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Background:
Systematic Review

Evolution of Amoxicillin-Based Mono-Antibiotic Regimens for Helicobacter pylori Eradication: From Ineffectiveness to Innovation—A Systematic Review

by
Chih-An Shih
1,2,†,
I-Ting Wu
3,†,
Deng-Chyang Wu
4,
Wei-Yi Lei
5,
Feng-Woei Tsay
6,
Tzung-Jiun Tsai
6,
Chung-Hung Tsai
7,
Ya-Chi Wu
7,
Wei-Chen Tai
8,* and
Ping-I Hsu
3,*
1
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Antai Medical Care Corporation, Antai Tian-Sheng Memorial Hospital, Pingtung 928, Taiwan
2
Department of Nursing, Meiho University, Pingtung 912, Taiwan
3
Division of Gastroenterology, Department of Internal Medicine, An Nan Hospital, China Medical University, Tainan 709, Taiwan
4
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5
Department of Medicine, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
6
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang Ming Chiao Tung University, Kaohsiung 813, Taiwan
7
Department of Family Medicine, An Nan Hospital, China Medical University, Tainan 709, Taiwan
8
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Microorganisms 2026, 14(3), 625; https://doi.org/10.3390/microorganisms14030625
Submission received: 29 December 2025 / Revised: 26 February 2026 / Accepted: 2 March 2026 / Published: 10 March 2026
(This article belongs to the Section Medical Microbiology)
Browse Figure
Versions Notes

Abstract

Mono-antibiotic therapy for Helicobacter pylori (H. pylori) infection minimizes unnecessary antibiotic exposure, reduces disruption of the gut microbiota, and lowers the risk of multidrug resistance. Although resistance of H. pylori to amoxicillin remains extremely low (<3%) worldwide, regular-dose amoxicillin monotherapy achieves eradication rates of less than 30%. Strategies to improve the efficacy of amoxicillin-based mono-antibiotic therapy include elevating intragastric pH with potent acid suppression, increasing the amoxicillin dose, and adding bismuth salts to the treatment regimen. This review evaluates the safety and effectiveness of six amoxicillin-based treatments for H. pylori. All regimens lasted 14 days and were studied in clinical trials published between 1 October 2014, and 1 October 2025. The pooled intention-to-treat and per-protocol eradication rates for each regimen were as follows: Regimen 1: Regular-dose amoxicillin + high-dose proton pump inhibitor (PPI): 84.7% (83/98) and 84.7% (83/98); Regimen 2: High-dose amoxicillin + high-dose PPI: 85.3% (3709/4347) and 89.9% (3692/4109); Regimen 3: Regular-dose amoxicillin + high-dose potassium-competitive acid blocker (PCAB): 86.0% (901/1048) and 91.2% (888/974); Regimen 4: High-dose amoxicillin + high-dose PCAB: 88.2% (1771/2009) and 93.5% (1720/1839); Regimen 5: Regular-dose amoxicillin + high-dose PCAB + bismuth: 84.9% (327/385) and 91.3% (327/358); Regimen 6: High-dose amoxicillin + high-dose PCAB + bismuth: 95.8% (115/120) and 98.4% (115/117). In conclusion, potent acid inhibition, escalation of amoxicillin dosage, and incorporation of bismuth can transform amoxicillin mono-antibiotic therapy from an ineffective approach into a highly effective eradication regimen for H. pylori infection.

1. Introduction

Helicobacter pylori (H. pylori) was previously known as Campylobacter pylori. The name change occurred after detailed analysis determined that the organism fit better in the new genus Helicobacter, rather than Campylobacter, due to its distinct characteristics.
H. pylori remains the principal etiological factor underlying chronic gastritis, peptic ulcer disease—including both gastric and duodenal ulcers—as well as gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma [1,2,3]. Current international recommendations advocate offering eradication therapy to all patients in whom H. pylori infection has been confirmed [4,5]. The success of eradication therapy is strongly influenced by antimicrobial susceptibility. In recent years, primary resistance of H. pylori to clarithromycin, metronidazole, and levofloxacin has risen substantially worldwide [6,7]. Contemporary surveillance studies report resistance rates ranging from 8–67% for clarithromycin, 35–74% for metronidazole, and 21–43% for levofloxacin, whereas resistance to amoxicillin (0–8%) and tetracycline (0–4%) remains comparatively low [6]. The marked increase in clarithromycin resistance has significantly compromised the efficacy of conventional triple therapy, with eradication rates falling below 80% in many regions. According to the Kyoto Global Consensus on H. pylori gastritis, empirical regimens should only be adopted if they consistently achieve eradication rates of at least 90% at the population level [8]. To meet this benchmark, several alternative first-line strategies have been developed, including bismuth-containing quadruple therapy and non-bismuth quadruple regimens such as sequential, concomitant, and hybrid therapies [9,10,11].
Although many international guidelines endorse bismuth quadruple therapy (BQT) as the preferred first-line option in settings with elevated clarithromycin resistance [9,10,11], its clinical application is not without drawbacks. BQT involves a relatively complicated dosing schedule and has been associated with a high incidence of treatment-related adverse events in large randomized controlled trials [12,13,14,15]. In two large-scales randomized controlled trials, nearly half to more than half of treated patients (48% and 56%, respectively) experienced adverse effects [14,15]. Commonly reported events include dysgeusia, tongue discoloration, darkened stools, nausea, and abdominal discomfort [16,17,18,19,20].
Clarithromycin-based non-bismuth quadruple regimens, particularly concomitant therapy, have been shown to maintain favorable eradication outcomes even in the presence of clarithromycin resistance [11]. Concomitant therapy consists of four agents—a proton pump inhibitor (PPI), clarithromycin, amoxicillin, and metronidazole—administered simultaneously throughout the entire treatment period. Evidence from meta-analytic data indicates that this regimen provides superior eradication rates compared with conventional standard triple therapy. Hybrid therapy, a modified clarithromycin-containing quadruple regimen developed by our group, represents another non-bismuth strategy [9]. This approach begins with 7 days of dual therapy comprising a PPI plus amoxicillin, followed by 7 days of quadruple therapy including a PPI, amoxicillin, clarithromycin, and metronidazole. In an initial pilot investigation conducted in Taiwan, hybrid therapy achieved eradication rates of 97.4% in the intention-to-treat (ITT) population and 99.1% in the per-protocol (PP) analysis [9]. Subsequently, a large multicenter randomized controlled trial demonstrated that 14-day hybrid therapy achieved efficacy comparable to 14-day BQT, with both regimens curing over 90% of patients in regions where clarithromycin resistance was moderate (approximately 17%) [15]. Notably, the incidence of adverse events was lower with hybrid therapy than with BQT. Despite its effectiveness, hybrid therapy requires the addition of two extra antibiotics during the second treatment phase, which may complicate dosing schedules and reduce patient acceptance in routine practice. To address this limitation, the treatment sequence was reversed—initiating therapy with a quadruple regimen followed by a dual regimen—thereby streamlining the medication schedule. This “reverse hybrid” strategy avoids introducing new drugs midway through therapy. A multicenter randomized trial confirmed that 14-day reverse hybrid therapy produced eradication rates similar to those achieved with 14-day BQT, while also demonstrating a more favorable safety profile [14]. Nevertheless, whether in the form of BQT, concomitant therapy, hybrid therapy, or reverse hybrid therapy, these regimens share a common characteristic: eradication relies on the use of two to three antibiotics.
Currently, the resistance rates to amoxicillin and tetracycline remain extremely low (<3%) in most countries [21,22]. Amoxicillin alone as mono-antibiotic therapy without an anti-acid agent has been used since 1988 for first-line anti-H. pylori treatment. Despite being treated with oral anti-H. pylori low-dose amoxicillin-alone monotherapy, amoxicillin by itself achieves less than a 30% eradication rate of H. pylori in Table 1 [23,24,25]. The clinical trial study showed 22 H. pylori-infected patients that received amoxicillin 375 mg treatment three times a day for 4 weeks. Eradication of H. pylori on culture was reduced from 45% immediately after treatment to 23% 4 weeks later in the amoxicillin-alone group [23]. Another clinical trial study showed 42 pediatric patients received amoxicillin 25 mg/kg twice daily for 4 weeks. Amoxicillin alone does not seem to be able to eradicate H. pylori in the long term, and its relapse rate is unacceptably high (73%) [25].
Strategies to improve the efficacy of amoxicillin-based mono-antibiotic therapy include elevating intragastric pH with potent acid suppression, increasing the amoxicillin dose, and adding bismuth salts to the treatment regimen. Elevating intragastric pH above 5.0 induces H. pylori to shift into a replicative state, thereby enhancing H. pylori susceptibility to amoxicillin [25]. Experimental data have shown that the antibacterial activity of amoxicillin against H. pylori is strongly influenced by intragastric pH. In vitro findings indicate that when the surrounding pH rises from 5.5 to 7.5, the minimal inhibitory concentration required to inhibit 90% of isolates (MIC90) declines markedly, from 0.5 mg/L to 0.06 mg/L [25]. These results suggest that optimizing acid suppression may significantly enhance the bactericidal effect of amoxicillin. Administration of high-dose proton pump inhibitors (PPIs) is capable of sustaining intragastric pH levels above 6, independent of CYP2C19 metabolic polymorphisms, thereby improving the antimicrobial effectiveness of amoxicillin [26]. Clinical evidence supports this pharmacologic rationale. In a randomized controlled study conducted in Taiwan, dual therapy consisting of high-dose amoxicillin combined with rabeprazole achieved an ITT eradication rate of 95%, which was superior to that observed with conventional triple therapy (81%) [27]. Beyond its favorable eradication performance, this dual regimen offers several practical advantages, including simplified dosing, a lower incidence of adverse events, and reduced exposure to additional antibiotics. Nevertheless, accumulating international data indicate that the therapeutic success of high-dose amoxicillin–PPI dual therapy is not uniform worldwide and appears to vary by geographic region.
Vonoprazan is a next-generation acid suppressant classified as a potassium-competitive acid blocker (P-CAB) [28,29]. Unlike conventional PPIs, it suppresses gastric acid secretion through reversible inhibition of the gastric H+/K+-ATPase. Pharmacodynamic studies have demonstrated that vonoprazan provides more potent and sustained acid suppression compared with standard PPIs. This enhanced and stable elevation of intragastric pH may improve the effectiveness of H. pylori eradication therapy by creating a more favorable environment for antibiotic activity. In terms of metabolism, vonoprazan is primarily processed in the liver via cytochrome P450 CYP3A4, with minor contributions from SULT2A1, CYP2C19, CYP2B6, and CYP2D6. Multiple randomized controlled trials as well as observational studies have consistently reported that a 7-day vonoprazan-based triple regimen achieves higher eradication rates than a 7-day PPI-based triple regimen when used as first-line therapy for H. pylori infection [28,29]. Furthermore, clinical studies suggest that vonoprazan combined with amoxicillin as dual therapy can yield eradication outcomes comparable to those of vonoprazan-containing triple therapy [26]. Another strategy to further optimize treatment efficacy involves the addition of bismuth. Bismuth compounds contribute to eradication through multiple mechanisms, including disruption of bacterial cell wall integrity and interference with mucosal adherence. In addition, bismuth suppresses key enzymatic functions of H. pylori, such as urease, phosphatase, and protease activities, thereby enhancing antibacterial effects [29].
Mono-antibiotic therapy for H. pylori infection minimizes unnecessary antibiotic exposure, reduces disruption of the gut microbiota, and lowers the risk of multidrug resistance. This review article aims to assess the effectiveness and safety of six 14-day amoxicillin-based regimens: (1) regular-dose amoxicillin with high-dose PPI, (2) high-dose amoxicillin with high-dose PPI, (3) regular-dose amoxicillin with high-dose PCAB, (4) high-dose amoxicillin with high-dose PCAB, (5) regular-dose amoxicillin with high-dose PCAB plus bismuth, and (6) high-dose amoxicillin with high-dose PCAB plus bismuth. In this study, high-dose amoxicillin was defined as dosage of amoxicillin ≥ 3 g/day.

2. Article Search

This systematic review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement to ensure methodological transparency and structured reporting [30]. The study protocol was prospectively registered in the PROSPERO database (registration number: CRD420261284583). The primary research question was defined as follows: among treatment-naïve patients with Helicobacter pylori infection, can 14-day amoxicillin-based mono-antibiotic regimens administered at regular or high doses achieve a per-protocol eradication rate of at least 90% when used as first-line therapy? A comprehensive literature search was conducted using PubMed, Embase, and the Cochrane Library. Search strategies combined controlled vocabulary and keywords related to “Helicobacter pylori” and “therapy” or “treatment,” targeting titles and abstracts. In addition to electronic database searches, manual screening of original research presented at major international conferences—including Digestive Disease Week (DDW), United European Gastroenterology Week (UEGW), Asia Pacific Digestive Disease Week (APDW), and meetings of the European Helicobacter Study Group—was undertaken. Eligible studies were restricted to English-language clinical trials published between 1 October 2014 and 1 October 2025 (Supplementary Materials).
Studies were considered eligible if they met the following criteria: (1) adult participants (≥18 years) receiving 14-day amoxicillin-based dual therapy with either a PPI or vonoprazan, or 14-day amoxicillin/vonoprazan/bismuth triple therapy as initial treatment for H. pylori infection; (2) randomized controlled trial design; (3) clearly reported eradication outcomes; and (4) publication in English. Exclusion criteria were: treatment duration shorter than 14 days; absence of confirmed H. pylori diagnosis before and after therapy using at least one validated diagnostic method (rapid urease test, histology, culture, or urea breath test); post-treatment assessment performed within four weeks of therapy completion; failure to report both ITT and PP results; publication solely as conference abstracts; or evaluation of rescue/salvage regimens.
Data extraction was conducted independently by two reviewers (C.A.S. and W.Y.L.) using a standardized collection form. Discrepancies were resolved through discussion with a third investigator (P.I.H.). Extracted variables included first author, year of publication, country of study, sample size, and eradication rates according to ITT and PP analyses. The initial search identified 1546 records. After removal of clearly irrelevant reports, reviews, meta-analyses, and non-clinical trial publications (n = 1488), the remaining studies underwent title and abstract screening. One duplicate record was excluded, resulting in 49 articles eligible for full-text review. Application of the predefined inclusion and exclusion criteria yielded 46 studies for final analysis. Statistical analyses were performed using MedCalc version 23.0.2 (MedCalc Software Ltd., Ostend, Belgium). The study selection process is illustrated in Figure 1.

2.1. Dual Therapies with Regular-Dose Amoxicillin/High-Dose PPI and High-Dose Amoxicillin/High-Dose PPI in the First-Line Treatment of H. pylori Infection

Table 2 presents the ITT and PP eradication outcomes of 14-day dual regimens combining regular- or high-dose amoxicillin with high-dose PPIs for first-line H. pylori therapy, based on randomized controlled trials published between 2014 and 2025 [16,17,18,19,20,27,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]. When data were pooled, the overall ITT eradication rates were 84.7% for regular-dose and 85.3% for high-dose amoxicillin regimens. Corresponding PP eradication rates were 84.7% and 89.9%, respectively. These findings indicate considerable geographic variability and demonstrate that such regimens do not reliably achieve the ≥90% eradication benchmark across different populations. Marked regional differences were evident. For example, a 14-day schedule consisting of amoxicillin 750 mg administered four times daily plus esomeprazole 40 mg three times daily achieved a PP eradication rate of 95.7% in a Taiwanese cohort [33]. In contrast, an identical dosing regimen evaluated in China resulted in a substantially lower PP eradication rate of 71.0% [42].
Several factors may account for the heterogeneity in treatment response observed with high-dose amoxicillin/PPI dual therapy. These include variations in local amoxicillin resistance rates, differences in the type and dosage of PPIs administered, genetic polymorphisms influencing PPI metabolism, medication adherence, body surface area (BSA), and dietary habits such as the intake of acidic foods. In a large multicenter randomized trial conducted by our group, both amoxicillin resistance and suboptimal adherence independently predicted treatment failure in patients receiving high-dose amoxicillin plus rabeprazole, with odds ratios of 8.2 and 8.6, respectively [20]. Within that study, eradication success was significantly reduced among patients harboring amoxicillin-resistant strains compared with those infected by susceptible strains (50% vs. 88%). Likewise, individuals with poor compliance demonstrated lower eradication rates than those who adhered well to therapy (40% vs. 87%). In addition, a separate Chinese study identified a BSA ≥ 1.69 m2 as the sole independent factor associated with eradication failure in high-dose amoxicillin/PPI dual therapy [48].
Regarding safety, pooled analyses showed that adverse events occurred in 13.3% (13/98) of patients receiving regular-dose regimens and 12.1% (517/4283) of those treated with high-dose regimens. Reported side effects were generally mild and most commonly included abdominal bloating, diarrhea, and nausea.

2.2. Dual Therapies with Regular-Dose Amoxicillin/High-Dose Vonoprazan and High-Dose Amoxicillin/High-Dose Vonoprazan in the First-Line Treatment of H. pylori Infection

Table 2 summarizes eradication outcomes from randomized controlled trials published between 2014 and 2025 evaluating 14-day dual regimens that combined vonoprazan with either regular- or high-dose amoxicillin as first-line therapy for H. pylori infection [47,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63]. When pooled, ITT eradication rates were 86.0% for regular-dose and 88.2% for high-dose amoxicillin regimens. Corresponding PP eradication rates reached 91.2% and 93.5%, respectively. Despite these generally favorable results, treatment performance was not uniform across regions and did not consistently meet the ≥90% target in all populations. In China, most randomized trials reported PP eradication rates exceeding 90% with high-dose amoxicillin/vonoprazan dual therapy. However, studies conducted in the United States and Taiwan demonstrated lower PP eradication rates of 81.2% [55] and 87.2% [64], respectively. These findings indicate that further optimization is required before this regimen can be universally recommended as a standard first-line approach.
At present, determinants of treatment failure with 14-day high-dose amoxicillin/vonoprazan dual therapy are not fully defined. A Taiwanese randomized controlled trial identified suboptimal medication adherence as an independent predictor of eradication failure (odds ratio 8.4) [64]. In that study, patients with poor compliance achieved a markedly lower eradication rate compared with those who adhered well to therapy (60.0% vs. 87.7%). Additionally, a Japanese clinical investigation reported that larger BSA was associated with reduced efficacy in patients receiving 7-day standard-dose vonoprazan dual therapy (vonoprazan twice daily plus amoxicillin 750 mg twice daily) [65]. Similarly, diminished eradication success with high-dose vonoprazan dual therapy was observed among individuals with higher BSA (79.6% for BSA ≥ 1.723 m2 vs. 90.8% for BSA < 1.723 m2).
Regarding safety, pooled adverse event rates were 17.4% (201/1152) for regular-dose therapy and 19.8% (417/2108) for high-dose amoxicillin/vonoprazan dual therapy. Importantly, no serious treatment-related complications were documented in association with high-dose regimens. Reported adverse events were generally mild and included nausea, diarrhea, and abdominal bloating. Notably, two large studies by Chey et al. [55] and Cheung et al. [61] described overall adverse event rates of 29.9% and 39%, respectively, with diarrhea being the most commonly reported symptom (5.2% and 12.0%, respectively).
Table 2. Eradication rates of 14-day regular-dose amoxicillin/high-dose PPI dual, high-dose amoxicillin/high-dose PPI dual, regular-dose amoxicillin/high-dose vonoprazan dual, high-dose amoxicillin/high-dose vonoprazan dual, bismuth/regular-dose amoxicillin/high-dose vonoprazan triple and bismuth/high-dose amoxicillin/high-dose vonoprazan triple for the first-line treatment of H. pylori infection in randomized control trials conducted between 2014 and 2025.
Table 2. Eradication rates of 14-day regular-dose amoxicillin/high-dose PPI dual, high-dose amoxicillin/high-dose PPI dual, regular-dose amoxicillin/high-dose vonoprazan dual, high-dose amoxicillin/high-dose vonoprazan dual, bismuth/regular-dose amoxicillin/high-dose vonoprazan triple and bismuth/high-dose amoxicillin/high-dose vonoprazan triple for the first-line treatment of H. pylori infection in randomized control trials conducted between 2014 and 2025.
14-Day Regular-Dose Amoxicillin/High-Dose PPI Dual Therapy and High-Dose Amoxicillin/High-Dose PPI Dual Therapy
Author
[Year]		CountryNo. of CasesRegimenEradication RateAdverse Events
ITTPP
Regular-dose amoxicillin
Sapmaz et al. [31]
[2017]		Turkey98rabeprazole 20 mg tid,
amoxicillin 750 mg tid		84.7% (83/98)84.7% (83/98)13.3% (13/98)
All   84.7% (83/98)84.7% (83/98)13.3% (13/98)
High-dose amoxicillin
Yang et al. [27]
[2015]		Taiwan150rabeprazole 20 mg qid,
amoxicillin 750 mg qid		95.3% (143/150)96.6% (143/148)23.0% (34/148)
Hu et al. [32]
[2017]		China87rabeprazole 20 mg qid,
amoxicillin 750 mg qid		81.6% (71/87)83.5% (71/85)3.4% (3/87)
Tai et al. [33]
[2019]		Taiwan120esomeprazole 40 mg tid,
amoxicillin 750 mg qid		91.7% (110/120)95.7% (110/115)9.6% (11/115)
Yang et al. [16]
[2019]		China116esomeprazole 20 mg qid,
amoxicillin 750 mg qid		87.9% (102/116)91.1% (102/112)6.3% (7/112)
Yu et al. [34]
[2019]		China80esomeprazole 40 mg bid,
amoxicillin 1000 mg tid		92.5% (74/80)96.1% (73/76)7.5% (6/80)
Song et al. [35]
[2020]		China380esomeprazole 20 mg qid,
amoxicillin 750 mg qid		87.1% (331/380)92.4% (329/356)17.6% (66/375)
Zhang et al. [36]
[2020]		China104esomeprazole 20 mg tid,
amoxicillin 1000 mg tid		83.5% (76/91)86.4% (76/88)5.0% (5/101)
Hwong-Ruey et al. [37]
[2020]		Malaysia97rabeprazole 20 mg qid,
amoxicillin 1000 mg qid		92.8% (90/97)93.8% (90/96)20.5% (20/97)
Shen et al. [38]
[2022]		China496esomeprazole 20 mg qid,
amoxicillin 750 mg qid		88.31% (438/496)91.63% (438/478)13.3% (66/496)
Guan et al. [17]
[2022]		China350esomeprazole 20 mg qid,
amoxicillin 1000 mg tid		89.4% (313/350)90.6% (308/340)12.9% (45/349)
Han et al. [39]
[2022]		China315esomeprazole 20 mg qid,
amoxicillin 750 mg qid		88.6% (279/315)90.4% (274/303)13.7% (43/314)
Shao et al. [18]
[2022]		China120rabeprazole 20 mg tid,
amoxicillin 1000 mg tid		85.8% (103/120)89.6% (103/115)13.0% (15/115)
Bi et al. [40]
[2022]		China329esomeprazole 40 mg tid,
amoxicillin 1000 mg tid		75.4% (248/329)81.3% (248/305)11.1% (34/305)
Liu et al. [19]
[2023]		China422esomeprazole 20 mg qid,
amoxicillin 1000 mg tid		90.3% (381/422)93.6% (381/407)13.5% (55/407)
Hsu et al. [20]
[2023]		Taiwan306rabeprazole 20 mg qid,
amoxicillin 750 mg qid		83% (255/306)87% (253/291)13.0% (40/305) 
Ding et al. [41]
[2023]		China134esomeprazole 40 mg bid,
amoxicillin 1000 mg tid		73.1% (98/134)83.1% (98/118)6.0% (8/134) 
Yun et al. [42]
[2023]		China108esomeprazole 40 mg tid,
amoxicillin 750 mg qid		65.7% (71/108)71.0% (71/100)2.0% (2/100)
Zhang et al. [43]
[2023]		China101ilaprazole 5 mg bid,
amoxicillin 1000 mg tid		92.1% (93/101)94.9% (93/98)13.9% (14/101)
Macedo et al. [44]
[2023]		Portugal50esomeprazole 40 mg bid,
amoxicillin 1000 mg alternating with
amoxicillin 500 mg qid		96.2% (48/50)95.9% (47/49)2.0% (1/50)
Valizadeh et al. [45]
[2024]		Iran114esomeprazole 40 mg bid,
amoxicillin 1000 mg tid		76.3% (87/114)79.1% (87/110)12.2% (14/114)
Han et al. [46]
[2025]		China160ilaprazole 10 mg bid,
amoxicillin 1000 mg tid		88.7% (142/160)92.2% (142/154)10.8% (17/157)
Yang et al. [47]
[2025]		China221esomeprazole 40 mg qid,
amoxicillin 750 mg qid		70.59% (156/221)93.94% (155/165)4.98% (11/221)
All   85.3% (3709/4347)89.9% (3692/4109)12.1% (517/4283)
14-day regular-dose amoxicillin/high-dose vonoprazan dual therapy and high-dose amoxicillin/high-dose vonoprazan dual therapy
Regular-dose amoxicillin
Zuberi et al. [49]
[2022]		Pakistan96vonoprazan 20 mg bid,
amoxicillin 1000 mg bid		89.6% (86/96)93.5% (86/92)13.0% (12/92)
Hu et al. [50]
[2023]		China55vonoprazan 20 mg bid,
amoxicillin 1000 mg bid		89.1% (49/55)94.1% (48/51)29.1% (16/55)
Hu et al. [51]
2024]		China95vonoprazan 20 mg bid,
amoxicillin 1000 mg bid		87.4% (83/95)96.5% (83/86)27.4% (26/95)
Liu et al. [52]
[2024]		China64vonoprazan 20 mg bid,
amoxicillin 750 mg tid		76.6% (49/64)90.6% (48/53)9.4% (6/64)
Fan et al. [53]
[2025]		China252vonoprazan 20 mg bid,
amoxicillin 1000 mg bid		79.4% (200/252)92.1% (197/214)27.2% (67/246) 
Peng et al. [54]
[2025]		China239vonoprazan 20 mg bid,
amoxicillin 1000 mg bid		91.6% (219/239)91.5% (215/235)11.7% (35/300)
Peng et al. [54]
[2025]		China247vonoprazan 20 mg bid,
amoxicillin 500 mg tid		87.0% (215/247)86.8% (211/243)13.0% (39/300)
All   86.0% (901/1048)91.2% (888/974)17.4% (201/1152)
High-dose amoxicillin
Chey et al. [55]
[2022]		USA265vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		78.5% (208 /265)81.2% (177/218)29.9% (104/348)
Yang et al. [56]
[2023]		China200vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		86% (172/200)92.5% (172/186)9.5% (17/200)
Peng et al. [57]
[2023]		China158vonoprazan 20 mg bid,
amoxicillin 750 mg qid		89.9% (142/158)97.9% (142/145)19.0% (30/158)
Hu et al. [58]
[2023]		China97vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		88.6% (86/97)95.5% (86/90)16.67% (15/90)
Hu et al. [50]
[2023]		China55vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		87.3% (48/55)95.9% (47/49)20.0% (11/55)
Jiang et al. [59]
[2024]		China200vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		94.0% (188/200)97.9% (188/192)19.0% (38/200)
Huang et al. [60]
[2024]		China102vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		92.2% (94/102)93.9% (93/99)13.7% (14/102)
Cheung et al. [61]
[2024]		China100vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		96.0% (96/100)96.7% (89/92)39.0% (39/100)
Liu et al. [52]
[2024]		China64vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		79.7% (51/64)94.3% (50/53)7.8% (5/64)
Lin et al. [62]
[2024]		China125vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		91.20% (114/125)93.39% (113/121)36.1% (44/122)
Peng et al. [54]
[2025]		China251vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		93.2% (234/251)93.2% (233/250)15.3% (46/300)
Song et al. [63]
[2025]		China209vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		88.0% (184/209)95.3% (181/190)17.6% (36/204)
Yang et al. [47]
[2025]		China183vonoprazan 20 mg bid,
amoxicillin 1000 mg tid		84.2% (154/183)96.8% (149/154)9.84% (18/165) 
All   88.2% (1771/2009)93.5% (1720/1839)19.8% (417/2108)
14-day bismuth/regular-dose amoxicillin/high-dose vonoprazan triple therapy and bismuth/high-dose amoxicillin/high-dose vonoprazan triple therapy
Regular-dose amoxicillin
Liang et al. [66]
[2024]		China300vonoprazan 20 mg bid,
amoxicillin 750 mg tid,
bismuth 220 mg bid		83.7% (251/300)90.9% (251/276)13.7% (41/300) 
Qi et al. [67]
[2025]		China85vonoprazan 20 mg bid,
amoxicillin 1000 mg bid,
bismuth 220 mg bid		89.4% (76/85)92.7% (76/82)4.9% (4/82)
All   84.9% (327/385)91.3% (327/358)11.8% (45/382)
High-dose amoxicillin
Hsu et al. [68]
[2026]		Taiwan120vonoprazan 20 mg bid,
amoxicillin 750 mg qid,
bismuth 300 mg qid		95.8% (115/120)98.4% (115/117)10.0% (12/120)
All   95.8% (115/120)98.4% (115/117)10.0% (12/120)
Abbreviations: bid, twice a day; tid, three times a day; qid, four times a day.

2.3. Triple Therapies with Bismuth/Regular-Dose Amoxicillin/High-Dose Vonoprazan and Bismuth/High-Dose Amoxicillin/High-Dose Vonoprazan in the First-Line Treatment of H. pylori Infection

Table 2 summarizes eradication outcomes from randomized controlled trials published between 2014 and 2025 that evaluated 14-day first-line regimens combining bismuth with vonoprazan and either regular- or high-dose amoxicillin for H. pylori infection [66,67,68]. When data were pooled, the ITT eradication rates were 84.9% (327/385) for regular-dose amoxicillin regimens and 95.8% (115/120) for high-dose amoxicillin regimens. Corresponding PP eradication rates were 91.3% (327/358) and 98.4% (115/117), respectively, indicating particularly robust performance with the high-dose amoxicillin combination. Bismuth compounds are known to potentiate antimicrobial activity through multiple complementary mechanisms. They exert direct antibacterial effects by inhibiting critical enzymes—including urease, F1-ATPase, and alcohol dehydrogenase—and by interfering with bacterial oxidative defense systems, acid resistance mechanisms, and adhesion to gastric epithelial cells. Through these actions, bismuth enhances the activity of co-administered antibiotics, resulting in synergistic effects that improve overall eradication outcomes. Incorporating bismuth into triple regimens has been shown to substantially increase cure rates, particularly in infections involving resistant strains, where improvements of approximately 30–40% have been reported.
One randomized controlled trial [66] evaluated a 14-day regimen consisting of vonoprazan 20 mg twice daily, amoxicillin 750 mg three times daily, and bismuth 220 mg twice daily. This combination achieved ITT and PP eradication rates of 83.7% and 90.9%, respectively. Importantly, its efficacy was comparable to that of a bismuth-containing quadruple regimen composed of esomeprazole, bismuth, clarithromycin, and amoxicillin. More recently, a multicenter randomized trial enrolling 360 participants directly compared three first-line strategies: 14-day bismuth/high-dose amoxicillin/high-dose vonoprazan triple therapy, high-dose amoxicillin/high-dose vonoprazan dual therapy, and a conventional clarithromycin-based triple regimen (amoxicillin/clarithromycin/rabeprazole) [68]. The results demonstrated that the bismuth-containing triple therapy achieved significantly higher eradication rates than either the dual therapy or the clarithromycin-based triple therapy (98.4% vs. 87.2% and 87.1%, respectively).

2.4. Long-Term Consequences of Prolonged High-Dose Amoxicillin Exposure

Antibiotic administration is well recognized to influence intestinal microbial composition and reduce microbial diversity, thereby perturbing the gut ecosystem. Emerging evidence indicates that extended exposure to amoxicillin induces distinct changes in both the gut microbiome and the resistome in adults. One notable observation was a decline in the proportion of short-chain fatty acid (SCFA)–producing bacterial taxa that are generally associated with intestinal health. Reassuringly, these microbiological shifts were not permanent; longitudinal follow-up demonstrated that the overall community structure largely recovered to its pre-treatment state approximately nine months after therapy [69]. Comparable findings have been reported in the context of H. pylori eradication therapy. In a randomized controlled trial evaluating 10-day high-dose vonoprazan–amoxicillin (VA) dual therapy, a temporary reduction in microbial diversity and alterations in taxonomic composition were detected immediately following treatment. However, these disturbances were reversed by the scheduled post-eradication assessment. Although transient dysbiosis was observed shortly after completion of therapy, restoration of the gut microbial profile occurred within four weeks [70]. Taken together, available data suggest that vonoprazan-based amoxicillin dual therapy induces only modest and reversible changes in the gut microbiota and SCFA-producing bacteria, with no evidence of sustained long-term disruption.

3. Limitations

Several limitations should be acknowledged when interpreting the findings of this systematic review. First, most of the eligible studies were conducted in China, which may restrict the generalizability of the results to other regions with different antibiotic resistance patterns, genetic backgrounds affecting drug metabolism, and population characteristics. Second, the overall number of included trials was limited, particularly those evaluating 14-day regimens that combine regular- or high-dose amoxicillin with vonoprazan and bismuth. The relatively small evidence base for this specific triple therapy reduces the certainty of pooled estimates. Third, representation from Western countries was sparse, with only two studies originating from the United States and Portugal. Consequently, the external validity of the proposed therapeutic strategies in Western healthcare settings remains uncertain and warrants further investigation. Finally, although aggregated eradication rates and adverse event frequencies were calculated, a formal quantitative meta-analysis was not undertaken. Specifically, statistical assessments of between-study heterogeneity and potential publication bias were not performed, which may limit the robustness and interpretability of the overall conclusions.

4. Conclusions

Current international guidelines generally advocate tailoring H. pylori eradication regimens according to regional clarithromycin resistance rates. Nevertheless, an alternative strategy—employing a single susceptible antibiotic supported by strong acid suppression—has attracted increasing attention. Such an approach may streamline therapeutic protocols, enhance medication adherence, and reduce unnecessary exposure to multiple antibiotics while still addressing the challenge of antimicrobial resistance. In this systematic review, pooled PP eradication rates were 84.7% for regular-dose amoxicillin combined with high-dose PPI, 89.9% for high-dose amoxicillin with high-dose PPI, 93.5% for high-dose amoxicillin with high-dose vonoprazan, and 98.4% for bismuth plus high-dose amoxicillin and high-dose vonoprazan. These findings underscore the importance of achieving profound and sustained acid suppression, optimizing amoxicillin dosing, and leveraging the synergistic effects of bismuth to maximize treatment efficacy within amoxicillin-based mono-antibiotic frameworks. Despite these encouraging results, caution is warranted. Considerable variability exists among treatment protocols, and most available evidence originates from East Asian populations. Consequently, the external validity of these observations remains uncertain. Well-powered, rigorously designed randomized controlled trials conducted across diverse geographic and resistance settings are needed to establish the broader applicability of these regimens and to clarify their position in standard clinical practice.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/microorganisms14030625/s1, PRISMA 2020 Checklist.

Author Contributions

P.-I.H. designed the research and drafted the studies. C.-A.S. reviewed the studies and drafted the initial manuscript. W.-Y.L. reviewed the studies. T.-J.T., C.-H.T. and Y.-C.W. analyzed the data. W.-C.T., D.-C.W., I.-T.W. and F.-W.T. critically reviewed the article. All authors have read and agreed to the published version of the manuscript.

Funding

The study was funded by the grants from the Research Foundation of An Nan Hospital, China Medical University (Grant Numbers: ANHRF113-23, ANHRF114-21 and ANHRF114-36), the Ministry of Science and Technology, Executive Yuan, Taiwan, ROC (Grant numbers: NSTC 112-2314-B-039-045, NSTC 113-2314-B-039-036 and NSTC 114-2314-B-039-077) and Chang Gung Memorial Hospital (CMRPG8L1302), Taiwan.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Suerbaum, S.; Michetti, P. Helicobacter pylori infection. N. Engl. J. Med. 2002, 347, 1175–1186. [Google Scholar] [CrossRef]
  2. Graham, D.Y.; Lew, G.M.; Klein, P.D.; Evans, D.G.; Evans, D.J., Jr.; Saeed, Z.A.; Malaty, H.M. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann. Intern. Med. 1992, 116, 705–708. [Google Scholar] [CrossRef]
  3. Sung, J.J.; Chung, S.C.; Ling, T.K.; Yung, M.Y.; Leung, V.K.; Ng, E.K.; Li, M.K.; Cheng, A.F.; Li, A.K. Antibacterial treatment of gastric ulcers associated with Helicobacter pylori. N. Engl. J. Med. 1995, 332, 139–142. [Google Scholar] [CrossRef]
  4. Asaka, M.; Kato, M.; Takahashi, S.; Fukuda, Y.; Sugiyama, T.; Ota, H.; Uemura, N.; Murakami, K.; Satoh, K.; Sugano, K.; et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter 2010, 15, 1–20. [Google Scholar] [CrossRef]
  5. Liou, J.M.; Malfertheiner, P.; Hong, T.C.; Cheng, H.C.; Sugano, K.; Shah, S.; Sheu, B.S.; Chen, M.J.; Chiang, T.H.; Chen, Y.C.; et al. Screening and eradication of Helicobacter pylori f or gastric cancer prevention: Taipei Global Consensus II. Gut 2025, 74, 1767–1791. [Google Scholar] [CrossRef]
  6. Shih, C.A.; Shie, C.B.; Hsu, P.I. Update on the first-line treatment of Helicobacter pylori infection in areas with high and low clarithromycin resistances. Therap. Adv. Gastroenterol. 2022, 15, 17562848221138168. [Google Scholar] [CrossRef]
  7. Wu, P.J.; Tsay, F.W.; Wu, D.C.; Yang, J.C.; Chuah, S.K.; Chen, K.Y.; Chen, C.L.; Lee, C.L.; Shih, C.A.; Liu, Y.H.; et al. Sequential changes of antibiotic resistances of Helicobacter pylori in Taiwan from 2019 to 2024. World. J. Gastroenterol. 2025, 31, 111380. [Google Scholar] [CrossRef]
  8. Sugano, K.; Tack, J.; Kuipers, E.J.; Graham, D.Y.; El-Omar, E.M.; Miura, S.; Haruma, K.; Asaka, M.; Uemura, N.; Malfertheiner, P. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015, 64, 1353–1367. [Google Scholar] [CrossRef]
  9. Hsu, P.I.; Wu, D.C.; Wu, J.Y.; Graham, D.Y. Modified sequential Helicobacter pylori therapy: Proton pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (hybrid) therapy for the final 7 days. Helicobacter 2011, 16, 139–145. [Google Scholar] [CrossRef]
  10. Fallone, C.A.; Chiba, N.; van Zanten, S.V.; Fischbach, L.; Gisbert, J.P.; Hunt, R.H.; Jones, N.L.; Render, C.; Leontiadis, G.I.; Moayyedi, P.; et al. The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults. Gastroenterology 2016, 151, 51–69. [Google Scholar] [CrossRef]
  11. Malfertheiner, P.; Megraud, F.; Rokkas, T.; Gisbert, J.P.; Liou, J.M.; Schulz, C.; Gasbarrini, A.; Hunt, R.H.; Leja, M.; O’Morain, C.; et al. Management of Helicobacter pylori infection: The Maastricht VI/Florence consensus report. Gut 2022, 71, 1724–1762. [Google Scholar] [CrossRef]
  12. Liou, J.M.; Fang, Y.J.; Chen, C.C.; Bair, M.J.; Chang, C.Y.; Lee, Y.C.; Chen, M.J.; Chen, C.C.; Tseng, C.H.; Hsu, Y.C.; 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, 2355–2365. [Google Scholar] [CrossRef]
  13. Malfertheiner, P.; Bazzoli, F.; Delchier, J.C.; Celiñski, K.; Giguère, M.; Rivière, M.; Mégraud, F.; Pylera Study Group. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: A randomised, open-label, non-inferiority, phase 3 trial. Lancet 2011, 377, 905–913, Erratum in Lancet 2011, 378, 1778. [Google Scholar]
  14. Hsu, P.I.; Tsay, F.W.; Graham, D.Y.; Tsai, T.J.; Tsai, K.W.; Kao, J.Y.; Peng, N.J.; Kuo, C.H.; Kao, S.S.; Wang, H.M.; et al. Equivalent Efficacies of Reverse Hybrid and Bismuth Quadruple Therapies in Eradication of Helicobacter pylori Infection in a Randomized Controlled Trial. Clin. Gastroenterol. Hepatol. 2018, 16, 1427–1433. [Google Scholar] [CrossRef]
  15. Tsay, F.W.; Wu, D.C.; Yu, H.C.; Kao, S.S.; Lin, K.H.; Cheng, J.S.; Wang, H.M.; Chen, W.C.; Sun, W.C.; Tsai, K.W.; et al. A Randomized Controlled Trial Shows that both 14-Day Hybrid and Bismuth Quadruple Therapies Cure Most Patients with Helicobacter pylori Infection in Populations with Moderate Antibiotic Resistance. Antimicrob. Agents Chemother. 2017, 61, e00140-17. [Google Scholar] [CrossRef]
  16. Yang, J.; Zhang, Y.; Fan, L.; Zhu, Y.J.; Wang, T.Y.; Wang, X.W.; Chen, D.F.; Lan, C.H. Eradication Efficacy of Modified Dual Therapy Compared with Bismuth-Containing Quadruple Therapy as a First-Line Treatment of Helicobacter pylori. Am. J. Gastroenterol. 2019, 114, 437–445, Erratum in Am. J. Gastroenterol. 2019, 114, 835. [Google Scholar] [CrossRef]
  17. Guan, J.L.; Hu, Y.L.; An, P.; He, Q.; Long, H.; Zhou, L.; Chen, Z.F.; Xiong, J.G.; Wu, S.S.; Ding, X.W.; et al. Comparison of high-dose dual therapy with bismuth-containing quadruple therapy in Helicobacter pylori-infected treatment-naive patients: An open-label, multicenter, randomized controlled trial. Pharmacotherapy 2022, 42, 224–232. [Google Scholar] [CrossRef]
  18. Shao, Q.Q.; Yu, X.C.; Yu, M.; Ma, J.; Zhao, J.B.; Yuan, L.; Qi, Y.B.; Hu, R.B.; Wei, P.R.; Xiao, W.; et al. Rabeprazole plus amoxicillin dual therapy is equally effective to bismuth-containing quadruple therapy for Helicobacter pylori eradication in central China: A single-center, prospective, open-label, randomized-controlled trial. Helicobacter 2022, 27, e12876. [Google Scholar] [CrossRef]
  19. Liu, D.N.; Wang, Q.Y.; Li, P.Y.; Wu, D.H.; Pan, J.; Chen, Z.Y.; Li, Y.Q.; Han, X.Y.; Lan, C.; Tang, J.; et al. Comparing high-dose dual therapy with bismuth-containing quadruple therapy for the initial eradication of Helicobacter pylori infection on Hainan Island: A randomized, multicenter clinical trial. Clin. Res. Hepatol. Gastroenterol. 2023, 47, 102125. [Google Scholar] [CrossRef]
  20. Hsu, P.I.; Chen, K.Y.; Tai, W.C.; Yang, J.C.; Tsay, F.W.; Liu, Y.H.; Chen, C.L.; Lee, C.L.; Yeh, H.Z.; Kuo, C.H.; et al. Hybrid, High-Dose Dual and Bismuth Quadruple Therapies for First-Line Treatment of Helicobacter pylori Infection in Taiwan: A Multicenter, Open-Label, Randomized Trial. Am. J. Gastroenterol. 2023, 118, 1184–1195. [Google Scholar] [CrossRef]
  21. Smith, S.M.; O’Morain, C.; McNamara, D. Helicobacter pylori resistance to current therapies. Curr. Opin. Gastroenterol. 2019, 35, 6–13. [Google Scholar] [CrossRef]
  22. Kuo, Y.T.; Liou, J.M.; El-Omar, E.M.; Wu, J.Y.; Leow, A.H.R.; Goh, K.L.; Das, R.; Lu, H.; Lin, J.T.; Tu, Y.K.; et al. Primary antibiotic resistance in Helicobacter pylori in the Asia-Pacific region: A systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 2017, 2, 707–715. [Google Scholar] [CrossRef]
  23. Rauws, E.A.; Langenberg, W.; Houthoff, H.J.; Zanen, H.C.; Tytgat, G.N. Campylobacter pyloridis-associated chronic active antral gastritis. A prospective study of its prevalence and the effects of antibacterial and antiulcer treatment. Gastroenterology 1988, 94, 33–40. [Google Scholar] [CrossRef]
  24. Glupczynski, Y.; Burette, A.; Labbe, M.; Deprez, C.; De Reuck, M.; Deltenre, M. Campylobacter pylori-associated gastritis: A double-blind placebo-controlled trial with amoxicillin. Am. J. Gastroenterol. 1988, 83, 365–372. [Google Scholar]
  25. Oderda, G.; Dell’Olio, D.; Morra, I.; Ansaldi, N. Campylobacter pylori gastritis: Long term results of treatment with amoxicillin. Arch. Dis. Child 1989, 64, 326–329. [Google Scholar] [CrossRef]
  26. Suzuki, S.; Gotoda, T.; Kusano, C.; Ikehara, H.; Ichijima, R.; Ohyauchi, M.; Ito, H.; Kawamura, M.; Ogata, Y.; Ohtaka, M.; et al. Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: A multicentre randomised trial in Japan. Gut 2020, 69, 1019–1026. [Google Scholar] [CrossRef]
  27. Yang, J.C.; Lin, C.J.; Wang, H.L.; Chen, J.D.; Kao, J.Y.; Shun, C.T.; Lu, C.W.; Lin, B.R.; Shieh, M.J.; Chang, M.C.; et al. High-dose dual therapy is superior to standard first-line or rescue therapy for Helicobacter pylori infection. Clin. Gastroenterol. Hepatol. 2015, 13, 895–905. [Google Scholar] [CrossRef]
  28. Inatomi, N.; Matsukawa, J.; Sakurai, Y.; Otake, K. Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases. Pharmacol. Ther. 2016, 168, 12–22. [Google Scholar] [CrossRef]
  29. Sakurai, Y.; Mori, Y.; Okamoto, H.; Nishimura, A.; Komura, E.; Araki, T.; Shiramoto, M. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects--A randomised open-label cross-over study. Aliment. Pharmacol. Ther. 2015, 42, 719–730. [Google Scholar] [CrossRef]
  30. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef]
  31. Sapmaz, F.; Kalkan, I.H.; Atasoy, P.; Basyigit, S.; Guliter, S. A Non-Inferiority Study: Modified Dual Therapy Consisting Higher Doses of Rabeprazole Is as Successful as Standard Quadruple Therapy in Eradication of Helicobacter pylori. Am. J. Ther. 2017, 24, e393–e398. [Google Scholar] [CrossRef]
  32. Hu, J.L.; Yang, J.; Zhou, Y.B.; Li, P.; Han, R.; Fang, D.C. Optimized high-dose amoxicillin-proton-pump inhibitor dual therapies fail to achieve high cure rates in China. Saudi J. Gastroenterol. 2017, 23, 275–280. [Google Scholar]
  33. Tai, W.C.; Liang, C.M.; Kuo, C.M.; Huang, P.Y.; Wu, C.K.; Yang, S.C.; Kuo, Y.H.; Lin, M.T.; Lee, C.H.; Hsu, C.N.; et al. A 14 day esomeprazole- and amoxicillin-containing high-dose dual therapy regimen achieves a high eradication rate as first-line anti-Helicobacter pylori treatment in Taiwan: A prospective randomized trial. J. Antimicrob. Chemother. 2019, 74, 1718–1724. [Google Scholar] [CrossRef]
  34. Yu, L.; Luo, L.; Long, X.; Liang, X.; Ji, Y.; Graham, D.Y.; Lu, H. High-dose PPI-amoxicillin dual therapy with or without bismuth for first-line Helicobacter pylori therapy: A randomized trial. Helicobacter 2019, 24, e12596. [Google Scholar] [CrossRef]
  35. Song, Z.; Zhou, L.; Xue, Y.; Suo, B.; Tian, X.; Niu, Z. A comparative study of 14-day dual therapy (esomeprazole and amoxicillin four times daily) and triple plus bismuth therapy for first-line Helicobacter pylori infection eradication: A randomized trial. Helicobacter 2020, 25, e12762. [Google Scholar] [CrossRef]
  36. Zhang, Y.; Zhu, Y.J.; Zhao, Z.; Zhao, J.T.; Wang, T.Y.; Yang, J.; Chen, D.F.; Lan, C.H. Efficacy of modified esomeprazole-amoxicillin dual therapies for Helicobacter pylori infection: An open-label, randomized trial. Eur. J. Gastroenterol. Hepatol. 2020, 32, 563–568. [Google Scholar] [CrossRef]
  37. Hwong-Ruey Leow, A.; Chang, J.V.; Goh, K.L. Searching for an optimal therapy for H pylori eradication: High-dose proton-pump inhibitor dual therapy with amoxicillin vs. standard triple therapy for 14 days. Helicobacter 2020, 25, e12723. [Google Scholar] [CrossRef]
  38. Shen, C.; Li, C.; Lv, M.; Dai, X.; Gao, C.; Li, L.; Zhang, Q.; Pan, W.; Liu, C.; Han, S.; et al. The prospective multiple-centre randomized controlled clinical study of high-dose amoxicillin-proton pump inhibitor dual therapy for H. pylori infection in Sichuan areas. Ann. Med. 2022, 54, 426–435. [Google Scholar] [CrossRef]
  39. Han, Y.Y.; Long, H.; Lin, Y.; He, Q.; Chen, W.G.; Ding, X.W.; Zhou, L.; An, P.; Wang, F.; Zhang, Z.Y.; et al. Optimized dual therapy for treatment-naive patients of Helicobacter pylori infection: A large-scale prospective, multicenter, open-label, randomized controlled study. Helicobacter 2022, 27, e12922. [Google Scholar] [CrossRef]
  40. Bi, H.; Chen, X.; Chen, Y.; Zhao, X.; Wang, S.; Wang, J.; Lyu, T.; Han, S.; Lin, T.; Li, M.; et al. Efficacy and safety of high-dose esomeprazole-amoxicillin dual therapy for Helicobacter pylori rescue treatment: A multicenter, prospective, randomized, controlled trial. Chin. Med. J. 2022, 135, 1707–1715. [Google Scholar] [CrossRef]
  41. Ding, Z.H.; Huang, Y.; Chen, J.N.; Luo, L.S.; Zhang, W.; Liang, X.; Lu, H. A randomized superiority clinical trial: Metronidazole improved the efficacy of high-dose dual therapy in Helicobacter pylori rescue treatment. J. Antimicrob. Chemother. 2023, 78, 828–831. [Google Scholar] [CrossRef] [PubMed]
  42. Yun, J.W.; Wang, C.; Yu, Y.; Xu, H.M.; Gou, L.Z.; Li, X.L.; Yi, G.R.; Lin, Y.M.; Han, T.Y.; Zhang, D.K. High-dose amoxicillin-proton pump inhibitor dual therapy as first-line treatment for Helicobacter pylori infection in Northwest China: A prospective, randomised controlled trial. Br. J. Clin. Pharmacol. 2023, 89, 232–241. [Google Scholar] [CrossRef]
  43. Zhang, X.D.; Zhang, D.Y.; Chen, R.X.; Chen, S.J.; Chen, C.; Zeng, F.; Huang, S.M.; Li, D.; Bai, F.H. Ilaprazole-amoxicillin dual therapy at high dose as a first-line treatment for Helicobacter pylori infection in Hainan: A single-center, open-label, noninferiority, randomized controlled trial. BMC Gastroenterol. 2023, 23, 249. [Google Scholar] [CrossRef]
  44. Macedo Silva, V.; Lima Capela, T.; Freitas, M.; Boal Carvalho, P.; Magalhães, J.; Cotter, J. A “new” option in Helicobacter pylori eradication: High-dose amoxicillin dual therapy outperforms bismuth quadruple therapy in a high dual resistance setting. Helicobacter 2023, 28, e12962. [Google Scholar] [CrossRef]
  45. Valizadeh Toosi, S.M.; Feyzi, S.; Kazemi, A. Comparison of the Efficacy of 12-day Concomitant Quadruple Therapy versus 14-day High dose Dual Therapy as a First-line Eradication Regimen. Korean J. Gastroenterol. 2024, 83, 150–156. [Google Scholar] [CrossRef] [PubMed]
  46. Han, Q.; Zu, M.; Du, S.; Guo, Y.; Zhu, Y.; Wang, Y.; Liu, X.; Guo, H.; Cheng, Y.; Ding, S. Different Doses of Ilaprazole for Dual Therapy Versus Bismuth-Quadruple Therapy for Helicobacter pylori Infection: A Three-Arm, Randomized Clinical Trial. Helicobacter 2025, 30, e70086. [Google Scholar] [CrossRef] [PubMed]
  47. Yang, X.E.; Zhang, S.J.; Liu, Y.; Yao, S.Y.; Zhang, S.X.; Liu, X.M.; Liang, L.X.; Wang, F. Amoxicillin high-dose dual therapy for Helicobacter pylori primary eradication: Proton pump inhibitor and potassium-competitive acid blocker, which’s better? World J. Gastroenterol. 2025, 31, 100863. [Google Scholar] [CrossRef]
  48. Guan, J.L.; Han, Y.Y.; Wang, M.R.; Xia, S.H.; Li, J.Y.; Zhang, M.Y.; Zhao, K.; Feng, L.N.; Zhang, Y.; Dong, R.N.; et al. Impact of body size on efficacy of high-dose dual therapy for Helicobacter pylori eradication. Helicobacter 2023, 28, e12953. [Google Scholar] [CrossRef]
  49. Zuberi, B.F.; Ali, F.S.; Rasheed, T.; Bader, N.; Hussain, S.M.; Saleem, A. Comparison of Vonoprazan and Amoxicillin Dual Therapy with Standard Triple Therapy with Proton Pump Inhibitor for Helicobacter Pylori eradication: A Randomized Control Trial. Pak. J. Med. Sci. 2022, 38, 965–969. [Google Scholar] [CrossRef]
  50. Hu, Y.; Xu, X.; Liu, X.S.; He, C.; Ouyang, Y.B.; Li, N.S.; Xie, C.; Peng, C.; Zhu, Z.H.; Xie, Y. Fourteen-day vonoprazan and low- or high-dose amoxicillin dual therapy for eradicating Helicobacter pylori infection: A prospective, open-labeled, randomized non-inferiority clinical study. Front. Immunol. 2023, 13, 1049908. [Google Scholar] [CrossRef]
  51. Hu, Y.; Huang, X.H.; Zhou, B.; Liu, M.L.; Liu, Y.F.; Yu, T.; Sun, P.; Tan, B.B.; Hu, Y.; Cheng, F. Vonoprazan and amoxicillin dual therapy for 14 days as the first-line treatment of Helicobacter pylori infection: A non-inferiority, randomized clinical trial. Helicobacter 2024, 29, e13045. [Google Scholar] [CrossRef]
  52. Liu, Z.; Sun, D.; Kou, L.; Jia, L.; Hao, J.; Zhou, J.; Zheng, W.; Gao, F.; Chen, X. Vonoprazan-amoxicillin dual therapy with different amoxicillin dosages for treatment-naive patients of Helicobacter pylori infection in China: A prospective, randomized controlled study. Eur. J. Gastroenterol. Hepatol. 2024, 36, 712–719. [Google Scholar] [CrossRef]
  53. Fan, X.; Shi, Y.; Li, Y.; Lin, X. Comparison of Vonoprazan and Low-Dose Amoxicillin Dual Therapy with Bismuth-Containing Quadruple Therapy for Naïve Helicobacter pylori Eradication: A Single-Center, Open-Label, Randomized Control Trial. Antibiotics 2025, 14, 990. [Google Scholar] [CrossRef]
  54. Peng, R.; Cai, P.; Zhang, Z.; Lv, S.; Chen, G.; Xu, Y.; He, B.; Sun, M.; Dai, X.; Yan, K. Efficacy of Three Amoxicillin Doses in Vonoprazan Dual Therapy for Helicobacter pylori Eradication: A Randomized Noninferiority Trial. Helicobacter 2025, 30, e70050. [Google Scholar] [CrossRef]
  55. Chey, W.D.; Mégraud, F.; Laine, L.; López, L.J.; Hunt, B.J.; Howden, C.W. Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial. Gastroenterology 2022, 163, 608–619. [Google Scholar] [CrossRef]
  56. Yang, F.; Yu, B.; Qin, L.; Dai, X. A randomized clinical study on the efficacy of vonoprazan combined with amoxicillin duo regimen for the eradication of Helicobacter pylori. Medicine 2023, 102, e35610. [Google Scholar] [CrossRef] [PubMed]
  57. Peng, X.; Chen, H.W.; Wan, Y.; Su, P.Z.; Yu, J.; Liu, J.J.; Lu, Y.; Zhang, M.; Yao, J.Y.; Zhi, M. Combination of vonoprazan and amoxicillin as the first-line Helicobacter pylori eradication therapy: A multicenter, prospective, randomized, parallel-controlled study. Clin. Exp. Med. 2023, 23, 4011–4019. [Google Scholar] [CrossRef] [PubMed]
  58. Hu, J.; Mei, H.; Su, N.Y.; Sun, W.J.; Zhang, D.K.; Fan, L.L.; He, P.; Pan, J.; Wang, X.W.; Zou, P.Y.; et al. Eradication rates of Helicobacter pylori in treatment-naive patients following 14-day vonoprazan-amoxicillin dual therapy: A multicenter randomized controlled trial in China. Helicobacter 2023, 28, e12970. [Google Scholar] [CrossRef]
  59. Jiang, G.; Luo, M.; Zheng, P.; Cong, Y.; Feng, Y.; Zhou, F. Eradication rate and safety of vonoprazan-amoxicillin dual therapy for Helicobacter pylori eradication: A randomized controlled trial. Scand. J. Gastroenterol. 2024, 59, 1229–1233. [Google Scholar] [CrossRef] [PubMed]
  60. Huang, X.P.; Liu, Y.J.; Lin, S.W.; Shao, Y.F.; Qiu, F.; Qiu, Q.W.; Xu, Z.K.; Chen, J.X.; Chen, L.H.; Lin, Z.Q.; et al. Vonoprazan-amoxicillin dual therapy for Helicobacter pylori eradication in Chinese population: A prospective, multicenter, randomized, two-stage study. World J. Gastroenterol. 2024, 30, 3304–3313. [Google Scholar] [CrossRef]
  61. Cheung, K.S.; Lyu, T.; Deng, Z.; Han, S.; Ni, L.; Wu, J.; Tan, J.T.; Qin, J.; Ng, H.Y.; Leung, W.K.; et al. Vonoprazan Dual or Triple Therapy Versus Bismuth-Quadruple Therapy as First-Line Therapy for Helicobacter pylori Infection: A Three-Arm, Randomized Clinical Trial. Helicobacter 2024, 29, e13133. [Google Scholar] [CrossRef] [PubMed]
  62. Lin, A.; Lin, Z.; Liu, Y.; Chen, S.; Shao, Y.; Qiu, F.; Xiao, Z.; Xu, Z.; Chen, L.; Chen, L. Ten-day versus 14-day vonoprazan-amoxicillin high-dose dual therapy for Helicobacter pylori eradication in China: A multicenter, open-label, randomized study. J. Gastroenterol. Hepatol. 2024, 39, 2645–2653. [Google Scholar] [CrossRef]
  63. Song, Z.; Zuo, X.; Zhang, Z.; Wang, X.; Lin, Y.; Li, Y.; Xu, X.; Huang, Y.; Wang, Q.; Shi, Y. Ten-Day Versus 14-Day Vonoprazan and Amoxicillin Dual Therapy for the Firstline Eradication of Helicobacter pylori Infection: A Multicenter, Randomized Controlled Trial. Helicobacter 2025, 30, e70070. [Google Scholar] [CrossRef] [PubMed]
  64. Hsu, P.I.; Shih, C.A.; Chen, C.L.; Chuah, S.K.; Yang, J.C.; Wu, D.C. Both 14-day vonoprazan triple therapy and 14-day rabeprazole reverse hybrid therapy are superior to 14-day vonoprazan high-dose dual therapy for the first-line anti-H. pylori treatment in populations with high rates of antibiotic resistance. Gastroenterology 2024, 166, S-431. [Google Scholar] [CrossRef]
  65. Eto, H.; Suzuki, S.; Kusano, C.; Ikehara, H.; Ichijima, R.; Ito, H.; Kawabe, K.; Kawamura, M.; Yoda, Y.; Nakahara, M.; et al. Impact of body size on first-line Helicobacter pylori eradication success using vonoprazan and amoxicillin dual therapy. Helicobacter 2021, 26, e12788. [Google Scholar] [CrossRef]
  66. Liang, J.W.; Xiong, S.; Jia, Y.G.; Xiao, D.; Tan, S.Y.; Cao, J.W.; Sun, J.; Tian, X.; Li, S.Y.; Chen, R.H.; et al. Comparison of vonoprazan bismuth-containing triple therapy with quadruple therapy in Helicobacter pylori-infected treatment-naive patients: A prospective multicenter randomized controlled trial. J. Gastroenterol. Hepatol. 2024, 39, 2293–2298. [Google Scholar] [CrossRef]
  67. Qi, Y.B.; Li, X.T.; Shao, Q.Q.; Xu, L.; Zhang, W.J.; Song, S.B.; Yan, Q.N.; Shi, S.Y.; Hu, R.B.; Mekky, A. Vonoprazan-containing Dual and Triple Therapies are Non-inferior to Bismuth-quadruple Therapy for Helicobacter pylori Eradication: A Single-center, Prospective, Open-label, Real-World Study. J. Gastrointestin. Liver Dis. 2025, 34, 295–303. [Google Scholar] [CrossRef] [PubMed]
  68. Hsu, P.I.; Wu, D.C. Transforming amoxicillin therapy into a grade-A eradication regimen with vonoprazan and bismuth: A multicenter randomized trial. Gastroenterology 2026, in press. [Google Scholar]
  69. Dhariwal, A.; Haugli Bråten, L.C.; Sturød, K.; Salvadori, G.; Bargheet, A.; Åmdal, H.; Junges, R.; Berild, D.; Zwart, J.A.; Storheim, K.; et al. Differential response to prolonged amoxicillin treatment: Long-term resilience of the microbiome versus long-lasting perturbations in the gut resistome. Gut Microbes 2023, 15, 2157200. [Google Scholar] [CrossRef]
  70. Hu, Y.; Xu, X.; Ouyang, Y.B.; He, C.; Li, N.S.; Xie, C.; Peng, C.; Zhu, Z.H.; Shu, X.; Xie, Y.; et al. Altered Gut Microbiota and Short-Chain Fatty Acids After Vonoprazan-Amoxicillin Dual Therapy for Helicobacter pylori Eradication. Front. Cell. Infect. Microbiol. 2022, 12, 881968. [Google Scholar] [CrossRef]
Microorganisms 14 00625 g001
Figure 1. PRISMA diagram of the literature search.
Figure 1. PRISMA diagram of the literature search.
Microorganisms 14 00625 g001
Table 1. Eradication rates of regular-dose amoxicillin-based mono-antibiotic therapies for the first-line treatment of H. pylori infection.
Table 1. Eradication rates of regular-dose amoxicillin-based mono-antibiotic therapies for the first-line treatment of H. pylori infection.
Author
[Year]		CountryNo. of CasesDurationRegimenEradication Rate
Rauws et al. [23]
[1988]		Netherlands224 weeksamoxicillin 375 mg bid22.7% (5/22)
Glupczynski et al. [24]
[1988]		Belgium458 daysamoxycillin suspension 20 mL (1000 g) bid0% (0/45)
Oderda et al. [25]
[1989]		Italy424 weeksamoxicillin 25 mg/kg bid27% (8/30)
Abbreviation: bid, twice a day.
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Shih, C.-A.; Wu, I.-T.; Wu, D.-C.; Lei, W.-Y.; Tsay, F.-W.; Tsai, T.-J.; Tsai, C.-H.; Wu, Y.-C.; Tai, W.-C.; Hsu, P.-I. Evolution of Amoxicillin-Based Mono-Antibiotic Regimens for Helicobacter pylori Eradication: From Ineffectiveness to Innovation—A Systematic Review. Microorganisms 2026, 14, 625. https://doi.org/10.3390/microorganisms14030625

AMA Style

Shih C-A, Wu I-T, Wu D-C, Lei W-Y, Tsay F-W, Tsai T-J, Tsai C-H, Wu Y-C, Tai W-C, Hsu P-I. Evolution of Amoxicillin-Based Mono-Antibiotic Regimens for Helicobacter pylori Eradication: From Ineffectiveness to Innovation—A Systematic Review. Microorganisms. 2026; 14(3):625. https://doi.org/10.3390/microorganisms14030625

Chicago/Turabian Style

Shih, Chih-An, I-Ting Wu, Deng-Chyang Wu, Wei-Yi Lei, Feng-Woei Tsay, Tzung-Jiun Tsai, Chung-Hung Tsai, Ya-Chi Wu, Wei-Chen Tai, and Ping-I Hsu. 2026. "Evolution of Amoxicillin-Based Mono-Antibiotic Regimens for Helicobacter pylori Eradication: From Ineffectiveness to Innovation—A Systematic Review" Microorganisms 14, no. 3: 625. https://doi.org/10.3390/microorganisms14030625

APA Style

Shih, C.-A., Wu, I.-T., Wu, D.-C., Lei, W.-Y., Tsay, F.-W., Tsai, T.-J., Tsai, C.-H., Wu, Y.-C., Tai, W.-C., & Hsu, P.-I. (2026). Evolution of Amoxicillin-Based Mono-Antibiotic Regimens for Helicobacter pylori Eradication: From Ineffectiveness to Innovation—A Systematic Review. Microorganisms, 14(3), 625. https://doi.org/10.3390/microorganisms14030625

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