Pharmacological therapy used in the elimination of Helicobacter pylori infection: A review

Table 1 Quantitative data summary

Therapy	Drug protocols	Experimental design	Side effects(% or number of patients)	Eradication rate	Compliance	Statistical significance	Ref.
Triple Therapy	Rabeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg twice daily for 7 or 10 d	Randomized, controlled trial carried out at the Gastroenterology Unit of The Lagos State University Teaching Hospital, Ikeja, Nigeria, from June 2012 to August 2013	No adverse effects were reported	7 d: 88.9% (UBT) 10 d: 86.2% (UBT)	Compliance was 100%	The 10-d treatment showed no significant advantage over the 7-d treatment	Onyekwere et al[16]
Triple Therapy	Esomeprazol regimen: esomeprazole 20 mg, clarithromycin 400 mg, and amoxicillin 750 mg for the first 7 d, with all drugs given twice daily Lansoprazole regimen: lansoprazole 30 mg, clarithromycin 400 mg, and amoxicillin 750 mg for the first 7 d, with all drugs given twice daily	Multicenter, randomized, open-label, non-inferiority trial performed at 20 hospitals with Osaka Gut Forum from May 2012 to February 2013 in Japan Samples: 268 patients equally divided between regimens	Esomeprazol regimen: Diarrhea (36.7%), Bitter taste (16.12%), Nausea (1%), Vomiting (3.2%), Eruption (3.2%), Fatigue (1%), Appetite loss (3.2%), Thirst (2.1%), Belching (1%), Bad breath (1%), Sore throat (1%), Joint paint (1%), Chest discomfort (2.1%), Floating (1%), Abdominal wind (1%), and Constipation (1%). Lansoprazole regimen: Diarrhea (41.31%), Bitter taste (16.12%), Nausea (1%), Eruption (3.2%), Headache (2%), Appetite loss (1%), Stomatitis (1%), Cheilitis (2.1%), Leg edema (1%), Abdominal wind (1%), Constipation (1%), and Pruritus ani (1%)	Group A: 69.4% (ITT), 76.9% (PP) Group B: 73.9% (ITT), 79.8% (PP)	Compliance of all patients except for 3 patients (50%, 79%, 86%) was 100% in the PP population and was excellent based on all patients’ medication diaries	Esomeprazole showed non-inferiority and safety in a 7-d triple therapy treatment for the eradication of H. pylori compared with lansoprazole	Nishida et al[27]
Triple Therapy	Group A: levofloxacin, 500 mg b.i.d., amoxicillin/clavulanate, 875 mg/125 mg b.i.d., and rabeprazole, 20 mg b.i.d. for 7 d Group B: clarithromycin, 500 mg b.i.d., amoxicillin, 1000 mg b.i.d., and rabeprazole, 20 mg b.i.d. for seven days	Single-center, prospective study performed between December 2007 and December 2009 in Taiwan	Group A: Abdominal pain (2), Flatus/abdominal fullness (1), Loose stool/diarrhea (3), Nausea/hiccough (4), Vomiting (2), Change in appetite (2), and Insomnia (1). Group B: Abdominal pain (2), Flatus/abdominal fullness (3), Loose stool/diarrhea (1), Nausea/hiccough (4), and Change in appetite (4)	Group A: 78.1% (ITT), 80.9% (PP) Group B: 57.5% (ITT), 61.8% (PP)	Group A: Lost to follow-up (n = 3) (lost contact, n = 1, withdrew, n = 2), Protocol violation n = 2) (received amoxicillin/clavulanate from ENT doctor before follow-up, n = 1, follow-up < 3 wk, n = 1 Group B: Lost to follow-up (n = 4), (withdrew, n = 4), Protocol violation (n = 1) (follow-up < 3 wk, n = 1)	Triple therapy with levofloxacin provided improved H. pylori eradication efficacy when compared with the standard triple therapy in eastern Taiwan	Chen et al[26]
Triple Therapy	Group A: triple therapy with clarithromycin for 10 d Group B: triple therapy with levofloxacin for 10 d	Prospective study performed from October 2010 to October 2011 at the Hospital of Lídice, Venezuela Samples: 81 patients, 42 in Group A, and 39 in Group B	Group A: Nausea and Diarrhea (20.33%) Group B: Nausea and Diarrhea (8.4%)	Group A: 66.66% Group B: 94.87% 1determination of H. pylori was performed using hematoxylin and eosin (HE) and Giemsa (when HE negative)	Not described	Treatment with levofloxacin was more effective than conventional triple therapy	Dib et al[11]
Triple Therapy	Esomeprazole, amoxicillin and clarithromycin for either 7 dor 14 d	Prospective, randomized, comparative trial of 7-d and 14-d triple therapy regimens conducted at the Aga Khan University Hospital, Nairobi Samples: 120 patients, 60 in the 7-d group, and 60 in the 14-d group	Headache, Nausea, Vomiting, Diarrhea, Loss of appetite, Taste disturbance, Abdominal pain and Rash. 17 (34%) were affected in the 7-d group, and 25 (53.2%) were affected in the 14-d group	7 d: 76.7% (ITT) and 92% (PP). 14 d: 73.3% (ITT) and 93.6% (PP)	Compliance was found to be inadequate (intake of < 90% of total tablets) in 1 patient (1.02%). Compliance was good in 97 (98.98%) of the participants	No significant difference between 7- and 14-d triple therapy regimens	Sokwala et al[15]
Triple Therapy	Rabeprazole group: rabeprazole 10 mg b.i.d., amoxicillin 750 mg b.i.d., and metronidazole 250 mg b.i.d (7 d) Lafutidine group: lafutidine 10 mg t.i.d., amoxicillin 750 mg b.i.d., and metronidazole 250 mg b.i.d. (7 d)	Prospective, randomized, comparative trial of 7-d second-line amoxicillin- and metronidazole-containing triple therapy study performed at the University of Toyama, Toyama, Japan. Samples: 52 patients, 26 in the rabeprazole group, and 26 in the lafutidine group	Rabeprazole group: Soft stool (3), Diarrhea (1), and Flatus (1). Lafutidine group: Soft stool (2), Diarrhea (1), and Abdominal bloating (1)	96.2% (ITT and PP) for both groups	All patients completed treatments according to the protocols, and the rate of compliance was 100%	The treatments with both the H2-receptor antagonist lafutidine and the PPI rabeprazole together with clarithromycin and metronidazole were similarly safe and effective in the eradication of H. pylori after the failure of clarithromycin-based regimens	Kudo et al[17]
Triple Therapy	Lansoprazole 30 mg, amoxicillin 1000 mg and moxifloxacin 400 mg for 7 d or 10 d	Prospective, randomized, comparative trial of 10-d vs 7-d moxifloxacin-based therapy conducted at Clinical Hospital Sveti Duh, Zagreb, Croatia. Samples: 150 patients divided equally into both groups	7-d group: Epigastric discomfort (3), Nausea/vomiting (2), Diarrhea (3), Constipation (1), Headache (1), and Skin rash (1). 10-d group: Pruritus (2), Metallic taste (2), Epigastric discomfort (4), Nausea/vomiting (3), Diarrhea (5), and Headache (2)	7 d: 76% (ITT) and 84% (PP) 10 d: 84% (ITT) and 90% (PP)	All patients were included in the ITT analysis. 12 patients (8%) did not complete the study for one of the following reasons: loss to follow-up (n = 1), refusal to go under a second endoscopy (n = 3), adverse effects leading to the discontinuation of treatment (n = 5), taking disapproved medication (n = 2) and taking less than 80% of the prescribed medicines (n = 1). Those patients were excluded from the PP analysis	Moxifloxacin-based treatment is an effective and safe option compared to standard triple regimens due to the increased prevalence of clarithromycin resistance observed in the standard regimens	Bago et al[18]
Triple Therapy	Group 1: levofloxacin 500 mg o.d., amoxicillin 1 g b.i.d and proton pump inhibitor b.i.d. for 10 d Group 2: levofloxacin 500 mg b.i.d., amoxicillin 1 g b.i.d. and proton pump inhibitor b.i.d. for 10 d	Single-center, randomized, open-label trial carried out in Ankara, Turkey Samples: 110 patients equally divided into two groups	Not described	Group 1: 60% Group 2: 72.7%	All patients completed the study	The efficacy of the triple therapy containing levofloxacin was not within the acceptable limits for first-line H. pylori eradication	Seven et al[24]
Triple Therapy	Group 1: clarithromycin 500 mg twice daily, amoxicillin 1000 mg twice daily, and esomeprazol 20 mg twice daily for 7 d Group 2: levofloxacin 500 mg once daily, amoxicillin 1000 mg twice daily, and esomeprazol 20 mg twice daily for 7 d Group 3: levofloxacin 500 mg once daily, clarithromycin 500 mg twice daily, and esomeprazol 20 mg twice daily for 7 d	Prospective, randomized, parallel-group, comparative, multicenter study carried out at 2 centers in the Kingdom of Saudi Arabia (Al Noor Hospital in Makkah and Al Ameed Polyclinic in Al Kharj) and the National Liver Institute in Egypt between November 2006 and May 2009 Samples: 450 patients equally distributed into groups	Group 1: Nausea (38), Taste disturbance (16), Diarrhea (30), Headache (16), and Abdominal pain (32) Group 2: Nausea (34), Taste disturbance (14), Diarrhea (28), Headache (16), and Abdominal pain (28) Group 3: Nausea (33), Taste disturbance (18), Diarrhea (22), Headache (17), and Abdominal pain (26)	Group 1: 78.6% (ITT), 81.3% (PP) Group 2: 84.7% (ITT), 86.7% (PP) Group 3: 90.6% (ITT), 93.7% (PP)	Of these 450 patients, 14 were excluded from the per protocol analysis; 3 due to poor compliance, 2 who had taken their breath test less than 42 d after the completion of treatment, and 9 who had not attended visit 3	The combined levofloxacin, clarithromycin and esomeprazol-based regimen as a first-line triple therapy for H. pylori eradication can allow for a more significant eradication rate with similar safety compared with the classic triple therapy	Assem et al[25]
Triple Therapy	Group 1: 20 mg omeprazol, 1 g amoxicillin, and 500 mg clarithromycin twice daily for 2 wk Group 2 (with vitamin C): 20 mg omeprazol, 1 g amoxicillin, 250 mg clarithromycin and 250 mg vitamin C twice daily for 2 wk	Prospective, randomized, controlled study conducted in Iran. Samples: 214 patients, 100 in Group 1, and 114 in Group 2	Not described	Group 1: 89% Group 2 (with vitamin C): 86.8%	Not described	Adding vitamin C might reduce the needed dosage of clarithromycin for the eradication of H. pylori	Kaboli et al[32]
Triple Therapy	Group 1: amoxicillin 500 mg b.i.d., metronidazole 500 mg b.i.d., bismuth 240 mg b.i.d. and omeprazole 20 mg b.i.d. Group 2 (with vitamin C): amoxicillin 500 mg b.i.d., metronidazole 500 mg b.i.d., bismuth 240 mg b.i.d., omeprazole 20 mg b.i.d. and vitamin C 500 mg/d	Randomized, controlled clinical trial performed at Taleghani Research Center of Gastroenterology and Liver Disease in Iran Samples: 312 patients, 162 in Group 1, and 150 in Group 2	Nausea, Loose stool, and Headache for both groups	Group 1: 48.8% (ITT), 56.4% (PP) Group 2: 78% (ITT), 83% (PP)	Twenty-two patients from group 1 did not terminate the course of treatment due to non-compliance and minor side effects. Nine patients from group 2 were excluded from the per-protocol analysis due to the discontinuation of treatment for minor side effects. In total, 141 patients completed the treatment course	Adding vitamin C to the H. pylori treatment regimen of amoxicillin, metronidazole and bismuth can significantly increase the H. pylori eradication rate	Zojaji et al[33]
Triple Therapy	Rabeprazole 20 mg b.i.d., clarithromycin 500 mg b.i.d., and amoxicillin 1 g b.i.d. for 7 d, for 10 d or for 14 d	Prospective, randomized, controlled study performed at 2 endoscopic centers in Greece Samples: 307 patients equally divided between the groups	Not described	7 d: 74.5% 10 d: 90.2% 14 d: 76% 1Campylobacter-like organism (CLO) test and histology	Not described	Both 10- and 14-d rabeprazole-based triple regimens reached eradication rates of above the threshold of 80% on an intention-to-treat basis	Karatapanis et al[40]
Triple Therapy	Levofloxacin group: levofloxacin 500 mg, esomeprazole 40 mg and clarithromycin 500 mg once daily Amoxicillin group: amoxicillin 1 g, esomeprazole 40 mg, and clarithromycin 500 mg twice daily	Prospective, randomized, open-label trial performed at the Keelung Chang- Gung Memorial Hospital in Taiwan. Samples: 189 patients, 90 in the levofloxacin group, and 99 in the amoxicillin group	Levofloxacin group: Taste distortion (3), Diarrhea (1), Dizziness (1), Headache (2), and Abdominal pain (1). Amoxicillin group: Diarrhea (1), Headache (1), Abdominal pain (2), Skin rash (4), and Taste distortion (4)	Levofloxacin groups: 78.9% (ITT), 83.5% (PP) Amoxicillin groups: 74.8% (ITT), 86% (PP)	Levofloxacin group: all patients completed the 7-d course of eradication therapy, but one became pregnant during the study period, one expired due to hepatocellular carcinoma, and three were lost to follow-up. Amoxicillin group: six failed to take all of the 7-d eradication drugs (four with skin allergies and two with intolerances to all drugs). The remaining seven patients were lost to follow-up	The efficacy and tolerability of once-daily levofloxacin-containing triple therapy were equal to those of the standard twice-daily triple therapy	Chen et al[22]
Triple Therapy	MTL regimen: moxifloxacin 400 mg once daily, tetracycline 500 mg four times a day, lansoprazole 30 mg twice daily and bismuth subcitrate at double dose of 300 mg twice daily for 14 d	Single-center, prospective, open-label study performed at the Gastroenterology Department of the Ankara Education and Research Hospital in Turkey in 2012. Sample: 74 patients	Darkening of stool (38.9%), Nausea (33.8%), Metallic taste (29.2%), Headache (18.4%), Vomiting (15.3%), Itching (12.3%), Abdominal pain (9.2%), Diarrhea (6.1%), Skin rash (6.1%), and Constipation (4.6%)	82.1% (ITT and PP)	Drug compliance was 98.6%	The addition of bismuth to the MTL regimen as a 2-wk course achieved a 82.1% eradication rate with relatively mild side effects	Ergül et al[2]
Sequential Therapy	Lansoprazole 30 mg b.i.d. and amoxicillin 1000 mg b.i.d. for the first five days followed by lansoprazole 30 mg b.i.d. and levofloxacin 500 mg b.i.d. for the remaining five days	Prospective, open-label study conducted at the Gastroenterology Outpatient Clinic in Turkey Sample: 40 patients	Nausea and Metallic Taste (8.4%)	67.5% (ITT), 71% (PP)	Thirty-eight patients completed the study	Levofloxacin-based sequential therapy had less efficacy	Güzelbulut et al[21]
Sequential Therapy	Group A: pantoprazole 40 mg b.i.d. and amoxicillin 1 g b.i.d. for 5 d followed by pantoprazole 40 mg b.i.d., tetracycline 500 mg q.i.d., and metronidazole 500 mg t.i.d. for the remaining 9 d Group B: pantoprazole 40 mg b.i.d. and amoxicillin 1 g b.i.d. for 5 d, followed by pantoprazole 40 mg b.i.d., tetracycline 500 mg q.i.d., metronidazole 500 mg t.i.d., and amoxicillin 1 g b.i.d. for the remaining 9 d	Prospective, randomized, controlled study performed at Haydarpas, a Numune Education and Research Hospital, Gastroenterology Outpatient Clinic, Istanbul, Turkey between January 2009 and April 2009. Sample: 112 patients equally divided onto the groups	Group A: Diarrhea (2), Nausea (2), and Abdominal discomfort (4) Group B: Diarrhea (3), Nausea (2), and Abdominal discomfort (2)	Group A: 82.1% (ITT), 83.6% (PP) Group B: 78.57% (ITT), 81.48% (PP)	None of the patients discontinued the therapy because of adverse effects	Extended duration of amoxicillin treatment during the entire tetracycline-containing sequential therapy period did not improve the H. pylori eradication rate	Cetinkaya et al[39]
Sequential Therapy	Pantoprazole 40 mg b.i.d. (30 minutes before meals for 14 d), colloidal bismuth subcitrate, 300 mg (equivalent to Bi2O3 120 mg) (two tablets at 1 hour before breakfast and dinner for 14 d), amoxicillin, 1 g b.i.d. (from day 1 to day 7), tetracycline 500 mg q.i.d. (an hour after meals and at bedtime from day 8 to day 14 with ample amounts of water), and metronidazole, 500 mg t.i.d. (after meals from day 8 to day 14)	Prospective, randomized, controlled study carried out at four medical centers in different geographic regions of Turkey. Sample: 142 patients equally divided into the groups	Diarrhea (1), Vaginal discharge (1), Facial swelling (1), Nausea/vomiting (1), Numbness of face and hands (1), Fever and Epigastric pain (1)	80.98% (ITT), 92% (PP)	Compliance was satisfactory (11 patients, four women and seven men, were unavailable for follow-up)	The 14-d modified sequential treatment, including bismuth, achieved significantly high eradication rates in patients with H. pylori infection, with five compliant patients and minor side effects	Uygun et al[41]
Sequential Therapy	A standard dosage of proton pump inhibitor (PPI) and amoxicillin 1 g for the first 5 d (both twice daily) followed by a standard dosage of PPI, levofloxacin 500 mg and tetracycline 500 mg for the remaining 5 d (all given twice daily) plus a standard dosage of PPI once daily every day for an additional 4 wk	Prospective study performed at a primary gastroenterological center located in South Italy[Servizio di Gastroenterologia Territoriale, ASL BAT, Andria (BT)]	Twenty-nine patients (24.37%) showed side effects. Two (1.68%) experienced severe side effects (vomiting, diarrhea, and abdominal pain) and withdrew from the study. The additional 27 patients (22.69%) experienced some side effects but completed the study	67.23% (ITT), 68.38% (PP)	One-hundred and one patients (84.87%) were fully compliant	A 10-d sequential triple therapy containing amoxicillin, levofloxacin and tetracycline seems to be effective and safe in curing resistant H. pylori infection	Tursi et al[42]
Quadruple Therapy	Group A (quadruple therapy with doxycycline): esomeprazole 20 mg b.i.d., bismuth potassium citrate 220 mg b.i.d., amoxicillin 1 g b.i.d. and doxycycline 100 mg b.i.d. for ten days Group B (quadruple therapy): esomeprazole 20 mg b.i.d., bismuth potassium citrate 220 mg b.i.d., metronidazole 400 mg b.i.d. and tetracycline 750 mg q. 6 h for ten days	An open-label, controlled study conducted from April 2010 to March 2011 in China Sample: 85 patients, 43 in Group A, and 42 in Group B	Group A: Nausea (2), Diarrhea (1), Headache (2), Abdominal pain (2), and Anorexia (2). Group B: Nausea (5), Diarrhea (2), Headache (2), Abdominal pain (5), Anorexia (4), Constipation (1), and Dizziness (1)	Group A: 67.4% (ITT), 72.5% (PP) Group B: 59.5% (ITT), 64.1% (PP)	Compliance was 100%	Quadruple therapy containing doxycycline is as effective as routine quadruple therapy for H. pylori eradication	Wang et al[49]
Quadruple Therapy	Group A: quadruple therapy with metronidazole, metronidazole 500 mg b.i.d, amoxicillin 1 g b.i.d, omeprazole 20 mg b.i.d, and bismuth 240 mg b.i.d Group B: quadruple therapy with azithromycin, azithromycin 500 mg once daily for 1 wk and amoxicillin 1 g b.i.d, omeprazole 20 mg b.i.d, and bismuth 240 mg b.i.d for 2 wk	Double-blind, randomized clinical trial conducted at Rasoule-Akram Hospital, Iran, in 2006 Sample: 60 patients equally divided between the groups	Not described	Group A: 68% (UBT) Group B: 69% (UBT)	Group A: five patients discontinued treatment because of the side effects of the treatment. Group B: one patient discontinued treatment because of the side effects of the treatment	No significant difference was observed between the two quadruple-therapy regimens that were tested	Agah et al[52]
Quadruple Therapy	Group A: quadruple therapy (2 wk), azithromycin 500 mg twice daily for 6 d and omeprazole 20 mg, amoxicillin 1 g, and bismuth 240 mg, all given twice daily for 2 wk Group B: quadruple therapy (3 g azithromycin for 1 wk), azithromycin 500 mg twice daily for 3 d and omeprazole 20 mg, amoxicillin 1 g, and bismuth 240 mg, all given twice daily for 1 wk Group C: quadruple therapy (1.5 g azithromycin for 1 wk): azithromycin 250 mg twice daily for 3 d and omeprazole 20 mg, amoxicillin 1 g, and bismuth 240 mg, all given twice daily for 1 wk	Prospective, open-label, randomized study performed in Iran Sample: 84 patients, 31 in Group A, 28 in Group B and 25 in Group C	The frequencies of drug side effects were as follows: Group A: 19.23% Group B: 7.6% Group C: 0%	Group A: 92% (UBT) Group B: 88.46% (UBT) Group C: 80% (UBT)	Not described	One-week quadruple regimens of 3 g azithromycin may be more favorable for H. pylori eradication	Rogha et al[53]
Sequential Therapy with Triple Therapy	Sequential therapy group (14 d): esomeprazole 40 mg b.i.d. and amoxicillin 1 g b.i.d. for the first week followed by esomeprazole 40 mg b.i.d., levofloxacin 500 mg q.d. and metronidazole 500 mg t.i.d. for the second week. Triple therapy group (2 wk): esomeprazole 40 mg b.i.d., amoxicillin 1 g b.i.d. and clarithromycin 500 mg b.i.d	Prospective, randomized, parallel-arm trial conducted at an outpatient center of an academic medical center in Turkey Sample: 150 patients equally divided among the groups	Twenty-two (14.6%) patients reported side effects, such as nausea (7), metallic taste (6), diarrhea (5), abdominal pain (4), vomiting (2) and rash (1). One patient in the sequential group stopped treatment because of severe nausea, vomiting and abdominal pain during the second week of treatment	Sequential therapy group: 90.2% (ITT) Triple therapy group: 50.7% (ITT)	Seventy-two patients in the sequential therapy group and 67 patients in the triple therapy group completed their regimens and were included in the per-protocol population	Both regimens were similarly well tolerated, and the side effects were comparable	Polat et al[38]
Sequential Therapy with Triple Therapy	Standard triple therapy: rabeprazole 20 mg, amoxicillin 1.0 g and clarithromycin 500 mg twice daily for 7 d, 10 d or 14 d Sequential treatment: amoxicillin 1.0 g and rabeprazole 20 mg twice daily for the first 5 d followed by rabeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg twice daily for the remaining 5 d (10 d total)	Prospective, open-label study performed from March 2008 to August 2011 at the Korea University Anam Hospital Sample: 460 patients equally divided among the groups	Triple therapy (7 d): Taste alteration (1), Loose stools (3), Abdominal distention (2), Nausea/vomiting (2), and Epigastric discomfort (3). Triple therapy (10 d): Taste alteration (1), Loose stools (3), Abdominal distention (3), Nausea/vomiting (4), Epigastric discomfort (2), and Itching (1). Triple therapy (14 d): Taste alteration (1), Loose stools (2), Abdominal distention (3), Nausea/vomiting (3), Epigastric discomfort (3), and Itching (3). Sequential therapy: Taste alteration (1), Loose stools (3), Abdominal distention (3), Nausea/vomiting (4), Epigastric discomfort (3), and Itching (1)	Triple therapy (7 d): 70.4% (UBT) Triple therapy (10 d): 74.7% (UBT) Triple therapy (14 d): 80% (UBT) Sequential therapy (14 d): 75.6% (UBT)	The compliance was greater than 95% for all groups	No significant differences between the 10-d sequential eradication therapy for H. pylori and any duration of the standard triple treatments were observed in the Korean patients	Choi et al[43]
Sequential Therapy with Quadruple Therapy	Quadruple therapy: esomeprazole 40 mg, amoxicillin 1 g, levofloxacin 500 mg and tinidazole 500 mg, all given twice daily for 5 consecutive days. Sequential therapy: esomeprazole 40 mg twice daily and amoxicillin 1 g twice daily for 5 d followed by esomeprazole 40 mg, levofloxacin 500 mg and tinidazole 500 mg, all given twice daily for 5 additional days	Prospective, randomized, controlled study performed between January and December 2011 in Italy. Sample: 468 patients. Each group consisted of 90 patients	Quadruple therapy: Diarrhea (9), Epigastric pain (6), Nausea (6), Vomiting (5), Glossitis (7), Bad taste/taste alteration (25), Headache (4), Itching (5), and Skin rash (5). Sequential therapy: Diarrhea (7), Epigastric pain (7), Nausea (5), Vomiting (3), Glossitis (6), Bad taste/taste alteration (24), Headache (3), Itching (2), and Skin rash (2)	Quadruple therapy: 92.2% (ITT), 95% (PP) Sequential therapy: 93.3% (ITT), 95.5% (PP)	Discontinuation of therapy: quadruple therapy; 4 patients (4.4%) Sequential therapy; 2 patients (2.2%)	Five days of levofloxacin-containing quadruple concomitant therapy was effective, safe, and less costly in eradicating H pylori infection compared with 10 d of levofloxacin-containing sequential therapy	Federico et al[30]
Sequential Therapy with Quadruple Therapy	Sequential therapy: esomeprazole 20 mg twice daily and amoxicillin 1 g twice daily for the first 5 d followed by esomeprazole 20 mg twice daily, clarithromycin 500 mg twice daily and metronidazole 400 mg four times daily for the subsequent 5 d Quadruple therapy: esomeprazole 20 mg twice daily, bismuth subcitrate 120 mg four times daily, tetracycline 500 mg four times daily and metronidazole 400 mg four times daily for a total of 10 d	Prospective, open-label, randomized, crossover study performed at the Department of Medicine, Queen Mary Hospital, Hong Kong, China. Sample: 357 patients. 179 in the sequential therapy group, and 178 in the quadruple therapy group	Sequential therapy: Nausea (1), Vomiting (2), Increased stool frequency (1), Abdominal pain (1), Skin rash (4), Taste disturbance (3), Dizziness (1), and Headache (1). Quadruple therapy: Nausea (6), Vomiting (4), Increased stool frequency (3), Abdominal pain (3), Skin rash (4), Taste disturbance (2), Dizziness (3), Headache (2), Insomnia (1), and Fatigue (1)	Sequential therapy: 89.4% (ITT), 95.2 (PP) Quadruple therapy: 92.7% (ITT), 98.9% (PP)	Sequential therapy: 92.7% and quadruple therapy: 91.6%	Both sequential therapy and modified bismuth containing quadruple therapy were highly effective as first-line therapies in eradicating H. pylori in Hong Kong Chinese patients with a low frequency of adverse events	Liu et al[55]
Sequential Therapy with Concomitant Therapy and Triple Therapy	Sequential therapy: pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily for 5 d followed by pantoprazole 40 mg, clarithromycin 500 mg and metronidazole 500 mg, all given twice daily for an additional 5 d Concomitant treatment: pantoprazole 40 mg, clarithromycin 500 mg, amoxicillin 1 g and metronidazole 500 mg, all given twice daily for 7 d Triple therapy: pantoprazole 40 mg, clarithromycin 500 mg, and amoxicillin 1 g, all given twice daily for 7 d	Open-label, randomized trial conducted at the Kaohsiung Veterans General Hospital in Taiwan Sample: 306 patients equally divided among groups	Sequential therapy: Constipation (1), Taste perversion (2), Headache (1), Anorexia (1), Nausea (5), Vomiting (5), Fatigue (1), and Others (1). Concomitant therapy: Abdominal pain (1), Diarrhea (1), Taste perversion (4), Headache (5), Anorexia (1), Nausea (7), Vomiting (7), and Others (3). Triple therapy: Constipation (1), Diarrhea (3), Taste perversion (1), Nausea (3), Vomiting (4), Skin rash (1), and Others (1)	Sequential therapy: 89.2% (ITT), 90% (PP) Concomitant therapy: 94.1% (ITT), 94.1% (PP) Triple therapy: 81.6% (ITT), 82.2% (PP)	All groups displayed similar compliance rates: triple therapy: 99.0% sequential therapy: 98.0%, concomitant therapy: 100%	Concomitant therapy is superior to standard triple therapy for H. pylori eradication and is less complex than sequential therapy because the drugs are not changed halfway through the treatment course	Hsu et al[54]
Quadruple Therapy with Triple Therapy	Group A: quadruple therapy; omeprazole 20 mg, metronidazole 500 mg, amoxicillin 1 g and bismuth subcitrate 240 mg, all given twice daily for 14 d Group B: triple therapy with penbactam; omeprazole 20 mg, clarithromycin 500 mg and penbactam 750 mg, all given twice daily for 14 d Group C: triple therapy: omeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g, all given twice daily for 14 d	A prospective double-blind, randomized clinical trial conducted at Taleghani Hospital in Tehran, Iran, from March 2007 to September 2011. Sample: 110 patients equally divided among each group	Group A: Dyspepsia (13), Diarrhea (8), Nausea (14), Abdominal pain (9), Stool abnormality (14), Dizziness (4), Headache (6), Cough (2), Bad taste (3), and Metallic taste (15). Group B: Dyspepsia (10), Diarrhea (6), Nausea (10), Abdominal pain (6), Stool abnormality (8), Dizziness (2), Headache (3), Cough (1), Bad taste (35), and Metallic taste (2). Group C: Dyspepsia (12), Diarrhea (14), Nausea (11), Abdominal pain (11), Stool abnormality (7), Dizziness (2), Headache (8), Cough (2), Bad taste (37), and Metallic taste (5)	Group A: 87% (UBT) Group B: 90.8% (UBT) Group C: 56% (UBT)	Not described	Two-week quadruple therapy showed a lower eradication rate compared to common triple treatment schedules when used as the first-line eradication treatment for H. pylori infection in Iranian population	Seyedmajidi et al[46]
Quadruple Therapy with Triple Therapy	Group A: quadruple therapy; omeprazole 20 mg, metronidazole 500 mg, amoxicillin 1 g and bismuth subcitrate 240 mg for 14 d Group B: triple therapy with penbactam; omeprazole 20 mg, clarithromycin 500 mg and penbactam 750 mg Group C: triple therapy: omeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g, all given twice daily	A prospective, double-blind, randomized clinical trial carried out at Taleghani Hospital in Tehran from March 2006 to September 2008 Sample: 330 patients, 110 in each group	Group A: Dyspepsia (13), Diarrhea (8), Nausea (14), Abdominal pain (9), Stool abnormality (14), Dizziness (4), Headache (6), Cough (2), Bad taste (3), and Metallic taste (15). Group B: Dyspepsia (10), Diarrhea (6), Nausea (10), Abdominal pain (8), Stool abnormality (2), Dizziness (3), Headache (1), Cough (1), Bad taste (35), and Metallic taste (2). Group C: Dyspepsia (12), Diarrhea (14), Nausea (11), Abdominal pain (11), Stool abnormality (7), Dizziness (2), Headache (8), Cough (2), Bad taste (37), Metallic taste (5)	Group A: 87% (UBT) Group B: 88.8% (UBT) Group C: 56% (UBT)	Not described	Two-week quadruple therapy showed a lower eradication rate compared to the common triple treatment schedules when used as the first-line eradication treatment for H. pylori infection in the Iranian population	Seyedmajidi et al[47]
Quadruple Therapy with Triple Therapy	Quadruple therapy: esomeprazole 20 mg, clarithromycin 0.5 g, amoxicillin 1.0 g, and bismuth potassium citrate 220 mg for 7 d Triple therapy: esomeprazole 20 mg, clarithromycin 0.5 g and amoxicillin 1.0 g for 7 d	Prospective, open-label, randomized study Sample: 136 patients divided equally between the groups	Not described	Quadruple therapy: 82.09% (ITT), 88.71% (PP) Triple therapy: 66.67% (ITT), 73.02% (PP)	Not described	Compared to the standard triple therapy regimen, the bismuth-containing quadruple therapy regimen has a higher eradication rate and is more cost effective than the triple therapy	Xu et al[48]
Quadruple Therapy with Triple Therapy	Triple therapy: proton pump inhibitor, amoxicillin 1,000 mg b.i.d., and clarithromycin 500 mg b.i.d. Quadruple therapy: proton pump inhibitor 12/h, metronidazole 500 mg t.i.d., tetracycline 500 mg q.i.d., and bismuth 300 mg q.i.d	Prospective, open-label study performed in Korea from 2001 to 2007 Sample: 4688 patients; 4198 in the triple therapy group, and 490 in the quadruple therapy group	Not described	UBT analyses: Triple therapy: 2001: 81.3%, 2002: 83.7% 2003: 80.1% 2004: 80.7% 2005: 82.0% 2006: 75.9% 2007: 77.5% Quadruple therapy: 2001: 77.3%, 2002: 86.2%, 2003: 95.6%, 2004: 95.9%, 2005: 89.6%, 2006: 83.2%, 2007: 86.4%	Not described	The eradication rate of the first-line therapy (triple therapy) has decreased over the last 7 yr, while that of the second-line therapy (quadruple therapy) has remained the same	Chung et al[8]
Quadruple Therapy with Triple Therapy	Triple therapy: rabeprazole 20 mg o.d., levofloxacin 500 mg o.d., and amoxicillin 1 g b.i.d. (4 tablets/d) for 7 d. Quadruple therapy: rabeprazole 20 mg, clarithromycin 500 mg, tinidazole 500 mg and bovine lactoferrin 200 mg, all given twice daily (10 tablets/d) for 7 d	Prospective, open-label, randomized, multicenter Italian study involving five hospitals (one northern, two central, two southern) Sample: 144 patients; 72 in the triple therapy group, and 72 in the quadruple therapy group	Triple therapy: eight (11.3%) patients presented with side effects, including diarrhea (2), abdominal pain (2), glossitis (2), pruritus (1), and vomiting (1). Quadruple therapy: seven (10.3%) patients presented with side effects, including diarrhea (3), abdominal pain (2), and taste disturbance (2)	Triple therapy: 68.1% (ITT), 68.2% (PP) Quadruple therapy: 72.2% (ITT), 76.5% (PP)	The reported compliance to the therapy was excellent in all groups, but one patient in the triple therapy group stopped the treatment after 6 d	The H. pylori eradication rates following both quadruple therapy with lactoferrin and low-dose, triple therapy with levofloxacin were low	Zullo et al[14]
Quadruple Therapy with Triple Therapy	Triple therapy: pantoprazole 40 mg b.i.d., amoxicillin, 1.0 g b.i.d. and clarithromycin 500 mg b.i.d. for 7 d. Quadruple therapy: pantoprazole 40 mg b.i.d., colloidal bismuth subcitrate, 220 mg b.i.d., metronidazole 400 mg t.i.d., and tetracycline 750 mg b.i.d. for 10 d	Single-center, randomized, open, parallel, controlled study performed at the Emergency Department, Renji Hospital, Shanghai Jiaotong University from 2008 to 2009 in China Sample: 170 patients; 85 in the triple therapy group, and 85 in the quadruple therapy group	Triple therapy (60%): Bitter taste, nausea, poor appetite, vomiting, drug eruption Quadruple therapy (42.3%): Bitter taste, nausea, poor appetite, diarrhea, vomiting, drug eruption	Triple therapy: 63.5% (ITT), 65.1% (PP) Quadruple therapy: 89.4% (ITT), 91.6% (PP)	All patients completed the study	The quadruple therapy was more effective than the triple therapy	Zheng et al[23]
Quadruple Therapy with Triple Therapy	Triple therapy: PPI b.i.d., clarithromycin 500 mg b.i.d., and amoxicillin 1 g b.i.d. for 1 wk Quadruple therapy: esomeprazole 20 mg b.i.d., tripotassium dicitrate bismuthate 300 mg q.i.d. (three tabs at 30 minutes before meals and one tab at 2 hours after dinner), metronidazole 500 mg t.i.d., and tetracycline 500 mg q.i.d. for 2 wk	Prospective, open-label, randomized study performed at the Seoul National University Bundang Hospital (SNUBH) in Korea from April 2003 to April 2009. Sample: 227 patients equally divided between the groups	Triple therapy: Nausea/vomiting (4), Epigastric soreness or pain (6), Bloating or dyspepsia (5), Weakness or dizziness (1), Regurgitation symptoms (2), and Anorexia (1) Quadruple therapy: Diarrhea (4), Neuromyopathy (2), Nausea/vomiting (22), Epigastric soreness or pain (12), Bloating or dyspepsia (5), Weakness or dizziness (5), Regurgitation symptoms (1), and Anorexia (1)	Triple therapy: 64.3% (ITT), 77.2% (PP) Quadruple therapy: 82.6% (ITT), 93.6% (PP)	Group A: 2 patients discontinued the treatment due to adverse events Group B: 9 patients discontinued the treatment due to adverse events	Two-week bismuth-containing quadruple therapy was more effective than the 1-wk treatment in Korean patients	Lee et al[51]

¹Method used for the detection of H. pylori.