Can Patients with Clarithromycin-Resistant Helicobacter pylori Infection Be Treated with a 7-Day Bismuth-Based Quadruple Therapy?

The efficacy of Helicobacter pylori treatment is primarily influenced by antimicrobial resistance and patient adherence. Empirical antibiotic therapy for H. pylori eradication, which is not guided by culture results, has led to increased antibiotic resistance and a subsequent decline in eradication rates. To mitigate these issues while administering empirical treatment that does not adhere to antimicrobial stewardship principles, it is essential to select regimens that are effective and supported by robust evidence for optimal duration. Clarithromycin resistance is a significant factor contributing to the global decrease in H. pylori eradication rates. Consequently, a 10- to 14-day bismuth quadruple therapy (BQT), non-BQT or concomitant therapy is recommended as an initial treatment in regions with high clarithromycin resistance.¹ Paradoxically, despite numerous guidelines advising against the use of clarithromycin-based triple therapy in areas with high resistance, many of these regions continue to endorse it as a first-line treatment.^2,3 The Maastricht V guidelines recommend that antibiotic susceptibility testing should be performed prior to the initiation of clarithromycin-based triple therapy in such areas.¹ We are now at a critical juncture where it may be necessary to discontinue empirical clarithromycin-based triple therapy.

This raises the question “Which regimen should be considered as first-line therapy for patients with clarithromycin resistance?”. To date, no consensus has been reached regarding the first-line treatment for patients with clarithromycin-resistant H. pylori. If BQT is employed, should it be administered for 14 days as in rescue therapy? Is there a possibility of shortening the treatment duration in these populations? Tailored therapy based on clarithromycin resistance testing has been evaluated in regions with high resistance, such as Korea and Japan. While most studies indicate that tailored therapy is both effective and safe, a recent Korean study found that a 10-day empirical BQT was more cost-effective than tailored therapy.⁴ However, the optimal duration of BQT as a first-line therapy in patients with clarithromycin resistance has yet to be established. Evidence suggests that a 10-day BQT is comparable to a 14-day regimen regarding eradication rates as a first-line therapy.^5-7 However, the efficacy of a 7-day regimen remains uncertain despite some retrospective studies suggesting its acceptability.

Resistance to metronidazole can be overcome by increasing the dose or treatment duration. Thus, a BQT regimen that includes full-dose metronidazole for 14 days can be expected to yield excellent eradication rates regardless of metronidazole resistance. Nonetheless, the eradication success rates of 7-day and, potentially, 10-day regimens are significantly influenced by metronidazole resistance, with success rates falling below 90% when resistance exceeds 30%.⁸ Consequently, some patients may require the full 14-day course, while others may achieve eradication with a shorter duration. Several studies have demonstrated that a 10-day regimen is as effective as a 14-day regimen when used as empirical first-line therapy.⁵ However, the relatively high incidence of adverse events (AEs) associated with BQT necessitates optimization to minimize treatment duration while preserving therapeutic efficacy.

In this issue of the Gut and Liver, Lim and Oh⁹ present the results of a randomized controlled trial comparing the efficacy of 7-day BQT to that of 14-day BQT as first-line therapy for clarithromycin-resistant H. pylori infection. The eradication rates in the per-protocol analysis were 86.5% (95% confidence interval [CI], 78.7% to 94.3%; 64/74) for the 7-day group and 93.2% (95% CI, 87.4% to 99.0%; 68/73) for the 14-day group (p=0.182). Although there was no statistically significant difference between the groups, the 86.5% eradication rate in the 7-day group fell short of the “acceptable” H. pylori cure rate criteria.² However, when including four patients from the 14-day group who only completed 7 days of the BQT regimen, the eradication rate improved to 87.2% in the per-protocol analysis, suggesting that the 7-day regimen could be an effective treatment option.

AEs during H. pylori eradication therapy significantly impact patient compliance. The incidence of AEs related to BQT has been reported to be considerably higher than that of other regimens. In BQT, a 10-day regimen has been shown to reduce the occurrence AEs compared to a 14-day regimen.¹⁰ In the current study, Lim and Oh⁹ reported clinically significant AEs in 18.2% (95% CI, 12.2% to 24.2%; 29/159) of patients, with no statistically significant difference between the 7-day and 14-day groups. Interestingly, the overall incidence of AEs, including mild events, was higher in the 7-day group (23.7% vs 14.1%; p=0.128), consistent with findings from previous retrospective studies.^6,9 One possible explanation for this outcome is that most AEs associated with BQT emerge within the first 7 days of treatment initiation. Furthermore, recall bias may have influenced these results, as AEs were assessed by questionnaire during the urea breath test at least 4 weeks after treatment completion. Since patients in the 14-day group completed the questionnaire at least a week later than those in the 7-day group, they may have had more difficulty recalling mild AEs. Although not statistically significant, the incidence of severe AEs requiring treatment discontinuation was higher in the 14-day group at 6.4% (95% CI, 1.0% to 11.8%), than for the 7-day group at 2.4% (95% CI, 0.9% to 5.8%). Therefore, further studies are needed to definitively assess the benefits associated with the 7-day regimen.

Currently, evidence indicates that the acceptable minimum duration for BQT is 10 days; however, this study suggests that it may be reduced to 7 days as first-line therapy for patients with confirmed clarithromycin resistance. Graham and Fischbach² have recommended that clinicians should ‘only use what works locally’ while disregarding consensus statements and society guidelines if they are not consistent with local results. This highlights the limitations of applying results from well-designed large-scale studies or guidelines to real-world clinical practice. Given the substantial regional variations in eradication success, this study can serve as a crucial reference in high clarithromycin resistance regions such as Korea, and potentially beyond. Can clarithromycin-resistant H. pylori-infected patients be effectively treated with BQT for only 7 days instead of 14? Lim and Oh provide valuable insights that may help answer this question. We hope their findings will be validated through future studies and pave the way for changes in clinical practice and guidelines.