14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose... Abstract Background Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown. Objectives To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy. Methods We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855. Results The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%–94.1%) and 91.6% (284 of 310, 95% CI 87.8%–94.3%) in the ITT analysis, respectively (difference −0.3%, 95% CI −4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001). Conclusions Optimized 14 day sequential therapy was non-inferior to, but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance. Introduction The eradication rate for Helicobacter pylori infection, a causal factor of peptic ulcer disease and gastric cancer,1–3 is decreasing due to the rising prevalence of antibiotic resistance.4–6 The efficacies of H. pylori eradication regimens may be optimized through the use of four-drug regimens (bismuth quadruple therapy, or concomitant therapy, or sequential therapy), extending its length to 14 days, and the use of a higher dosage of proton pump inhibitor (PPI).7–24 Sequential therapy given for 10 days has been extensively compared with triple therapy and concomitant therapy of various treatment lengths in randomized controlled trials (RCTs).12,13,16 Meta-analysis of these trials showed that 10 day sequential therapy was more effective than 7 or 10 day triple therapy, but was not superior to 14 day triple therapy.12,14,18 A recent meta-analysis of RCTs showed that the efficacy of 10 day sequential therapy was superior to 5 day concomitant therapy, similar to 7 day concomitant therapy, but was inferior to 10 day concomitant therapy.25 Therefore, the Maastricht V Consensus and the Toronto Consensus recommended against the use of 10 day sequential therapy for the first-line treatment of H. pylori infection.9,10 However, sequential therapy remains one of the treatment choices in the ACG guideline.11 Recently, we showed that 10 day bismuth quadruple therapy, but not 10 day concomitant therapy, was superior to 14 day triple therapy in Taiwan where the prevalence of clarithromycin resistance was ∼15%.17 Therefore, we conducted this RCT to compare the efficacy and tolerability of optimized 14 day sequential therapy containing high-dose esomeprazole and 10 day bismuth quadruple therapy in first-line therapy. The efficacy of bismuth quadruple therapy and optimized 14 day sequential therapy in second-line rescue therapy and factors that might affect their efficacies were also assessed. Finally, we constructed the Hp-normogram26 to estimate the efficacy of the two regimens in regions with a different prevalence of antibiotic resistance. Patients and methods Trial design and settings The Institutional Review Board of each participating hospital approved this open-label, multicentre, randomized trial. Written informed consent was obtained from all patients prior to enrolment. The Clinical Trial.gov registration identifier is NCT03156855. Participants We recruited both symptomatic and asymptomatic adult subjects (≥20 years of age) in seven medical centres in Taiwan. The recruitment criteria and exclusion criteria were similar to our previous trials.13,16,17 Symptomatic patients who underwent oesophagogastroduodenoscopy due to dyspepsia or other symptoms were invited to a screening programme for H. pylori. Patients with at least two positive tests among histology, rapid urease test, culture and serology were eligible for enrolment (Criterion 1). Asymptomatic subjects who underwent gastric cancer screening with a single positive 13C-urea breath test (13C-UBT) were also eligible for enrolment (Criterion 2). Patients with any one of the following criteria were excluded from the study: (i) history of prior H. pylori eradication therapy; (ii) history of gastrectomy; (iii) severe concurrent illness or non-curative malignancy; (iv) pregnant or lactating women; (v) contraindication or previous allergic reactions to the study drugs; and (vi) patients who could not give informed consent for themselves. Study research staff explained the purpose and eligibility requirements of the study to potential participants. Randomization, blinding and intervention Eligible patients were randomized to receive either one of the following regimens: (i) optimized sequential therapy for 14 days (ST14): esomeprazole 40 mg and amoxicillin 1 g for 7 days, followed by esomeprazole 40 mg, clarithromycin 500 mg and metronidazole 500 mg for another 7 days (all given twice daily), or (ii) bismuth quadruple therapy for 10 days (BQ10): esomeprazole 40 mg twice daily, bismuth tripotassium dicitrate 300 mg (KCB F.C. Tablets; Swiss Pharm, Taiwan) four times a day, tetracycline 500 mg four times a day and metronidazole 500 mg three times a day for 10 days. The block randomization sequence with a block size of 4 in a 1:1 ratio was generated by computer. The sequence was concealed in an opaque envelope and kept by an independent research assistant (Miss Huang) in the Call Centre, the National Taiwan University Hospital (NTUH), until intervention was assigned. The study nurses from each centre contacted the independent assistant to obtain the next allocation number by phone after having obtained the written informed consents from eligible subjects to ensure adequate allocation concealment. All investigators were blind to the randomization sequence. Patients who remained positive for H. pylori after first-line 14 day sequential therapy or 10 day bismuth quadruple therapy were retreated with 10 day bismuth quadruple therapy and 14 day sequential therapy, respectively. The dosage and frequency of each regimen in the second-line treatment were the same as that of the first-line treatment. Outcome assessment The primary endpoint of the study was the eradication rate in the first-line therapy. The secondary endpoints were the frequency of adverse effects and the compliance with the first-line therapy and the eradication rates in the second-line therapy. The eradication status was determined by 13C-UBT at least 6 weeks after completion of treatment. All subjects were asked to discontinue histamine-2 blocker and PPI for at least 2 weeks before 13C-UBT. The breath samples at baseline and 30 min after taking the urea kit containing 75 mg 13C-urea were assayed in the Taipei Institute of Pathology using an infrared spectrometer that produced computer-generated results. Positive result was defined as a delta value of ≥4 units as in our previous studies.10,25 All subjects were informed of the common side effects of the study drugs before eradication therapy and were asked to record these symptoms during treatment. We also arranged a standardized outpatient clinic interview at the end of treatment. The research staff assessed the adverse events and compliance using a pre-defined case report form and counted the pills not taken by the subjects. Compliance was defined as low when they took <80% of the study drugs. Determination of phenotypic and genotypic resistance and CYP2C19 polymorphism Agar dilution test was used to determine the MICs in the central laboratory in NTUH.27 The resistance breakpoints for clarithromycin, amoxicillin, metronidazole, levofloxacin and tetracycline were defined as ≥1, ≥0.5, ≥8, >1 and >0.5 mg/L, respectively.27 The 23S rRNA mutations were genotyped by PCR followed by direct sequencing using the automatic sequencer (ABI PRISM 3100 Genetic Analyzer; Applied Biosystems).27 The VacA signal region (s1/2) and midregion (m1/2) mosaics were determined by the PCR method as described previously.13,16 The CYP2C19 polymorphism was genotyped by PCR followed by RFLP.28 Statistical analysis We assumed the eradication rate of the optimized 14 day sequential therapy to be 94% and estimated a sample size of at least 310 in each group to detect a 7% difference in the eradication rate to give a statistical power of 80% at a 5% significance level on a two-sided test, assuming lost to follow-up rate of 10%. The sample size also allows adequate power to test the hypothesis that sequential therapy for 14 days is not inferior to bismuth quadruple therapy for 10 days by 5% to give a statistical power of 80% at a 5% significance level on a one-sided test. All randomized subjects were included in the ITT analysis of the eradication rate in the first-line therapy, the primary endpoint of this study. All protocol violators, such as patients with unknown H. pylori status after eradication therapy or those who took <80% of study drugs, were excluded from the PP analysis. Patients with missing data on the safety issue were not included in the analysis. Categorical data were compared using the χ2 test or Fisher’s exact test as appropriate. Continuous data were compared with Student’s t-test and expressed as mean (SD). All P values were two-tailed, with the level of statistical significance specified as 0.05. The statistical analyses were performed using the SPSS statistical software (version 21) for Windows. The 95% CI of the eradication rate of each regimen was calculated. Ancillary analysis Multiple logistic regression analyses with the following predictors of interest: age, gender, gastric ulcer, duodenal ulcer, clarithromycin resistance (genotypic resistance using gastric biopsy specimen), compliance and CYP2C19 polymorphism were used to evaluate factors affecting the eradication rates. Patients with missing data were excluded in the regression analyses. We also constructed the Hp-normogram to predict the efficacies of the two regimens in regions with a different prevalence of clarithromycin resistance.26 The data required for model generation were based on the eradication rates of ST14 and BQ10 according to the antibiotic resistance in the ITT and PP analysis, which were obtained from the present study. Assuming the eradication rate in strains susceptible and resistant to clarithromycin were A and B, respectively, the predicted eradication rate of that regimen would be A×(1 − p)+B × p, where the prevalence of clarithromycin was p (0≤p≤1). The predicted efficacies of ST14 and BQ10 according to the prevalence of clarithromycin resistance were plotted using Excel (Microsoft Office 2010; Microsoft Corporation, WA, USA). Results Baseline data and characteristics From 23 September 2015 to 31 July 2017, a total of 620 patients were randomized (Figure 1). We performed biopsy for culture in 485 patients who underwent endoscopy due to upper gastrointestinal symptoms. Genotyping of 23S rRNA in gastric biopsy tissues was done in 471 patients. H. pylori was isolated in 394 patients and antibiotic susceptibility data were available in 383 patients. Characteristics were similar across the two randomized groups (Table 1). There were no significant differences in the characteristics among patients recruited according to criterion 1 and 2 (Table S1, available as Supplementary data at JAC Online). The characteristics of patients with and without susceptibility tests were also similar (Table S2). Detailed information is available in the Supplementary data. Table 1. Demographic characteristics and prevalence of antibiotic resistance Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA All values are percentage (n/N), unless otherwise indicated. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; PM, poor metabolizer; NA: not available. a Defined as consumption of alcohol at least three times a week. Table 1. Demographic characteristics and prevalence of antibiotic resistance Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA All values are percentage (n/N), unless otherwise indicated. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; PM, poor metabolizer; NA: not available. a Defined as consumption of alcohol at least three times a week. Table 2. Eradication rates in the first- and second-line therapies Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Table 2. Eradication rates in the first- and second-line therapies Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Figure 1. View largeDownload slide CONSORT diagram. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Figure 1. View largeDownload slide CONSORT diagram. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. H. pylori eradication rates The eradication rates for ST14 and BQ10 were 91.3% (283 of 310, 95% CI 87.4%–94.1%) and 91.6% (284 of 310, 95% CI 87.8%–94.3%) in the ITT analysis, respectively, and were 93.9% (279 of 297, 95% CI 90.4%–96.3%) and 95.5% (277 of 290, 95% CI 92.3%–97.5%) in the PP analysis, respectively (Table 2). ST14 was not inferior to BQ10 in the ITT analysis (difference −0.3%, 95% CI −4.7% to 4.4%, P = 0.886). In the second-line therapy, the eradication rate in BQ10 for patients who failed on ST14 was 80.0% (8 of 10, 95% CI 44.2%–96.5%, Table 2). The eradication rate of ST14 for patients who failed on BQ10 was 50.0% (5 of 10, 95% CI 20.1%–79.9%). Following two courses of antibiotic treatment, there was no significant difference in the overall eradication rates between the two algorithms of ST14/BQ10 and BQ10/ST14 in both the ITT and PP analyses (Table 2). Adverse effects and compliance The frequencies of any adverse effects in patients treated with ST14 and BQ10 were 36.7% (113 of 308, 95% CI 31.4%–42.4%) and 74.4% (230 of 309, 95% CI 69.1%–79.1%), respectively (P < 0.0001, Table 3). The frequencies of dizziness, nausea, vomiting, and darkened stool were significantly higher in patients treated with BQ10 than those treated with ST14 (Table 3). The compliance (taking at least 80% of the drugs) was similar in patients treated with ST14 and BQ10 (Table 3). The frequency of adverse effects in the second-line treatment is shown in Table S3. Table 3. Adverse effects in the first-line therapy Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Table 3. Adverse effects in the first-line therapy Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Eradication rates according to antibiotic resistance, host CYP2C19 polymorphism and bacterial virulence factors Clarithromycin resistance significantly affected the eradication rate of ST14, as shown in Table 4 (PP analysis). The results were consistent using different methods (genotypic and phenotypic) to detect clarithromycin resistance. The efficacy of BQ10 was not affected by clarithromycin or metronidazole resistance. The efficacies of ST14 and BQ10 were not significantly different in strains susceptible to both clarithromycin and metronidazole. However, the efficacy of BQ10 was higher than ST14 in the presence of clarithromycin resistance. The eradication rates of ST14 and BQ10 therapies were both significantly affected by compliance, but were not affected by the presence of gastric ulcer or duodenal ulcer, host CYP2C19 polymorphism, or bacterial virulence factors in the univariate analysis (Table 4). The ORs and 95% CI in the univariate analysis are shown in Table S4. The eradication rates in subgroups in the first-line therapy according to ITT analysis are shown in Table S5. A total of 226 and 227 patients with drug susceptibility data were included in the multiple logistic regression analyses in patients treated with ST14 and BQ10, respectively. Multiple regression analyses showed that clarithromycin resistance significantly affected the efficacy of ST14, whereas poor compliance significantly affected the efficacy of BQ10 (Table 4). Genotypic resistance (23S rRNA mutations) to clarithromycin using gastric biopsy tissues or H. pylori strains correlated well with phenotypic resistance detected by agar dilution test (Table S6). Table 4. Factors affecting eradication rates in the first-line therapy (PP analysis) Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; CLR, clarithromycin; MTZ, metronidazole; S, susceptible; R, resistant; PM, poor metabolizer; IM, intermediate metabolizer; EM, extensive metabolizer. a ITT analysis. b ORs in the multiple logistic regression models adjusted for clarithromycin resistance, compliance, CYP2C19 polymorphism, age, gender, gastric ulcer and duodenal ulcer according to ITT analysis. Table 4. Factors affecting eradication rates in the first-line therapy (PP analysis) Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; CLR, clarithromycin; MTZ, metronidazole; S, susceptible; R, resistant; PM, poor metabolizer; IM, intermediate metabolizer; EM, extensive metabolizer. a ITT analysis. b ORs in the multiple logistic regression models adjusted for clarithromycin resistance, compliance, CYP2C19 polymorphism, age, gender, gastric ulcer and duodenal ulcer according to ITT analysis. Hp-normogram The predicted efficacies of ST14 and BQ10 according to the prevalence of clarithromycin resistance are shown in Figure S1. The eradication rates of S14 and BQ10 in strains susceptible and resistant to clarithromycin as shown in Table 4 were used for the prediction. The eradication rate of both ST14 and BQ10 appeared to be >90% in regions with lower clarithromycin resistance (Figure S1). However, BQ10 appeared to be more effective than ST14 in regions with higher clarithromycin resistance. Discussion To the best of our knowledge, this is the first randomized trial to provide direct evidence that optimized 14 day sequential therapy was non-inferior to 10 day bismuth quadruple therapy and may be used as an alternative therapy in populations with low and intermediate clarithromycin resistance. Both regimens were highly effective (>90%) in first-line therapy, but the frequency of adverse effects was significantly lower in patients treated with the optimized 14 day sequential therapy. Bismuth quadruple therapy is effective as recue therapy for patients who fail after optimized sequential therapy. However, 14 day sequential therapy is not effective as rescue therapy for patients who fail after bismuth quadruple therapy. The eradication rates of the optimized 14 day sequential therapy were 78.6% and 71.4% in the presence of single clarithromycin resistance and dual clarithromycin and metronidazole resistance, respectively, indicating that such an optimized regimen can partly overcome the clarithromycin resistance. The prediction model (Hp-normogram) derived from the results of this trial further suggest that the optimized 14 day sequential therapy may be an alternative first-line therapy in populations with low and intermediate clarithromycin resistance (<20%). The results from this trial showed that efficacy of sequential therapy can be optimized through the addition of metronidazole, extending its treatment length to 14 days, and the use of a higher dosage of PPI. Meta-analysis of randomized trials showed that extending the treatment length of triple therapy to 14 days was superior to 7 or 10 day triple therapies.15 Earlier trials and meta-analysis showed that 10 day sequential therapy was superior to 7 or 10 day triple therapy.29,30 However, subsequent trials and meta-analysis showed that 10 day sequential therapy was not superior to 14 day triple therapy.12,13,16,22 Besides, the eradication rate of 10 day sequential therapy was <50% for patients infected with dual clarithromycin- and metronidazole-resistant strains.12,13,16 Therefore, more recent consensus reports recommended against the use of sequential therapy (10 day).9,10 However, the situation is the same for concomitant therapy. Although several earlier trials showed that concomitant therapy given for 5, 7 or 10 days was superior to triple therapy given for 7 or 10 days,31 a large randomized trial showed that 5 day concomitant therapy was inferior to 14 day triple therapy in Latin America.22 Our recent randomized trial further showed that 10 day concomitant therapy was not superior to 14 day triple therapy in Taiwan.17 A non-randomized trial showed that the optimized 14 day concomitant therapy was superior to 14 day triple therapy in Spain.23 Therefore, the Toronto Consensus and the Maastricht V Consensus reports recommended the use of 14 day concomitant therapy as alternative first-line therapy.9,10 Our previous randomized trial in Taiwan and subsequent meta-analysis showed that 14 day sequential therapy was superior to 14 day triple therapy.13,14 The result from this trial further showed that the optimized 14 day sequential therapy containing high-dose esomeprazole was non-inferior but better tolerated than 10 day bismuth quadruple therapy. The optimized 14 day sequential therapy contains only half the amount of antibiotics, is less costly than the optimized 14 day concomitant therapy and may be reconsidered as the first-line treatment for H. pylori infection. The eradication rate of 10 day bismuth quadruple therapy was already 95.5% in the PP analysis. Therefore, the benefit of extending the bismuth quadruple therapy to 14 days might be limited. However, whether reducing the frequency of tetracycline and metronidazole and extending its treatment length to 14 days may reduce the frequencies of adverse effects and increase the eradication rate in the ITT analysis deserves further investigation in future trials. The relatively low eradication rate of sequential therapy for strains with dual resistance to clarithromycin and metronidazole is a concern. However, our study showed that the use of high-dose PPI may partly overcome this problem. In vitro studies have shown higher MICs for amoxicillin and clarithromycin in acidic environments.32 Meta-analysis of randomized trials also showed that the use of a higher dose of PPI may increase the efficacy of standard triple therapy compared with a standard dose of PPI.20 Recent studies further showed that optimized 14 day concomitant therapy containing high-dose esomeprazole was highly effective (>90%) and could overcome the dual clarithromycin and metronidazole resistance in Spain and Greece where the clarithromycin resistance rates were 18% and 40%, respectively.23,24,33 Our results showed that the efficacy of the optimized 14 day sequential therapy was 78.6% in single clarithromycin-resistant strains and was 71.4% in dual clarithromycin- and metronidazole-resistant strains. The strengths of this study included the large sample size, analysis of antibiotic resistance and assessment of the efficacy of optimized 14 day sequential therapy and bismuth quadruple therapy in the second-line rescue therapy. The result from this trial provides evidence that optimized 14 day sequential therapy is not inferior to bismuth quadruple therapy. Both regimens were highly effective (grade A regimens according to the report card of H. pylori eradication)34 in regions with clarithromycin resistance of ∼15%. The determination of antibiotic resistance allowed us to predict the efficacy of the two regimens in regions with different prevalences of clarithromycin resistance. However, the inference from the Hp-normogram suggests that bismuth quadruple therapy would be more effective than the optimized 14 day sequential therapy in regions with high clarithromycin resistance. Although a previous trial has shown that 10 day sequential therapy was not superior to 10 day bismuth quadruple therapy in Hong Kong,35 we further demonstrated that 14 day sequential therapy was non-inferior to 10 day bismuth quadruple therapy. Besides, antibiotic resistance was not determined in that trial.35 There are some limitations of this study. First, the complexity of sequential therapy and bismuth quadruple therapy might limit their widespread application in first-line treatment. However, a single capsule containing bismuth, tetracycline and metronidazole is available that can simplify the drug administration of bismuth quadruple therapy. Besides, several types of inexpensive and convenient pill dispenser have been developed to simplify the drug administration of variable dosage and frequency. Second, the use of two recruitment criteria might introduce selection bias. However, the characteristics among patients recruited using different criteria were not significantly different owing to adequate randomization (Table S1). Third, the MIC was not available in 38% of study participants because culture was not done in 135 patients (21.7%) and the culture rate (81.2%, 394 of 485) was less than perfect. However, the demographic characteristics and the eradication rates were also similar among those with and without the MIC test in the two treatment groups, indicating that the confounding effect has been minimized through randomization (Table S2). Finally, the optimized 14 day sequential therapy is not recommended in regions with high clarithromycin resistance. Bismuth quadruple therapy, levofloxacin-containing sequential therapy or levofloxacin-containing concomitant therapy would be more effective and are the treatments of choice in such circumstances.21,36,37 Conclusions The optimized 14 day sequential therapy was not inferior to and was better tolerated than 10 day bismuth quadruple therapy in first-line therapy for H. pylori infection. Both regimens achieved high eradication rates (>90%) in Taiwan where the clarithromycin resistance rate was 15%. Optimization of sequential therapy through extending its treatment length to 14 days and the use of a higher dosage of PPI may increase its efficacy against dual-resistant strains and may be used as first-line therapy in regions with low to intermediate clarithromycin resistance. However, quadruple therapy remains the treatment of choice in regions with high clarithromycin resistance. Acknowledgements The authors express their special thanks to the Eighth Core Lab, Department of Medical Research, National Taiwan University Hospital and the Taipei Institute of Pathology for their technological support. G. Twu was a summer student in the central laboratory of National Taiwan University. Members of the Taiwan Gastrointestinal Disease and Helicobacter Consortium Steering committee: Jyh-Ming Liou (Taipei), Yi-Chia Lee (Taipei), Jaw-Town Lin (Taipei), Chun-Ying Wu (Taipei), Jeng-Yih Wu (Kaohsiung), Ching-Chow Chen (Taipei), Chun-Hung Lin (Taipei), Yu-Ren Fang (Yun-Lin), Ming-Jong Bair (Taitung), Jiing-Chyuan Luo (Taipei) and Ming-Shiang Wu (Taipei).  Others investigators of the Taiwan Helicobacter Consortium in this study: Tsu-Yao Cheng (Taipei), Ping-Huei Tseng (Taipei), Han-Mo Chiu (Taipei), Chun-Chao Chang (Taipei), Chien-Chun Yu (Yun-Lin), Min-Chin Chiu (Yun-Lin), Yen-Nien Chen (Hsinchu), Wen-Hao Hu (Hsinchu), Chu-Kuang Chou (Chia-Yi), Chi-Ming Tai (Kaohsiung), Ching-Tai Lee (Kaohsiung), Wen-Lun Wang (Kaohsiung) and Wen-Shiung Chang (Taipei). Funding This work was supported by the National Taiwan University Hospital (NTUH 106-T05 to J-M. L.), the Ministry of Science and Technology, Executive Yuan, ROC, Taiwan (105-2628-B-002-045-MY3, TCTC-TR2 106-2321-B-002-025, and 105-2325-B-002-042), the Ministry of Health and Welfare of Taiwan (MOHW106-TDU-B-211-113002 and MOHW107-TDU-B-211-123002 to J-M. L. and M-S. W.), and the Taipei Institute of Pathology (TIP-106-001 to J-M. L.). The funding source had no role in study design, data collection, analysis or interpretation, report writing, or the decision to submit this paper for publication. Transparency declarations None to declare. Author contributions J-M. L. is the guarantor. The study was conceived by J-M. L., with input from M-J. B. and M-S. W. and all the other listed contributors from the Taiwan Gastrointestinal Disease and Helicobacter Consortium. J-M. L designed the study and wrote the protocol. J-M. L., C-C. C., Y-J. F., P-Y. C., C-Y. C., C-K. C., M-J. C., C-H. T., J-Y. L., T-H. Y., M-C. C., J-J. Y., C-C. K., J-C. L., W-F. H., W-H. H., M-H. T., J-T. L., Y-C. L., M-J. B., and M-S. W. recruited patients to the study. C-T. S. contributed to the histological assessment. G. T. contributed to genotyping and culture. J-M. L. prepared the statistical analyses. J-M. L. drafted the article that was critically revised by M-S. W. and M-J. B. All authors commented on drafts and approved the final version. Supplementary data Figure S1 and Tables S1 to S6 appear as Supplementary data at JAC Online. References 1 Ford AC , Forman D , Hunt RH et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials . BMJ 2014 ; 348 : g3174 . Google Scholar CrossRef Search ADS PubMed 2 Lee YC , Chiang TH , Chou CK et al. Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis . Gastroenterology 2016 ; 150 : 1113 – 24 . Google Scholar CrossRef Search ADS PubMed 3 Sugano K , Tack J , Kuipers EJ et al. Kyoto global consensus report on Helicobacter pylori gastritis . Gut 2015 ; 64 : 1353 – 67 . Google Scholar CrossRef Search ADS PubMed 4 Megraud F , Coenen S , Versporten A et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption . Gut 2013 ; 62 : 34 – 42 . Google Scholar CrossRef Search ADS PubMed 5 Kuo YT , Liou JM , El-Omar EM et al. Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: a systematic review and meta-analysis . Lancet Gastroenterol Hepatol 2017 ; 2 : 707 – 15 . Google Scholar CrossRef Search ADS PubMed 6 Liou JM , Chang CY , Chen MJ et al. The primary resistance of Helicobacter pylori in Taiwan after the national policy to restrict antibiotic consumption and its relation to virulence factors—A nationwide study . PLoS One 2015 ; 10 : e0124199 . Google Scholar CrossRef Search ADS PubMed 7 Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits . Gastroenterology 2015 ; 148 : 719–31.e3. 8 Vakil N , Megraud F. Eradication therapy for Helicobacter pylori . Gastroenterology 2007 ; 133 : 985 – 1001 . Google Scholar CrossRef Search ADS PubMed 9 Malfertheiner P , Megraud F , O'Morain CA et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report . Gut 2017 ; 66 : 6 – 30 . Google Scholar CrossRef Search ADS PubMed 10 Fallone CA , Chiba N , van Zanten SV et al. The Toronto Consensus for the treatment of Helicobacter pylori infection in adults . Gastroenterology 2016 ; 151 : 51–69.e14. 11 Chey WD , Leontiadis GI , Howden CW et al. ACG clinical guideline: treatment of Helicobacter pylori infection . Am J Gastroenterol 2017 ; 112 : 212 – 39 . Google Scholar CrossRef Search ADS PubMed 12 Gatta L , Vakil N , Vaira D , Scarpignato C. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy . BMJ 2013 ; 347 : f4587. Google Scholar CrossRef Search ADS PubMed 13 Liou JM , Chen CC , Chen MJ et al. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial . Lancet 2013 ; 381 : 205 – 13 . Google Scholar CrossRef Search ADS PubMed 14 Liou JM , Chen CC , Lee YC et al. Systematic review with meta-analysis: 10- or 14-day sequential therapy vs. 14-day triple therapy in the first line treatment of Helicobacter pylori infection . Aliment Pharmacol Ther 2016 ; 43 : 470 – 81 . Google Scholar CrossRef Search ADS PubMed 15 Yuan Y , Ford AC , Khan KJ et al. Optimum duration of regimens for Helicobacter pylori eradication . Cochrane Database Syst Rev 2013 ; issue 12 : CD008337 . 16 Liou JM , Chen CC , Chang CY et al. Sequential therapy for 10 days versus triple therapy for 14 days in the eradication of Helicobacter pylori in the community and hospital populations: a randomised trial . Gut 2016 ; 65 : 1784 – 92 . Google Scholar CrossRef Search ADS PubMed 17 Liou JM , Fang YJ , Chen CC et al. Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial . Lancet 2016 ; 388 : 2355 – 65 . Google Scholar CrossRef Search ADS PubMed 18 Yeo YH , Shiu SI , Ho HJ et al. First-line Helicobacter pylori eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis . Gut 2018 ; 67 : 20 – 7 . Google Scholar CrossRef Search ADS PubMed 19 Murakami K , Sakurai Y , Shiino M et al. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study . Gut 2016 ; 65 : 1439 – 46 . Google Scholar CrossRef Search ADS PubMed 20 McNicholl AG , Linares PM , Nyssen OP et al. Meta-analysis: esomeprazole or rabeprazole vs. first-generation pump inhibitors in the treatment of Helicobacter pylori infection . Aliment Pharmacol Ther 2012 ; 36 : 414 – 25 . Google Scholar CrossRef Search ADS PubMed 21 Malfertheiner P , Bazzoli F , Delchier JC et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomized, open-label, non-inferiority, phase 3 trial . Lancet 2011 ; 377 : 905 – 13 . Google Scholar CrossRef Search ADS PubMed 22 Greenberg ER , Anderson GL , Morgan DR et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomized trial . Lancet 2011 ; 378 : 507 – 14 . Google Scholar CrossRef Search ADS PubMed 23 Molina-Infante J , Lucendo AJ , Angueira T et al. Optimised empiric triple and concomitant therapy for Helicobacter pylori eradication in clinical practice: the OPTRICON study . Aliment Pharmacol Ther 2015 ; 41 : 581 – 9 . Google Scholar CrossRef Search ADS PubMed 24 Molina-Infante J , Romano M , Fernandez-Bermejo M et al. Optimized nonbismuth quadruple therapies cure most patients with Helicobacter pylori infection in populations with high rates of antibiotic resistance . Gastroenterology 2013 ; 145 : 121 – 8.e1 . Google Scholar CrossRef Search ADS PubMed 25 Wang Y , Zhao R , Wang B et al. Sequential versus concomitant therapy for treatment of Helicobacter pylori infection: an updated systematic review and meta-analysis . Eur J Clin Pharmacol 2018 ; 74 : 1 – 13 . Google Scholar CrossRef Search ADS PubMed 26 Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype . Helicobacter 2016 ; 21 : 85 – 90 . Google Scholar CrossRef Search ADS PubMed 27 Liou JM , Chang CY , Sheng WH et al. Genotypic resistance in Helicobacter pylori strains correlates with susceptibility test and treatment outcomes after levofloxacin- and clarithromycin-based therapies . Antimicrob Agents Chemother 2011 ; 55 : 1123 – 9 . Google Scholar CrossRef Search ADS PubMed 28 Tseng PH , Lee YC , Chiu HM et al. A comparative study of proton-pump inhibitor tests for Chinese reflux patients in relation to the CYP2C19 genotypes . J Clin Gastroenterol 2009 ; 43 : 920 – 5 . Google Scholar CrossRef Search ADS PubMed 29 Vaira D , Zullo A , Vakil N et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial . Ann Intern Med 2007 ; 146 : 556 – 63 . Google Scholar CrossRef Search ADS PubMed 30 Zullo A , De Francesco V , Hassan C et al. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis . Gut 2007 ; 56 : 1353 – 7 . Google Scholar CrossRef Search ADS PubMed 31 Gisbert JP , Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori . Aliment Pharmacol Ther 2011 ; 34 : 604 – 17 . Google Scholar CrossRef Search ADS PubMed 32 Mégraud F , Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing . Clin Microbiol Rev 2007 ; 20 : 280 – 322 . Google Scholar CrossRef Search ADS PubMed 33 Gisbert JP , McNicholl AG. Optimization strategies aimed to increase the efficacy of H. pylori eradication therapies . Helicobacter 2017 ; 22 : e12392. Google Scholar CrossRef Search ADS 34 Graham DY , Lu H , Yamaoka Y. A report card to grade Helicobacter pylori therapy . Helicobacter 2007 ; 12 : 275 – 8 . Google Scholar CrossRef Search ADS PubMed 35 Liu KS , Hung IF , Seto WK et al. Ten day sequential versus 10 day modified bismuth quadruple therapy as empirical first-line and second-line treatment for Helicobacter pylori in Chinese patients: an open label, randomised, crossover trial . Gut 2014 ; 63 : 1410 – 5 . Google Scholar CrossRef Search ADS PubMed 36 Romano M , Cuomo A , Gravina AG et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial . Gut 2010 ; 59 : 1465 – 70 . Google Scholar CrossRef Search ADS PubMed 37 Federico A , Nardone G , Gravina AG et al. Efficacy of 5-day levofloxacin-containing concomitant therapy in eradication of Helicobacter pylori infection . Gastroenterology 2012 ; 143 : 55–61.e1. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
D.O.I.
10.1093/jac/dky183
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Abstract

Abstract Background Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown. Objectives To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy. Methods We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855. Results The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%–94.1%) and 91.6% (284 of 310, 95% CI 87.8%–94.3%) in the ITT analysis, respectively (difference −0.3%, 95% CI −4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001). Conclusions Optimized 14 day sequential therapy was non-inferior to, but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance. Introduction The eradication rate for Helicobacter pylori infection, a causal factor of peptic ulcer disease and gastric cancer,1–3 is decreasing due to the rising prevalence of antibiotic resistance.4–6 The efficacies of H. pylori eradication regimens may be optimized through the use of four-drug regimens (bismuth quadruple therapy, or concomitant therapy, or sequential therapy), extending its length to 14 days, and the use of a higher dosage of proton pump inhibitor (PPI).7–24 Sequential therapy given for 10 days has been extensively compared with triple therapy and concomitant therapy of various treatment lengths in randomized controlled trials (RCTs).12,13,16 Meta-analysis of these trials showed that 10 day sequential therapy was more effective than 7 or 10 day triple therapy, but was not superior to 14 day triple therapy.12,14,18 A recent meta-analysis of RCTs showed that the efficacy of 10 day sequential therapy was superior to 5 day concomitant therapy, similar to 7 day concomitant therapy, but was inferior to 10 day concomitant therapy.25 Therefore, the Maastricht V Consensus and the Toronto Consensus recommended against the use of 10 day sequential therapy for the first-line treatment of H. pylori infection.9,10 However, sequential therapy remains one of the treatment choices in the ACG guideline.11 Recently, we showed that 10 day bismuth quadruple therapy, but not 10 day concomitant therapy, was superior to 14 day triple therapy in Taiwan where the prevalence of clarithromycin resistance was ∼15%.17 Therefore, we conducted this RCT to compare the efficacy and tolerability of optimized 14 day sequential therapy containing high-dose esomeprazole and 10 day bismuth quadruple therapy in first-line therapy. The efficacy of bismuth quadruple therapy and optimized 14 day sequential therapy in second-line rescue therapy and factors that might affect their efficacies were also assessed. Finally, we constructed the Hp-normogram26 to estimate the efficacy of the two regimens in regions with a different prevalence of antibiotic resistance. Patients and methods Trial design and settings The Institutional Review Board of each participating hospital approved this open-label, multicentre, randomized trial. Written informed consent was obtained from all patients prior to enrolment. The Clinical Trial.gov registration identifier is NCT03156855. Participants We recruited both symptomatic and asymptomatic adult subjects (≥20 years of age) in seven medical centres in Taiwan. The recruitment criteria and exclusion criteria were similar to our previous trials.13,16,17 Symptomatic patients who underwent oesophagogastroduodenoscopy due to dyspepsia or other symptoms were invited to a screening programme for H. pylori. Patients with at least two positive tests among histology, rapid urease test, culture and serology were eligible for enrolment (Criterion 1). Asymptomatic subjects who underwent gastric cancer screening with a single positive 13C-urea breath test (13C-UBT) were also eligible for enrolment (Criterion 2). Patients with any one of the following criteria were excluded from the study: (i) history of prior H. pylori eradication therapy; (ii) history of gastrectomy; (iii) severe concurrent illness or non-curative malignancy; (iv) pregnant or lactating women; (v) contraindication or previous allergic reactions to the study drugs; and (vi) patients who could not give informed consent for themselves. Study research staff explained the purpose and eligibility requirements of the study to potential participants. Randomization, blinding and intervention Eligible patients were randomized to receive either one of the following regimens: (i) optimized sequential therapy for 14 days (ST14): esomeprazole 40 mg and amoxicillin 1 g for 7 days, followed by esomeprazole 40 mg, clarithromycin 500 mg and metronidazole 500 mg for another 7 days (all given twice daily), or (ii) bismuth quadruple therapy for 10 days (BQ10): esomeprazole 40 mg twice daily, bismuth tripotassium dicitrate 300 mg (KCB F.C. Tablets; Swiss Pharm, Taiwan) four times a day, tetracycline 500 mg four times a day and metronidazole 500 mg three times a day for 10 days. The block randomization sequence with a block size of 4 in a 1:1 ratio was generated by computer. The sequence was concealed in an opaque envelope and kept by an independent research assistant (Miss Huang) in the Call Centre, the National Taiwan University Hospital (NTUH), until intervention was assigned. The study nurses from each centre contacted the independent assistant to obtain the next allocation number by phone after having obtained the written informed consents from eligible subjects to ensure adequate allocation concealment. All investigators were blind to the randomization sequence. Patients who remained positive for H. pylori after first-line 14 day sequential therapy or 10 day bismuth quadruple therapy were retreated with 10 day bismuth quadruple therapy and 14 day sequential therapy, respectively. The dosage and frequency of each regimen in the second-line treatment were the same as that of the first-line treatment. Outcome assessment The primary endpoint of the study was the eradication rate in the first-line therapy. The secondary endpoints were the frequency of adverse effects and the compliance with the first-line therapy and the eradication rates in the second-line therapy. The eradication status was determined by 13C-UBT at least 6 weeks after completion of treatment. All subjects were asked to discontinue histamine-2 blocker and PPI for at least 2 weeks before 13C-UBT. The breath samples at baseline and 30 min after taking the urea kit containing 75 mg 13C-urea were assayed in the Taipei Institute of Pathology using an infrared spectrometer that produced computer-generated results. Positive result was defined as a delta value of ≥4 units as in our previous studies.10,25 All subjects were informed of the common side effects of the study drugs before eradication therapy and were asked to record these symptoms during treatment. We also arranged a standardized outpatient clinic interview at the end of treatment. The research staff assessed the adverse events and compliance using a pre-defined case report form and counted the pills not taken by the subjects. Compliance was defined as low when they took <80% of the study drugs. Determination of phenotypic and genotypic resistance and CYP2C19 polymorphism Agar dilution test was used to determine the MICs in the central laboratory in NTUH.27 The resistance breakpoints for clarithromycin, amoxicillin, metronidazole, levofloxacin and tetracycline were defined as ≥1, ≥0.5, ≥8, >1 and >0.5 mg/L, respectively.27 The 23S rRNA mutations were genotyped by PCR followed by direct sequencing using the automatic sequencer (ABI PRISM 3100 Genetic Analyzer; Applied Biosystems).27 The VacA signal region (s1/2) and midregion (m1/2) mosaics were determined by the PCR method as described previously.13,16 The CYP2C19 polymorphism was genotyped by PCR followed by RFLP.28 Statistical analysis We assumed the eradication rate of the optimized 14 day sequential therapy to be 94% and estimated a sample size of at least 310 in each group to detect a 7% difference in the eradication rate to give a statistical power of 80% at a 5% significance level on a two-sided test, assuming lost to follow-up rate of 10%. The sample size also allows adequate power to test the hypothesis that sequential therapy for 14 days is not inferior to bismuth quadruple therapy for 10 days by 5% to give a statistical power of 80% at a 5% significance level on a one-sided test. All randomized subjects were included in the ITT analysis of the eradication rate in the first-line therapy, the primary endpoint of this study. All protocol violators, such as patients with unknown H. pylori status after eradication therapy or those who took <80% of study drugs, were excluded from the PP analysis. Patients with missing data on the safety issue were not included in the analysis. Categorical data were compared using the χ2 test or Fisher’s exact test as appropriate. Continuous data were compared with Student’s t-test and expressed as mean (SD). All P values were two-tailed, with the level of statistical significance specified as 0.05. The statistical analyses were performed using the SPSS statistical software (version 21) for Windows. The 95% CI of the eradication rate of each regimen was calculated. Ancillary analysis Multiple logistic regression analyses with the following predictors of interest: age, gender, gastric ulcer, duodenal ulcer, clarithromycin resistance (genotypic resistance using gastric biopsy specimen), compliance and CYP2C19 polymorphism were used to evaluate factors affecting the eradication rates. Patients with missing data were excluded in the regression analyses. We also constructed the Hp-normogram to predict the efficacies of the two regimens in regions with a different prevalence of clarithromycin resistance.26 The data required for model generation were based on the eradication rates of ST14 and BQ10 according to the antibiotic resistance in the ITT and PP analysis, which were obtained from the present study. Assuming the eradication rate in strains susceptible and resistant to clarithromycin were A and B, respectively, the predicted eradication rate of that regimen would be A×(1 − p)+B × p, where the prevalence of clarithromycin was p (0≤p≤1). The predicted efficacies of ST14 and BQ10 according to the prevalence of clarithromycin resistance were plotted using Excel (Microsoft Office 2010; Microsoft Corporation, WA, USA). Results Baseline data and characteristics From 23 September 2015 to 31 July 2017, a total of 620 patients were randomized (Figure 1). We performed biopsy for culture in 485 patients who underwent endoscopy due to upper gastrointestinal symptoms. Genotyping of 23S rRNA in gastric biopsy tissues was done in 471 patients. H. pylori was isolated in 394 patients and antibiotic susceptibility data were available in 383 patients. Characteristics were similar across the two randomized groups (Table 1). There were no significant differences in the characteristics among patients recruited according to criterion 1 and 2 (Table S1, available as Supplementary data at JAC Online). The characteristics of patients with and without susceptibility tests were also similar (Table S2). Detailed information is available in the Supplementary data. Table 1. Demographic characteristics and prevalence of antibiotic resistance Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA All values are percentage (n/N), unless otherwise indicated. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; PM, poor metabolizer; NA: not available. a Defined as consumption of alcohol at least three times a week. Table 1. Demographic characteristics and prevalence of antibiotic resistance Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA Characteristic ST14 (N = 310) BQ10 (N = 310) P value First-line therapy  recruited criterion 2 11.3 (35/310) 10 (31/310) 0.854  male 51.3 (159/310) 54.2 (168/310) 0.469  age, years, mean (SD) 52.6 (13.0) 53.7 (13.1) 0.325  cigarette smoking 20.6 (64/310) 20 (62/310) 0.842  alcohol consumptiona 3.2 (10/310) 6.5 (20/310) 0.092  gastric ulcer disease 33.9 (100/295) 35.9 (106/295) 0.604  duodenal ulcer 23.1 (68/295) 29.8 (88/295) 0.076  CYP2C19-PM 14.6 (42/287) 14.8 (42/283) 0.944  BMI, kg/m2, median (SD) 24.4 (3.7) 24.8 (4.3) 0.206  obesity 22.6 (70/310) 24.8 (77/310) 0.509  23S rRNA mutation (tissue) 13.6 (32/235) 15.3 (36/236) 0.613  23S rRNA mutation (strain) 10.5 (20/190) 14.5 (26/179) 0.278 Antibiotic resistances  clarithromycin 12.1 (23/190) 14.5 (28/193) 0.489  metronidazole 24.2 (46/190) 23.3 (45/193) 0.837  amoxicillin 3.2 (6/190) 3.6 (7/193) 0.800  levofloxacin 16.3 (31/190) 21.2 (41/193) 0.217  tetracycline 5.3 (10/190) 7.8 (15/193) 0.320 H. pylori tests positive  serology 95.4 (272/285) 96.4 (269/279) 0.547  rapid urease test 92.5 (235/254) 91.4 (243/266) 0.480  histology 98.2 (268/273) 95.7 (264/276) 0.089  culture 82.2 (198/241) 81.0 (196/242) 0.384  13C-UBT 100 (85/85) 100 (65/65) NA All values are percentage (n/N), unless otherwise indicated. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; PM, poor metabolizer; NA: not available. a Defined as consumption of alcohol at least three times a week. Table 2. Eradication rates in the first- and second-line therapies Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Table 2. Eradication rates in the first- and second-line therapies Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 Eradication rate [%, (n/N)] and 95% CI ST14 BQ10 Difference (%) P value First-line therapy  ITT analysis 91.3 (283/310) 91.6 (284/310) −0.3 0.886   95% CI 87.4–94.1 87.8–94.3 −4.7 to 4.4  PP analysis 93.9 (279/297) 95.5 (277/290) −1.6 0.393   95% CI 90.4–96.3 92.3–97.5 −5.2 to 2 Second-line therapy  ITT analysis 80 (8/10) 50 (5/10) 30 0.160   95% CI 44.2–96.5 20.1–79.9 −9.7 to 69.7  PP analysis 88.9 (8/9) 50 (5/10) 38.9 0.141   95% CI 50.7–99.4 20.1–79.9 1.7 to 76.1 After two treatments  ITT analysis 93.9 (291/310) 93.2 (289/310) 0.6 0.744   95% CI 90.4–96.2 89.7–95.7 −3.2 to 4.5  PP analysis 99.7 (287/288) 98.3 (282/287) 1.5 0.123   95% CI 97.8–100 95.8–99.4 −0.3 to 3.1 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Figure 1. View largeDownload slide CONSORT diagram. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Figure 1. View largeDownload slide CONSORT diagram. ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. H. pylori eradication rates The eradication rates for ST14 and BQ10 were 91.3% (283 of 310, 95% CI 87.4%–94.1%) and 91.6% (284 of 310, 95% CI 87.8%–94.3%) in the ITT analysis, respectively, and were 93.9% (279 of 297, 95% CI 90.4%–96.3%) and 95.5% (277 of 290, 95% CI 92.3%–97.5%) in the PP analysis, respectively (Table 2). ST14 was not inferior to BQ10 in the ITT analysis (difference −0.3%, 95% CI −4.7% to 4.4%, P = 0.886). In the second-line therapy, the eradication rate in BQ10 for patients who failed on ST14 was 80.0% (8 of 10, 95% CI 44.2%–96.5%, Table 2). The eradication rate of ST14 for patients who failed on BQ10 was 50.0% (5 of 10, 95% CI 20.1%–79.9%). Following two courses of antibiotic treatment, there was no significant difference in the overall eradication rates between the two algorithms of ST14/BQ10 and BQ10/ST14 in both the ITT and PP analyses (Table 2). Adverse effects and compliance The frequencies of any adverse effects in patients treated with ST14 and BQ10 were 36.7% (113 of 308, 95% CI 31.4%–42.4%) and 74.4% (230 of 309, 95% CI 69.1%–79.1%), respectively (P < 0.0001, Table 3). The frequencies of dizziness, nausea, vomiting, and darkened stool were significantly higher in patients treated with BQ10 than those treated with ST14 (Table 3). The compliance (taking at least 80% of the drugs) was similar in patients treated with ST14 and BQ10 (Table 3). The frequency of adverse effects in the second-line treatment is shown in Table S3. Table 3. Adverse effects in the first-line therapy Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Table 3. Adverse effects in the first-line therapy Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 Percentage of patients affected (n/N) ST14 BQ10 P value Any adverse effects 36.7 (113/308) 74.4 (230/309) <0.0001 Dizziness 9.8 (30/307) 27.3 (84/308) <0.0001 Skin rash 2 (6/307) 4.2 (13/308) 0.104 Headache 2.6 (8/307) 5.5 (17/308) 0.067 Taste distortion 9.1 (28/307) 5.2 (16/308) 0.059 Abdominal pain 6.5 (20/307) 11.7 (36/308) 0.026 Nausea 9.4 (29/307) 24.7 (76/308) <0.0001 Diarrhoea 13 (40/307) 8.4 (26/308) 0.066 Constipation 1.6 (5/307) 1.6 (5/308) 1.000 Bloating 6.5 (20/307) 10.7 (33/308) 0.064 Vomiting 2.6 (8/307) 12 (37/308) <0.0001 Tongue discoloration 2 (6/307) 2.9 (9/308) 0.437 Darkened stool 2.3 (7/307) 43.8 (135/308) <0.0001 Took <80% of drugs 2.3 (7/308) 4.2 (13/309) 0.175 Took the drugs correctly 97.7 (302/309) 95.5 (295/309) 0.120 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days. Eradication rates according to antibiotic resistance, host CYP2C19 polymorphism and bacterial virulence factors Clarithromycin resistance significantly affected the eradication rate of ST14, as shown in Table 4 (PP analysis). The results were consistent using different methods (genotypic and phenotypic) to detect clarithromycin resistance. The efficacy of BQ10 was not affected by clarithromycin or metronidazole resistance. The efficacies of ST14 and BQ10 were not significantly different in strains susceptible to both clarithromycin and metronidazole. However, the efficacy of BQ10 was higher than ST14 in the presence of clarithromycin resistance. The eradication rates of ST14 and BQ10 therapies were both significantly affected by compliance, but were not affected by the presence of gastric ulcer or duodenal ulcer, host CYP2C19 polymorphism, or bacterial virulence factors in the univariate analysis (Table 4). The ORs and 95% CI in the univariate analysis are shown in Table S4. The eradication rates in subgroups in the first-line therapy according to ITT analysis are shown in Table S5. A total of 226 and 227 patients with drug susceptibility data were included in the multiple logistic regression analyses in patients treated with ST14 and BQ10, respectively. Multiple regression analyses showed that clarithromycin resistance significantly affected the efficacy of ST14, whereas poor compliance significantly affected the efficacy of BQ10 (Table 4). Genotypic resistance (23S rRNA mutations) to clarithromycin using gastric biopsy tissues or H. pylori strains correlated well with phenotypic resistance detected by agar dilution test (Table S6). Table 4. Factors affecting eradication rates in the first-line therapy (PP analysis) Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; CLR, clarithromycin; MTZ, metronidazole; S, susceptible; R, resistant; PM, poor metabolizer; IM, intermediate metabolizer; EM, extensive metabolizer. a ITT analysis. b ORs in the multiple logistic regression models adjusted for clarithromycin resistance, compliance, CYP2C19 polymorphism, age, gender, gastric ulcer and duodenal ulcer according to ITT analysis. Table 4. Factors affecting eradication rates in the first-line therapy (PP analysis) Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 Eradication rate [% (n/N)] Subgroups ST14 BQ10 23S rRNA mutation (genotypic, gastric tissue)  no 99 (193/195) 96.3 (182/189)  yes 80 (24/30) 96.9 (31/32) 23S rRNA mutation (genotypic, strain)  no 98.8 (158/160) 97.9 (141/144)  yes 72.2 (13/18) 95.7 (22/23) Clarithromycin resistance (phenotypic)  susceptible 98.8 (158/160) 97.4 (150/154)  resistant 76.2 (16/21) 96 (24/25) Metronidazole resistance (phenotypic)  susceptible 97.1 (133/137) 97.1 (135/139)  resistant 93.2 (41/44) 97.5 (39/40) Amoxicillin resistance (phenotypic)  susceptible 96 (168/175) 97.1 (167/172)  resistant 100 (6/6) 100 (7/7) Clarithromycin and metronidazole resistance (phenotypic)  CLR-S and MTZ-S 99.2 (122/123) 96.7 (118/122)  CLR-S and MTZ-R 97.3 (36/37) 100 (32/32)  CLR-R and MTZ-S 78.6 (11/14) 100 (17/17)  CLR-R and MTZ-R 71.4 (5/7) 87.5 (7/8) Compliance (took at least 80% of the drugs)a  yes 92.7 (279/301) 93.6 (277/296)  no 57.1 (4/7) 53.8 (7/13) Gastric ulcer  present 93.6 (88/94) 94.9 (94/99)  absent 95.8 (181/189) 95.5 (169/177) Duodenal ulcer  present 97 (64/66) 94 (79/84)  absent 94.5 (205/217) 95.8 (184/192) CYP2C19 polymorphism  PM 92.7 (38/41) 95.1 (39/41)  IM/EM 94.9 (223/235) 95.1 (212/223) VacA  m1 96.8 (60/62) 98.3 (57/58)  m2 95.6 (109/114) 97.2 (105/108) Multivariate analysesb [adjusted OR (95% CI)a, P value]  compliancea (poor versus good) 6.4 (0.38–107.4), P = 0.196 17.1 (3.5–84.5), P = 0.0005  clarithromycin (genotypic, tissue)a (resistance versus no resistance) 10.1 (2.9–35.5), P = 0.0003 2.2 (0.6–8.4), P = 0.25 ST14, sequential therapy for 14 days; BQ10, bismuth quadruple therapy for 10 days; CLR, clarithromycin; MTZ, metronidazole; S, susceptible; R, resistant; PM, poor metabolizer; IM, intermediate metabolizer; EM, extensive metabolizer. a ITT analysis. b ORs in the multiple logistic regression models adjusted for clarithromycin resistance, compliance, CYP2C19 polymorphism, age, gender, gastric ulcer and duodenal ulcer according to ITT analysis. Hp-normogram The predicted efficacies of ST14 and BQ10 according to the prevalence of clarithromycin resistance are shown in Figure S1. The eradication rates of S14 and BQ10 in strains susceptible and resistant to clarithromycin as shown in Table 4 were used for the prediction. The eradication rate of both ST14 and BQ10 appeared to be >90% in regions with lower clarithromycin resistance (Figure S1). However, BQ10 appeared to be more effective than ST14 in regions with higher clarithromycin resistance. Discussion To the best of our knowledge, this is the first randomized trial to provide direct evidence that optimized 14 day sequential therapy was non-inferior to 10 day bismuth quadruple therapy and may be used as an alternative therapy in populations with low and intermediate clarithromycin resistance. Both regimens were highly effective (>90%) in first-line therapy, but the frequency of adverse effects was significantly lower in patients treated with the optimized 14 day sequential therapy. Bismuth quadruple therapy is effective as recue therapy for patients who fail after optimized sequential therapy. However, 14 day sequential therapy is not effective as rescue therapy for patients who fail after bismuth quadruple therapy. The eradication rates of the optimized 14 day sequential therapy were 78.6% and 71.4% in the presence of single clarithromycin resistance and dual clarithromycin and metronidazole resistance, respectively, indicating that such an optimized regimen can partly overcome the clarithromycin resistance. The prediction model (Hp-normogram) derived from the results of this trial further suggest that the optimized 14 day sequential therapy may be an alternative first-line therapy in populations with low and intermediate clarithromycin resistance (<20%). The results from this trial showed that efficacy of sequential therapy can be optimized through the addition of metronidazole, extending its treatment length to 14 days, and the use of a higher dosage of PPI. Meta-analysis of randomized trials showed that extending the treatment length of triple therapy to 14 days was superior to 7 or 10 day triple therapies.15 Earlier trials and meta-analysis showed that 10 day sequential therapy was superior to 7 or 10 day triple therapy.29,30 However, subsequent trials and meta-analysis showed that 10 day sequential therapy was not superior to 14 day triple therapy.12,13,16,22 Besides, the eradication rate of 10 day sequential therapy was <50% for patients infected with dual clarithromycin- and metronidazole-resistant strains.12,13,16 Therefore, more recent consensus reports recommended against the use of sequential therapy (10 day).9,10 However, the situation is the same for concomitant therapy. Although several earlier trials showed that concomitant therapy given for 5, 7 or 10 days was superior to triple therapy given for 7 or 10 days,31 a large randomized trial showed that 5 day concomitant therapy was inferior to 14 day triple therapy in Latin America.22 Our recent randomized trial further showed that 10 day concomitant therapy was not superior to 14 day triple therapy in Taiwan.17 A non-randomized trial showed that the optimized 14 day concomitant therapy was superior to 14 day triple therapy in Spain.23 Therefore, the Toronto Consensus and the Maastricht V Consensus reports recommended the use of 14 day concomitant therapy as alternative first-line therapy.9,10 Our previous randomized trial in Taiwan and subsequent meta-analysis showed that 14 day sequential therapy was superior to 14 day triple therapy.13,14 The result from this trial further showed that the optimized 14 day sequential therapy containing high-dose esomeprazole was non-inferior but better tolerated than 10 day bismuth quadruple therapy. The optimized 14 day sequential therapy contains only half the amount of antibiotics, is less costly than the optimized 14 day concomitant therapy and may be reconsidered as the first-line treatment for H. pylori infection. The eradication rate of 10 day bismuth quadruple therapy was already 95.5% in the PP analysis. Therefore, the benefit of extending the bismuth quadruple therapy to 14 days might be limited. However, whether reducing the frequency of tetracycline and metronidazole and extending its treatment length to 14 days may reduce the frequencies of adverse effects and increase the eradication rate in the ITT analysis deserves further investigation in future trials. The relatively low eradication rate of sequential therapy for strains with dual resistance to clarithromycin and metronidazole is a concern. However, our study showed that the use of high-dose PPI may partly overcome this problem. In vitro studies have shown higher MICs for amoxicillin and clarithromycin in acidic environments.32 Meta-analysis of randomized trials also showed that the use of a higher dose of PPI may increase the efficacy of standard triple therapy compared with a standard dose of PPI.20 Recent studies further showed that optimized 14 day concomitant therapy containing high-dose esomeprazole was highly effective (>90%) and could overcome the dual clarithromycin and metronidazole resistance in Spain and Greece where the clarithromycin resistance rates were 18% and 40%, respectively.23,24,33 Our results showed that the efficacy of the optimized 14 day sequential therapy was 78.6% in single clarithromycin-resistant strains and was 71.4% in dual clarithromycin- and metronidazole-resistant strains. The strengths of this study included the large sample size, analysis of antibiotic resistance and assessment of the efficacy of optimized 14 day sequential therapy and bismuth quadruple therapy in the second-line rescue therapy. The result from this trial provides evidence that optimized 14 day sequential therapy is not inferior to bismuth quadruple therapy. Both regimens were highly effective (grade A regimens according to the report card of H. pylori eradication)34 in regions with clarithromycin resistance of ∼15%. The determination of antibiotic resistance allowed us to predict the efficacy of the two regimens in regions with different prevalences of clarithromycin resistance. However, the inference from the Hp-normogram suggests that bismuth quadruple therapy would be more effective than the optimized 14 day sequential therapy in regions with high clarithromycin resistance. Although a previous trial has shown that 10 day sequential therapy was not superior to 10 day bismuth quadruple therapy in Hong Kong,35 we further demonstrated that 14 day sequential therapy was non-inferior to 10 day bismuth quadruple therapy. Besides, antibiotic resistance was not determined in that trial.35 There are some limitations of this study. First, the complexity of sequential therapy and bismuth quadruple therapy might limit their widespread application in first-line treatment. However, a single capsule containing bismuth, tetracycline and metronidazole is available that can simplify the drug administration of bismuth quadruple therapy. Besides, several types of inexpensive and convenient pill dispenser have been developed to simplify the drug administration of variable dosage and frequency. Second, the use of two recruitment criteria might introduce selection bias. However, the characteristics among patients recruited using different criteria were not significantly different owing to adequate randomization (Table S1). Third, the MIC was not available in 38% of study participants because culture was not done in 135 patients (21.7%) and the culture rate (81.2%, 394 of 485) was less than perfect. However, the demographic characteristics and the eradication rates were also similar among those with and without the MIC test in the two treatment groups, indicating that the confounding effect has been minimized through randomization (Table S2). Finally, the optimized 14 day sequential therapy is not recommended in regions with high clarithromycin resistance. Bismuth quadruple therapy, levofloxacin-containing sequential therapy or levofloxacin-containing concomitant therapy would be more effective and are the treatments of choice in such circumstances.21,36,37 Conclusions The optimized 14 day sequential therapy was not inferior to and was better tolerated than 10 day bismuth quadruple therapy in first-line therapy for H. pylori infection. Both regimens achieved high eradication rates (>90%) in Taiwan where the clarithromycin resistance rate was 15%. Optimization of sequential therapy through extending its treatment length to 14 days and the use of a higher dosage of PPI may increase its efficacy against dual-resistant strains and may be used as first-line therapy in regions with low to intermediate clarithromycin resistance. However, quadruple therapy remains the treatment of choice in regions with high clarithromycin resistance. Acknowledgements The authors express their special thanks to the Eighth Core Lab, Department of Medical Research, National Taiwan University Hospital and the Taipei Institute of Pathology for their technological support. G. Twu was a summer student in the central laboratory of National Taiwan University. Members of the Taiwan Gastrointestinal Disease and Helicobacter Consortium Steering committee: Jyh-Ming Liou (Taipei), Yi-Chia Lee (Taipei), Jaw-Town Lin (Taipei), Chun-Ying Wu (Taipei), Jeng-Yih Wu (Kaohsiung), Ching-Chow Chen (Taipei), Chun-Hung Lin (Taipei), Yu-Ren Fang (Yun-Lin), Ming-Jong Bair (Taitung), Jiing-Chyuan Luo (Taipei) and Ming-Shiang Wu (Taipei).  Others investigators of the Taiwan Helicobacter Consortium in this study: Tsu-Yao Cheng (Taipei), Ping-Huei Tseng (Taipei), Han-Mo Chiu (Taipei), Chun-Chao Chang (Taipei), Chien-Chun Yu (Yun-Lin), Min-Chin Chiu (Yun-Lin), Yen-Nien Chen (Hsinchu), Wen-Hao Hu (Hsinchu), Chu-Kuang Chou (Chia-Yi), Chi-Ming Tai (Kaohsiung), Ching-Tai Lee (Kaohsiung), Wen-Lun Wang (Kaohsiung) and Wen-Shiung Chang (Taipei). Funding This work was supported by the National Taiwan University Hospital (NTUH 106-T05 to J-M. L.), the Ministry of Science and Technology, Executive Yuan, ROC, Taiwan (105-2628-B-002-045-MY3, TCTC-TR2 106-2321-B-002-025, and 105-2325-B-002-042), the Ministry of Health and Welfare of Taiwan (MOHW106-TDU-B-211-113002 and MOHW107-TDU-B-211-123002 to J-M. L. and M-S. W.), and the Taipei Institute of Pathology (TIP-106-001 to J-M. L.). The funding source had no role in study design, data collection, analysis or interpretation, report writing, or the decision to submit this paper for publication. Transparency declarations None to declare. Author contributions J-M. L. is the guarantor. The study was conceived by J-M. L., with input from M-J. B. and M-S. W. and all the other listed contributors from the Taiwan Gastrointestinal Disease and Helicobacter Consortium. J-M. L designed the study and wrote the protocol. J-M. L., C-C. C., Y-J. F., P-Y. C., C-Y. C., C-K. C., M-J. C., C-H. T., J-Y. L., T-H. Y., M-C. C., J-J. Y., C-C. K., J-C. L., W-F. H., W-H. H., M-H. T., J-T. L., Y-C. L., M-J. B., and M-S. W. recruited patients to the study. C-T. S. contributed to the histological assessment. G. T. contributed to genotyping and culture. J-M. L. prepared the statistical analyses. J-M. L. drafted the article that was critically revised by M-S. W. and M-J. B. All authors commented on drafts and approved the final version. Supplementary data Figure S1 and Tables S1 to S6 appear as Supplementary data at JAC Online. References 1 Ford AC , Forman D , Hunt RH et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials . BMJ 2014 ; 348 : g3174 . Google Scholar CrossRef Search ADS PubMed 2 Lee YC , Chiang TH , Chou CK et al. Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis . Gastroenterology 2016 ; 150 : 1113 – 24 . Google Scholar CrossRef Search ADS PubMed 3 Sugano K , Tack J , Kuipers EJ et al. Kyoto global consensus report on Helicobacter pylori gastritis . Gut 2015 ; 64 : 1353 – 67 . Google Scholar CrossRef Search ADS PubMed 4 Megraud F , Coenen S , Versporten A et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption . Gut 2013 ; 62 : 34 – 42 . Google Scholar CrossRef Search ADS PubMed 5 Kuo YT , Liou JM , El-Omar EM et al. Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: a systematic review and meta-analysis . Lancet Gastroenterol Hepatol 2017 ; 2 : 707 – 15 . Google Scholar CrossRef Search ADS PubMed 6 Liou JM , Chang CY , Chen MJ et al. The primary resistance of Helicobacter pylori in Taiwan after the national policy to restrict antibiotic consumption and its relation to virulence factors—A nationwide study . PLoS One 2015 ; 10 : e0124199 . Google Scholar CrossRef Search ADS PubMed 7 Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits . Gastroenterology 2015 ; 148 : 719–31.e3. 8 Vakil N , Megraud F. Eradication therapy for Helicobacter pylori . Gastroenterology 2007 ; 133 : 985 – 1001 . Google Scholar CrossRef Search ADS PubMed 9 Malfertheiner P , Megraud F , O'Morain CA et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report . Gut 2017 ; 66 : 6 – 30 . Google Scholar CrossRef Search ADS PubMed 10 Fallone CA , Chiba N , van Zanten SV et al. The Toronto Consensus for the treatment of Helicobacter pylori infection in adults . Gastroenterology 2016 ; 151 : 51–69.e14. 11 Chey WD , Leontiadis GI , Howden CW et al. ACG clinical guideline: treatment of Helicobacter pylori infection . Am J Gastroenterol 2017 ; 112 : 212 – 39 . Google Scholar CrossRef Search ADS PubMed 12 Gatta L , Vakil N , Vaira D , Scarpignato C. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy . BMJ 2013 ; 347 : f4587. Google Scholar CrossRef Search ADS PubMed 13 Liou JM , Chen CC , Chen MJ et al. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial . Lancet 2013 ; 381 : 205 – 13 . Google Scholar CrossRef Search ADS PubMed 14 Liou JM , Chen CC , Lee YC et al. Systematic review with meta-analysis: 10- or 14-day sequential therapy vs. 14-day triple therapy in the first line treatment of Helicobacter pylori infection . Aliment Pharmacol Ther 2016 ; 43 : 470 – 81 . Google Scholar CrossRef Search ADS PubMed 15 Yuan Y , Ford AC , Khan KJ et al. Optimum duration of regimens for Helicobacter pylori eradication . Cochrane Database Syst Rev 2013 ; issue 12 : CD008337 . 16 Liou JM , Chen CC , Chang CY et al. Sequential therapy for 10 days versus triple therapy for 14 days in the eradication of Helicobacter pylori in the community and hospital populations: a randomised trial . Gut 2016 ; 65 : 1784 – 92 . Google Scholar CrossRef Search ADS PubMed 17 Liou JM , Fang YJ , Chen CC et al. Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial . Lancet 2016 ; 388 : 2355 – 65 . Google Scholar CrossRef Search ADS PubMed 18 Yeo YH , Shiu SI , Ho HJ et al. First-line Helicobacter pylori eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis . Gut 2018 ; 67 : 20 – 7 . Google Scholar CrossRef Search ADS PubMed 19 Murakami K , Sakurai Y , Shiino M et al. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study . Gut 2016 ; 65 : 1439 – 46 . Google Scholar CrossRef Search ADS PubMed 20 McNicholl AG , Linares PM , Nyssen OP et al. Meta-analysis: esomeprazole or rabeprazole vs. first-generation pump inhibitors in the treatment of Helicobacter pylori infection . Aliment Pharmacol Ther 2012 ; 36 : 414 – 25 . Google Scholar CrossRef Search ADS PubMed 21 Malfertheiner P , Bazzoli F , Delchier JC et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomized, open-label, non-inferiority, phase 3 trial . Lancet 2011 ; 377 : 905 – 13 . Google Scholar CrossRef Search ADS PubMed 22 Greenberg ER , Anderson GL , Morgan DR et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomized trial . Lancet 2011 ; 378 : 507 – 14 . Google Scholar CrossRef Search ADS PubMed 23 Molina-Infante J , Lucendo AJ , Angueira T et al. Optimised empiric triple and concomitant therapy for Helicobacter pylori eradication in clinical practice: the OPTRICON study . Aliment Pharmacol Ther 2015 ; 41 : 581 – 9 . Google Scholar CrossRef Search ADS PubMed 24 Molina-Infante J , Romano M , Fernandez-Bermejo M et al. Optimized nonbismuth quadruple therapies cure most patients with Helicobacter pylori infection in populations with high rates of antibiotic resistance . Gastroenterology 2013 ; 145 : 121 – 8.e1 . Google Scholar CrossRef Search ADS PubMed 25 Wang Y , Zhao R , Wang B et al. Sequential versus concomitant therapy for treatment of Helicobacter pylori infection: an updated systematic review and meta-analysis . Eur J Clin Pharmacol 2018 ; 74 : 1 – 13 . Google Scholar CrossRef Search ADS PubMed 26 Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype . Helicobacter 2016 ; 21 : 85 – 90 . Google Scholar CrossRef Search ADS PubMed 27 Liou JM , Chang CY , Sheng WH et al. Genotypic resistance in Helicobacter pylori strains correlates with susceptibility test and treatment outcomes after levofloxacin- and clarithromycin-based therapies . Antimicrob Agents Chemother 2011 ; 55 : 1123 – 9 . Google Scholar CrossRef Search ADS PubMed 28 Tseng PH , Lee YC , Chiu HM et al. A comparative study of proton-pump inhibitor tests for Chinese reflux patients in relation to the CYP2C19 genotypes . J Clin Gastroenterol 2009 ; 43 : 920 – 5 . Google Scholar CrossRef Search ADS PubMed 29 Vaira D , Zullo A , Vakil N et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial . Ann Intern Med 2007 ; 146 : 556 – 63 . Google Scholar CrossRef Search ADS PubMed 30 Zullo A , De Francesco V , Hassan C et al. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis . Gut 2007 ; 56 : 1353 – 7 . Google Scholar CrossRef Search ADS PubMed 31 Gisbert JP , Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori . Aliment Pharmacol Ther 2011 ; 34 : 604 – 17 . Google Scholar CrossRef Search ADS PubMed 32 Mégraud F , Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing . Clin Microbiol Rev 2007 ; 20 : 280 – 322 . Google Scholar CrossRef Search ADS PubMed 33 Gisbert JP , McNicholl AG. Optimization strategies aimed to increase the efficacy of H. pylori eradication therapies . Helicobacter 2017 ; 22 : e12392. Google Scholar CrossRef Search ADS 34 Graham DY , Lu H , Yamaoka Y. A report card to grade Helicobacter pylori therapy . Helicobacter 2007 ; 12 : 275 – 8 . Google Scholar CrossRef Search ADS PubMed 35 Liu KS , Hung IF , Seto WK et al. Ten day sequential versus 10 day modified bismuth quadruple therapy as empirical first-line and second-line treatment for Helicobacter pylori in Chinese patients: an open label, randomised, crossover trial . Gut 2014 ; 63 : 1410 – 5 . Google Scholar CrossRef Search ADS PubMed 36 Romano M , Cuomo A , Gravina AG et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial . Gut 2010 ; 59 : 1465 – 70 . Google Scholar CrossRef Search ADS PubMed 37 Federico A , Nardone G , Gravina AG et al. Efficacy of 5-day levofloxacin-containing concomitant therapy in eradication of Helicobacter pylori infection . Gastroenterology 2012 ; 143 : 55–61.e1. © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: May 29, 2018

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