treated with vancomycin followed by NTCD to prevent further recurrences, with one success and one failure. Epidemiologic studies of hospitalized patients using weekly rectal swab cultures demonstrated that asymptomatic colonization of patients by toxigenic C. difficile was much more common than CDI, but also that the rate of asymptomatic NTCD colonization of patients was unexpectedly high. Development of molecular strain typing of C. difficile was instrumental in characterizing different strains of both toxigenic C. difficile and NTCD leading to identification of NTCD strains that were effective human colonizers. These strains were reintroduced in hamsters in the 1990s and shown to prevent CDI efficiently and durably when challenged with epidemic toxigenic C. difficile strains. One strain of NTCD, NTCD-M3, was manufactured under cGMP standards and was demonstrated to be safe in a phase 1 volunteer trial. NTCD-M3 was then tested in a phase 2 double-blind placebo controlled trial for the prevention of recurrent CDI in patients experiencing their first CDI episode or first CDI recurrence. NTCD-M3 was given at doses of 104 or 107 spores per day orally for 7 or 14 days following successful treatment of CDI with vancomycin and/or metronidazole. CDI recurred in 30% of placebo patients and 11% of all NTCD-M3 patients (p = 0.006); recurrence rate for the best dose, 107 spores/d × 7 days, was 5% (p = 0.01 vs. placebo). Detection of colonization predicted prevention success; among the 86 patients who were colonized with NTCD-M3 the recurrence rate was 2% vs. 31% in patients who received NTCD-M3 but were not colonized (p < 0.001). Additional trials of NTCD-M3 for primary prevention of CDI and prevention of CDI recurrence seem warranted by these promising results.
Highlights
The purpose of this review is to summarize the experimental, pre-clinical, and clinical data for the use of non-toxigenic Clostridioides difficile (NTCD) for prevention of C. difficile infection (CDI) caused by toxigenic strains of C. difficile
Additional experiments showed (1) that protection was dependent upon live NTCD organisms; heat-killed NTCD did not protect hamsters, (2) that protection was dependent upon NTCD colonization; decolonization with vancomycin resulted in no protection against toxigenic challenge, and (3) that protection was specific to C. difficile; attempts to colonize with C. perfringens, C. bifermentans, and C. beijerincki, failed, and C. sporogenes colonized but failed to protect against toxigenic C. difficile challenge
The results of the experiment clearly show the advantage of an antibiotic resistant NTCD strain in preventing CDI, and suggest that an antibiotic susceptible strain can be effective if administered daily past the end of antibiotic administration, FIGURE 3 | Colonization by nontoxigenic restriction endonuclease analysis (REA) types and prevention of Clostridium difficile-associated disease (CDAD) in hamsters
Summary
The purpose of this review is to summarize the experimental, pre-clinical, and clinical data for the use of non-toxigenic Clostridioides difficile (NTCD) for prevention of C. difficile infection (CDI) caused by toxigenic strains of C. difficile. NTCD strains in which the pathogenicity locus (PaLoc) for the main C. difficile virulence factors, toxin A and B is replaced by a 115 bp sequence occur naturally. Multiple investigators have published convincing results of experiments over the last 35 years that demonstrate the efficacy of NTCD as a colonizing bacterial agent that prevents infection with toxigenic strains of C. difficile in animals and humans. A definitive mechanism for this protection remains to be determined, the effectiveness of this approach in multiple animal models and human clinical observations and trials suggests that it is a safe and effective biotherapeutic strategy that could be used for both primary prevention of CDI and prevention of CDI recurrence
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