Clinical Impact of High-dose Esomeprazole-amoxicillin Dual Therapy as Rescue Treatment for Helicobacter pylori Infection

Abstract

Objective:

This study aimed to compare the effectiveness and safety of high-dose dual therapy (HDDT) using esomeprazole and amoxicillin to furazolidone-based quadruple therapy (FBQT) in treating nonresponsive patients with Helicobacter pylori (H. pylori) infection.

Materials and Methods:

A total of 209 patients with H. pylori infection, who had previously received ineffective treatment and visited an outpatient clinic, were randomly assigned to either the HDDT or FBQT groups. All patients underwent a 14-day treatment regimen, and the success rates of H. pylori eradication and safety of the treatment regimens were assessed 4 weeks posttreatment.

Results:

Following the 14-day treatment period, the intention-to-treat (ITT) analysis revealed eradication rates of 93.6% for HDDT and 86.9% for FBQT. In the per-protocol (PP) analysis, eradication rates were 94.5% for HDDT and 88.7% for FBQT. No significant difference in eradication rates was observed between the two groups. HDDT exhibited significantly lower rates of adverse reactions (9.1% in ITT and 9.2% in PP) compared with FBQT (58.6% in ITT and 59.8% in PP). Multivariate analysis identified interval time, alkaline phosphatase, and serum creatinine level as factors influencing the eradication rate. The area under the receiver operating curve of the interval time between the FBQT group and the HDDT group and the success of H. pylori eradication were 0.622 and 0.578, respectively. The optimal salvage treatment intervals were determined as 6 months for FBQT and 1 year for HDDT.

Conclusion:

HDDT using high-dose esomeprazole and amoxicillin demonstrated efficacy in treating H. pylori infection, with the added benefits of reduced side effects and improved medication compliance compared with FBQT. HDDT can be considered a rescue treatment option when other methods fail, with treatment intervals optimized accordingly.

Chronic infection with Helicobacter pylori (H. pylori) is associated with various gastrointestinal complications, including chronic gastritis, gastric cancer (GC), peptic ulcers, and mucosa-associated lymphoid tissue lymphoma.^1,2 With a global infection rate exceeding 50%, the prevalence of H. pylori varies geographically.³ Particularly in developing countries like China, where the average infection rate surpasses 55.8%, individuals face a heightened risk of H. pylori–related ailments.⁴ Notably, H. pylori infection is implicated in ∼90% of GC cases, leading the World Health Organization to classify it as a class I carcinogen for GC.⁵ Therefore, eradicating H. pylori infection is crucial for preventing GC and managing severe active gastritis and peptic ulcers effectively.

The misuse and overuse of antibiotics have contributed to the rise of antibiotic resistance in H. pylori, posing significant challenges to its eradication. High levels of antibiotic resistance significantly impede efforts to prevent and treat H. pylori infections. Studies conducted in China have demonstrated substantial resistance of H. pylori to commonly prescribed macrolides, quinolones, and nitroimidazole antibiotics. A recent multivariate retrospective cross-sectional study reported resistance rates of 78.6% to metronidazole, 10.1% to clarithromycin, 25.1% to levofloxacin, 0.5% to amoxicillin, and 0.8% to furazolidone.^6,7 Interestingly, resistance to furazolidone and amoxicillin appears comparably low, aligning with prevalence rates observed in the Fujian province.⁸

The efficacy of H. pylori treatment is significantly influenced by gastric acid inhibition and the duration of acid suppression induced by acid-suppressing medications.^9,10 Acid-suppressing drugs diminish H. pylori activity by inhibiting urease activity and raising gastric pH, thereby impeding bacterial colonization of the gastric mucosa. Furthermore, these drugs heighten H. pylori’s susceptibility to antibiotics, augmenting the bactericidal effects of treatment. In high-dose dual therapy (HDDT), administering a high dose of proton pump inhibitors (PPIs) achieves more potent acid suppression and sustains elevated gastric pH levels for extended periods, thereby enhancing antibiotic activity and increasing H. pylori eradication rates.¹¹ These adjustments improve H. pylori eradication efficacy, particularly in patients who have not responded to alternative therapeutic approaches.

Given the strong acid suppression capabilities and reduced antibiotic resistance associated with HDDT using PPIs and amoxicillin, numerous researchers have explored its efficacy.^12,13 HDDT and furazolidone-based quadruple therapy (FBQT) demonstrate comparable or superior H. pylori eradication rates as first-line treatments compared with traditional triple or quadruple therapy methods, with fewer adverse reactions reported.¹⁴ However, the effectiveness of these regimens remains unclear for patients resistant to other H. pylori eradication methods. Therefore, we conducted a prospective, randomized, multicenter study to evaluate the safety and efficacy of HDDT as a treatment option for H. pylori–resistant patients.

MATERIALS AND METHODS

Study Design

This prospective, multicenter, open-label, noninferiority, randomized, controlled trial aimed to demonstrate the noninferiority of high-dose esomeprazole-amoxicillin dual therapy (HDDT) compared with FBQT as a salvage regimen for H. pylori infection. The study was conducted at several medical centers, including Zhongshan Hospital (Xiamen, Fujian, China), the Third Hospital of Xiamen (Xiamen, Fujian, China), the Second Affiliated Hospital of Xiamen Medical College (Xiamen, Fujian, China), and Zhongshan Hospital Affiliated to Fudan University (Shanghai, China). An epidemiologist and a statistician were involved in the study, contributing to the study design and data analysis. Eligible patients were randomized in pairs according to a central computer-generated randomization list, with each patient sequentially assigned a number at each center. Patients were then allocated to receive either a 14-day HDDT or FBQT treatment regimen.

Demographic Information

Patients in whom H. pylori infection was diagnosed despite multiple attempts to treat the infection were enrolled in the study. We primarily recruited patients who met the inclusion criteria and visited the outpatient clinic between January 2022 and December 2023. Four to 6 weeks after completing the initial treatment, patients underwent a ¹³C-urea breath test (¹³C-UBT). Those who tested positive for H. pylori infection, indicating treatment failure, were included in the study. A total of 209 patients were recruited and randomly assigned to either the HDDT group (high-dose esomeprazole combined with amoxicillin) or the FBQT group (standard-dose esomeprazole, furazolidone, amoxicillin, and bismuth potassium citrate) using a digital table method. Demographic and clinical information of all participants was documented during the enrollment phase. All participants were required to return to the hospital for a follow-up ¹³C-UBT examination 4 weeks after completing the course of treatment. The interval time represents the period starting from when prior attempts to treat the infection fail, until the present rescue therapy.

The study protocol received approval from the Hospital Ethics Committee (No. B2021-009), and all patients provided written informed consent. A clinical trial registration number (No. NCT05176821) was assigned to the randomized controlled trial, which was conducted in accordance with the CONSORT statement guidelines.

Study Criteria

We included patients with H. pylori infection who had previously shown resistance to standard triple therapy and quadruple therapy (with or without bismuth). The inclusion criteria were as follows: (1) patients aged between 18 and 75 years, regardless of gender, (2) patients who had undergone pathologic examination and received a diagnosis of chronic gastritis or peptic ulcer, (3) positive results on the ¹³C-UBT, indicating H. pylori infection, (4) patients who had not previously been treated with furazolidone for H. pylori infection, and (5) a period of more than 2 months since the last eradication therapy for H. pylori.

The exclusion criteria were as follows: (1) unwillingness or contraindications for gastroscopy examination, (2) a history of allergic reactions to any medication in the protocol, (3) administration of PPIs, H2 receptor antagonists, furazolidone antibiotics, or bismuth agents to patients within 4 weeks before rescue treatment, (4) evidence of severe heart, lung, liver, kidney, or other systemic diseases, (5) administration of systemic corticosteroids, anticoagulants, or platelet aggregation inhibitors (unless using <100 mg/d of aspirin), (6) pregnancy and lactation, (7) a history of drug abuse or alcoholism within 1 year before the study, (8) a history of organ-related diseases such as gastrointestinal tumors and tumors in other locations, (9) active bleeding or iron deficiency anemia, (10) mental illness, and (11) participation in other clinical trials within 3 months before the study.

The withdrawal criteria were as follows: (1) occurrence of severe or unknown adverse reactions and (2) voluntary withdrawal from the study by the patient.

Treatment Regimen

Participants meeting the inclusion criteria were allocated into 2 groups and received treatment over 14 days: (1) Participants allocated to the HDDT group received a dosage of 20 mg esomeprazole (AstraZeneca Pharmaceutical) 4 times daily, meticulously administered before meals and at bedtime, in conjunction with 750 mg of amoxicillin (Zhejiang Jinhua Kangenbei Biopharmaceutical Co., Ltd.) administered 4 times daily post-meals and at bedtime. (2) Conversely, participants assigned to the FBQT group were administered a regimen consisting of 20 mg esomeprazole (AstraZeneca Pharmaceutical) twice daily, to be taken before breakfast and dinner, alongside 100 mg of amoxicillin (Zhejiang Jinhua Kangenbei Biopharmaceutical Co., Ltd.) twice daily post-breakfast and dinner, complemented by 100 mg of furazolidone (Yunpeng Pharmaceutical Group Co., Ltd.) and 240 mg of bismuth potassium citrate capsules (Hunan Warrant Chiral Pharmaceutical Co., Ltd.), both administered twice daily post-breakfast and dinner.

Follow-up and Efficacy Evaluation

After the treatment period, all participants underwent thorough follow-up assessments facilitated through telephone consultations or outpatient visits, ensuring comprehensive monitoring of any adverse events that may have transpired during treatment. Notably, meticulous documentation of such events was undertaken, and the investigators carefully scrutinized their correlation with the administered medication. Adverse events encompassed a spectrum of symptoms including but not limited to diminished appetite, bloating, nausea, vomiting, abdominal discomfort, diarrhea, dizziness, headaches, skin rash, fatigue, fever, and assorted manifestations. After participants’ self-reporting of adverse events, investigators conducted a systematic reassessment and categorized them based on severity into mild (if the discomfort did not impede routine activities), moderate (if it hindered normal functioning), or severe (if it necessitated therapy cessation).¹⁵

Moreover, adherence to the prescribed medication regimen was monitored, with compliance being deemed satisfactory if patients adhered to ≥80% of the prescribed medication.¹⁶ Concurrently, treatment outcomes were thoroughly documented, capturing both compliance metrics and patient responses.

In assessing treatment efficacy, all participants underwent a standardized follow-up ¹³C-UBT at the designated hospital 4 weeks post-rescue treatment culmination. The success criterion for H. pylori infection eradication was contingent upon the attainment of a negative test outcome, indicating successful clearance of the infection.

Calculation of Sample Size and Statistical Analysis

For the noninferiority clinical trial, the sample size is estimated by PASS 2021 software. Based on the previous literature, the sample size was determined before commencing the study. The eradication rates of H. pylori with furazolidone therapy were reported at 91.9% in intention-to-treat (ITT) analysis.¹⁷ To evaluate the noninferiority of HDDT compared with FBQT, a noninferiority margin of -15% was established with a one-sided α of 0.025 and β of 0.2. Considering a dropout rate of 20%, at least 130 participants (65 patients for each group) would be required in the noninferiority trial.

Statistical analyses were conducted using SPSS Statistics software, version 20.0 (IBM Inc.). Continuous variables were expressed as mean ± SD and analyzed using Student t tests. Categorical variables were presented as percentages and compared using χ² tests or Fisher exact tests. H. pylori eradication rates and adverse event incidences were assessed through ITT and per-protocol (PP) analyses.¹⁸ Univariate and multivariate logistic regression analyses were performed to investigate factors influencing H. pylori eradication rates, with odds ratios (ORs) and 95% CIs calculated for each independent variable. Furthermore, the receiver operating characteristic (ROC) curve was utilized to examine the relationship between the interval of H. pylori salvage therapy and the success of eradication, determining the optimal cutoff value through the maximum Youden Index. Results were deemed statistically significant at P <0.05.

RESULTS

Baseline Characteristics of the Participants

The trial profile depicted in Figure 1 illustrates the screening process conducted from January 2022 to December 2023, encompassing a total of 257 patients assessed for eligibility. Ultimately, 209 patients were deemed eligible for inclusion in the ITT analysis. Among these, 99 patients were assigned to the FBQT group, whereas 110 patients were allocated to the HDDT group. Subsequently, the PP analysis comprised 206 participants, with 97 individuals in the FBQT group and 109 in the HDDT group, following the exclusion of participants lost to follow-up or those intolerant to adverse events. Baseline characteristics between the FBQT and HDDT groups, except for dyspepsia and the interval time, exhibited no significant disparities (Table 1). Notably, log transformation was applied to interval times before analyzing continuous variables due to their significantly skewed distribution. In addition, a comparison of blood biomarker levels between the FBQT and HDDT groups before eradication therapy revealed nonsignificant differences (Table 2).

FIGURE 1.

Study flowchart. FBQT indicates furazolidone-based quadruple therapy; HDDT, high-dose dual therapy; ITT, intention-to-treat; PP, per-protocol.

TABLE 1.

Baseline Characteristics of the Participants Infected With H. Pylori in Whom Eradication Treatment Had Failed at Least Once

Variables	FBQT group (N = 99)	HDDT group (N = 110)	P
Gender (M:F)	53:46	58:52	0.907*
Age (y), mean±SD	41.21±11.30	42.83±12.74	0.336†
Hypertension, n (%)	9 (9.1)	6 (5.5)	0.309*
Diabetes, n (%)	3 (3.0)	1 (0.9)	0.347‡
Family history of GC, n (%)	5 (5.1)	1 (0.9)	0.103‡
Peptic ulcer, n (%)
No	72 (72.7)	86 (78.2)	0.270*
Yes	14 (14.2)	8 (7.3)	—
Uncertain	13 (13.1)	16 (14.5)	—
Dyspepsia, n (%)	6 (6.1)	0	0.010‡
GERD, n (%)	8 (8.1)	4 (3.6)	0.168*
No. previous eradication, n (%)
1	83 (83.8)	83 (75.5)	0.289‡
2	14 (14.2)	22 (20.0)	—
≥3	2 (2.0)	5 (4.5)	—
Interval time (log-transformed), mean±SD	5.87±0.88	6.18±0.90	0.013†
Drugs of previous treatment regimens, n (%)
Amoxicillin	73 (73.7)	80 (72.7)	0.869*
Clarithromycin	75 (75.8)	80 (72.7)	0.617*
Levofloxacin	29 (29.3)	37 (33.6)	0.500*
Metronidazole	36 (36.4)	54 (49.1)	0.064*

^*χ² tests.

^†Student t tests.

^‡Fisher exact tests.

FBQT indicates furazolidone-based quadruple therapy; GC, gastric cancer; GERD, gastroesophageal reflux disease; HDDT, high-dose dual therapy

TABLE 2.

Blood Biomarker Levels of the FBQT and HDDT Groups Before Eradication Therapy

Blood biochemistry tests (mean±SD)	FBQT group (N = 99)	HDDT group (N = 110)	P*
Hb (g/L)	137.81±12.91	140.83±23.21	0.241
WBC (109/L)	6.17±1.37	5.96±1.68	0.325
Neutrophil (109/L)	3.31±1.03	3.47±1.41	0.340
Lymphocyte (109/L)	2.07±0.52	1.93±0.65	0.081
PLT (109/L)	241.84±48.58	245.67±56.48	0.601
ALT (U/L)	20.98±9.03	21.46±11.05	0.735
AST (U/L)	21.19±6.81	21.78±6.67	0.531
ALP (U/L)	56.65±17.92	56.97±25.40	0.917
GGT (U/L)	24.99±15.18	25.66±19.15	0.783
TB (umol/L)	9.92±4.93	10.10±5.15	0.799
BUN (mmol/L)	5.30±7.30	5.57±8.10	0.795
Creatinine (umol/L)	70.39±16.75	69.17±19.23	0.627
UA (umol/L)	334.86±83.80	335.34±79.29	0.966

^*Student t tests.

ALP indicates alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FBQT, furazolidone-based quadruple therapy; GGT, Gamma-glutamyl transferase; Hb, hemoglobin; HDDT, high-dose dual therapy; PLT, platelet; TB, total bilirubin; UA, urine acid; WBC, white blood cell.

Efficacy of Helicobacter pylori Eradication Therapy, and Medication Compliance

The results from the ITT analysis revealed H. pylori eradication rates of 86.9% (86/99) for the FBQT group and 93.6% (103/110) for the HDDT group. Similarly, in the PP analysis, the eradication rates were 88.7% (86/97) for the FBQT group and 94.5% (103/109) for the HDDT group (Table 3). Statistical analysis indicated no significant difference in H. pylori eradication rates between the two groups in either the ITT (P = 0.097) or PP analysis (P = 0.129). Notably, the lower boundary of the 95% CI for the difference in eradication rates was not lower than the preset noninferiority limit of -15% specified in the protocol (-1.30% for the ITT analysis and -1.79% for the PP analysis). Consequently, the efficacy of H. pylori eradication in the HDDT group was established as noninferior to that of the FBQT group. Furthermore, the HDDT group exhibited significantly better compliance (P < 0.001) compared with the FBQT group (Table 3).

TABLE 3.

H. pylori Eradication Rates and Medicine Compliance in the FBQT and HDDT Groups

Items	FBQT group;% (n/N)	HDDT group; % (n/N)	Rate difference (95% CI)	P*
Eradication rate
PP	88.7 (86/97) 80.6 to 94.2	94.5 (103/109) 88.4 to 98.0	5.84 (-1.79 to 13.46)	0.129
ITT	86.9 (86/99) 78.6 to 92.8	93.6 (103/110) 87.3 to 97.4	6.77 (-1.30 to 14.83)	0.097
Medication compliance
PP	88.7 (86/97) 80.6 to 94.2	100.0 (109/109) 96.7 to 100.0	11.34 (5.03 to 17.65)	<0.001
ITT	86.9 (86/99) 78.6 to 92.8	99.1 (109/110) 95.0 to 100.0	12.22 (5.34 to 19.11)	<0.001

^*χ² tests.

FBQT indicates furazolidone-based quadruple therapy; HDDT, high-dose dual therapy; ITT, intention-to-treat; PP, per-protocol.

Rates of Adverse Events

In the PP analysis, adverse events were documented in 58 (59.8%) participants in the FBQT group and 10 (9.2%) participants in the HDDT group. Notably, the overall incidence of adverse events was markedly lower in the HDDT group compared with the FBQT group (P < 0.001). Among the reported adverse events, commonly observed manifestations included dysgeusia, ventosity, nausea, emesis, abdominal pain, diarrhea, dizziness, headache, skin rash, fatigue, and fever. In the ITT and PP analyses, the HDDT group had significantly lower rates of common adverse events than the FBQT group except for skin rash and fever (Table 4). Furthermore, there were no noteworthy disparities observed in the occurrence of severe adverse effects between the HDDT and FBQT groups.

TABLE 4.

Rates of Adverse Events in the FBQT and HDDT Groups

Outcomes	FBQT group; % (n/N)	HDDT group; % (n/N)	Rate difference (95% CI)	P
Overall adverse events
PP	59.8 (58/97) 49.3 to 69.6	9.2 (10/109) 4.5 to 16.2	50.62 (39.46 to 61.78)	<0.001*
ITT	58.6 (58/99) 48.2 to 68.4	9.1 (10/110) 4.4 to 16.1	49.49 (38.40 to 60.59)	<0.001*
Severe adverse effects
PP	3.1 (3/97) 0.6 to 8.8	0.9 (1/109) 0.0 to 5.0	2.18 (-1.71 to 6.06)	0.344†
ITT	3.0 (3/99) 0.6 to 8.6	0.9 (1/110) 0.0 to 5.0	2.12 (-1.69 to 5.94)	0.347†
Dysgeusia
PP	15.5 (15/97) 8.9 to 24.2	1.8 (2/109) 0.2 to 6.5	13.63 (6.01 to 21.25)	<0.001*
ITT	15.2 (15/99) 8.7 to 23.8	1.8 (2/110) 0.2 to 6.4	13.33 (5.84 to 20.82)	<0.001*
Ventosity
PP	12.4 (12/97) 6.6 to 20.6	1.8 (2/109) 0.2 to 6.5	10.54 (3.52 to 17.56)	0.003*
ITT	12.1 (12/99) 6.4 to 20.2	1.8 (2/110) 0.2 to 6.4	10.33 (3.41 to 17.2)	0.003*
Nausea
PP	13.4 (13/97) 7.3 to 21.8	1.8 (2/109) 0.2 to 6.5	11.57 (4.33 to 18.8)	0.001*
ITT	13.1 (13/99) 7.2 to 21.4	1.8 (2/110) 0.2 to 6.4	11.31 (4.21 to 18.42)	0.002*
Emesis
PP	14.4 (14/97) 8.1 to 23.0	1.8 (2/109) 0.2 to 6.5	12.60 (5.16 to 20.03)	<0.001*
ITT	14.1 (14/99) 8.0 to 22.6	1.8 (2/110) 0.2 to 6.4	12.32 (5.02 to 19.63)	<0.001*
Abdominal pain
PP	4.1 (4/97) 1.1 to 10.2	0.0 (0/109) 0.0 to 3.3	4.12 (0.17 to 8.08)	0.048†
ITT	4.0 (4/99) 1.1 to 10.0	0.0 (0/110) 0.0 to 3.3	4.04 (0.16 to 7.92)	0.049†
Diarrhea
PP	11.3 (11/97) 5.8 to 19.4	3.7 (4/109) 1.0 to 9.1	7.67 (0.44 to 14.9)	0.034*
ITT	11.1 (11/99) 5.7 to 19.0	3.6 (4/110) 1.0 to 9.0	7.47 (0.36 to 14.59)	0.037*
Dizziness
PP	14.4 (14/97) 8.1 to 23.0	2.8 (3/109) 0.6 to 7.8	11.68 (4.04 to 19.32)	0.002*
ITT	14.1 (14/99) 8.0 to 22.6	2.7 (3/110) 0.6 to 7.8	11.41 (3.91 to 18.92)	0.003*
Headache
PP	7.2 (7/97) 3.0 to 14.3	0.9 (1/109) 0.0 to 5.0	6.30 (0.85 to 11.75)	0.027†
ITT	7.1 (7/99) 2.9 to 14.0	0.9 (1/110) 0.0 to 5.0	6.16 (0.81 to 11.51)	0.028†
Skin rash
PP	5.2 (5/97) 1.7 to 11.6	0.9 (1/109) 0.0 to 5.0	4.24 (-0.51 to 8.99)	0.102†
ITT	5.1 (5/99) 1.7 to 11.4	0.9 (1/110) 0.0 to 5.0	4.14 (-0.52 to 8.81)	0.103†
Fatigue
PP	8.2 (8/97) 3.6 to 15.6	1.8 (2/109) 0.2 to 6.5	6.41 (0.39 to 12.44)	0.049†
ITT	8.1 (8/99) 3.6 to 15.3	1.8 (2/110) 0.2 to 6.4	6.26 (0.34 to 12.18)	0.049†
Fever
PP	1.0 (1/97) 0.0 to 5.6	0.0 (0/109) 0.0 to 3.3	1.03 (-0.98 to 3.04)	0.471†
ITT	1.0 (1/99) 0.0 to 5.5	0.0 (0/110) 0.0 to 3.3	1.01 (-0.96 to 2.98)	0.474†

^*χ² tests.

^†Fisher exact tests.

FBQT indicates furazolidone-based quadruple therapy; HDDT, high-dose dual therapy; ITT, intention-to-treat; PP, per-protocol.

Factors Associated With the Eradication Rate of Helicobacter pylori

In the multivariate logistic regression analysis, 4 variables emerged as significant predictors of H. pylori eradication rates. These included belonging to the HDDT group (OR = 5.66, 95% CI: 1.20 to 26.74), interval time (OR = 2.21, 95% CI: 1.05 to 4.64), alkaline phosphatase (ALP; OR = 0.95, 95% CI: 0.92 to 0.98), and creatinine levels (OR = 0.91, 95% CI: 0.86 to 0.96; Table 5).

TABLE 5.

Multivariate Analysis of the Influencing Factors of H. Pylori Eradication

Variables	β	SE	OR	95% CI	P
Eradication regimens
FBQT group	Reference	—	—	—	—
HDDT group	1.73	0.79	5.66	1.20 to 26.74	0.029
Gender
Female	Reference	—	—	—	—
Male	1.34	0.96	3.83	0.59 to 24.90	0.160
Age	0.04	0.03	1.04	0.98 to 1.10	0.190
Hypertension
No	Reference	—	—	—	—
Yes	−0.85	1.47	0.43	0.02 to 7.53	0.561
Peptic ulcer
No	Reference	—	—	—	—
Yes	0.25	0.97	1.28	0.19 to 8.55	0.801
Uncertain	−0.03	1.05	0.97	0.12 to 7.50	0.975
GERD
No	Reference	—	—	—	—
Yes	0.44	1.37	1.55	0.11 to 22.65	0.751
No. previous eradication
1	Reference	—	—	—	—
2	−1.17	0.91	0.31	0.05 to 1.83	0.196
3	−2.68	1.51	0.07	0.00 to 1.32	0.076
Interval time (LN-transform)	0.79	0.38	2.21	1.05 to 4.64	0.036
Medication compliance
Bad	Reference	—	—	—	—
Well	−0.37	1.38	0.69	0.05 to 10.41	0.791
Hb	−0.02	0.02	0.98	0.95 to 1.01	0.232
WBC	1.01	0.63	2.74	0.79 to 9.44	0.111
Neutrophil	−0.44	0.73	0.64	0.15 to 2.66	0.540
Lymphocyte	−0.43	0.91	0.65	0.11 to 3.88	0.639
PLT	−0.01	0.01	0.99	0.98 to 1.00	0.054
ALT	0.11	0.06	1.11	0.99 to 1.26	0.085
AST	−0.11	0.07	0.90	0.78 to 1.04	0.152
ALP	−0.05	0.02	0.95	0.92 to 0.98	0.004
GGT	−0.02	0.02	0.99	0.95 to 1.03	0.471
TB	0.06	0.07	1.06	0.92 to 1.23	0.398
BUN	0.22	0.30	1.24	0.69 to 2.25	0.473
Creatinine	−0.10	0.03	0.91	0.86 to 0.96	0.001
UA	0.01	0.01	1.01	1.00 to 1.01	0.280

ALP indicates alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; GERD, gastroesophageal reflux disease; GGT, Gamma-glutamyl transferase; Hb, hemoglobin; LN, natural logarithm; OR, odds ratio; PLT, platelet; TB, total bilirubin; UA, urine acid; WBC, white blood cell.

Cutoff Value of Interval Time Affecting Helicobacter pylori Eradication

The optimal timing for H. pylori salvage therapy remains uncertain. Therefore, we utilized ROC curves to determine the optimal timing for salvage therapy within the 2 eradication regimens. The area under the ROC curve (AUC) for the FBQT group was 0.622 (95% CI: 0.406 to 0.838), whereas the AUC for the HDDT group was 0.578 (95% CI: 0.329 to 0.826). The maximum Youden Index and corresponding best cutoff values for the 2 groups were identified as follows: FBQT group (maximum Youden Index = 0.359, cutoff value = 176.5) and HDDT group (maximum Youden Index = 0.298, cutoff value = 349.5; Fig. 2). These findings suggest that the optimal interval for initiating rescue treatment of H. pylori with the FBQT regimen is ∼6 months, whereas for the HDDT regimen, it is ∼1 year.

FIGURE 2.

ROC curve. ROC curve depicting interval time versus eradication success in the FBQT group (A) and HDDT group (B). FBQT indicates furazolidone-based quadruple therapy; HDDT, high-dose dual therapy; ROC, receiver operating characteristic.

DISCUSSION

H. pylori infection stands as a prevalent chronic bacterial ailment, impacting over 50% of the global populace. However, infection rates fluctuate contingent on factors, such as geographic location, ethnicity, age, and gender. Notably, the global prevalence of H. pylori is on the decline, although certain developing nations witness an escalation in prevalence due to factors like environmental hygiene and socioeconomic status.^1,2,19 This infection can lead to a spectrum of gastrointestinal disorders including GC, chronic atrophic gastritis, mucosa-associated lymphoid tissue lymphoma, and peptic ulcers. Eradication of H. pylori significantly reduces the risk of GC development and alleviates gastrointestinal complications. In China, quadruple therapy involving bismuth drugs is recommended as the primary treatment for H. pylori elimination.²⁰ However, rising antibiotic resistance and suboptimal patient compliance pose challenges to the effectiveness of eradication therapy. Approximately 3% to 10% of patients necessitate rescue therapy after 2 or more treatment failures due to persistent H. pylori infection.²¹ With the emergence of antimicrobial resistance, the significance of rescue therapy has amplified alongside the necessity for effective eradication strategies.

FBQT has demonstrated high efficacy as a first-line treatment for H. pylori eradication, boasting eradication rates of up to 95.5%.²² However, FBQT is associated with a range of adverse events, predominantly gastrointestinal reactions, such as nausea, vomiting, and diarrhea, alongside fever, rash, and pulmonary toxicity.²³ Due to the elevated incidence of adverse reactions, furazolidone is primarily reserved for rescue therapy in H. pylori infection. Notably, some studies have highlighted the efficacy and safety of HDDT involving amoxicillin and a PPI in H. pylori treatment.²⁴ The time-dependent nature of amoxicillin suggests that increased dosage and frequency may enhance bactericidal activity. Moreover, high doses of PPIs can sustain elevated gastric pH levels, augmenting amoxicillin’s efficacy and H. pylori eradication rates. For instance, Yang et al²⁵ conducted a study involving 168 patients who had previously failed H. pylori eradication, randomly allocating them to HDDT, sequential therapy, or triple therapy groups. HDDT exhibited superior efficacy with an eradication rate of 89.3% (95% CI: 80.9% to 97.6%), outperforming the other treatment modalities. Similarly, Bi et al²⁶ administered HDDT and quadruple therapy as rescue regimens for 658 patients with H. pylori treatment failure, achieving comparable eradication rates between HDDT and quadruple therapy based on bismuth.

High-dose PPI-amoxicillin dual therapy emerges as an effective rescue regimen for H. pylori infection due to its optimization of treatment by elevating the dose and frequency of potent medications while reducing the utilization of inappropriate drugs. Implementation of dual therapy holds promise in mitigating antibiotic overuse, thereby potentially reducing adverse treatment effects, including alterations in gut microbiota and global H. pylori resistance prevalence. In addition, owing to its simplicity, safety, and cost-effectiveness, this regimen may foster greater patient acceptance and treatment compliance.

A meta-analysis of 15 randomized clinical trials underscores the safety and tolerability of HDDT, showing a significant decrease in adverse events compared with other treatments (Relative Risk = 0.48, 95% CI: 0.37 to 0.64, P < 0.001).²⁷ Notably, HDDT exhibits a lower overall incidence of adverse events compared with FBQT, with no notable difference in serious adverse reactions between the two groups (Table 3). The predominant adverse effects associated with HDDT include diarrhea and dizziness, typically resolving shortly after treatment cessation.

Moreover, multivariate analysis identifies the HDDT group, interval time, ALP, and creatinine level as factors associated with H. pylori eradication rates (Table 5). However, further investigation is warranted to elucidate the precise mechanisms underlying the association between these factors and H. pylori eradication rates, particularly interval time. The optimal timing for rescue treatment of patients with H. pylori eradication failure remains undetermined. To address this, we conducted a ROC curve analysis, suggesting that 6 months and 1 year may be the optimal intervals for rescue treatment in the FBQT and HDDT groups, respectively (Fig. 2). One of the reasons affecting the time intervals of different therapies may be the development of bacterial resistance. The bacteria may develop resistance to certain antibiotics over time, especially if similar or cross-resistant drugs were used in the initial treatment. Therefore, to prevent further resistance development or to exploit a window where the bacteria are still vulnerable, using FBQT as soon as 6 months might be efficient when the bacteria are still vulnerable. In terms of HDDT, since resistance to amoxicillin is likely low, it can suppress bacterial growth for a longer duration, making a longer interval (eg, 1 y) before rescue treatment more feasible without significantly compromising efficacy. Other significant factors may include the reduction of side effects, individual variation, and pharmacokinetics that need further investigation in the future.

In the present study, a negative association was observed between improved H. pylori eradication with elevated levels of ALP and creatinine. ALP is an enzyme linked to the metabolism mainly in the liver and bones. H. pylori infection is known to contribute to various gastrointestinal disorders, including those affecting the liver.²⁸ Successful eradication of H. pylori may reduce liver inflammation or other related issues, leading to a decrease in ALP levels. In addition, creatinine is a waste product from muscle metabolism that is filtered out of the blood by the kidneys, and elevated levels of creatinine can indicate kidney dysfunction. H. pylori infection is a potential risk factor for kidney damage.²⁸ Therefore, eradication of H. pylori may improve renal function, leading to better excretion of creatinine.

Another strategy for H. pylori eradication is using the potassium-competitive acid blocker (P-CAB) plus 1 or 2 antibiotics. One of the common P-CABs is vonoprazan, which is different from conventional PPIs and could effectively inhibit H⁺ and K⁺-ATPase in the gastric parietal cells.²⁹ In a United States and Europe cohort, the dual combination of vonoprazan plus amoxicillin produces an eradication rate of 78.5%, whereas a triple combination of vonoprazan plus amoxicillin plus clarithromycin gives 84.7%.³⁰ Other studies in Japan and Thailand cohort reported a higher rate between 92.6 and 96.7 with a triple combination of vonoprazan plus amoxicillin plus clarithromycin,^31–33 similar to the eradication rate of HDDT in the present study. One of the reasons behind the low efficacy of P-CAB dual therapy could be the less bactericidal effects of only one antibiotic than 2 antibiotics. In addition, the commonly used dosage of vonoprazan is 20 mg twice a day, which may cause weaker acid-suppressing effects than the high dosage of esomeprazole at 20 mg 4 times daily. Genetic variation of different geographical populations may be another contributing factor as well.

This multicenter randomized controlled trial confirms the efficacy of high-dose amoxicillin combined with esomeprazole (HDDT) as comparable to classic FBQT, with the HDDT group exhibiting a lower incidence of adverse events. Furthermore, our study suggests optimal timeframes of 6 months for rescue treatment in the FBQT group and 1 year in the HDDT group. However, limitations such as the absence of blinding, small sample size, and the exclusion of factors like diabetes in subgroup analyses underscore the need for further validation through randomized controlled double-blind trials. In addition, future studies should explore 24-hour intragastric pH levels and CYP2C19 genotypes to evaluate gastric acid inhibition extent and optimize dual therapy efficacy in resistant strains.

The study showed that using high-dose amoxicillin combined with esomeprazole demonstrates efficacy comparable to classic FBQT in rescuing patients from H. pylori infection, with the HDDT group exhibiting a lower incidence of adverse reactions and requiring fewer medications. These findings support the utilization of HDDT as a salvage eradication regimen for H. pylori. The optimal interval of salvage therapy for the HDDT eradication regimen was 1 year.