Standard triple therapy is still the preferred regimen in areas where the predominant strain is susceptible to CLR. However, studies have reported worrisome levels of resistance to agents such as CLR and MET [16]. CLR-resistant H. pylori has been designated a high priority by the World Health Organization. The use of standard triple therapy is generally decreasing, and guidelines for children with H. pylori infection recommend that bismuth and non-bismuth quadruple therapy be used as first-line therapy in areas with high antibiotic resistance, based on adult studies. The present randomised controlled study showed unsatisfactory eradication rates (< 80%) of 14-day standard triple therapy (PPI + AMO + CLR), 14-day bismuth quadruple therapy (PPI + AMO + CLR + Bismuth) and sequential therapy (PPI + AMO and PPI + CLA + MET). Eradication success is primarily influenced by good adherence and low antibiotic resistance. The need to take the medication as prescribed was constantly emphasised throughout the treatment process in this study, and the overall drug adherence among children who completed the therapy exceeded 90%. Although we failed to obtain antimicrobial susceptibility testing results, another of our contemporaneous studies determined primary resistance rates in our area of 45.3% for CLR and 73.6% for MET and a dual resistance rate of 28.3% for CLR and MET [17]. The high rate of resistance to CLR and MET helps to explain the low eradication rates. In our area, CLR-based therapy should not be recommended as the first-line treatment.
Bismuth was initially mainly used as a mucosal protective agent for peptic ulcer and gastritis. In vitro, the combination of bismuth and antibiotic has shown a synergistic bacteriostatic and bactericidal effect in H. pylori treatment [18]. Accordingly, bismuth-containing therapy has become an effective alternative treatment to overcome antimicrobial resistance. In a review of studies conducted in children from 2011 to 2021, Lai et al. demonstrated that bismuth-based therapy had higher eradication rates [19]. A paediatric population study in Shanghai showed eradication rates of 89.8% for bismuth-based quadruple therapy and of 74.1% for standard triple therapy, in a population with CLR resistance in 18.5% and dual CLR and MET resistance in 18.5% [20]. However, the present study indicated that bismuth-based quadruple therapy had comparable efficacy to standard triple therapy (78.9% vs. 70%), which is inconsistent with the results of other studies. We believe that the unsatisfactory eradication rate for bismuth-based quadruple therapy may be related to the resistance. It is unclear whether higher antibiotic resistance has a greater impact on the eradication rate of bismuth-based quadruple therapy. Several adult studies have also reported that CLR and MET resistance are risk factors for failure of bismuth-based quadruple therapy and suggested that bismuth regimens not be recommended when the strains develop dual CLR/MET resistance or when there is a high level of metronidazole resistance with a minimum inhibitory concentration MIC > 32 µg/mL [21–23]. Currently, the impact of antibiotic resistance on the efficiency of bismuth in children is unclear, and further multicentre clinical studies should be performed.
In most studies, 10-day sequential therapy eradication appeared to be superior to 14-day standard triple therapy [19]. The Chinese consensus on H. pylori infection recommends sequential therapy as first-line therapy in areas where CLR resistance exceeds 20%. However, it remains controversial whether 10-day sequential therapy is better than 14-day standard triple therapy because a growing number of studies reached inconsistent conclusions, finding a similar or even inferior efficacy for sequential therapy [20, 24, 25]. In the present study, we found a shocking eradication rate of 50% in 10-day sequential therapy. An unacceptably low efficacy of 56.1% was also reported in a Turkish study with 25.7% CLR resistance [10]. The reasons for the results are unknown. Bontems et al. identified a lower eradication rate in children with CLR resistance than in those without resistance [26]. In addition, sequential therapy exposes children to three different antibiotics, and the ESPGHAN/NASPGHAN guidelines recommend against the use of sequential therapy in treatment-naïve children when the strain is CLR resistant or susceptibility testing is not available. Several adult studies have proposed that the efficacy of sequential therapy can be improved by extending the duration and have reported that 14-day sequential treatment is better than 14-day triple therapy [27]. A retrospective study in children also concluded that 14-day sequential therapy tended to be better than 14-day triple treatment. Moreover, a novel 14-day bismuth-based sequential therapy has been reported in Turkish children with H. pylori infection; it achieved a high eradication rate of 92% [28]. However, the efficacy and practicality of the above-mentioned new regimens and adverse antibiotic events need to be further explored based on antibiotic sensitivity testing. The latest 2022 Chinese expert consensus on children with H. pylori infection [29] no longer recommends sequential therapy as the first-line treatment, which is consistent with our current results.
In this study, we also evaluated symptoms in the children with H. pylori infection. It is worth mentioning that there was no significant difference in symptom improvement between the two groups of children with or without H. pylori eradication. A similar result was also reported in a randomised controlled study [30]. This suggests that H. pylori infection may not be the main cause of these symptoms. Therefore, nonspecific clinical manifestations should not be an indication for H. pylori testing and eradication therapy in children. This opinion is also supported by a meta-analysis indicating that the prevalence of abdominal symptoms was not different between H. pylori-positive and -negative children [31]. The updated JSPGHAN 2020 guidelines recommend testing for H. pylori in children with alarm signs rather than in children diagnosed with functional abdominal pain. The guidelines also propose that a paediatrician discuss the advantages and disadvantages of eradication therapy before treatment, in contrast to the ‘test and treat’ principle used in adults.
A limitation of this study is that antibiotic susceptibility testing was not conducted and that the relationship between antibiotic resistance and the eradication regimen was absent. Nevertheless, another of our studies performed in the same hospital has provided useful information on the antibiotic resistance of H. pylori strains. Despite the aforementioned limitation, this study comprises a randomised controlled trial with few biases that compared standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection.