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

Table 1 Eradication rates by therapeutic regimen

Year	Ref.	Type of study	Rescue therapy	Duration	Eradication rate
2014	Lim et al[13]	Randomized clinical trial	Group A: lansoprazole (30 mg, 12/12 h), amoxicillin (1 g, 8/8 h), and rifabutin 150 mg (12/12 h)	7 d	ITT: 78.1%; PP: 80.6%
2014	Lim et al[13]	Randomized clinical trial	Group B: lansoprazole (60 mg, 12/12 h), amoxicillin (1 g, 8/8 h), and rifabutin 150 mg (12/12 h)	7 d	ITT: 96.3%; PP: 100%
2014	Furuta et al[14]	Randomized clinical trial	RAS: rabeprazole (10 mg, 8/8 h or 12/12 h), amoxicillin (500 mg, 6/6 h), sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 84.1%; PP: 86.4%
2014	Furuta et al[14]	Randomized clinical trial	RAS: rabeprazole, amoxicillin (500 mg, 6/6 h), sitafloxacin (100 mg, 12/12 h)	14 d	ITT: 88.9%; PP: 90.9%
2014	Furuta et al[14]	Randomized clinical trial	RMS: rabeprazole, metronidazole (250 mg, 12/12 h), sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 90.9%; PP: 90.9%
2014	Furuta et al[14]	Randomized clinical trial	RMS: rabeprazole, metronidazole (250 mg, 12/12 h), sitafloxacin (100 mg, 12/12 h)	14 d	ITT: 87.2%; PP: 91.1%
2014	Gisbert et al[15]	Prospective multicenter observational study	PPI (standard dose, 12/12 h), bismuth subcitrate (120 mg 8/8 h or 240 mg, 12/12 h), tetracycline (250 mg, 6/6 h or 500 mg 8/8 h or 500 mg, 6/6 h), and metronidazole (250 mg, 8/8 h or 250 mg, 6/6 h or 500 mg, 8/8 h or 500 mg, 6/6 h)	7-14 d	ITT: 65.0%; PP: 67.0%
2014	Okimoto et al[16]	Randomized clinical trial	RAL: rabeprazole (10 mg, 12/12 h), amoxicillin (750 mg, 12/12 h), levofloxacin (500 mg, 24/24 h)	10 d	ITT: 45.8%; PP: 45.8%
2014	Okimoto et al[16]	Randomized clinical trial	RA: rabeprazole (10 mg, 6/6 h) and amoxicillin (500 mg, 6/6 h)	14 d	ITT: 40.7%; PP: 45.8%
2015	Paoluzi et al[17]	Randomized clinical trial	Esomeprazole (20 mg, 12/12 h), levofloxacin (500 mg, 12/12 h), doxycycline (100 mg, 12/12 h)	7 d	ITT: 40.0%; PP: 43.0%
2015	Paoluzi et al[17]	Randomized clinical trial	Esomeprazole (20 mg, 12/12 h), levofloxacin (500 mg, 12/12 h), doxycycline (100 mg, 12/12 h), Lactobacillus casei DG (24 billion units)	7 d	ITT: 54%; PP: 55%
2016	Muller et al[18]	Non-randomized clinical trial	Pylera® (140 mg potassium bismuth subcitrate, 125 mg metronidazole, 125 mg tetracycline, 6/6 h), omeprazole (20 mg, 12/12 h)	10 d	ITT: 83.0%; PP: 87.0%
2016	Mori et al[19]	Randomized clinical trial	Third-line: esomeprazole (20 mg, 6/6 h), amoxicillin (500 mg, 6/6 h), and rifabutin (300 mg, 24/24 h)	10 d	ITT: 83.3%; PP: 81.8%
2016	Mori et al[19]	Randomized clinical trial	Third-line: esomeprazole (20 mg, 6/6 h), amoxicillin (500 mg, 6/6 h), and rifabutin (300 mg, 24/24 h)	14 d	ITT: 94.1%; PP: 91.7%
2016	Mori et al[19]	Randomized clinical trial	Fourth-line: esomeprazole (20 mg, 6/6 h), amoxicillin (500 mg, 6/6 h), and rifabutin (300 mg, 24/24 h)	10 d	ITT: 77.9%; PP: 77.9%
2016	Mori et al[19]	Randomized clinical trial	Fourth-line: esomeprazole (20 mg, 6/6 h), amoxicillin (500 mg, 6/6 h), and rifabutin (300 mg, 24/24 h)	14 d	ITT:90.9%; PP: 90.9%
2016	Mori et al[20]	Randomized clinical trial	Esomeprazole (20 mg, 12/12 h), amoxicillin (500 mg, 6/6 h), and sitafloxacin (100 mg, 12/12 h)	10 d	ITT: 81.0%; PP: 82.0%
2016	Mori et al[20]	Randomized clinical trial	Esomeprazole (20 mg, 12/12 h), metronidazole (250 mg, 12/12 h), and sitafloxacin (100 mg, 12/12 h)	10 d	ITT: 72.4%; PP: 76.4%
2016	Chen et al[21]	Randomized clinical trial	Lansoprazole (30 mg, 12/12 h), potassium bismuth subcitrate (220 mg, 12/12 h), metronidazole (400 mg, 6/6 h), and amoxicillin (1 g, 8/8 h)	14 d	ITT: 88.5%; PP: 93.7%
2016	Chen et al[21]	Randomized clinical trial	Lansoprazole (30 mg, 12/12 h), potassium bismuth subcitrate (220 mg, 12/12 h), metronidazole (400 mg, 6/6 h), and tetracycline (500 mg, 6/6 h)	14 d	ITT: 87.2%; PP: 95.3%
2016	Noh et al[22]	Non-randomized clinical trial	PPI (standard dose, 12/12 h), levofloxacin (500 mg, 24/24 h), and amoxicillin (1 g, 12/12 h)	7 d	ITT: 58.3%; PP: 58.3%
2016	Noh et al[22]	Non-randomized clinical trial	PPI (standard dose, 12/12 h), levofloxacin (500 mg, 24/24 h), and amoxicillin (1 g, 12/12 h)	10 d	ITT: 62.5%; PP: 68.2%
2016	Noh et al[22]	Non-randomized clinical trial	PPI (standard dose, 12/12 h), levofloxacin (500 mg, 24/24 h), and amoxicillin (1 g, 12/12 h)	14 d	ITT: 73.7%; PP: 93.3%
2016	Hirata et al[23]	Non-randomized clinical trial	Esomeprazole (20 mg, 12/12 h), amoxicillin (750 mg, 12/12 h), sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 83.0%; PP: 83.0%
2017	Rodríguez de Santiago et al[24]	Multicenter observational prospective study	Pylera® (140 mg potassium bismuth subcitrate, 125 mg metronidazole, 125 mg tetracycline, 3 capsules, 6/6 h) and esomeprazole (40 mg, 12/12 h) or omeprazole (40 mg, 12/12 h)	10 d	ITT: 80.2%; PP: 84.4%
2017	Costa et al[25]	Single-center observational retrospective study	SGT	-	ITT: 59.5%; PP: 61.5%
2017	Puig et al[26]	Multicenter observational prospective study	Esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 8/8 h), and metronidazole (500 mg, 8/8 h)	14 d	ITT: 62.0%; PP: 63.0%
2018	Fiorini et al[27]	Non-randomized clinical trial	Esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 12/12 h), rifabutin (150 mg, 24/24 h)	12 d	PP: 87.9%
2018	Liou et al[28]	Randomized clinical trial	Clinical trial 1: sequential susceptibility-guided therapy: esomeprazole (40 mg, 12/12 h) and amoxicillin (1 g, 12/12 h), for the first 7 d followed by metronidazole (500 mg, 12/12 h) and levofloxacin (250 mg, 12/12 h) or clarithromycin (500 mg, 12/12 h) or doxycycline (100 mg, 12/12 h), for another 7 d. Sequential empirical therapy: esomeprazole (40 mg, 12/12 h) and amoxicillin (1 g, 12/12 h) for the first 7 d, followed by metronidazole (500 mg, 12/12 h) and doxycycline (100 mg, 12/12 h), for another 7 d	14 d	SGT ITT: 81.0%, PP: 80.0%; Sequential empirical therapy ITT: 60.0%, PP: 60.0%
2018	Liou et al[28]	Randomized clinical trial	Clinical trial 2: sequential SGT: esomeprazole (40 mg, 12/12 h) and amoxicillin (1 g, 12/12 h) for the first 7 d followed by metronidazole (500 mg, 12/12 h) and levofloxacin (250 mg, 12/12 h) or clarithromycin (500 mg, 12/12 h) or tetracycline (500 mg, 12/12 h) for another 7 d. Sequential empirical therapy: esomeprazole (40 mg, 12/12 h) and amoxicillin (1 g, 12/12 h) for the first 7 d followed by metronidazole (500 mg, 12/12 h) and tetracycline (100 mg, 12/12 h) for another 7 d	14 d	SGT ITT: 78.0%, PP: 78.4%; Sequential empirical therapy ITT: 72.2%, PP: 74.4%
2018	Huang et al[29]	Non-randomized clinical trial	SGT: esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 12/12 h) and tetracycline (500 mg, 6/6 h) or metronidazole (500 mg, 8/8 h) or levofloxacin (500 mg, 24/24 h)	14 d	ITT: 81.4%; PP: 89.7%
2018	Huang et al[29]	Non-randomized clinical trial	Empirical quadruple therapy: esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 12/12 h), tetracycline (500 mg, 6/6 h), and metronidazole (500 mg, 8/8 h)	14 d	ITT: 51.8%; PP: 58.3%
2019	Saito et al[30]	Non-randomized clinical trial	Esomeprazole (20 mg, 12/12 h), amoxicillin (750 mg, 12/12 h), and sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 54.2%; PP: 56.5%
2019	Saito et al[30]	Non-randomized clinical trial	Vonoprazan (20 mg, 12/12 h), amoxicillin (750 mg, 12/12 h), and sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 93.0%; PP: 93.0%
2019	Sue et al[31]	Randomized clinical trial	Vonoprazan (20 mg, 12/12 h) amoxicillin 750 mg, (12/12 h), and sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 75.8%; PP: 83.3%
2019	Sue et al[31]	Randomized clinical trial	Lansoprazole (30 mg, 12/12 h) or rabeprazole (10 mg, 12/12 h) or esomeprazole (20 mg, 12/12 h), amoxicillin (750 mg, 12/12 h), and sitafloxacin 100 mg, 12/12 h)	7 d	ITT: 53.3%; PP: 57.1%
2019	Ribaldone et al[32]	Non-randomized clinical trial	Fifth-line: rifabutin (150 mg, 12/12 h), amoxicillin (1 g, 12/12 h), and omeprazole (20 mg, 12/12 h), esomeprazole (40 mg, 12/12 h), pantoprazole (40 mg, 12/12 h) rabeprazole (40 mg, 12/12 h), or lansoprazole (30 mg, 12/12 h)	14 d	ITT: 71.5%; PP: 72.7%
2020	Liu et al[33]	Single center observational retrospective study	Lactobacilli acidophilus (1g, 8/8 h), esomeprazole (20mg, 12/12 h), potassium bismuth subcitrate (220 mg, 12/12 h), tetracycline (750 mg, 12/12 h), and furazolidone (100 mg, 12/12 h)	Lactobacilli acidophilus for 14 d and the others for 10 d	ITT: 92.0%; PP: 91.8%
2020	Sugimoto et al[34]	Single center observational retrospective study	Vonoprazan (20mg, 12/12 h), amoxicillin (500 mg, 6/6 h), and sitafloxacin (100 mg, 12/12 h)	7 d	ITT: 87.5%; PP: 87.5%
2020	Saracino et al[35]	Single center observational retrospective study	Third-line: esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 12/12 h), and rifabutin (150 mg, 24/24 h)	12 d	ITT: 56.1%; PP: 68.5%
2020	Saracino et al[35]	Single center observational retrospective study	Fourth-line: esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 12/12 h), and rifabutin (150 mg, 24/24 h)	12 d	ITT: 54.5%; PP: 63.1%
2020	Saracino et al[35]	Single center observational retrospective study	Fifth-line or more: esomeprazole (40 mg, 12/12 h), amoxicillin (1 g, 12/12 h), and rifabutin (150 mg, 24/24 h)	12 d	ITT: 24.4%; PP: 30.3%
2020	Saracino et al[35]	Single center observational retrospective study	Third-line: Pylera® (140 mg potassium bismuth subcitrate, 125 mg metronidazole, 125 mg tetracycline, 6/6 h) and esomeprazole (20 mg, 12/12 h)	10 d	ITT: 87.5%; PP: 91.3%
2020	Saracino et al[35]	Single center observational retrospective study	Fourth-line: Pylera® (140 mg potassium bismuth subcitrate, 125 mg de metronidazole, 125 mg tetracycline, 3 capsules, 6/6 h) and esomeprazole (20 mg, 12/12 h)	10 d	ITT: 83.9%; PP: 89.6%
2020	Saracino et al[35]	Single center observational retrospective study	Fifth-line or more: Pylera® (140 mg potassium bismuth subcitrate, 125 mg metronidazole, 125 mg tetracycline, 3 capsules, 6/6 h) and esomeprazole (20 mg, 12/12 h)	10 d	ITT: 71.9%; PP: 74.2%
2020	Hirata et al[36]	Non-randomized clinical trial	Fourth-line: vonoprazan (20 mg, 12/12 h), amoxicillin (750 mg, 12/12 h), and rifabutin (150 mg, 12/12 h)	10 d	ITT: 100.0%; PP: 100.0%
2020	Ji et al[37]	Randomized clinical trial	Susceptibility-guided quadruple therapy: rabeprazole (10 mg, 12/12 h), colloidal bismuth (200 mg, 12/12 h), 2 sensitive antibiotics	14 d	PP: 86.49%
2020	Ji et al[37]	Randomized clinical trial	Rabeprazole (10 mg, 12/12 h), colloidal bismuth (200 mg, 12/12 h), amoxicillin (1 g, 12/12 h), levofloxacin (500 mg, 24/24 h), or furazolidone (100 mg, 12/12 h)	14 d	PP: 82.4%
2020	Mori et al[38]	Non-randomized clinical trial	Esomeprazole (20 mg, 12/12 h), amoxicillin (500 mg, 6/6 h), and sitafloxacin (100 mg, 12/12 h)	10 d	ITT: 81.6%; PP: 81.6%
2020	Nyssen et al[39]	Multicentric observational retrospective study	Bismuth and tetracycline-based quadruple therapy: PPI, bismuth salts (120 mg, 6/6 h or 240 mg, 12/12 h), metronidazole (500 mg, 8/8 h), and tetracycline (500 mg, 6/6 h)	10 d	ITT: 66.0%; PP: 66.0%
2020	Nyssen et al[39]	Multicentric observational retrospective study	Bismuth and tetracycline-based quadruple therapy: PPI, bismuth salts (120 mg, 6/6 h or 240 mg, 12/12 h), metronidazole (500 mg, 8/8 h), and tetracycline (500 mg, 6/6 h)	14 d	ITT: 82.0%; PP: 83.0%
2020	Nyssen et al[39]	Multicentric observational retrospective study	Bismuth and doxycycline-based quadruple therapy: PPI, bismuth salts (120 mg, 6/6 h or 240 mg, 12/12 h), metronidazole (500 mg, 8/8 h), and doxycycline (100 mg, 12/12 h)	10 d	ITT: 63.0%; PP: 63.0%
2020	Nyssen et al[39]	Multicentric observational retrospective study	Bismuth and doxycycline-based quadruple therapy: PPI, bismuth salts (120 mg, 6/6 h or 240 mg, 12/12 h), metronidazole (500 mg, 8/8 h), and doxycycline (100 mg, 12/12 h)	14 d	ITT: 70.0%; PP: 71.0%
2020	Nyssen et al[39]	Multicentric observational retrospective study	Bismuth-based quadruple therapy, three-in-one, Pylera®: PPI and Pylera®	10 d	ITT: 88.0%; PP: 88.0%
2020	Nyssen et al[39]	Multicentric observational retrospective study	Bismuth-based quadruple therapy, three-in-one, Pylera®: PPI and Pylera®	14 d	ITT: 100.0%; PP: 100.0%
2020	Kuo et al[40]	Non-randomized clinical trial	Rifabutin (150 mg, 12/12 h), amoxicillin (1 g, 12/12 h), and esomeprazole (40 mg, 12/12 h)	10 d	ITT: 77.5%; PP: 79.5%

ITT: Intention to treat; PP: Per protocol; PPI: Proton pump inhibitor; RAS: Rabeprazole, amoxicillin, and sitafloxacin; RMS: Rabeprazole, metronidazole, and sitafloxacin; SGT: Susceptibility-guided therapy.