Bismuth-Based quintuple therapy: a step beyond quadruple regimens in H. Pylori treatment and the impact of patient compliance

Abstract

Background

Helicobacter pylori (H. pylori) infection is one of the most common infections affecting humanity. As the level of development and socio-economic status of countries decreases, the prevalence of H. pylori infection increases. Although numerous H. pylori eradication regimens have been tested in recent years, the desired level of eradication success has not been achieved. In this study, we aimed to evaluate the effectiveness of alternative treatment protocols.

Methods

Patients who presented to our clinic between 2023 and 2024 were included in the study. The patient groups were treated with Rabeprazole (R), Metronidazole (M), Amoxicillin (A), and Bismuth (B) (RMAB), or with Esomeprazole (E), Metronidazole (M), Tetracycline (T), and Bismuth (B) (EMTB) regimens. Patients who were resistant to both RMAB and EMTB treatment protocols received quintuple therapy with RTAMB and ETAMB. All patients were thoroughly informed about their treatment process, management of side effects, and adherence to the therapy.

Results

A total of 611 patients who received H. pylori treatment were included in the study. Of the participants, 60.7% were women, and the mean age was 53.7 ± 15.2 years. For post-treatment response evaluation, 73.5% (n = 449) of the patients returned to our clinic. The overall H. pylori eradication success rate for the entire patient group was 49.6%. The success rates for patients receiving RMAB and EMTB treatments were 48.2% and 51.3%, respectively. Among the group of patients who were under controlled supervision and had optimal treatment compliance (n = 449), the success rates for the RMAB and EMTB treatments were found to be 66.9% and 68.5%, respectively. A total of 105 patients who were resistant to the RMAB and EMTB treatments were given RTAMB and ETAMB therapy. Of these patients, 96.2% complied with the treatment and underwent a response evaluation. The eradication success rates for patients treated with the RTAMB and ETAMB protocols were 65.6% and 67.6%, respectively.

Conclusion

In this study, we demonstrated that bismuth-based quintuple therapy can be used as an alternative to bismuth-based quadruple therapies and other high-risk treatments. However, we also highlighted the critical importance of treatment adherence.

Background

Helicobacter pylori (H. pylori) infection is a significant health problem that affects nearly half of the world’s population [1]. The World Health Organization has classified H. pylori as a Group 1 carcinogen. While the annual incidence of H. pylori infection is between 0.5% and 1% in developed countries, this rate is around 10% in developing countries. Despite the high prevalence and incidence of the infection, and the availability of well-established criteria and treatment algorithms for first- and second-line regimens, current treatment success rates are not at desired levels. The failure of H. pylori eradication therapy is significantly influenced not only by antimicrobial drug resistance but also by patient non-compliance due to medication side effects and the complexity of the regimens [2]. Furthermore, there is no clear recommendation for third-line and salvage therapy in cases of non-responsive, resistant H. pylori infection [3]. Therefore, there is a need to establish safe, effective, and accessible salvage therapies for patients.

In this study, we aimed to investigate the effect of bismuth subsalicylate (BS)-based quadruple therapies—Rabeprazole, Amoxicillin, Metronidazole, Bismuth (RAMB) and Esomeprazole, Tetracycline, Metronidazole, Bismuth (ETMB)—on eradication, as a potential approach before third-line therapy. We also sought to evaluate the impact of increasing patient compliance on eradication success. Additionally, we aimed to explore the efficacy of BS-based quintuple therapies (RTAMB and ETAMB), created by adding an extra antibiotic to the regimen, as an alternative second-line therapy for patients who did not benefit despite good compliance.

Methods

Study design and participants

Patients over the age of 18 who presented to the Gastroenterology Department of Necmettin Erbakan University Faculty of Medicine with dyspeptic complaints between January 2023 and January 2024 were included in the study. A total of 611 patients who met the inclusion criteria were enrolled. The presence of H. pylori infection prior to eradication therapy was confirmed either by a positive H. pylori stool antigen test and/or histopathological evaluation in patients who underwent endoscopy in our endoscopy unit. Patients’ age, gender, and comorbidities were recorded.

Patients who had used antibiotics, proton pump inhibitors (PPIs), H2 receptor blockers, bismuth compounds, non-steroidal anti-inflammatory drugs (NSAIDs), or antacids within the 4 weeks prior to the study were excluded. In addition, patients with liver cirrhosis, malignancy, those who were pregnant or breastfeeding, and those with a known allergy to any of the drugs included in the treatment protocols were excluded. Patients who had undergone gastrectomy for any reason or had received prior H. pylori eradication therapy were also not included in the study.

Treatment protocols

Two treatment protocols were applied for first-line therapy. The treatment protocol consisting of Rabeprazole (R), Metronidazole (M), Amoxicillin (A), and Bismuth (B), and the treatment protocol consisting of Esomeprazole (E), Metronidazole (M), Tetracycline (T), and Bismuth (B) were used. RMAB and EMTB therapies were planned to be administered to patients for 14 days.

RMAB protocol

Rabeprazole (20 mg twice daily), Metronidazole (500 mg three times daily), Amoxicillin (1 g twice daily), and Bismuth (300 mg four times daily).

EMTB protocol

Esomeprazole (40 mg twice daily), Metronidazole (500 mg three times daily), Tetracycline (500 mg twice daily), and Bismuth (300 mg four times daily).

For patients who failed first-line RMAB and EMTB treatments, second-line therapies RTAMB and ETAMB protocols were applied.

RTAMB protocol

Rabeprazole (20 mg twice daily), Tetracycline (500 mg twice daily), Amoxicillin (1 g twice daily), Metronidazole (500 mg three times daily), and Bismuth (300 mg four times daily).

ETAMB protocol

Esomeprazole (40 mg twice daily), Tetracycline (500 mg twice daily), Amoxicillin (1 g twice daily), Metronidazole (500 mg three times daily), and Bismuth (300 mg four times daily).

The treatment duration for both protocols was planned as 7 days. The 7-day five-drug treatment regimen is based on the principles of providing easy access to treatment for patients, our experience at our center, and avoiding drugs that may cause high antibiotic resistance.

Treatment process and evaluation

Patients were informed about H. pylori eradication therapy and guided on the steps they needed to follow during the treatment process. Adherence to the treatment protocols was regularly monitored in the clinic. Patients experiencing any issues during the treatment were supported either through phone calls or by inviting them to the clinic as needed. Two months after the completion of the treatment, patients underwent a stool antigen test. A negative stool antigen test was considered indicative of successful eradication.

Patients whose treatment outcomes could not be evaluated were contacted at least once by phone, informed, and invited to the clinic for assessment of their treatment results. All patients were instructed at the start of the treatment to inform our clinic if any side effects occurred and/or if they experienced any adverse reactions. Similarly, detailed information was provided to the patients regarding how and when the treatment evaluation would be conducted. Good adherence was defined as patients who followed the prescribed treatment regimen accurately, attended scheduled follow-up visits on time, and promptly reported any side effects that occurred. Adherence was assessed through patient interviews, medication counts when available, and regular telephone or in-person follow-ups. For patients who discontinued treatment due to side effects, the suspected drug was identified based on direct patient reports and confirmed by clinicians who monitored the patient by assessing the timing, type, and severity of symptoms.

Statistical analysis

The data were analyzed using SPSS version 19 (Armonk, NY: IBM Corp). Means and standard deviations were calculated for continuous variables, while frequencies and percentages were calculated for categorical variables. Treatment success was determined based on H. pylori eradication.

Ethical approval

The trial was conducted in compliance with the current version of the Declaration of Helsinki and the good clinical practice guidelines. Written informed consent was obtained from all participating patients, and all personal information was kept confidential. This study received ethics approval from Ethics Committee of NEÜ Faculty of Medicine (approval number: 2025/5489).

Results

Baseline characteristics of the study participants

A total of 611 patients who received H. pylori treatment were included in the study. Of the participants, 60.6% (n = 370) were female, and the mean age was 53.7 ± 15.2 years. For post-treatment response evaluation, 73.5% (n = 449) of the patients presented to our clinic. The remaining patients were contacted by phone and invited back for a response evaluation. However, the treatment response could not be assessed for these patients as they did not return to the clinic. The comorbidities and general characteristics of our patient group are shown in Table 1. Treatment protocols and their success are summarized in the treatment flow diagram (Fig. 1).

Table 1.

Clinical and demographical data of the groups

	All Patients	Patients Compliant with Treatment
Age (Years)	53.7 ± 15.2	54.3 ±15.7
Male(n,%)	370 (60.6)	275 (61.2)
BS-based quadruple treatment
RMAB(n,%)	336 (55)	242 (53.9)
EMTB (n,%)	275 (45)	207 (46.1)
BS-based quintuple therapy
RTAMB (n,%)	66 (62.9)	64 (63.4)
ETAMB (n,%)	39 (37.1)	37 (36.6)
Presence of Comorbidity
Presence of DM (n,%)	57 (9.3)	50 (11.2)
Presence of HT (n,%)	121 (19.8)	95 (21.2)
Presence of Asthma (n,%)	63 (10.3)	49 (10.2)
Presence of CAD (n,%)	45 (7.4)	37 (8.2)
No comorbidities	398 (65.1)	280 (62.4)

BS: Bismuth

RMAB: Rabeprazole, Metronidazole, Amoxicillin, Bismuth

EMTB: Esomeprazole, Metronidazole, Tetracycline, Bismuth

RTAMB: Rabeprazole, Tetracycline, Amoxicillin, Metronidazole, Bismuth

ETAMB: Esomeprazole, Tetracycline, Amoxicillin, Metronidazole, Bismuth

DM: Diabetes mellitus

CAD: Coronary artery disease

HT: Hypertension

Fig. 1.

Treatment flow diagram. RMAB: Rabeprazole, Metronidazole, Amoxicillin, Bismuth. EMTB: Esomeprazole, Metronidazole, Tetracycline, Bismuth. RTAMB: Rabeprazole, Tetracycline, Amoxicillin, Metronidazole, Bismuth. ETAMB: Esomeprazole, Tetracycline, Amoxicillin, Metronidazole, Bismuth

First-line treatment success

In our study group, 55% (n=336) received RMAB therapy, while 45% received EMTB therapy. The overall H. pylori eradication success rate was 49.6% (n=303). Treatment success rates for patients receiving RMAB and EMTB therapies were 48.2% and 51.3%, respectively.

Among the group of patients (n=449) who were under supervision during the treatment and had optimal adherence, 53.9% received RMAB therapy. In this group with optimal treatment compliance, the overall eradication success rate for both protocols was found to be 67.5% (n=303). The H. pylori eradication success rates for patients treated with the RMAB and EMTB protocols were 66.9% and 68.5%, respectively.

The results from the first-line treatment group indicate that treatment adherence and close monitoring of the treatment process play a significant role in the success of H. pylori eradication. The higher success rates among patients with good treatment adherence suggest that close follow-up during the treatment process improves treatment outcomes.

Second-line treatment success

A total of 146 patients (32.5%) with an inadequate response to first-line therapy were evaluated for a new treatment protocol. Of these, 71.9% (n=105) received the quintuple therapy protocol. The number of patients who received the RTAMB and ETAMB protocols were determined to be 66 (62.9%) and 39 (37.1%), respectively. Following the treatment, 96.2% of the patients (n=101) demonstrated treatment adherence and presented to our clinic for a response evaluation.

In the overall patient group, the H. pylori eradication rate was found to be 63.8% (n=67), while in the group with optimal treatment adherence, this rate was 66.3% (n=67). Among the patients treated with the RTAMB protocol, the eradication success rate was 65.6%, whereas for those treated with the ETAMB protocol, it was 67.6%.

These results obtained after second-line therapy demonstrate that alternative treatment protocols offer an effective solution, particularly for patients who do not respond to initial therapy. The increase in success rates highlights the importance of treatment adherence and the efficacy of alternative treatment regimens.

Adverse Events

When the entire patient group was evaluated, 24 patients (4%) developed side effects. Eight patients experienced nausea, four had abdominal pain, eight had an allergic reaction, and four had vomiting. Of these, 10 patients were unable to complete the treatment due to side effects. Of the patients who could not complete the treatment, 3 discontinued due to tetracycline side effects, 2 due to metronidazole side effects, and 5 due to bismuth side effects.

Discussion

Half of the world's population is infected with H. pylori, and the risk of this infection is inversely proportional to socioeconomic status. In 2015, H. pylori gastritis was recognized as an infectious disease, and it was recommended that all patients receive treatment [4]. While H. pylori causes duodenal and gastric ulcers in 20–30% of infected individuals, gastric cancers and, specifically, gastric MALT lymphomas develop in 1–4%. In cases of MALT lymphoma, H. pylori infection is detectable in 85–92% of cases. Furthermore, epidemiological studies have demonstrated a strong association between H. pylori and gastric cancer [5, 6]. The 2020 Taipei Global Consensus underscored the role of H. pylori eradication in achieving the goal of reducing or eliminating deaths from gastric cancer [7].

Despite many years of research and efforts to develop treatment protocols for H. pylori eradication, the overall treatment success remains poor compared to other infectious diseases [8]. Factors contributing to failure in H. pylori eradication include drug resistance, medication side effects, irregular use of antibiotics, patient non-compliance, inappropriate duration and dosing of medications, increased bacterial load, and genetic variability among H. pylori strains [9]. It has been observed that global resistance rates have increased when comparing treatment-naïve and post-treatment cases, with clarithromycin resistance rising from 32.6% to 69%, metronidazole from 35.3% to 45.8%, levofloxacin from 13.2% to 36.4%, and tetracycline from 2.1% to 2.9% [10]. In light of these data, according to the 2017 American Gastroenterological Association guideline and Maastricht V, if the first-line clarithromycin-based triple therapy fails, the recommended second-line treatments are bismuth-containing quadruple therapy or levofloxacin-containing triple therapy. The 2021 update to the Maastricht VI Consensus Report stated that molecular tests (e.g., PCR) should be considered to base antibiotic selection on solid evidence, optimize empirical treatment strategies, and determine new treatment strategies for selecting both first-line and salvage therapies. As a general approach in the guideline, it is recommended that all infected patients be treated. First-line treatments are suggested based on antibiotic susceptibility data. If clarithromycin resistance is present, bismuth quadruple therapy (PPI + bismuth + tetracycline + metronidazole, 10–14 days) is recommended, whereas a four-drug regimen (PPI + amoxicillin + clarithromycin + metronidazole, 10–14 days) is recommended in low-resistance regions. Levofloxacin-containing triple therapy (PPI + amoxicillin + levofloxacin, 10–14 days) can be a salvage option if resistance is favorable. Rifabutin-based triple therapy (PPI + amoxicillin + rifabutin, 10–14 days) and vonoprazan-amoxicillin dual therapy (7–14 days) show equivalent efficacy to bismuth-based regimens [11, 12]. According to a systematic review and meta-analysis published in Turkey in 2023 (based on 20 studies, a total of 1556 strains), the average clarithromycin resistance was found to be 26.7%, and the average levofloxacin resistance was 19.6% [13]. Therefore, in our study, we chose not to use clarithromycin and levofloxacin in the quadruple antibiotic therapy due to resistance. Furthermore, because of the difficulty in obtaining vonoprazan and rifabutin in our country, we chose to apply the quintuple (RTAMB, ETAMB) treatment protocol as an alternative treatment method for patients who did not respond to therapy.

Altıntaş et al. and Güliter et al. reported H. pylori eradication rates of 43.5% and 45.8%, respectively, with classic triple therapy [14, 15]. In contrast, another study from Korea reported a 94% eradication rate with a 14-day classic triple therapy plus bismuth subsalicylate [16]. A study conducted in Asia reported that the success rates for classic triple therapy and bismuth-based protocols were over 80% and 90%, respectively [17]. A study by Graham et al. [18] also found that adding BS to a 14-day regimen of PPI + amoxicillin-clavulanic acid + metronidazole increased the eradication rate from 81.3% to 88.5%. Based on the fact that adding BS improves eradication success, we also preferred BS-based treatment protocols for all our patients. Our success rates for the adherent group (66.9% with RMAB and 68.5% with EMTB) were comparable to those in the literature. Increasing patient adherence significantly boosts the success of H. pylori eradication therapy. A 2023 meta-analysis including 19 randomized controlled trials in developing countries showed that eradication rates could be increased to as high as 80.2% through adherence-enhancing strategies such as patient education and follow-up [19, 20]. Similarly, an analysis from the European H. pylori registry (hp-eureg2024) involving over 38,000 patients found that eradication rates were significantly higher in individuals with a treatment adherence rate of ≥90% (93% vs. 64%) [21]. In our study, the success rate was low in the group of patients receiving quadruple therapy who did not maintain adherence during the treatment. However, in cases where additional communication was provided to improve patient adherence, the success rates increased (from 48.2% to 66.9% in patients receiving RMAB and from 51.3% to 68.5% in those receiving EMTB). This clearly demonstrates the critical role of adherence-enhancing strategies in improving the effectiveness of H. pylori eradication therapy. Mori et al. reported a 91% eradication success rate with a 14-day rifabutin-based triple therapy as third-line treatment [22], while another study achieved a 100% eradication rate with a 10-day regimen of rifabutin, vonoprazan, and amoxicillin [23, 24]. The effectiveness of new treatment agents in third-line therapy has become evident. On the other hand, Ribaldone et al. reported that 7.3% of patients using new third-line agents experienced at least one side effect, and 1.3% discontinued treatment [25]. Rifabutin use has been associated with serious adverse effects such as myelotoxicity [1]. Rifabutin is primarily used to treat tuberculosis and other mycobacteria, particularly in immunocompromised patients or those with HIV. Its widespread use for H. pylori eradication is restricted due to the potential for developing drug resistance. While rifabutin's use is encouraged for third-line and salvage therapy in specific cases, its associated resistance and side effects highlight the need for developing alternative second-line treatments. A prospective study from China (2015–2016) reported a 75.4% eradication rate with a 5-day, bismuth subsalicylate (BS)-based quintuple therapy. Interestingly, despite high patient adherence (over 97%), the side effect rate was high at around 32% [26]. In contrast, a retrospective study from South Korea (2018–2022) demonstrated that this same quintuple combination improved both eradication rates and patient adherence [27]. In our study, we observed very few side effects in the group with optimal adherence, with an exceptionally low number of patients discontinuing treatment due to side effects. However, ensuring treatment adherence remains a significant challenge. Despite our best efforts to fully inform all patients, maintain frequent communication to help manage the treatment process, and provide support for side effects, we found that overall treatment adherence for the entire patient group was quite low at just 73.5% (n=449). In our study, even in well-adherent patients, eradication rates remained below the ≥90% treatment success rate recommended by the ACG and Maastricht guidelines. This discrepancy likely reflects increasing regional antibiotic resistance, differences in patient compliance, and the limited availability of alternative regimens such as rifabutin- or vonoprazan-based therapies. Furthermore, our study did not consider individual factors such as age, the presence of comorbidities, or low education level, and attempted to treat a very heterogeneous patient group. Most studies in the literature were conducted with naive, highly educated, and small patient groups. Despite these limitations, our findings are particularly relevant for real-world clinical settings in regions where treatment options are limited and antibiotic resistance is common. The study highlights the importance of adherence and supports the continued use of bismuth-based regimens as practical, accessible first-line or salvage options. Ensuring high adherence remains vital to improving eradication outcomes, and strategies such as patient education, structured follow-up, and simplified treatment instructions may further enhance adherence and treatment success.

Drug resistance, medication side effects, and poor treatment adherence are the most significant causes of treatment failure. Appropriate drug selection, enhancing patient adherence, and managing side effects contribute to higher treatment success rates. In our study, it was observed that providing patients with detailed information about their treatment protocols and ensuring close follow-up significantly improved the success of the bismuth-based quadruple therapy by increasing adherence and minimizing adverse effects. For patients who did not respond to the BS-based quadruple therapy, we administered bismuth-based quintuple therapy protocols (RTAMB, ETAMB), achieving success rates of 65.6% and 67.6%, respectively. Our study suggests that the BS-based quintuple regimen may serve as an effective alternative salvage therapy. Considering that the use of drugs such as rifabutin and levofloxacin as routine or alternative salvage treatments may lead to undesirable side effects and the development of resistance, we believe that the BS-based quintuple therapy offers a viable and effective salvage treatment option.

Abbreviations

H. pylori

Helicobacter pylori

R

Rabeprazole

M

Metronidazole

A

Amoxicillin

B

Bismuth

E

Esomeprazole

M

Metronidazole

T

Tetracycline

B

Bismuth

RAMB

Rabeprazole, Amoxicillin, Metronidazole, Bismuth

EMTB

Esomeprazole, Metronidazole, Tetracycline, and Bismuth

PPIs

Proton pump inhibitors

NSAIDs

Non-steroidal anti-inflammatory drugs

Authors' contributions

R.D. conceptualized and designed the study and drafted the manuscript. M.A. conceptualized and designed the study. R.D., U.C.H., and Y.A. recruited patients and entered data and wrote the manuscript. M.B., UC, R.Y. and R.D. were involved in data analysis. M.K., A.D. provided intellectual input. R.D. were involved in supervision.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

All data will be available by the corresponding author in a reasonable request.

Declarations

Ethical approval and consent to participate

The trial was conducted in compliance with the current version of the Declaration of Helsinki and the good clinical practice guidelines. Written informed consent was obtained from all participating patients, and all personal information was kept confidential. This study received ethics approval from Ethics Committee of NEÜ Faculty of Medicine (approval number: 2025/5489).

Competing interests

The authors declare no competing interests.