Inclusion Criteria:

• ≥ 18 years old.
• Medical record documentation of recurrent CDI per the study definition, that includes either: a) at least one recurrence after a primary episode and has completed at least one round of standard-of-care oral antibiotic therapy or b) has had at least two episodes of severe CDI resulting in hospitalization within the last year.
• A positive stool test for the presence of toxigenic C. difficile within 30 days prior to 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 2 consecutive days) while taking antibiotics during screening.
• Willing and able to have an enema(s).
• Willing and able to complete the stool and serum testing required for the study.
• Agrees not to take non-dietary probiotics through 8 weeks after receiving the last study enema (including OTC and prescription).
• Agrees not to take any oral vancomycin, metronidazole, fidaxomicin, rifaximin, nitazoxanide and 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.
• 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 antibiotic therapy for a condition other than CDI.
• Previous fecal transplant, RBX2660 treatment, receipt of CDI vaccine or treatment with CDI monoclonal antibodies prior to study enrollment.
• History of inflammatory bowel disease (IBD), e.g., ulcerative colitis, Crohn’s disease, or microscopic colitis.
• Diagnosis of irritable bowel syndrome (IBS) as determined by Rome III criteria.
• History of chronic diarrhea.
• History of celiac disease.
• Disease symptoms (diarrhea) caused by a confirmed intestinal pathogen other than C. difficile.
• Currently has a colostomy.
• Intraabdominal surgery within the last 60 days.
• Evidence of active, severe colitis.
• History of short gut syndrome or motility disorders.
• Requires the regular use of medications to manage bowel hypermotility.
• Planned therapy in the next 3 months that may cause diarrhea (e.g., chemotherapy).
• Planned surgery requiring perioperative antibiotics within 6 months of study enrollment.
• Life expectancy of < 6 months.
• Compromised immune system (e.g., HIV infection with CD4 count <200/mm3; inherited/primary immune disorders; immunodeficient or immunosuppressed due to a medical condition or medication).
  • Note: Eligible HIV patients who have a CD4 count >200/mm3 who are on stable, highly active anti-retroviral therapy may be considered for enrollment.
• Taking systemic steroids > 20 mg prednisone a day or prednisone-equivalent, or is expected to be on steroids (> 20 mg prednisone a day or equivalent) after enrollment through 8 weeks after completing the assigned study treatment.
  • Note: Eligible patients taking a steroid dose equivalent to prednisone 20 mg/day for >2 weeks, antimetabolites (e.g., azathioprine, 6-mercaptopurine, or low-dose methotrexate for autoimmune disease), calcineurin inhibitors (e.g., tacrolimus and cyclosporine), or mycophenolate mofetil may be enrolled only after consultation with the Medical Monitor, and only if the doses have been stable (except for drug therapeutic monitoring adjustments for calcineurin inhibitors) for 90 days and have not been associated with diarrhea prior to the current episode of CDI.
• An absolute neutrophil count of <1000 cells/μL during screening.
• Known or suspected current (< 90 days) illicit drug use. Note: marijuana use is allowed.
• Participant is unable to discontinue opioids (unless on a stable dose with no increase in dose planned for the duration of the study).
  • Note: Opioids are permitted as needed as long as participants are on a stable dose at the time of randomization and expect to maintain the same dose until the 8 week follow-up visit OR if the participant has been on short-term (i.e., ≤ 14 days) opioid treatment and there is anticipation of a dose decrease or cessation of use during the course of the study. Participants who only receive a few doses at the time of presentation of CDI may be considered for participation. Investigator should consult on any clarification of the opioid doses/treatment with the Medical Monitor.
• Pregnant, breastfeeding, or intends to become pregnant during study participation.
• Participating in a clinical trial of another investigational product (drug, device or other) and has not completed the required follow-up period.
• Subject, in the opinion of the investigator, for whatever reason, should be excluded from the study.