Potential Unnecessity of Bismuth in Standard Triple Therapy for Clarithromycin-Susceptible <i>Helicobacter pylori</i> Infection

Seon Woo Oh; Keun Sol Min; Hyung Geun Kim; Sunmi Lee; Chul-Hyun Lim; Jung-Hwan Oh

doi:10.7704/kjhugr.2024.0077

Korean J Helicobacter Up Gastrointest Res > Volume 25(1); 2025 > Article

Oh, Min, Kim, Lee, Lim, and Oh: Potential Unnecessity of Bismuth in Standard Triple Therapy for Clarithromycin-Susceptible Helicobacter pylori Infection

Original Article

The Korean Journal of Helicobacter and Upper Gastrointestinal Research 2025;25(1):48-53.

Published online: March 7, 2025

DOI: https://doi.org/10.7704/kjhugr.2024.0077

Potential Unnecessity of Bismuth in Standard Triple Therapy for Clarithromycin-Susceptible Helicobacter pylori Infection

Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author Jung-Hwan Oh, MD, PhD Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 1021 Tong Il-ro, Eunpyeong-gu, Seoul 03312, Korea E-mail: ojh@catholic.ac.kr

Received December 30, 2024; Revised January 25, 2025; Accepted February 8, 2025;

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives

The standard first-line treatment for Helicobacter pylori infection typically involves proton pump inhibitors, amoxicillin, and clarithromycin (PAC), yet the eradication success rates are not entirely satisfactory. Recognizing bismuth’s antibacterial properties and its potential to enhance antibiotic efficacy, this study compared the eradication success rates of a 7-day course of PAC with bismuth (PACB) versus PAC alone in patients with clarithromycin-susceptible H. pylori infections.

Methods

We conducted a retrospective review at Eunpyeong St. Mary’s Hospital involving 499 patients with confirmed clarithromycin-susceptible H. pylori infection. These patients were treated either with PACB or PAC for 7 days. Clarithromycin resistance-associated point mutations were evaluated using reverse transcriptase polymerase chain reaction. Successful eradication was confirmed by a negative ¹³C-urea breath test.

Results

Of the patients, 261 received PACB therapy, and 238 received PAC therapy. The intention-to-treat analysis showed eradication success rates of 82.8% (216/261) for PACB and 89.1% (212/238) for PAC (p=0.093). The per-protocol analysis revealed eradication rates of 85.3% (215/252) for PACB and 90.5% (210/232) for PAC (p=0.081). The incidence of adverse effects was similar between the two groups, with 41.3% (104/252) in the PACB group and 34.1% (79/232) in the PAC group (p=0.102).

Conclusions

Adding bismuth to the standard 7-day PAC regimen did not significantly increase eradication rates in patients with clarithromycin-susceptible H. pylori infections compared to PAC alone.

Key words: Bismuth; Clarithromycin; Helicobacter pylori; Proton pump inhibitors; Reverse transcriptase polymerase chain reaction

INTRODUCTION

Standard triple therapy (STT), comprising a proton pump inhibitor (PPI), clarithromycin, and amoxicillin, has long been the conventional treatment for Helicobacter pylori infection [1]. However, its efficacy has significantly diminished recently due to the increasing prevalence of antibiotic resistance [2]. Notably, clarithromycin resistance rates between 18%–46% have been reported among South Koreans, with such resistance linked to eradication failures [3]. The Maastricht VI guidelines recommend against using STT as first-line therapy if clarithromycin resistance rates exceed 15% [1]. In these cases, a bismuth-containing quadruple regimen is advised as the initial treatment in South Korea; however, this alternative often results in severe adverse events and challenges with patient adherence. Furthermore, several meta-analyses have questioned the superiority of this quadruple regimen over STT [4-6], leading to its continued use in clinical practice. The revised Korean evidence-based clinical practice guidelines now recommend 14 days of STT as empirical therapy. Yet, the success rate of this extended-duration STT reaches only 73.8%, falling short of the desired 80% eradication rate [7]. As a result, research continues into alternative drug combinations, though their efficacy is still under investigation.

Bismuth is known for its effectiveness against bacteria and its ability to enhance the efficacy of antibiotics [8]. In addition to its effectiveness, bismuth-containing STT regimens are generally safe for most patients. The most common adverse events associated with these regimens are gastrointestinal symptoms, such as nausea, diarrhea, and abdominal pain, which are typically mild and transient [9]. Therefore, incorporating bismuth into the STT regimen could represent a viable strategy. Our study evaluated the impact of adding bismuth to the 7-day STT regimen for clarithromycin-sensitive H. pylori infections, as 7-day STT alone has been reported to achieve approximately 85% success in such cases [10]. Additionally, because reverse transcriptase-polymerase chain reaction (RT-PCR) cannot detect all clarithromycin resistance mutations, we sought to determine whether bismuth could help overcome undetected resistance through its known mechanisms. This study assessed the efficacy of adding bismuth to STT for eradicating H. pylori strains susceptible to clarithromycin. It aimed to compare the eradication rates of a 7-day course of STT with bismuth versus a 7-day course of STT alone in patients with clarithromycin-susceptible H. pylori infections.

METHODS

Study population

This retrospective study was conducted at Eunpyeong St. Mary’s Hospital from 2021 to 2023. It received approval from the Ethical Review Committee of the Catholic Medical Center of Korea and was registered with the Institutional Review Board (PC23RESI0269). Because the study was retrospective in nature, a waiver of consent was submitted. We included patients who received first-line therapy and had never been treated for H. pylori. Only patients without clarithromycin resistance, as determined by RT-PCR, and who received 7 days of treatment were enrolled. We excluded those prescribed 10 or 14 days of treatment, as these regimens fell outside the scope of our study. Additionally, we excluded patients under 20 or over 85 years of age due to potential age-related variations in treatment response. Those with severe comorbidities, such as heart or respiratory diseases, severe thrombocytopenia, decompensated cirrhosis, or chronic kidney disease, were also excluded due to the potential impact on treatment outcomes. Furthermore, we excluded patients who had taken antibiotics, bismuth, or non-steroidal anti-inflammatory drugs within the previous four weeks to ensure the accuracy of our results. Patients with a history of antibiotic allergies, as well as pregnant and breastfeeding women, were also excluded.

Diagnosis of H. pylori

The diagnosis of H. pylori infection was established through Giemsa staining and RT-PCR. Patients confirmed to have the infection by Giemsa staining underwent RT-PCR to assess clarithromycin resistance. To detect clarithromycin resistance-associated point mutations (A2142G and A2143G), RT-PCR was conducted using the U-TOP HPy-ClaR detection kit (SEASUN BIOMATERIALS) [11].

H. pylori eradication regimen and determination of eradication success

Some patients received PAC therapy (a PPI [lansoprazole, 30 mg, twice daily]+amoxicillin [1 g, twice daily]+ clarithromycin [500 mg, twice daily]) for 7 days, while others underwent PACB treatment (tripotassium bismuthate [DENOL^®; GC Biopharma, 300 mg, two tablets twice daily]) for the same duration. Patients without clarithromycin-resistant infections were treated with either PACB or PAC for 7 days. Eradication success was verified by a urea breath test (13^C-urea breath test [POCone^®; Otsuka Electronics Co., Ltd.]) between 4 and 8 weeks following the conclusion of the therapy [10,11].

Adverse events

Adverse events were assessed using a questionnaire at the end of treatment. The questionnaire categorized the intensity of adverse events as mild to moderate or severe, based on the extent to which they disrupted ordinary daily activities [11]. Adverse events that led to the discontinuation of the medication were classified as severe.

Compliance

Subjects were excluded for poor adherence if they took less than 85% of their prescribed medication. This threshold was selected based on prior research indicating that adherence rates below 85% correlate with diminished treatment efficacy [10,11]. By applying this criterion, we aimed to ensure that our results were not compromised by poor medication adherence.

Statistical analysis

Statistical analyses were performed using SAS version 9.4 (SAS Institute). H. pylori eradication rates were evaluated using both intention-to-treat (ITT) and per-protocol (PP) analyses. Nominal variables were analyzed using the chi-square and Fisher’s exact tests. Continuous variables were assessed using the independent t-test or the Wilcoxon rank-sum test. A p-value of less than 0.05 was considered statistically significant.

RESULTS

Baseline characteristics

Among the 499 patients, 261 were in the PACB group and 238 in the PAC group for the ITT analysis. Twelve patients were lost to follow-up, including one dropout in the PACB group and two in the PAC group, who were non-compliant. In the PP analysis, there were 252 patients in the PACB group and 232 in the PAC group (Fig. 1). No statistically significant differences were observed in sex, age, smoking/drinking status, or comorbidities between the two groups (Table 1). However, there was a statistically significant difference in endoscopic diagnosis between the PACB and PAC groups (p=0.003), with a higher proportion of peptic ulcer cases in the PAC group and more gastritis cases in the PACB group. The body mass index was higher in the PAC group than in the PACB group.

Eradication rates between PACB and PAC

In an ITT analysis, the eradication rates between the PACB (n=261) and PAC (n=238) groups showed that the PACB group had a success rate of 82.8% (216/261), while the PAC group had a success rate of 89.1% (212/238). In the PP analysis, the success rates were 85.3% (215/252) for the PACB group and 90.5% (210/232) for the PAC group (Fig. 2). There was no significant difference in the success rates between the two groups in either the ITT or PP analyses (p=0.093, 0.081, respectively).

Adverse events

The most common adverse events were gastrointestinal symptoms, including diarrhea, abdominal pain, nausea, bloating, a bitter taste, and dyspepsia. In the PP analysis, adverse events occurred in 37.8% (183/484) of patients. The incidence rates of adverse events were 41.3% (104/252) in the PACB group and 34.1% (79/232) in the PAC group (p=0.102). There was no significant difference in the incidence of adverse events between the PACB and PAC groups (Table 2). Regarding the severity of adverse events, mild to moderate events occurred in 39.3% (99/252) of the PACB group and 32.8% (76/232) of the PAC group, while severe events were rare in both groups (2.0% vs. 1.3%, p=0.233). Table 3 summarizes the frequency of specific adverse events in the PACB and PAC therapy groups. The most common adverse events were diarrhea (23.2%), bitter taste (16.4%), heartburn (11.2%), and abdominal bloating (10.4%).

DISCUSSION

This study found that PACB therapy was not superior to PAC therapy in eradicating treatment-naïve cases of clarithromycin-susceptible H. pylori infection. Previous studies have explored the addition of bismuth to STT in patients with unconfirmed clarithromycin resistance, yielding varied results. In one study, PACB therapy, administered for either 10 or 14 days, treated unconfirmed clarithromycin-resistant H. pylori infection. According to ITT analysis, the 10-day therapy achieved an 88% eradication success rate, while the 14-day therapy reached 93% [12]. Another study, which compared the efficacy of bismuth without testing for clarithromycin resistance, reported a cure rate of 91.5% for the PACB regimen and 81.4% for PAC, demonstrating bismuth’s efficacy [13]. A study using a 7-day eradication regimen showed that incorporating bismuth did not lead to a meaningful benefit, with success rates of 79.3% for PACB therapy and 81.7% for PAC in the absence of confirmed clarithromycin resistance, showing no significant difference [14]. Another study confirmed the effectiveness of bismuth by checking for clarithromycin resistance at the study’s end [15]. A 14-day course of PACB therapy, in the absence of confirmed clarithromycin resistance, resulted in success rates of 87.9% in the ITT analysis and 90.4% in the PP analysis. In this study, in patients with clarithromycin resistance confirmed by PCR, 14 days of PACB therapy resulted in a 77.1% eradication rate, suggesting that PACB therapy may be an appropriate option in the absence of confirmed clarithromycin resistance. Considering existing research, the use of bismuth as an addition to STT proves effective with a 14-day treatment regimen when clarithromycin resistance testing is unavailable.

Antibiotic resistance is the most significant factor influencing the success of eradication therapies. A retrospective analysis of 247 patients tested for antibiotic resistance, who were treated empirically with STT, revealed that patients susceptible to both clarithromycin and amoxicillin exhibited an eradication rate of 85.9%. In contrast, eradication rates were 75.0% in patients susceptible to clarithromycin but resistant to amoxicillin, and only 44.4% in patients resistant to clarithromycin but susceptible to amoxicillin [16]. These findings—particularly in patients susceptible to both clarithromycin and amoxicillin—suggest that there may be other relevant factors impacting eradication success beyond the accuracy of antibiotic resistance tests. Resistance to amoxicillin and inadequate acid inhibition may also influence eradication outcomes in patients susceptible to clarithromycin. Furthermore, the RT-PCR technique used in this study has limitations in its ability to detect all mutations; specifically, it was unable to identify A2143C point mutations or resistance to amoxicillin. The RT-PCR method successfully identified only two mutations (A2142G, A2143G) associated with clarithromycin resistance. To address these limitations, the objective of this study was to investigate whether adding bismuth to the conventional STT could increase the eradication rate in patients without clarithromycin resistance, based on two-point mutations commonly used in clinical practice.

In environments where resistance testing is available, tailoring H. pylori treatment based on resistance test results could enhance eradication success rates. As determined by RT-PCR, the success rate of 1-week PAC therapy in clarithromycin-susceptible patients was not exceptionally high in our previous study, achieving 81.3% in the ITT analysis and 85.2% in the PP analysis [10]. Although these rates were higher than those reported for 14 days of empirical therapy, they were not entirely satisfactory. Adding bismuth to PAC might enhance eradication rates. One potential mechanism is the inhibition of H. pylori’s adhesion to gastric epithelial cells, which directly disrupts the bacterial cell wall, leading to lysis [17]. A recent study demonstrated that while bismuth did not exhibit direct synergistic effects with antibiotics, it showed in vitro susceptibility to H. pylori [18]. Moreover, bismuth is known to exert a synergistic effect with antibiotics such as clarithromycin [19], potentially improving the bactericidal performance of the therapy, even against resistant strains. This study was conducted with the expectation that adding bismuth might increase the success rate in patients with clarithromycin-susceptible H. pylori. However, PACB therapy did not prove superior to PAC therapy in terms of success rates. A recent meta-analysis showed that adding bismuth increased the eradication success rate, contrasting our results, with no difference in adverse events [20]. Regarding adverse events, the PACB group exhibited a higher frequency and severity of adverse events, though the difference was not statistically significant between the two groups.

Korean guidelines recommend 14 days of PAC therapy as the first-line treatment in situations where RT-PCR is not available [7]. However, patient compliance with the 14-day regimen is low, largely due to the prolonged therapy duration and side effects [21]. Furthermore, the success rate of 14-day empiric therapy is lower than expected at 78.1%, which can be attributed to the increasing prevalence of clarithromycin-resistant H. pylori. Given these factors, individualized therapy based on susceptibility testing is strongly recommended [22]. In light of these findings, it is unlikely that adding bismuth to PAC would significantly improve eradication rates in H. pylori cases identified as susceptible to clarithromycin. Nevertheless, incorporating bismuth into empiric therapy may still offer benefits.

A strength of this study is its focus on clarithromycin-susceptible patients and the comparison of bacteriological success rates between PACB and PAC therapies. Few trials have analyzed the effectiveness of PACB therapy after testing for clarithromycin resistance. To date, most studies assessing the benefits of bismuth have not included tests for clarithromycin resistance. The results of the current study indicate that PACB is not superior to PAC therapy alone in treating clarithromycin-susceptible H. pylori, suggesting that the addition of bismuth is unnecessary for these bacteria.

However, there are several limitations to this study. Firstly, it was retrospective in nature. Secondly, it was conducted at a single center, rather than being a multicenter randomized controlled trial. It involved a retrospective analysis of patients treated for H. pylori by two gastroenterologists at the same center. To address some of the limitations inherent in retrospective studies, the addition of bismuth starting at a specific time was compared with data from previously treated patients. Future well-designed multicenter studies are necessary to further investigate the usefulness of bismuth. Overall, our findings show no significant difference in the success rate when treating patients with PACB compared to PAC for 7 days in cases with confirmed clarithromycin susceptibility. Therefore, adding bismuth to triple therapy is unsuitable for patients with clarithromycin-susceptible H. pylori infection.

Notes

Availability of Data and Material

The datasets generated or analyzed during the study are not publicly available due to the limitation of retrospective study but are available from the corresponding author on reasonable request.

Conflicts of Interest

Jung-Hwan Oh, a contributing editor of the Korean Journal of Helicobacter and Upper Gastrointestinal Research, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.

Funding Statement

None

Acknowledgements

None

Authors’ Contribution

Conceptualization: Chul-Hyun Lim, Jung-Hwan Oh. Data curation: all authors. Formal analysis: Seon Woo Oh, Chul-Hyun Lim, Jung-Hwan Oh. Methodology: Chul-Hyun Lim, Jung-Hwan Oh. Writing—original draft: Seon Woo Oh, Jung-Hwan Oh. Writing—review & editing: Seon Woo Oh, Chul-Hyun Lim, Jung-Hwan Oh. Approval of final manuscript: all authors.

Fig. 1.

Study flow chart. ITT, intention-to-treat analysis; PP, per-protocol analysis; PAC, proton pump inhibitors, amoxicillin, and clarithromycin; PACB, PAC with bismuth.

Fig. 2.

Eradication rates between PACB and PAC therapy groups in per-protocol analysis. PAC, proton pump inhibitors, amoxicillin, and clarithromycin; PACB, PAC with bismuth.

Table 1.

Basic characteristics between PACB and PAC therapy groups

Characteristics	Total (n=484)	PACB (n=252)	PAC (n=232)	p-value
Age (yr)	58.3±11.6	59.2±10.8	57.4±12.3	0.096
Sex, male	242 (50.0)	124 (49.2)	118 (50.9)	0.716
BMI (kg/m²)	23.8±3.2	23.5±3.0	24.3±3.5	0.046
Comorbidities				0.508
Hypertension	141 (28.5)	68 (26.2)	73 (31.2)
DM	64 (13.0)	35 (13.5)	29 (12.4)
Chronic liver disease	13 (2.6)	8 (3.1)	5 (2.1)
Smoking				0.886
Current	57 (14.6)	30 (15.1)	27 (14.1)
Alcohol history				0.471
Current	145 (37.1)	77 (38.7)	68 (35.4)
Endoscopic diagnosis				0.003
Peptic ulcer (including ulcer scar)	151 (31.2)	66 (26.2)	85 (36.6)
Gastritis	284 (58.7)	166 (65.9)	118 (50.9)
Neoplasm	49 (10.1)	20 (7.9)	29 (12.5)

Data are presented as mean±standard deviation or n (%).

PAC, proton pump inhibitors, amoxicillin, and clarithromycin; PACB, PAC with bismuth; BMI, body mass index; DM, diabetes mellitus.

Table 2.

Comparison of adverse events and their severity between PACB and PAC therapy groups

Category	PACB (n=252)	PAC (n=232)	Total (n=484)	p-value
No	148 (58.7)	153 (66.0)	301 (62.2)	0.102
Yes	104 (41.3)	79 (34.1)	183 (37.8)
Mild-moderate	99 (39.3)	76 (32.8)	175 (36.2)	0.233
Severe	5 (2.0)	3 (1.3)	8 (1.6)

Data are presented as n (%).

PAC, proton pump inhibitors, amoxicillin, and clarithromycin; PACB, PAC with bismuth.

Table 3.

Frequency and comparison of adverse events between PACB and PAC therapy groups

Category	PACB (n=149)	PAC (n=101)	Total (n=250)
Diarrhea	28 (18.8)	30 (29.7)	58 (23.2)
Bitter taste	24 (16.1)	17 (16.8)	41 (16.4)
Heartburn	21 (14.1)	7 (6.9)	28 (11.2)
Abdominal bloating	17 (11.4)	9 (8.9)	26 (10.4)
Nausea	11 (7.4)	7 (6.9)	18 (7.2)
Dyspepsia	8 (5.4)	8 (7.9)	16 (6.4)
Loss of appetite	10 (6.7)	3 (3.0)	13 (5.2)
Headache	6 (4.0)	3 (3.0)	9 (3.6)
Abdominal pain	3 (2.0)	4 (4.0)	7 (2.8)
Dry mouth	2 (1.3)	4 (4.0)	6 (2.4)
Itching	5 (3.4)	1 (1.0)	6 (2.4)
Fatigue	2 (1.3)	3 (3.0)	5 (2.0)
Dizziness	4 (2.7)	0 (0.0)	4 (1.6)
Skin rash	3 (2.0)	1 (1.0)	4 (1.6)
Constipation	3 (2.0)	0 (0.0)	3 (1.2)
Reflux	1 (0.7)	1 (1.0)	2 (0.8)
Vomiting	1 (0.7)	1 (1.0)	2 (0.8)
Edema	0 (0.0)	1 (1.0)	1 (0.4)
Taste alteration	0 (0.0)	1 (1.0)	1 (0.4)

Data are presented as n (%).

PAC, proton pump inhibitors, amoxicillin, and clarithromycin; PACB, PAC with bismuth.

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