Third-line and rescue therapy for refractory Helicobacter pylori infection: A systematic review

Table 2 Adverse effects

Ref.	Therapeutic scheme	Adverse effects, n	Total rate
Okimoto et al[16], 2014	Dual therapy: rabeprazole and amoxicillin	n = 24. Loose stools/diarrhea: 5 (20.8%); nausea: 1 (4.2%); skin rash: 0 (0%)	25%
Okimoto et al[16], 2014	Triple therapy: rabeprazole, amoxicillin, and levofloxacin	n = 24. Loose stools/diarrhea: 5 (20.8%); nausea: 0 (0%); skin rash: 1 (4.2%)	25%
Lim et al[13], 2014	Triple therapy: lansoprazole, amoxicillin, and rifabutin	Group A (n = 32). Epigastric pain: 3 (9.3%); epigastric discomfort: 2 (6.2%); asthenia: 1 (3.1%); nausea: 1 (3.1%); change in urine color: 1 (3.1%); drowsiness: 1 (3.1%); lip discomfort: 1 (3.1%); treatment was discontinued because of adverse effects: 1 (3.1%)	15.5%
Lim et al[13], 2014	Triple therapy: lansoprazole, amoxicillin, and rifabutin	Group B (n = 27). Epigastric pain: 1 (3.7); epigastric discomfort: 1 (3.7); asthenia: 0 (0%); nausea: 1 (3.7); urine color change: 0 (0%); drowsiness: 0 (0%), lip discomfort: 0 (0%)
Furuta et al[14], 2014	Triple therapy: rabeprazole, sitafloxacin, and amoxicillin or metronidazole	RAS, 7 d (n = 44). Diarrhea: 9 (20.4%); loose stools: 20 (45.4%)	65.9%
Furuta et al[14], 2014	Triple therapy: rabeprazole, sitafloxacin, and amoxicillin or metronidazole	RAS, 14 d (n = 45). Diarrhea: 12 (26.6%); loose stools: 17 (37.7%)	64.4%
Furuta et al[14], 2014	Triple therapy: rabeprazole, sitafloxacin, and amoxicillin or metronidazole	RMS, 7 d (n = 44). Diarrhea: 8 (18.2%); loose stools: 17 (38.6%)	56.8%
Furuta et al[14], 2014	Triple therapy: rabeprazole, sitafloxacin, and amoxicillin or metronidazole	RMS, 14 d (n = 47). Diarrhea: 12 (25.5%); loose stools: 26 (55.3%)	86.3%
Paoluzi et al[17], 2015	Triple therapy: esomeprazole, levofloxacin, and doxycycline	n = 142. Swelling:; flavor perversion; mild diarrhea; treatment was discontinued because of adverse effects: 1 (0.7%)	7.7%
Mori et al[19], 2016	Triple therapy: esomeprazole, amoxicillin, and rifabutin	10-d group (n = 12). Fever: 2 (16.6%); diarrhea: 0 (0%); headache: 3 (25%); liver dysfunction: 2 (16.6%); loose stools: 2 (16.6%); urine discoloration: 1 (8.3%); allergy: 1 (8.3%); leukopenia: 1 (8.3%); stomatitis: 1 (8.3%); dysgeusia: 1 (8.3%); vertigo: 0 (0%); fatigue: 0 (0%); photophobia: 0 (0%); treatment was discontinued because of adverse effects: 1 (8.3%)	75%
Mori et al[19], 2016	Triple therapy: esomeprazole, amoxicillin, and rifabutin	14-d group (n = 17). Fever: 6 (35%); diarrhea: 5 (29.4%); headache: 3 (17.7%); liver dysfunction: 3 (17.7%); loose stools: 2 (11.8%); urine discoloration: 3 (17.7%); allergy: 2 (11.8%); leukopenia: 1 (5.9%); stomatitis: 0 (0%); dysgeusia: 0 (0%); vertigo: 1 (5.9%); fatigue: 1 (5.9%); photophobia: 1 (5.9%); treatment was discontinued because of adverse effects: 5 (29.4%)	94.1%
Mori et al[20], 2016	Triple therapy: esomeprazole, amoxicillin, and sitafloxacin	EAS (n = 63). Diarrhea: 11 (17.5%); loose stools: 9 (14.2%); constipation: 1 (1.5%); abdominal pain: 3 (4.8%); dyspepsia: 2 (3.2%); dysgeusia: 7 (11.1%); stomatitis: 3 (4.8);; allergy: 2 (3.2%); pruritus: 1 (1.5%); headache: 0 (0%); fatigue: 1 (1.5%); fever: 0 (0%); treatment was discontinued because of adverse effects: 1 (1.5%)	47.6%
Mori et al[20], 2016	Triple therapy: esomeprazole, metronidazole, and sitafloxacin	EMS (n = 58). Diarrhea: 15 (25.8%); loose stools: 8 (13.8%); constipation: 2 (3.4%); abdominal pain: 2 (3.4%); dyspepsia: 1 (1.7%); dysgeusia: 5 (8.6%); stomatitis: 2 (3.4%); ; allergy: 1 (1.7%); pruritus: 1 (1.7%); headache: 2 (3.4%); fatigue: 0; fever: 1 (1.7%); treatment was discontinued because of adverse effects: 1 (1.7%)	51.7%
Noh et al[22], 2016	Triple therapy: PPI, amoxicillin, and levofloxacin	-	-
Hirata et al[23], 2016	Triple therapy: esomeprazole, amoxicillin, and sitafloxacin	n = 30. Diarrhea: 5 (15.7%); rash: 1 (3.3%); asthma attack: 1 (3.3%); stomatitis: 1 (3.3%); cystitis: 1 (3.3%)	26.6%
Puig et al[26], 2017	Triple therapy: esomeprazole, amoxicillin, and metronidazole	n = 68. Diarrhea: 13 (20.0%); swelling: 3 (4.0%); dyspepsia: 14 (21.0%); taste disturbance: 23 (35.0%); nausea/vomiting: 10 (15.0%); asthenia: 4 (6.0%); others: 3 (4.0%); treatment was discontinued because of adverse effects: 2 (3.0%)	58.0%
Fiorini et al[27], 2018	Triple therapy: esomeprazole, amoxicillin, and rifabutin	n = 254. Nausea or vomiting: 6 (2.5%); abdominal pain: 13 (5.4%); mild diarrhea: 12 (5.1%); headache: 4 (1.6%); itching: 4 (1.6%); taste change: 4 (1.6%); myalgia: 1 (0.5%)	18.3%
Saito et al[30], 2019	Triple therapy: esomeprazole, amoxicillin, and sitafloxacin	-	-
Saito et al[30], 2019	Triple therapy: vonoprazan, amoxicillin, and sitafloxacin	-	-
Sue et al[31], 2019	Triple therapy: vonoprazan, amoxicillin, and sitafloxacin	n = 33. Diarrhea: 16 (50%); dysgeusia: 5 (15%); nausea: 1 (4%); anorexia: 3 (8%); abdominal pain: 5 (15%); heartburn: 6 (19%); headache: 4 (12%); eructations: 12 (35%); general malaise: 5 (16%); abdominal swelling: 12 (35%); urticaria: 3 (8%); treatment was suspended because of adverse effects: 2 (6.0%)	-
Sue et al[31], 2019	Triple therapy: lansoprazole or rabeprazole or esomeprazole, amoxicillin, and sitafloxacin	n = 30. Diarrhea: 15 (51%); dysgeusia: 5 (17%); nausea: 5 (17%); anorexia: 4 (13%); abdominal pain: 6 (21%); heartburn: 4 (13%); headache: 2 (8%); eructations: 2 (8%); general malaise: 2 (8%); abdominal swelling: 6 (21%); urticaria: 2 (8%)	-
Ribaldone et al[32], 2019	Triple therapy: omeprazole or esomeprazole or pantoprazole or rabeprazole or lansoprazole, amoxicillin, and rifabutin	n = 302. Abdominal/epigastric pain: 9 (3.0%); nausea/vomiting: 7 (2.3%); diarrhea: 2 (0.7%); fatigue: 1 (0.3%); headache: 1 (0.3%); oral candidiasis: 1 (0.3%); allergy: 1 (0.3%); treatment was discontinued because of adverse effects: 4 (1.3%)	7.3%
Sugimoto et al[34], 2020	Triple therapy: vonoprazan, amoxicillin, and sitafloxacin	n = 32. Diarrhea: 4 (12.5%); loose stools: 2 (6.2%); abdominal pain: 2 (6.2%); allergic reaction: 0 (0%); others: 1 (3.1%)	28.1%
Saracino et al[35], 2020	Triple therapy: esomeprazole, amoxicillin, and rifabutin	n = 270. Diarrhea: 21 (9.3%); abdominal pain: 20 (8.8%); nausea: 17 (7.7%); headache: 15 (6.6%); dyspepsia: 14 (6.0%); treatment was discontinued because of adverse effects: 3 (1.3%)	46.4%
Saracino et al[35], 2020	BQT-Pylera: Pylera® and esomeprazole	n = 153. Nausea: 43 (29.7); drowsiness: 35 (24.1%); asthenia: 33 (22.8%); dyspepsia: 28 (19.3%); diarrhea: 26 (17.9%); treatment was discontinued because of adverse effects: 8 (5.2%)	65.5%
Hirata et al[36], 2020	Triple therapy: vonoprazan, amoxicillin, and rifabutin	n = 19. Diarrhea: 4 (21.0%); headache: 1 (5.2%); taste change: 1 (5.2%); ear fullness: 1 (5.2%)	42.0%
Gisbert et al[15], 2014	BQT: Bismuth, PPI, tetracycline, and metronidazole	n = 192. Nausea: 24 (12%); abdominal pain: 22 (11%); metallic taste: 17 (8.5%); diarrhea: 16 (8%); asthenia: 15 (7.5%); vomiting: 13 (6.5%); headache: 2 (1%); oral injury: 1 (0.5%); dizziness: 1 (0.5%); myalgia: 1 (0.5%)	22.0%
Chen et al[21], 2016	BQT: bismuth, lansoprazole, metronidazole, and amoxicillin	n = 156. Flavor distortion: 2 (1.3%); dyspepsia: 2 (1.3%); nausea: 30 (19.2%); vomiting: 4 (2.6%); abdominal pain: 1 (0.7%); swelling: 8 (5.1%); diarrhea: 1 (0.7%); dizziness: 10 (6.4%); headache: 2 (1.3%); skin rash: 3 (1.9%); fatigue: 2 (1.3%); fever: 1 (0.7%); treatment was discontinued because of adverse effects: 8 (5.2%)	34.0%
Rodríguez de Santiago et al[24], 2017	BQT-Pylera: Pylera® and esomeprazole or omeprazole	n = 101. Dyspepsia: 43 (43.9%); asthenia: 35 (35.7%); dysgeusia: 34 (34.7%); nausea: 26 (26.5%); abdominal pain: 25 (25.5%); abdominal swelling: 20 (20.4%); hyporexia: 19 (19.4%); diarrhea: 14 (14.3%); headache: 13 (13.3%); myalgia: 13 (13.3%); heartburn: 7 (7.1%); flatulence: 8 (8.1%); urticaria/eczema: 5 (5.1%); paresthesia: 4 (4.1%); arthralgia: 4 (4.1%); drowsiness: 3 (3.1%); cough: 3 (3.1%); depression: 3 (3.1%); oral aphthous ulcers: 2 (2.7%); itching: 2 (2.7%); mucous candidiasis: 2 (2.7%); insomnia: 1 (1.4%); constipation: 1 (1.4%); hypertensive crisis: 1 (1.4%)	67.3%
Huang et al[29], 2018	N-BQT: esomeprazole, amoxicillin, tetracycline, and metronidazole	n = 24. Abdominal pain: 3 (12.5%); nausea/vomiting: 3 (12.5%); constipation: 1 (4.2%); dizziness: 1 (4.2%); headache: 1 (4.2%); skin rash: 0 (0%); diarrhea: 0 (0%)	29.2%
Huang et al[29], 2018	Susceptibility-guided therapy	n = 39, Abdominal pain: 3 (7.7%); nausea/vomiting: 3 (7.7%); constipation: 2 (5.1%); dizziness: 0 (0%); headache: 1 (2.6%); skin rash: 1 (2.6%); diarrhea: 0 (0%)	25.6%
Liu et al[33], 2020	BQT: bismuth, esomeprazole, tetracycline, furazolidone, and Lactobacillus acidophilus	n = 50. Loose stools: 1 (2.0%); dizziness: 4 (8.0%); skin rash: 2 (4.0%); foot joint pain: 1 (2.0%); dry mouth: 3 (6.0%)	20.0%
Ji et al[37], 2020	BQT: bismuth, rabeprazole, amoxicillin, levofloxacin or furazolidone	n = 191. Abdominal pain: 4 (2.09%); constipation: 2 (1.04%); nausea: 11 (5.7); diarrhea: 5 (2.6%); flatulence: 7 (3.6%); skin rash: 5 (2.6%); pruritus: 1 (0.5%); dysgeusia: 1 (0.5%); headache: 3 (1.6%); anorexia: 0 (0%); dizziness: 8 (4.1%); dyspepsia: 6 (3.1%); drowsiness: 0 (0%); Fever: 2 (1.0%); paresthesia: 1 (0.5%); tachycardia: 2 (1.0%); vomiting: 1 (0.5%); fatigue: 2 (1.0%); suspended treatment because of adverse effects: 6 (3.1%)	20.4%
Ji et al[37], 2020	Susceptibility-guided therapy	n = 163. Abdominal pain: 8 (4.9%); constipation: 2 (1.2%); nausea: 10 (6.2%); diarrhea: 3 (1.8%); flatulence: 9 (5.5%); skin rash: 2 (1.2%); pruritus: 3 (1.8%); dysgeusia: 6 (3.7%); headache: 2 (1.2%); anorexia: 1 (0.6%); dizziness: 3 (1.8%); dyspepsia: 1 (0.6%); drowsiness: 1 (0.6%); fever: 1 (0.6%); paresthesia: 0 (0%); tachycardia: 0 (0%); vomiting: 0 (0%); fatigue: 0 (0%); treatment was discontinued because of adverse effects: 2 (1.2%)	23.3%
Nyssen et al[39], 2020	BQT-Pylera: Pylera® and PPI	n = 275. Nausea: 45 (16.0%); metallic taste: 13 (4.7%); diarrhea: 44 (16.0%); vomiting: 27 (9.8%); fatigue: 33 (12.0%); abdominal pain: 22 (8.0%); anorexia: 32 (12.0%)	42.0%
Nyssen et al[39], 2020	BQT: bismuth, PPI, metronidazole, and tetracycline	n = 85. nausea: 35 (41.0%); metallic taste: 30 (35.0%); diarrhea: 22 (26.0%); vomiting: 15 (18.0%); fatigue: 10 (12.0%); abdominal pain: 5 (5.9%); anorexia: 6 (7.1%)	52.0%
Nyssen et al[39], 2020	BQT: bismuth, PPI, metronidazole, and doxycycline	n = 94. nausea: 12 (13.0%); metallic taste: 5 (5.3%); diarrhea: 3 (3.2%); vomiting: 3 (3.2%); fatigue: 4 (4.3%); abdominal pain: 4 (4.3%); anorexia: 0 (0%)	30.0%
Costa et al[25], 2017	Susceptibility-guided therapy	n = 42. Abdominal pain: 7 (16.7%); diarrhea: 5 (11.9%); nausea: 4 (9.5%); vomiting: 3 (7.1%); change in taste sensation: 1 (2.3%); treatment was discontinued because of adverse effects: 2 (4.7%)	35.7%
Liou et al[28], 2018	Susceptibility-guided therapy	Clinical Trial 1 (n = 21). Rash: 0 (0%); dizziness: 4 (19.0%); headache: 1 (4.8%); taste distortion: 0 (0%); swelling: 1 (4.8%); abdominal pain: 0 (0%); nausea: 1 (4.8%); vomiting: 0 (0.0%); diarrhea: 2 (9.5%); constipation: 0 (0.0%)	42.9%
Liou et al[28], 2018	Susceptibility-guided therapy	Clinical Trial 2 (n = 202). Skin rash: 5 (2.5%); dizziness: 25 (12.4%); headache: 8 (4.0%); taste distortion: 7 (3.5%); swelling: 22 (10.9%); abdominal pain: 9 (4.5%); nausea: 38 (18.8%); vomiting: 14 (6.9%); diarrhea: 4 (2.0%); constipation: 1 (0.5%)	51.0%
Liou et al[28], 2018	N-BQT: esomeprazole, amoxicillin, metronidazole, and tetracycline	Clinical Trial 2 (n = 202). Skin rash: 3 (1.5%); dizziness: 18 (8.9%); headache: 11 (5.5%); taste distortion: 9 (4.5%); swelling: 11 (5.5%); abdominal pain: 6 (3.0%); nausea: 30 (14.9%); vomiting: 6 (3.0%); diarrhea: 14 (6.9%); constipation: 4 (2.0%)	50.5%
Liou et al[28], 2018	N-BQT: esomeprazole, amoxicillin, metronidazole, and doxycycline	Clinical Trial 1 (n = 20). Rash: 0 (0%); dizziness: 3 (15.0%); headache: 2 (10.0%); taste distortion: 1 (5.0%); swelling: 0 (0%); abdominal pain: 2 (10.0%); nausea: 1 (5.0%); vomiting: 0 (0%); diarrhea: 3 (15.0%); constipation: 1 (5.0%)	55.0%

BQT: Bismuth quadruple therapy; EAS: Esomeprazole, amoxicillin, and sitafloxacin; EMS: Esomeprazole, metronidazole, and sitafloxacin; N-BQT: Non-bismuth quadruple therapy; PPI: Proton pump inhibitor; RAS: Rabeprazole, amoxicillin, and sitafloxacin; RMS: Rabeprazole, metronidazole, and sitafloxacin.