Exploring effectiveness of Metronidazole, Bismuth, and Rifaximin in treating small intestinal bacterial overgrowth and irritable bowel syndrome: A systematic review

Table 1 Characteristics of studies using Metronidazole, n (%)

Number	Ref.	Year of publication	Study design and setting	Number of patients enrolled with summary	Intervention used	Comparison used	Patients achieved outcome (intervention group)	Patients achieved outcome (comparison group)
1	Marie et al[23]	2009	Non-randomized, uncontrolled, prospective	51	Intermittent rotating antibiotics (7 days/month for 3 months)	None	21/49	N/A
2	Feng et al[24]	2021	Non-randomized, prospective	14	Antibiotic course	Placebo	6	2
3	Menees et al[25]	2012	Non-randomized, uncontrolled, prospective	51	Norfloxacin and Metronidazole intermittently	None	11	N/A
4	Tauber et al[27]	2014	Non-randomized, uncontrolled, prospective	37	Amoxicillin, Ciprofloxacin, and Metronidazole in succession	None	6	N/A
5	Mouillot et al[26]	2020	Retrospective cohort study	101	Gentamicin/Metronidazole and Metronidazole alone	None	20	23
6	García-Collinot et al[28]	2020	Clinical pilot study	40	Metronidazole alone	Saccharomyces boulardii alone	2	4
7	Tahan et al[29]	2013	Noncontrolled open clinical trial, community-based	20	Trimethoprim-sulfamethoxazole (30 mg/kg/day) and Metronidazole (20 mg/kg/day) for 14 days	None	19	N/A
8	Marie et al[23]	2009	Prospective observational cohort study, single tertiary care center	51	Rotating antibiotic therapy (Norfloxacin/Metronidazole)	None	22	N/A
9	Lauritano et al[30]	2009	Randomized controlled trial, catholic university of Rome	142	Metronidazole 750 mg/day for 7 days	Rifaximin 1200 mg/day for 7 days	31	45
10	Lauritano et al[31]	2008	Randomized controlled trial	142	Metronidazole 750 mg/day	Rifaximin 1200 mg/day	53 patients (Metronidazole)	67 patients (Rifaximin)
11	Lauritano et al[31]	2008	Cross-sectional study	51	Rotating antibiotic therapy (Norfloxacin/Metronidazole)	None	22 patients (improvement)	N/A
12	Dear et al[32]	2005	Clinical trial, hospital-based	12	Metronidazole	No fiber diet	6 patients: Significant reduction in hydrogen and methane production	N/A
13	Di Stefano et al[33]	2005	RCT, hospital setting	14	Metronidazole	Rifaximin	12 patients showed greater improvement in symptom severity	7 patients showed improvement (Rifaximin)
14	Di Stefano et al[33]	2005	RCT, hospital setting	14	Metronidazole	Rifaximin	12 patients showed greater improvement in symptom severity	7 patients showed improvement (Rifaximin)
15	Di Stefano et al[33]	2005	RCT, hospital setting	14	Metronidazole	Rifaximin	12 patients showed greater improvement in symptom severity	7 patients showed improvement (Rifaximin)
16	Melchior et al[34]	2017	Pilot controlled phase II study	16	Metronidazole (n = 8, 10 days)	Subcutaneous (n = 8, 10 days)	7 patients (87.5%) showed > 50% reduction in flatus incontinence episodes (from 18.2 ± 16.2 to 3.5 ± 3.1 episodes)	1 patient (12.5%) showed > 50% reduction in flatus incontinence episodes (from 11.1 ± 12 to 8 ± 9.7 episodes)
17	Thakur et al[35]	2009	Randomized, controlled	24	Metronidazole, 7 days	None	9 (improvement in stool scores)	0 (not reported)
18	Richard et al[36]	2021	Retrospective, single-center study	223	Metronidazole (500 mg, 3 ×/day for 10 days/month for 3 months)	Single antibiotic (Metronidazole) vs rotating antibiotics	36/69 (52.2%) achieved remission	62/124 (50.0%) achieved remission
19	Richard et al[36]	2021	Retrospective, single-center study	223	Metronidazole (500 mg, 3 ×/day for 10 days/month for 3 months) + Norfloxacin (400 mg, 2 ×/day for 10 days/month for 3 months) or Metronidazole + Ofloxacin	Rotating antibiotics vs single antibiotics	21/30 (70.0%) achieved remission	62/124 (50.0%) achieved remission
20	Pérez Aisa et al[37]	2019	Prospective cohort study, single-center	60	Rifaximin, Metronidazole, Ciprofloxacin	None	12 patients (small intestinal bacterial overgrowth + group, after treatment)	N/A
21	Konrad et al[38]	2018	Randomized single-blind clinical trial	116	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Metronidazole 2 × 500 mg for 10 days	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Rifaximin 3 × 400 mg for 10 days	18 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 16	21 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 18
22	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Antibiotics (Metronidazole, Rifaximin, other) + probiotics	None	39 (partial/full symptom improvement)	N/A
23	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Metronidazole + probiotics	None	13 (81.2)	10 (32.3)
24	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Metronidazole	None	7 (36.8)	7 (36.8)
25	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Antibiotics (Metronidazole, Rifaximin, other)	None	12 (63.2)	9 (32.0)
26	Peinado Fabregat et al[39]	2022	Retrospective cohort study	54	Metronidazole, Rifaximin	None	12 (71.4)	N/A
27	Lauritano et al[30]	2009	Open-Label randomized trial	71 intervention each group	Rifaximin (1200 mg/day)	Metronidazole (750 mg/day)	45	31
28	Castiglione et al[22]	2003	Open-Label randomized trial	15 intervention, 14 placebo	Metronidazole (750 mg/day)	Ciprofloxacin (1000 mg/day)	13	14

LHBT: Lactulose hydrogen breath test; N/A: Not available; RCT: Randomized controlled trial; UBT: Urease breath test.

Table 2 Characteristics of studies using Rifaximin, n (%)

Number	Ref.	Year of publication	Number of patients enrolled with summary	Intervention used	Comparison used	Patients achieved outcome (intervention group)	Patients achieved outcome (comparison group)
1	Schmulson and Frati-Munari[41]	2019	1851	Proton pump inhibitors	None	1333/1851	Not specified
2	Pimentel et al[43]	2011	87	Rifaximin 550 mg 3 times a day for 14 days	Placebo	Abdominal bloating: 10/38; abdominal pain: 11/41; stool consistency: 8/47	Abdominal bloating: 5/35; abdominal pain: 4/40; stool consistency: 8/44
3	Sharara et al[77]	2006	126	Rifaximin 550 mg 3 times a day for 14 days	Placebo	Abdominal bloating: 10/38; abdominal pain: 11/41; stool consistency: 8/47	Abdominal bloating: 22/42; abdominal pain: 21/44; stool consistency: 20/43
4	Kaye et al[44]	1995	20	Rifaximin 550 mg three times daily for 14 days	None	10	N/A
5	Parodi et al[42]	2021	55	Rifaximin 400 mg 3 times/day for 10 days	None	22	N/A
6	Mozaffari et al[45]	2014	1258 (Phase III)	Rifaximin (550 mg three times daily)	Placebo	1022	N/A
7	Shah et al[46]	2022	21	Rifaximin 550 mg BID for 10 days	None	17	N/A
8	Shah et al[47]	2012	1187	Rifaximin 400 mg 3 times/day for 10 days	Placebo	846	N/A
9	Shah et al[47]	2012	623	Rifaximin 550 mg 3 times/day for 14 days	Placebo	846	N/A
10	Colecchia et al[48]	2006	636	B. longum W11 (5 × 109 cells)	None	509	N/A
11	Fanigliulo et al[49]	2006	70	Rifaximin followed by B. longum W11	Rifaximin alone	57	N/A
12	Di Pierro et al[50]	2021	45	Rifaximin + B. longum W11	Rifaximin alone	9	N/A
13	Safwat et al[51]	2020	96	Rifaximin 550 mg three times daily for 2-4 weeks	N/A (single-arm study)	66	N/A
14	Li et al[52]	2020	30	400 mg Rifaximin orally, three times daily for 2 weeks	Healthy controls (no medication)	10	4
15	Mouillot et al[26]	2020	101	Rifaximin (550 mg in morning and evening for 7 days)	None	3	N/A
16	Barkin et al[53]	2019	443	Rifaximin 550 mg TID for 14 days	Amoxicillin-clavulanic acid	47.4% (for hydrogen-positive)	75% (3/4 on amoxicillin-clavulanic acid)
17	Lee et al[54]	2019	198	Rifaximin treatment for 4-12 weeks	None	162	N/A
18	Ghoshal et al[55]	2018	23	Rifaximin (400 mg thrice daily for 14 days)	Placebo	6	0
19	Tuteja et al[56]	2019	50	Rifaximin 550 mg, twice daily for 2 weeks	Placebo	N/A	N/A
20	Oh et al[57]	2018	776	Rifaximin	None	Increased from 22.7% (2006) to 66.7% (2016)	N/A
21	Furnari et al[58]	2019	23	Rifaximin (1200 mg for 14 days)	None	9 out of 10, 4 out of 10 in Rifaximin group	2 out of 6, 2 out of 6
22	Jo et al[59]	2018	25	Rifaximin (800 mg twice daily for 14 days)	None	6	N/A
23	Moraru et al[60]	2014	331	Rifaximin 1200 mg/day for 7 days	Control group (20 IBS patients without antibiotic therapy)	49	1
24	Moraru et al[60]	2014	331	Rifaximin 1200 mg/day for 7 days	Control group (20 IBS patients without antibiotic therapy)	76	0
25	Pimentel et al[61]	2014	37 (32 included in ITT analysis)	Rifaximin + Neomycin	Neomycin + placebo	15	11
26	Kim et al[62]	2019	529	Rifaximin treatment for SIBO	None	60	N/A
27	Rosania et al[63]	2013	40 (14 males, 26 females)	Rifaximin 400 mg/day for 7 days followed by Lactobacillus case	Rifaximin followed by short chain fructo-oligosaccharides	33	27
28	Dima et al[64]	2012	15	Seven days of Rifaximin + 10 days of probiotics	None	14	N/A
29	Weinstock et al[65]	2011	16 (14 included in analysis)	Rifaximin 550 mg three times daily for 10 days	None	8	N/A
30	Pimentel et al[43]	2011	1260	Rifaximin 550 mg, three times daily for 2 weeks	Placebo	511	402
31	Chang et al[66]	2011	50	Rifaximin 1200 mg daily for 10 days	Placebo	N/A	N/A
32	Pimentel et al[67]	2011	552	Rifaximin 1200 mg daily for 10 days	None	111	N/A
33	Pimentel et al[67]	2011	552	Rifaximin retreatment	None	414	N/A
34	Pimentel et al[67]	2011	552	Rifaximin retreatment	None	Median time to relapse: > 4 months	N/A
35	Collins et al[68]	2011	75 children with community-acquired pneumonia	Rifaximin 550 mg TID for 10 days	Placebo 550 mg TID for 10 days	44 children normalized their LBT, 20% normalized breath test	19 children normalized their breath test
36	Low et al[69]	2010	100	Rifaximin, Neomycin	Rifaximin, Neomycin, placebo	87 patients with Rifaximin + Neomycin (Methane eradicated)	28 patients with Rifaximin alone, 33 with Neomycin alone
37	Parodi et al[70]	2009	130 IBS, 70 FB, 70 controls	Rifaximin for SIBO	Healthy controls, IBS without SIBO, FB without SIBO	17 out of 24 positive GBT patients achieved normalization; 15 out of 17 showed GISS improvement	N/A
38	Lauritano et al[30]	2009	142	Rifaximin 1200 mg/day for 7 days	Metronidazole 750 mg/day for 7 days	45	31
39	Lauritano et al[31]	2008	142	Rifaximin 1200 mg/day	Metronidazole 750 mg/day	67 patients (Rifaximin)	53 patients (Metronidazole)
40	Lauritano et al[31]	2008	200	Antibiotic therapy (Rifaximin or other)	None	134 patients (Rifaximin)	N/A
41	Lauritano et al[31]	2008	130	Rifaximin 1200 mg/day	None	82 patients	N/A
42	Lauritano et al[31]	2008	142	Rifaximin 1200 mg/day	None	90 patients (SIBO resolution)	N/A
43	Lauritano et al[31]	2008	80	Rifaximin 1200 mg/day	None	55 patients (Rifaximin group)	N/A
44	Parodi et al[42]	2008	55 patients (30 with SIBO)	Rifaximin 1200 mg/day for 7 days	None	22	N/A
45	Weinstock et al[71]	2008	13	Rifaximin 1200 mg/day for 10 days	None	10 of 13 patients (77%) achieved ≥ 80% improvement in RLS symptoms. The 5 of 13 achieved 100% resolution of RLS symptoms	N/A
46	Weinstock et al[71]	2008	13	Rifaximin 400 mg 3 times/day for 10 days (for two patients)	None	2	N/A
47	Weinstock et al[71]	2008	13	Rifaximin 800 mg/day for 12 months (for propositus patient)	None	1	N/A
48	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	7 patients with moderate to great improvement in IC, 12 patients with moderate to great improvement in GI	N/A
49	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	7 patients with moderate to great improvement in IC and GI symptoms	N/A
50	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	5 patients with flat-line test results	N/A
51	Weinstock et al[72]	2008	17 patients with IC and GI symptoms	Rifaximin (10-day course)	None	12 patients with moderate to great improvements in GI and 7 patients with moderate to great improvements in IC	N/A
52	Yang et al[73]	2008	98	Rifaximin 1200 mg/day	Non-Rifaximin antibiotics (Neomycin, Doxycycline, Augmentin)	58 (first response), 16 (retreatment)	27 (non-Rifaximin antibiotics), 2 (retreatment with Doxycycline, Augmentin, Neomycin)
53	Yang et al[73]	2008	61	Various non-Rifaximin antibiotics	Rifaximin	N/A	27 (first response), 2 (retreatment)
54	Fanigliulo et al[49]	2006	41	Rifaximin 400 mg for 10 days/month + B. longum W11 (granulated suspension for 6 days on alternate weeks)	Rifaximin 400 mg for 10 days/month	41 (reported improvement in symptoms, P = 0.010)	29 (group B)
55	Fanigliulo et al[49]	2006	29	Rifaximin 400 mg for 10 days/month	Rifaximin + B. longum W11 (group A)	29 (reported improvement in symptoms, P = 0.002)	41 (group A)
56	Oh et al[74]	2025	70	Rifaximin 200 mg four times daily for 14 days	Rifaximin 200 mg four times daily for 14 days and probiotics once daily for 28 days	IBS-SSS score were 65.7% in the combination therapy group	IBS-SSS score were 31.4% in the monotherapy group
57	Pimentel et al[75]	2006	87	Rifaximin	Placebo	43	44
58	Peralta et al[76]	2009	97	Rifaximin 1200 mg/day for 7 days	None	28 patients (BTLact turned negative; symptom score reduced from 2.3 to 0.9)	26 patients (BTLact still positive; symptom score unchanged)
59	Sharara et al[76]	2006	124	Rifaximin (550 mg, 3 ×/day)	Placebo	26/63 (Phase 2), 18/63 (Phase 3)	14/61 (Phase 2), 7/61 (Phase 3)
60	Tursi et al[78]	2003	15	Rifaximin 800 mg/day for 1 week	None	10 (all symptoms resolved)	N/A
61	Corazza et al[79]	1988	6	Rifaximin 800 mg/day for 5 days	None	4 patients with negative hydrogen breath test	N/A
62	Corazza et al[79]	1988	6	Rifaximin 1200 mg/day for 5 days	None	4 patients with negative hydrogen breath test	N/A
63	Scarpellini et al[80]	2013	40	40 children with IBS, 64% SIBO-positive	None	25 patients symptom improvement seen in those with normalized LBT	N/A
64	Zhuang et al[81]	2020	78	Patients with IBS-D	None	45	N/A
65	Chojnacki et al[82]	2022	80	Rifaximin 550 mg/day for 2 weeks	None	40	N/A
66	Chojnacki et al[82]	2022	80	Rifaximin 550 mg/day for 2 weeks	None	40	N/A
67	Rezaie et al[83]	2019	93 (LBT sub study)	2-week Rifaximin course	Placebo	Abdominal pain (Rifaximin + LBT-positive): 37/62; bloating (Rifaximin + LBT-positive): 37/62; stool consistency (Rifaximin + LBT-positive): 37/62; IBS symptoms (Rifaximin + LBT-positive): 37/62	Abdominal pain (Rifaximin + LBT-negative): 8/31; bloating (Rifaximin + LBT-negative): 7/31; stool consistency (Rifaximin + LBT-negative): 7/31; IBS symptoms (Rifaximin + LBT-negative): 8/31
68	Rezaie et al[83]	2019	93	2-week Rifaximin course	Placebo	7/45 (15.6%) no symptom recurrence (overall response group)	N/A
69	Di Stefano et al[33]	2005	14	Rifaximin	Metronidazole	7 patients showed improvement in symptom severity	10 patients showed improvement (Metronidazole)
70	Di Stefano et al[33]	2005	14	Rifaximin	Metronidazole	7 patients showed improvement in symptom severity	10 patients showed improvement (Metronidazole)
71	Di Stefano et al[33]	2005	14	Rifaximin	Metronidazole	7 patients showed improvement in symptom severity	10 patients showed improvement (Metronidazole)
72	Scarpellini et al[84]	2007	162	Rifaximin 1600 mg/day	Rifaximin 1200 mg/day	85 patients normalized GBT, 75% symptom relief	69 patients normalized GBT, 60% symptom relief
73	Furnari et al[85]	2010	77	Rifaximin + PHGG	Rifaximin alone	34/40 (SIBO eradication, ITT analysis)	23/37 (SIBO eradication, ITT analysis)
74	Furnari et al[85]	2010	77	Rifaximin + PHGG	Rifaximin alone	31/34 (symptomatic improvement in eradicated patients)	20/23 (symptomatic improvement in eradicated patients)
75	Meyrat et al[86]	2012	150	Rifaximin (550 mg, 3 times daily for 14 days)	None	106 (bloating), 106 (diarrhea), 106 (flatulence), 106 (pain), 106 (reduced well-being)	N/A
76	Schoenfeld et al[87]	2014	1103	Rifaximin (550 mg and extended-release 800-2400 mg/day)	Placebo	579 patients (any AE), 59 (headache), 50 (URTI), 48 (nausea), 41 (abdominal pain), 37 (diarrhea), 37 (UTI)	436 patients (any AE), 51 (headache), 47 (URTI), 31 (nausea), 39 (abdominal pain), 26 (diarrhea), 18 (UTI)
77	Tursi et al[88]	2005	90	Rifaximin + Mesalazine for 10 days, then Mesalazine alone for 8 weeks	None	SIBO eradicated in 52 of 53 patients (all but one patient)	N/A
78	Ohkubo et al[89]	2023	12	Rifaximin (4-week treatment)	Placebo	3 patients (75%) achieved SIBO eradication at week 4	0 patients achieved SIBO eradication at week 4
79	Cash et al[90]	2017	2579	Rifaximin (550 mg, 3 times/day, 14 days)	Placebo	561 patients (52.2% of 1074 responders in open-label), 245 patients (38.6% of 636 in double-blind Rifaximin group)	188 patients (29.6% of 636 in double-blind placebo group)
80	Cash et al[90]	2017	636	Rifaximin (550 mg, 3 times/day for 14 days)	Placebo	245 patients (38.6% of 636) achieved MCID	188 patients (29.6% of 636) achieved MCID
81	Jolley[91]	2011	162	Rifaximin 1200 mg/day	None	79 (global improvement ≥ 50%)	N/A
82	Jolley[91]	2011	81	Rifaximin 2400 mg/day	None	38 (global improvement ≥ 50%)	N/A
83	Jolley[91]	2011	24	Rifaximin 2400 mg/day	None	13 (global improvement ≥ 50%)	N/A
84	Jolley[91]	2011	16	Rifaximin 2400 mg/day	None	6 (global improvement ≥ 50%)	N/A
85	Chedid et al[40]	2014	67	Rifaximin (oral, non-absorbable antibiotic)	Herbal therapy	23 (34)	17 (46)
86	Vicari et al[92]	2014	95	Rifaximin (200 mg, 2 tablets BID for 7 days a month) and VSL#3 (450 × 109 CFU/day)	None	16 patients (6Tx/6-) had positive sperm culture after 12 months of treatment	3 patients (12-) had positive sperm culture after 12 months with no treatment
87	Vicari et al[92]	2014	95	Rifaximin (200 mg, 2 tablets BID for 7 days a month) and VSL#3 (450 × 109 CFU/day)	None	9 patients (12Tx) achieved positive sperm culture	16 patients (6Tx/6-) achieved positive sperm culture
88	Vicari et al[92]	2014	95	Rifaximin (200 mg, 2 tablets BID for 7 days a month) and VSL#3 (450 × 109 CFU/day)	None	8 patients (6Tx/6-) had stable prostatitis	24 patients (12-) had worsening prostatitis (prostate-vesiculitis/prostate-vesiculo-epididymitis)
89	Liu et al[93]	2022	127	Rifaximin (200 mg × 3 per day for 4 weeks)	Placebo	24 patients and IBSN (15 patients) IBS-SSS abdominal pain significantly decreased in both patients with breath test positive	IBSN patients had no significant changes in Bowel Symptom Frequency scores or abdominal pain, minor improvements noted in IBS-SSS
90	Lembo et al[94]	2020	2579 (open-label); 328 (double-blind)	Rifaximin 550 mg TID for 2 weeks	Placebo	170/328	131/308
91	Lembo et al[94]	2020	328 (second treatment course)	Repeat Rifaximin 550 mg TID	Placebo	131/308	123/275
92	Castiglione et al[95]	2024	124	Rifaximin	Placebo	44/64 NIH-CPSI, 40/64 IBS-SSS, IL-6 reduction, IL-10 increase, Leukocyte decrease	2/60 NIH-CPSI, 3/60 IBS-SSS, IL-6 increase, IL-10 increase, Leukocyte decrease
93	Zhang et al[96]	2015	60	Rifaximin therapy	Placebo	11 out of 26 reduced minimal hepatic encephalopathy (42.3%)	N/A
94	Chojnacki et al[97]	2021	80 (40 SIBO-D, 40 SIBO-C)	Rifaximin 1200 mg daily for 14 days	None	Decreased LHBT hydrogen (12/40 in both groups had < 20 ppm post-treatment); decreased 5-hydroxyindoleacetic acid	N/A
95	Bae et al[98]	2015	36	Rifaximin 4 weeks	None	51 abdominal pain/discomfort improvement, 45/36 bloating improvement, 54 diarrhea improvement, 25 fatigue improvement	N/A
96	Bae et al[98]	2015	43	Rifaximin 8 weeks	None	38 abdominal pain/discomfort improvement, 45/36 bloating improvement, 41 diarrhea improvement, 32 fatigue improvement	N/A
97	Bae et al[98]	2015	23	Rifaximin 12 weeks	None	51 abdominal pain/discomfort improvement, 45/36 bloating improvement, 54 diarrhea improvement, 23 fatigue improvement
98	Black et al[99]	2020	9844	Rifaximin 550 mg three times daily	Placebo	3938	4922
99	DuPont et al[100]	2005	210	Rifaximin 200 mg daily, BID, TID	Placebo	153 (73% efficacy)	57 (27% efficacy)
100	Riddle et al[101]	2007	95	Rifaximin 1100 mg daily	Placebo	64 (67% efficacy)	31 (33% efficacy)
101	Martinez-Sandoval et al[102]	2010	201	Rifaximin 600 mg daily	Placebo	137 (68% efficacy)	64 (32% efficacy)
102	Flores et al[103]	2011	98	Rifaximin 550 mg daily	Placebo	28 (28% efficacy)	70 (72% efficacy)
103	Shah et al[104]	2023	1112	Antibiotic therapy	Healthy controls	669 Patients 60% of systemic sclerosis-patients showed symptom improvement	N/A
104	Khaw et al[105]	2022	328 (7-63 patients per study)	PERT, Rifaximin, Colesevelam	None	Improvement reported in all intervention groups	N/A
105	Wang et al[106]	2021	874	Rifaximin (400-1600 mg/day)	Placebo/active controls	516 (ITT: 59%)	N/A
106	Petrone et al[107]	2011	57	Rifaximin (2-week course)	None	45 (SIBO positive)	N/A
107	Pérez Aisa et al[37]	2019	60	Rifaximin, Metronidazole, Ciprofloxacin	None	12 patients (SIBO+ group, after treatment)	N/A
108	Boltin et al[108]	2014	19	Rifaximin 400 mg × 3/day for 14 days	None	8	N/A
109	Lacy et al[109]	2023	9255	Rifaximin (14-day course; avg. duration 0.6 months; 1.2 fills)	Eluxadoline (30-day course; avg. duration 3.5 months; 2.9 fills)	TFI ≥ 30 days: 5412	TFI ≥ 30 days: 1441
110	Pimentel et al[110]	2017	103	Rifaximin	Placebo	Decreased MIC50 values at week 23 for Bacteroides, high susceptibility for Clostridioides difficile	Similar susceptibility to Rifaximin and Rifampin in placebo
111	Pimentel et al[110]	2017	103	Rifampin	Placebo	Higher MIC for Bacteroides, consistent susceptibility in Enterobacteriaceae	Higher MIC for Bacteroides, similar susceptibility in Enterobacteriaceae
112	Fodor et al[111]	2019	103	Rifaximin (550 mg, three times daily)	Placebo	37 (based on significant shifts in microbial taxa)	36 (small shifts, non-significant)
113	Parodi et al[112]	2008	113	Rifaximin 400 mg every 8 hours for 10 days	Placebo	20 (from Rifaximin group)	0 (from placebo group)
114	Parodi et al[112]	2008	113	Rifaximin 400 mg every 8 hours for 10 days	Placebo	6 (from Rifaximin group)	0 (from placebo group)
115	Parodi et al[112]	2008	113	Rifaximin 400 mg every 8 hours for 10 days	Placebo	2 (from Rifaximin group)	2 (from placebo group)
116	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	125	97
117	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	39	20
118	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	56	36
119	Lembo et al[113]	2016	636	Rifaximin 550 mg TID	Placebo	153	127
120	Majewski et al[114]	2007	20	Rifaximin 800 mg/day for 4 weeks	None	15 (symptom improvement) + 10 (GBT normalization)	N/A
121	Konrad et al[38]	2018	116	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Rifaximin 3 × 400 mg for 10 days	Pantoprazole 2 × 40 mg, Amoxicillin 2 × 1000 mg, Metronidazole 2 × 500 mg for 10 days	21 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 18	18 (normal LHBT); 19 (UBT < 4.0‰); pain reduced below 3 points in 16
122	Peinado Fabregat et al[39]	2022	54	Antibiotics (Metronidazole, Rifaximin, other) + probiotics	None	39 (partial/full symptom improvement)	N/A
123	Peinado Fabregat et al[39]	2022	54	Rifaximin + probiotics	None	13 (76.5)	8 (32.0)
124	Peinado Fabregat et al[39]	2022	54	Rifaximin	None	13 (76.5)	13 (77.3)
125	Peinado Fabregat et al[39]	2022	54	Antibiotics (Metronidazole, Rifaximin, other)	None	12 (63.2)	9 (32.0)
126	Peinado Fabregat et al[39]	2022	54	Metronidazole, Rifaximin	None	12 (71.4)	N/A
127	Vicari et al[115]	2017	160 (45 type IIIa + IBS, 40 type IIIb + IBS, 75 IBS alone)	Rifaximin followed by VSL#3 probiotics	None	32/45 (type IIIa), 10/40 (type IIIb) for NIH-CPSI; 35/45 (type IIIa) and 13/40 (type IIIb) for IBS-SSS	N/A
128	Pimentel et al[43]	2011	1260 (623 in TARGET 1, 637 in TARGET 2)	Rifaximin 550 mg 3 times/day for 14 days	Placebo 3 times/day for 14 days	309 (TARGET 1)/316 (TARGET 2) in Rifaximin group	314 (TARGET 1)/320 (TARGET 2) in placebo group
129	Peralta et al[76]	2009	97	Rifaximin 1200 mg/day for 7 days	None	28 patients: BTLact negative, significant symptom reduction (P = 0.003)	26 patients: BTLact still positive, no symptom change
130	Muratore et al[116]	2023	N/A (model-based study)	Rifaximin 550 mg 3 × daily for 2 weeks (hydrogen breath test-directed)	TCA	N/A (model estimate)	N/A (model estimate)
131	Lacy et al[109]	2023	1258 + 2438 (open-label phase)	550 mg Rifaximin TID for 2 weeks	Placebo	624 (from Trials 1 and 2); 2438 (open-label)	634
132	Shah et al[117]	2019	624	Rifaximin 550 mg TID for 2 weeks	TCA	254	66
133	Enko et al[118]	2016	125	Rifaximin 600 mg/day for 10 days	None	26/30	N/A
134	Gravina et al[119]	2015	9	Rifaximin for SIBO eradication	Placebo/no treatment for SIBO	3/4 patients with isolated SIBO eradicated	1/2 patients with SIBO non-eradicated
135	Pimentel et al[43]	2011	1260	Rifaximin 550 mg TID for 2 weeks	Placebo	254	201
136	Sherwin et al[120]	2020	73	Rifaximin 550 mg TID for 14 days	None	17/23 high adherers reported improvement	22/50 Low adherers reported improvement
137	Zeber-Lubecka et al[121]	2016	31	Rifaximin 1200 mg/day for 10 days	None	21	N/A
138	Zeber-Lubecka et al[121]	2016	11	Rifaximin 1200 mg/day for 10 days	None	7	N/A
139	Zeber-Lubecka et al[121]	2016	30	Rifaximin 1200 mg/day for 10 days	None	16	N/A
140	Pimentel et al[4]	2003	126	Rifaximin 400 mg TID for 10 days	Placebo	84 (of 111 IBS patients)	3 (of 15 controls)
141	Shah et al[122]	2010	1585	Breath Test (hydrogen and methane)	Healthy controls	1076	509
142	Meyrat et al[86]	2012	150	Rifaximin 550 mg TID for 14 days	None	106	N/A
143	Ford et al[123]	2018	1805	Rifaximin (550 mg TID for 14 days)	Placebo	810	651
144	Fodor et al[111]	2019	636	Rifaximin (repeated courses, 2 × 14 days)	Placebo	290	216
145	Enko and Kriegshäuser[124]	2017	50	Rifaximin	None	30	N/A
146	Pimentel et al[4]	2003	111	Rifaximin	Placebo	41	23
147	Wigg et al[125]	2001	43	Rifaximin	Placebo	28	15
148	Song et al[126]	2021	88	Antibiotics	None	55	N/A
149	Collins et al[68]	2011	49 intervention, 26 placebo	Rifaximin (1650 mg/day)	Placebo	9	3
150	Chang et al[66]	2011	11 intervention, 16 placebo	Rifaximin (1200 mg/day)	Placebo	2	3
151	Furnari et al[85]	2010	37 Rifaximin, 40 Rifaximin + partially hydrolyzed guar gum	Rifaximin (1200 mg/day) + partially hydrolyzed guar gum	Rifaximin	34	23
152	Lauritano et al[30]	2009	71 intervention each group	Rifaximin (1200 mg/day)	Metronidazole (750 mg/day)	45	31
153	García-Cedillo et al[127]	2024	N/A	400 mg Rifaximin-alpha every 8 hours for 2 weeks	N/A	60% reported improvement in abdominal pain, 44% in bloating, 36% in flatulence, 60% in borborygmi, and 72% in stool consistency	A negative lactulose-Hydrogen Breath Test result for SIBO was documented in 32% of patients
154	Stefano et al[128]	2000	10 intervention, 11 comparison	Rifaximin (1200 mg/day)	Chlortetracycline (999 mg/day)	7	3
155	Esposito et al[129]	2007	73	Rifaximin 1200 mg/day for 7 days	None	19 patients with negative breath test	N/A
156	Zhao et al[130]	2016	63	Rifaximin	None	45 patients with resolved SIBO	N/A
157	Zhuang et al[131]	2018	30 IBS-D patients, 13 healthy controls	Rifaximin 400 mg twice daily for 2 weeks	Healthy controls	SIBO eradicated in 9/14 SIBO patients, significant GI symptom relief in all patients	N/A
158	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	24 (Rifaximin), 9 (control)	9 (Rifaximin), 9 (control)
159	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	26 (Rifaximin), 8 (control)	8 (Rifaximin), 8 (control)
160	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	31 (Rifaximin), 9 (control)	9 (Rifaximin), 9 (control)
161	Tocia et al[132]	2021	44	Rifaximin 1200 mg/day, 10 days/month for 3 months	Control group	15 (Rifaximin), 6 (control)	6 (Rifaximin), 6 (control)
162	Lee et al[133]	2019	378	Rifaximin	None	0.6 kg weight gain in lowest body weight quartile group	N/A
163	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients (33.33%) turned negative for SIBO, improvement in GISS scores	N/A
164	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed significant improvement in diarrhea	N/A
165	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed improvement in abdominalgia	N/A
166	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed improvement in bloating	N/A
167	Deng et al[134]	2016	18	Rifaximin (550 mg, 3 times daily for 10 days)	None	6 patients showed global improvement in GISS	N/A
168	Yoon et al[135]	2018	51	Rifaximin	None	26 patients showed improvement	N/A
169	Schoenfeld et al[87]	2014	95	Rifaximin 275 mg twice daily for 2 weeks	Placebo	13	9
170	Schoenfeld et al[87]	2014	190	Rifaximin 550 mg twice daily for 2 weeks	Placebo	29	15
171	Schoenfeld et al[87]	2014	96	Rifaximin 550 mg twice daily for 4 weeks	Placebo	9	7
172	Schoenfeld et al[87]	2014	624	Rifaximin 550 mg three times daily for 2 weeks	Placebo	68	32
173	Schoenfeld et al[87]	2014	98	Rifaximin 1100 mg twice daily for 2 weeks	Placebo	16	9

AEs: Adverse events; B. longum: Bifidobacterium longum; BID: Twice a day; BTLact: Breath test with lactulose; CFU: Colony-forming units; FB: Functional bloating; GBT: Glucose breath test; GI: Gastrointestinal; GISS: Global IBS Symptom Score; IBS: Irritable bowel syndrome; IBS-D: Diarrhea-predominant irritable bowel syndrome; IBSN group: Patients with breath test negative; IBS-SSS: Irritable bowel syndrome-Severity Scoring System; IC: Interstitial cystitis; IL: Interleukin; ITT: Intent to treat; LBT: Lactulose breath testing; LHBT: Lactulose Hydrogen Breath Test; MCID: Minimally clinically important difference; MIC: Minimum inhibitory concentration; N/A: Not available; NIH-CPSI: National Institutes of Health Chronic Prostatitis Symptom Index; RLS: Restless legs syndrome; SIBO: Small intestinal bacterial overgrowth; TCA: Tricyclic Antidepressants; TID: Three times a day; URTI: Upper respiratory tract infection; UTI: Urinary tract infection.

Table 3 Characteristics of studies using Bismuth

Number	Ref.	Year of publication	Study design and setting	Number of patients enrolled with summary	Intervention used	Comparison used	Patients achieved outcome (intervention group)	Patients achieved outcome (comparison group)
1	Thazhath et al[139]	2013	Retrospective observational	12	CBS 120-480 mg/day	None	7	N/A
2	Thazhath et al[139]	2013	Retrospective observational	4	CBS 120-480 mg/day	None	3	N/A
3	Thazhath et al[139]	2013	Retrospective observational	4	CBS 120-480 mg/day	None	2	N/A
4	Thazhath et al[139]	2013	Retrospective observational	5	CBS 120-480 mg/day	None	0	N/A
5	Daghaghzadeh et al[140]	2018	Randomized controlled trial, clinical setting	119	Bismuth subcitrate 120 mg twice daily (before meals)	Placebo group (60 patients)	Pain severity reduced from 55 to 32, fewer days of pain, improvement in bloating and daily life	Pain severity reduced from 57 to 53, no significant change in pain days or bloating, no improvement in daily life

CBS: Colloidal Bismuth subcitrate; N/A: Not applicable.