Short-course therapy for diarrhea-predominant irritable bowel syndrome: understanding the mechanism, impact on gut microbiota, and safety and tolerability of rifaximin

Figures & data

Table 1 Therapies for the management of patients with IBS-D

Therapeutic class	Example of therapy	Dosing
Antibiotics	Rifaximin	550 mg tid for 14 days
Antispasmodics	Dicyclomine Hyoscyamine	10–20 mg qd–qid 0.125–0.25 mg every 4 hours as needed
Bile acid sequestrants	Cholestyramine Colesevelam Colestipol	9 g bid–tid 625 mg qd–bid 2 g qd–bid
Diet	Low gluten/gluten-free Low FODMAP	Daily Daily
Mixed opioid agonist/antagonist	Eluxadoline	100 mg bid
Opioid agonists	Loperamide	2–4 mg as needed; titrated to 16 mg/d
Peppermint oil	Enteric-coated capsules	250–750 mg bid–tid
Probiotics	Multiple products	Daily
Selective serotonin reuptake inhibitors	Citalopram Paroxetine Sertraline	10–40 mg qd 10–40 mg qd 25–100 mg qd
Tricyclic antidepressants	Amitriptyline Desipramine	10–50 mg qhs 25–100 mg qhs
5-HT3 antagonists	Alosetron Ondansetrona	0.5–1 mg bid (women only) 4–8 mg tid

Note:

a Not indicated for use in patients with IBS. Adapted from Gastroenterology, 150(6), Lacy BE, Mearin F, Chang L, et al, Bowel disorders, 1393–1407, Copyright (2016), with permission from Elsevier.¹

Abbreviations: 5-HT₃, serotonin; bid, twice daily; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; IBS, irritable bowel syndrome; IBS-D, diarrhea-predominant irritable bowel syndrome; qd, once daily; qhs, nightly at bedtime; qid, four times daily; tid, three times daily.

Table 2 Summary of meta-analyses of randomized, controlled studies of antibiotics and probiotics in patients with IBS

Publication	Patient inclusion criteria	RCTs in meta-analysis, n	Outcomes
Antibiotics
Li et al^Citation42	• Adults aged ≥18 years • IBS diagnosis	4 (n=1803 pts)	• Remission of overall IBS symptoms, rifaximin vs placebo − End of treatment: OR, 1.2 (95% CI, 1.1–1.3; p=0.0008) − End of follow-up: OR, 1.4 (95% CI, 1.2–1.6; p<0.0001) • Adverse events, rifaximin vs placebo − Abdominal pain (n=3 studies): OR, 1.01 (95% CI, 0.98–1.03; p=0.6) − Nausea (n=3 studies): OR, 1.0 (95% CI, 0.98–1.02; p=0.8) − Vomiting (n=3 studies): OR, 0.99 (95% CI, 0.98–1.01; p=0.3) − Headache (n=3 studies): OR, 1.01 (95% CI, 0.98–1.03; p=0.6)
Menees et al^Citation43	• IBS diagnosis (according to Manning, Kruis, Rome I, Rome II, Rome III criteria)	5 (n=1803 pts)	• Improvement of global IBS symptoms, rifaximin vs placebo − 42.2% vs 32.4%; OR, 1.6 (95% CI, 1.2–2.0; p<0.001) • Improvement in bloatinga, rifaximin vs placebo (n=4 studies) − 41.6% vs 31.7%; OR, 1.6 (95% CI, 1.2–2.0; p<0.001)
Probiotics
Zhang et al^Citation41	• IBS diagnosis (Rome III criteria) • Treatment ≥7 days	Overall: 21	• Overall symptom response (n=16 studies; n=1275 pts) − Probiotics vs placebo: 53.3% vs 27.7% (RR, 1.8; 95% CI, 1.3–2.6) • Abdominal pain response (n=13 studies; n=889) − Probiotics vs placebo: SMD, −0.3 (95% CI, −0.6 to 0.1) • Bloating (n=13 studies; n=890 pts) − Probiotics vs placebo: SMD, −0.2 (95% CI, −0.5 to 0.1) • QOL (n=9 studies; n=629 pts) − Probiotics vs placebo: SMD=0.3 (95% CI, 0.1–0.5)
Didari et al^44,b	• IBS diagnosis (Rome II and III criteria, and International Classification of Health Problems in Primary Care and World Organization of Family Doctors)	Overall: 15 (n=1793 pts)	• Global symptom response (n=2 studies) − Probiotics vs placebo: RR, 2.4 (95% CI, 1.1–5.2; p=0.02) • Adequate general symptoms improvement (n=6 studies) − Probiotics vs placebo: RR, 2.1 (95% CI, 1.1–4.3; p=0.03) • Abdominal pain response (n=2 studies) − Probiotics vs placebo: RR, 2.0 (95% CI, 1.1–3.4; p=0.01)
Ford et al^Citation45	• Adults aged >16 years with IBS • Treatment ≥7 days • Follow-up ≥7 days	• Overall: 35 − Combination probiotics: 19 − Lactobacillus: 8 − Bifidobacterium: 3 − Escherichia: 2 − Bifidobacterium or Lactobacillus: 1 − Saccharomyces: 1 − Streptococcus: 1	• Persistent or unimproved symptoms (n=23 studies; n=2575 pts) − Probiotics vs placebo: 55.8% vs 73.1% (RR, 0.8; 95% CI, 0.7–0.9) • Global IBS or abdominal pain scores (n=24 studies; n=2026 pts) − SMD=−0.3 (95% CI, −0.4 to −0.1) • Bloating (n=17 studies; n=1446 pts) − SMD=−0.2 (95% CI, −0.3 to −0.03) • Flatulence (n=10 studies; n=741 pts) − SMD=−0.2 (95% CI, −0.4 to −0.07) • Urgency (n=6 studies; n=635 pts) − SMD=−0.1 (95% CI, −0.3 to 0.1) • Adverse events (n=24 studies; n=2407 pts) − Probiotics vs placebo: 16.5% vs 13.8% (RR, 1.2; 95% CI, 1.02–1.4)
Moayyedi et al^Citation46	• Adults aged >16 y with IBS • Treatment ≥7 days • Follow-up ≥7 days	• Overall: 18 − Combination probiotics: 9 − Lactobacillus: 6 − Bifidobacterium: 3 − Lactobacillus and Bifidobacterium: 1 − Streptococcus: 1	• Overall symptom response (n=15 studies; n=1351 pts) − Probiotics vs placebo: SMD=−0.3 (95% CI, −0.6 to −0.07) • Persistent or unimproved overall symptoms (n=10 studies; n=918 pts) − Probiotics vs placebo: RR, 0.7 (95% CI, 0.6–0.9) • Abdominal pain response (n=9 studies; n=834 pts) − Probiotics vs placebo: SMD=−0.5 (95% CI, −0.9 to −0.1; p=0.02) • Bloating (n=7 studies; n=682 pts) − Probiotics vs placebo: SMD=−0.5 (95% CI, −1.1 to 0.02; p=0.06) • Flatulence (n=6 studies; n=566 pts) − Probiotics vs placebo: SMD=−0.2 (95% CI, −0.4 to −0.01; p=0.04) • Urgency (n=3 studies; n=394 pts) − Probiotics vs placebo: SMD=−0.1 (95% CI, −0.3 to 0.1; p=0.5) • Adverse events (n=3 studies; n=407 pts) − Probiotics vs placebo: RR, 0.9 (95% CI, 0.6–1.4)

Notes:

a At 10–14 days after treatment;⁴³

b number of patients not reported for individual outcomes. Data from references 41–46.

Abbreviations: CI, confidence interval; IBS, irritable bowel syndrome; OR, odds ratio; QOL, quality of life; pts, patients; RCT, randomized controlled trial; RR, relative risk; SMD, standard mean difference.

Figure 1 Repeat treatment trial study design and efficacy outcomes.⁵³

Notes: ^aSimultaneously meeting weekly response criteria for abdominal pain (≥30% decrease from baseline in mean weekly pain score) and stool consistency (≥50% decrease from baseline in number of days/week with Bristol Stool Scale type 6 or 7 stool) during ≥2 of the first 4 weeks posttreatment; ^bin patients with response to open-label rifaximin 4 weeks posttreatment, during the 18-week treatment-free observation phase; ^cp=0.03; ^dp=0.02; ^eDefined as the percentage of patients with response through the end of the first 6-week treatment-free observation phase and through the end of the second repeat treatment phase; ^fp=0.007; ^gDefined as adequate relief in both abdominal pain and stool consistency throughout the first double-blind repeat phase (through the 6-week treatment-free observation phase); ^hp=0.04; ⁱpercentage of patients with improvement from baseline ≥1 point in weekly average bloating score for ≥2 of 4 weeks of primary evaluation period.
Abbreviations: EOS, end of study; tid, three times daily.

Table 3 Summary of safety of rifaximin 550 mg with nonconstipation IBSa

Patients with AEs	Patients, n (%)
	Rifaximin 550 mg (n=1008)	Placebo (n=829)
Any AE	529 (52.5)	436 (52.6)
Most common AEsb
Headache	55 (5.5)	51 (6.2)
Upper respiratory tract infection	45 (4.5)	47 (5.7)
Nausea	41 (4.1)	31 (3.7)
Abdominal pain	40 (4.0)	39 (4.7)
Diarrhea	35 (3.5)	26 (3.1)
Urinary tract infection	32 (3.2)	18 (2.2)
Nasopharyngitis	26 (2.6)	39 (4.7)
Sinusitis	23 (2.3)	23 (2.8)
Vomiting	20 (2.0)	12 (1.4)
Back pain	20 (2.0)	19 (2.3)
Drug-related AEs	124 (12.3)	89 (10.7)
Serious AEs
Any serious AE	15 (1.5)	18 (2.2)
Drug-related serious AEs	1 (0.1)	2 (0.2)
Discontinuations related to AEs	19 (1.9)	14 (1.7)

Notes:

a Pooled data from patients receiving rifaximin 550 mg bid for 2 or 4 weeks in a phase IIb clinical study or rifaximin 550 mg tid for 2 weeks in two phase III studies;

b AEs reported in ≥2% of patients in either group. Adapted from Schoenfeld P, Pimentel M, Chang L, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39(10):1161–1168. With permission from John Wiley and Sons.⁶¹

Abbreviations: AE, adverse event; bid, twice daily; IBS, irritable bowel syndrome; tid, three times daily.

Table 4 Benefit to harm evaluation of treatment for patients with IBS-Da,b

Treatment	Number needed to treat	Number needed to harm	Number of patients benefiting for one patient harmedc
Alosetron	7.5	19.4	2.6
Tricyclic antidepressants	8	18.3	2.3
Rifaximin	10.6	8971	846

Notes:

a Eluxadoline data were not available at time study was conducted;

b based on discontinuation data due to an adverse event;

c ratio of the number needed to treat to the number needed to harm. Adapted from Am J Med, 125(4), Shah E, Kim S, Chong K, Lembo A, Pimentel M, Evaluation of harm in the pharmacotherapy of irritable bowel syndrome, 381–393, Copyright (2012), with permission from Elsevier,⁶² with additional data from Shah E, Pimentel M. Aliment Pharmacol Ther. 2014;39(9):973–983.⁶³

Abbreviation: IBS-D, diarrhea-predominant irritable bowel syndrome.

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