Objectives: The primary objective of this trial is to evaluate the efficacy of a 14-day course of RNIB21 TID versus placebo in providing adequate relief from IBS symptoms over a 14-week study duration in patients with IBS-D. Secondary objectives include: - Assessment of the safety and tolerability of RNIB21; and - Evaluation of the systemic exposure profile of rifaximin and N-acetylcysteine (NAC) after oral administration of RNIB21. Endpoints: Co-Primary Endpoint: Proportion of patients that achieve weekly response defined as: - A 30% improvement compared to baseline on the weekly average score of worst daily abdominal pain; and - A 50% reduction in the number of days per week with at least one stool consistency of Type 6 or 7 on the Bristol Stool Scale (BSS) compared to baseline, for at least 2 of the 4 weeks of the Primary Evaluation Period (PEP). Key Secondary Endpoints: - Proportion of patients that achieve weekly response as defined above for at least 50% of the total duration of the PEP and Follow-Up Period (i.e., 6 of 12 weeks after RNIB21 treatment). - Proportion of patients that achieve response during the treatment free Follow-Up Period and have no recurrence through Week 14(i.e., weeks 7-14). Secondary Endpoints: - Assessment of the safety through evaluation of physical exam, vital signs, clinical laboratory tests, and adverse events (AEs). - Quantitation of plasma rifaximin and NAC concentrations after single and multiple doses with estimation of appropriate pharmacokinetic parameters of systemic disposition. - Stool frequency observed during the PEP compared to baseline. - Additional endpoints to evaluate improvement in specific parameters such as stool frequency, relief of bloating symptoms, and sustained IBS symptom free monthly responders. Exploratory Endpoints: - Change from baseline each week over the duration of the 12-weekpost-treatment study duration on the following symptoms collected on the Daily IBS Symptom Questionnaire: o Number of bowel movements (Q3) o Mean stool form score (Q4) o Mean abdominal pain and discomfort score (Q5) o Mean bloating score (Q6) o Sense of urgency score (Q7) - Change from baseline of the Lactulose Breath Test. - Change from baseline on the IBS Quality of Life Questionnaire.