This Phase 2, multicenter, open-label single-arm segment (2A) followed by a double-blind, randomized, active-controlled segment (2B) is designed to evaluate ACX-362E in the treatment of CDI. Segment 2A of this trial is an open-label cohort of approximately 20 subjects in approximately 5 study centers in the United States and Canada. In Segment 2A, approximately 20 subjects with diarrhea caused by C. difficile will be treated with ACX-362E 450 mg orally for 10 days. All subjects will be followed for recurrence for 28 2 days. After 10 subjects have completed treatment and again after all subjects have completed treatment, a Trial Oversight Committee will assess the safety and tolerability, and, as data allow, efficacy, to make recommendation regarding whether the study should continue.

Subjects will be evaluated for cure, safety, and tolerability. All subjects in both segments will have stool samples tested for microbiome profiles. Pharmacokinetic (PK) testing for systemic exposure will be performed on blood samples in Segment 2A. Stool samples will be tested for study drug concentration.