Helicobacter pylori (H. pylori) infection and related diseases are a major global health concern. Approximately 44% of the global population is infected with H. pylori (Malfertheiner et al., 2017). The prevalence of upper gastrointestinal diseases is increasing in elderly populations worldwide. Approximately 53%–73% of elderly peptic ulcer patients are infected with H. pylori; however, elderly H. pylori-positive patients are less likely to receive treatment (Pilotto, 2004). Peptic ulcers are currently the main impact of H. pylori on healthcare resources, and older patients are at the greatest risk, as the mortality rate from peptic ulcers increases from approximately 1 in 100 000 at age 20 to 2-3 in 100 000 at age 70 (Bank et al., 1986). The Fifth Chinese National Consensus Report on management highly recommends that patients with peptic ulcers receive eradication of H. pylori (Liu et al., 2018). A study conducted by Leung et al. (Leung et al., 2018) demonstrated that among patients infected with H. pylori who received eradication therapy, the gastric cancer risk was significantly lower in the elderly compared with the matched general population highlighting the importance of eradication therapy for elderly patients.

A proton pump inhibitor (PPI) and the antibiotics clarithromycin and amoxicillin/metronidazole, the so-called standard triple therapy, are used as the first-line eradication therapy for H. pylori infection, worldwide (Salles and Mégraud, 2007). However, this kind of treatment may cause resistance-associated H. pylori eradication failure due to increasing antimicrobial resistance. Bismuth-containing quadruple therapy (BQT) is commonly used in China and is superior to the standard triple therapy (Xie et al., 2018). In general, elderly patients show a low tolerance and compliance to H. pylori eradication therapy (Salles and Mégraud, 2007). In some countries and regions, it is difficult to obtain drugs such as bismuth and tetracycline. Moreover, the risk of adverse effects of H. pylori eradication therapy increases in elderly patients. Therefore, comprehensive benefit and risk assessment for elderly patients undergoing H. pylori eradication treatment are essential.

In the 1990s, some European scholars proposed a dual therapy regimen of PPI plus an antibiotic, but compared with the triple regimen proposed in early guidelines, this regimen has a lower eradication rate, so it is not widely used in clinical treatment (Unge et al., 1989). However, according to some recent literature reports, increasing the dose of PPI and/or amoxicillin in the dual therapy regimen can effectively eradicate H. pylori (Goh et al., 2012; Attumi and Graham, 2014; Yang et al., 2015; Yu et al., 2019). Some studies have shown that the drug resistance of the bismuth quadruple regimen after eradication failure is significantly higher than that of the dual therapy (Ren et al., 2014). In China, the rural population accounts for the main proportion of patients with H. pylori infection. In regard to elderly patients, the instructions for taking two drugs are more concise and easier to understand than the instructions for taking four drugs. Several meta-analyses have compared the efficacy and safety of dual therapy and other regimens, and all of them concluded that PPI-amoxicillin is equally effective as other commonly used therapeutic regimens in the eradication of H. pylori (Gao et al., 2020a; Li et al., 2021). Therefore, high-dose dual therapy (HT) may be an effective eradication regimen for elderly patients who are not allergic to penicillin.

The widespread presence of H. pylori in elderly patients and the role of H. pylori in peptic ulcers, precancerous lesions of gastric cancer, gastric cancer, and gastric lymphoma (MALT) make a diagnosis and eradication therapy particularly important in this population. However, there is currently no consensus or guideline on H. pylori eradication therapy in elderly patients. Therefore, it is of practical significance to develop a safe and effective H. pylori eradication program for elderly patients, which is worthy of further study.

In the current study, we conducted the first, randomized, controlled trial to comparing the efficacy of 14-day hybrid and 14-day bismuth quadruple therapies for the first-line treatment of H. pylori infection in elderly patients. Although dual therapy is not currently recommended as the first-line regimen for treating H pylori infection, many studies have reported an effective eradication rate of this regimen (Ren et al., 2014; Yang et al., 2015; Tai et al., 2019). Our results showed that both regimens achieved a successful eradication rate, and HT with pantoprazole and amoxicillin was efficient with a rate of 93.0% in the PP analysis, 91.7% in the mITT analysis and 89.3% in the ITT analysis. Side effects were few although a minority of patients in the BQT group complained of vomiting due to clarithromycin. The HT was generally well tolerated by patients.

Currently, there are no specific guidelines regarding the management of H. pylori infection in elderly patients. With the increased antibiotic resistance of H. pylori, due to previous multiple exposures to antibiotics, elderly patients fail their intended eradication therapy. Moreover, H. pylori microbiology summarizes the existing evidence for first- and second-line treatment regimens that may be considered for special populations such as the elderly. Elderly patients generally have renal or liver dysfunction, which might affect drug accumulation. As BQT contains more antibiotics than HT, patients tend to experience more side effects. Individual treatment needs to be performed in elderly patients.

The globally increasing antibiotic resistance in recent years is an important cause of first-line H pylori eradication failure (Graham and Fischbach, 2010). To overcome this problem, there are several novel therapies such as sequential therapy, non-bismuth quadruple therapy, and hybrid therapy that have achieved high eradication rates in first-line H pylori eradication (Liou et al., 2013; Liou et al., 2016). Recently, dual therapy has gained attention as both first-line and rescue therapy. However, studies from the different regions show different cure rates, probably due to different dosages of PPI and amoxicillin (Graham et al., 2010; Kwack et al., 2016; Park et al., 2017). Some comments on the heterogeneity of the results with HT should be included. In this respect, some meta-analyses showed higher HT effectiveness in studies in Asian countries than in European countries (Yang et al., 2019b; Gao et al., 2020a; Zhu et al., 2020). There have also been several dual-therapy studies conducted in China, and most of them show successful eradication rates with fewer adverse events (Hu et al., 2017; Tai et al., 2019; Gao et al., 2020b; Song et al., 2020; Zhang et al., 2020; Zou et al., 2021; Shen et al., 2022) (Table 4). Therefore, we questioned whether high-dose and high-frequency amoxicillin-PPI dual therapy could be widely used in elderly patients.

Amoxicillin is widely used in the treatment of H pylori infections; it is one of the most active antimicrobials against H pylori in vivo with a minimum inhibitory concentration of ≤0.01–0.1 mg/L (Hirschl and Rotter, 1996). An improvement in acid inhibition extending into the nighttime hours, maintaining an intragastric pH of 6 or above, would greatly improve the eradication rates of a regiment (Marcus et al., 2012). Several studies have tested the effect of a total daily dose of amoxicillin on the cure rate. There is evidence that a dose of 3 g per day can achieve an effective eradication rate (Kwack et al., 2016; Li et al., 2021).

Sufficient acid inhibition is necessary because intragastric pH is one of the critical determinants and amoxicillin is acid labile. In aition, other factors influence the efficacy of treating H. pylori infection. The PPI potency has a strong ability to reliably maintain a relatively high intragastric pH. A previous study evaluating the efficacy of different PPIs combined with bismuth quadruple regimens for H. pylori eradication demonstrated that the eradication rates between different PPI regimens were similar in treating H. pylori infection (Kan et al., 2020). To achieve a reliable cure rate, a high dose of PPI that is unaffected by CYP2C19 genotypes may be needed. The pantoprazole-based eradication program was less affected by the CYP2C19 polymorphism (Fu et al., 2021). In this study, we used 40 mg pantoprazole which is relatively unaffected by CYP2C19 metabolism. A study conducted by Zullo et al. (2015) showed that a 10-day HT (esomeprazole 40 mg three times daily and amoxicillin 1 g three times daily) was effective and safe as a first-line treatment for H. pylori infection in Italy. However, the eradication rate was below 90%. Ping et al. (Hsu et al., 2018) found that H pylori infection was eradicated in 96.6% of patients who received reverse hybrid therapy (pantoprazole 40 mg plus amoxicillin 1 g twice daily for 14 days, and clarithromycin 500 mg plus metronidazole 500 mg twice daily for the first 7 days). Therefore, the regimen of 40 mg pantoprazole plus 3 g amoxicillin per day may be a favorable choice for elderly patients.

In the HT group, there were 11 patients who concomitantly and continually took medications, such as statins, hypotension, hypoglycemics, and antiplatelet drugs. Successful eradication was achieved in 10 of these patients. Thus, a dual regimen with fewer antibiotics would be an option for older patients or those with multiple comorbidities. Adverse events occurred in 10.6% (8/75) of patients, which was similar to most reports (Tai et al., 2019; Zou et al., 2021). Nausea, diarrhea, and abdominal pain were the most frequently occurring adverse events. All adverse events disappeared spontaneously after treatment.

Our study had some limitations. First, we did not perform susceptibility testing which was directly correlated. Second, we did not measure the patients’ intragastric pH value or CYP2C19 genotype. This was also a single-center study. A multicenter study should be conducted to confirm our findings.

In conclusion, our data showed that a 14-day regimen with pantoprazole 40 mg 3 times daily and amoxicillin 1,000 mg 3 times daily achieved an H. pylori eradication rate of 89.3%. This HT had few side effects and avoided the prevalence of antibiotic resistance. Clinicians can choose this treatment when considering H. pylori eradication in elderly patients.