Inclusion Criteria:

• ≥ 18 years old.
• Medical record documentation of either:
  • recurrent CDI per the study definition, that includes at least one recurrence after a primary episode and has completed at least one round of standard-of-care oral antibiotic therapy; or
  • has had at least two episodes of severe CDI resulting in hospitalization.
• A positive stool test for the presence of toxigenic C. difficile or C. difficile toxin within 30 days prior to or on date of enrollment.
• 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, i.e., Bristol Stool Scale type 6-7, stools/day for the two consecutive days prior to the washout period) while taking antibiotics during screening.
• Willing and able to have an enema(s).
• Willing and able to complete the stool and blood testing required for the study.
• Agrees to not take non-dietary probiotics through 8 weeks after receiving the last study enema (including OTC and prescription).
• Agrees to not take any oral vancomycin, metronidazole, fidaxomicin, rifaximin, nitazoxanide, bezlotoxumab, or IVIG through the 8-week follow-up assessment unless newly prescribed by a treating investigator during the course of the study as a result of recurrent CDI diagnosis.
  • Note: Use of IVIG for treatment of a non-CDI indication is allowed.
• Agrees to practice a form of effective contraception during study participation; does not apply to persons with documented non-child bearing potential.
• Has a negative urine pregnancy test at the time of enrollment and on the day of each enema prior to administration (persons of child-bearing potential only).
• Willing and able to provide informed consent, and local privacy authorization as applicable.
• Willing and able to complete the required Subject Diary.
• Willing and able to meet all study requirements, including attending all assessment visits and telephone calls.

Exclusion Criteria:

• A known history of refractory CDI.
• Currently has continued CDI diarrhea despite being on a course of antibiotics prescribed for CDI treatment.
• Requires systemic antibiotic therapy for a condition other than CDI.
• Fecal microbiota transplant (FMT) within the past 6 months.
• FMT with an associated serious adverse event related to the FMT product or procedure.
• Bezlotoxumab (CDI monoclonal antibodies) if received within the last year.
• Disease symptoms (diarrhea) caused by a confirmed intestinal pathogen other than C. difficile.
• Currently has a colostomy.
• Intraabdominal surgery within the last 60 days.
  • Note: laparoscopic procedures that do not involve the GI tract are permitted.
• Planned surgery requiring perioperative antibiotics through the 8-week follow-up assessment.
• Life expectancy of < 6 months.
• CD4 count <200/mm3 during Screening.
• An absolute neutrophil count of <1000 cells/μL during Screening.
• Known or suspected current (< 90 days) illicit drug use.
  • Note: marijuana use is allowed.
• Pregnant, breastfeeding, or intends to become pregnant during study participation.
• Participating in a clinical study of another investigational product (drug, device or other) and has not completed the required follow-up period.
• Subject is eligible for another RBX2660 study.
• Subject, in the opinion of the investigator, for whatever reason, should be excluded from the study.