This is a prospective, multicenter, open-label Phase 3 study of a microbiota suspension of intestinal microbes. Patients who have had at least one recurrence of CDI after a primary episode and have completed at least one round of standard-of-care oral antibiotic therapy or have had at least two episodes of severe CDI resulting in hospitalization may be eligible for the study. Subjects may receive a second RBX2660 enema if they are deemed treatment failures following the initial enema per the protocol-specified treatment failure definition.

This is a prospective, multicenter, open-label Phase 3 study of a microbiota suspension of intestinal microbes. The primary assessments for this study are (i) safety via assessment of treatment-emergent adverse events and (ii) efficacy of RBX2660 preventing recurrent episodes of CDI measured at 8 weeks after treatment. Follow-up office visits occur at 1 week and 8 weeks after completing the initial study treatment. Telephone assessments occur at 4 weeks, and 4 and 6 months after the study. Patients who have had at least one recurrence of CDI after a primary episode and have completed at least one round of standard-of-care oral antibiotic therapy or have had at least two episodes of severe CDI resulting in hospitalization may be eligible for the study. Subjects may receive a second RBX2660 enema if they are deemed treatment failures following the initial enema per the protocol-specified treatment failure definition.

Inclusion Criteria:

1. ≥ 18 years old.
2. Medical record documentation of either: a) a current diagnosis or history of recurrent CDI as determined by the treating physician, b) or has had at least two episodes of severe CDI resulting in hospitalization.
3. Is currently taking or was just prescribed antibiotics to control CDI related diarrhea at the time of enrollment. [Note: Subject's CDI diarrhea must be controlled (<3 unformed/loose stools/day) while taking antibiotics during screening.]

Exclusion Criteria:

1. Has continued CDI diarrhea despite being on a course of antibiotics prescribed for CDI treatment.
2. Requires systemic antibiotic therapy for a condition other than CDI.
3. Fecal microbiota transplant (FMT) within the past 6 months.
4. FMT with an associated serious adverse event related to the FMT product or procedure.
5. Bezlotoxumab (CDI monoclonal antibodies) if received within the last year.
6. CD4 count <200/mm^3 during Screening.
7. An absolute neutrophil count of <1000 cells/µL during Screening.
8. Pregnant, breastfeeding, or intends to become pregnant during study participation.