Helicobacter pylori is the primary etiologic cause of gastric adenocarcinoma (Lee et al., 2016; Hooi et al., 2017; Chiang et al., 2021). A recent systematic review reported that eradication resulted in a 46% reduced incidence of and 39% reduced mortality from gastric cancer (de Martel et al., 2020; Ford et al., 2020). The Kyoto global consensus and Houston consensus conferences recommend treating all individuals with proven H. pylori infection (Sugano et al., 2015; El-Serag et al., 2018). Traditionally, eradication for H. pylori was based on a standard triple regimen consisting of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin. However, this regimen is no longer recommended without susceptibility testing due to the high rates of clarithromycin resistance in many countries (Malfertheiner et al., 2011; Yeo et al., 2018).

Many current guidelines recommend bismuth quadruple therapy (BQT) as first-line therapy in areas with high clarithromycin resistance because BQT is less affected by antibiotic resistance (Fallone et al., 2016; Chey et al., 2017; Malfertheiner et al., 2017; Chen et al., 2019; Jung et al., 2020; Shah et al., 2021). However, BQT is difficult to use due to its frequent dosing, side effects, and availability (Howden and Graham, 2021). According to the recent European Registry, BQT users reported higher rates of side effects than those on other regimens (Nyssen et al., 2021a). BQT is generally recommended for 14 days rather than 7 or 10 days (Fallone et al., 2019; Kim et al., 2020; Shah et al., 2021). This is because prolonging the duration of metronidazole use to 14 days is expected to overcome resistance. However, few studies have confirmed this in clinical trials.

Several studies reported that clarithromycin-based triple therapy was affected by past macrolides exposure (Boltin et al., 2019; Kwon et al., 2019). There have been studies examining the relationship between past metronidazole exposure and BQT eradication rates. However, no meaningful additional analysis was performed other than the eradication rate due to the small number of patients (McNulty et al., 2012; Boltin et al., 2020; Lee et al., 2020). Our purpose was to investigate whether past metronidazole exposure influenced the eradication rates of the BQT regimen. We also examined the eradication rates according to the BQT duration in patients with or without metronidazole exposure.

Current guidelines recommend BQT as empirical therapy because it has proven to be effective in areas with high antibiotic resistance (Fallone et al., 2016; Chey et al., 2017; Malfertheiner et al., 2017; Chen et al., 2019; Shah et al., 2021). Metronidazole resistance is high in many countries, and a recent study reported global resistance rates to be 40–70% (Savoldi et al., 2018; Schubert et al., 2020; Megraud et al., 2021). BQT 14 days is generally recommended in areas with high metronidazole resistance as extending the duration to 14 days is expected to overcome resistance. In our clinical practice, patients often complain of difficulty taking BQT for 14 days due to the complexity of the regimen and adverse events. According to a European Registry survey from 2013 to 2018, patients prescribed BQT had the highest risk of adverse events compared with other eradication regimens (Nyssen et al., 2021b). A systematic review reported that adverse events increased as the BQT duration prolonged from 7 to 14 days (Yuan et al., 2013). These studies suggest that the dosage frequency and adverse events of BQT can affect patient compliance. There is also little evidence that increasing BQT duration to 14 days is more effective than 7 or 10 days in patients with metronidazole resistance.

Metronidazole resistance is not easy to demonstrate. Culture tests can confirm antibiotic resistance. However, H. pylori are intricate to incubate, and the long time deters its use in clinical practice. The E-test, widely used to measure antibiotic resistance, is known to overestimate metronidazole resistance (Osato et al., 2001). An in vitro test for metronidazole resistance is not an absolute preclusion criterion for use because in vitro resistance does not reliably correlate with H. pylori eradication failure. A recent study reported no association between metronidazole resistance determined by molecular-based experiments and eradication success (Argueta et al., 2021). Phenotypic methods for metronidazole resistance testing are not well standardized, and results can vary depending on the method used, which can result in lower predictive value.

In our study, we found that past metronidazole exposure lowered the BQT eradication rate. Prolonging the BQT duration to 14 days significantly increased eradication rates in patients with past exposure. The eradication rates of BQT <14 days in patients without exposure were similar to BQT 14 days. This suggest that BQT regimens of shorter duration may be effective in patients without metronidazole exposure history or metronidazole resistance. For patients suspected with a past metronidazole exposure, BQT should be prescribed for 14 days or levofloxacin-based regimens may be considered in areas with low quinolone resistance.

A previous study investigated the relationship between the dose of past macrolides exposure and the eradication rate of standard triple therapy (Boltin et al., 2019). They reported that increased macrolides exposure was associated with lower eradication rates. To our knowledge, no study examined if the duration of past metronidazole exposure and the interval from exposure to eradication affected the eradication rate. In our study, the eradication rate decreased as the duration of past metronidazole exposure increased. However, the interval from metronidazole exposure to BQT prescription was not related to the eradication rate. Based on our results, BQT 14 days may be recommended for patients with suspected past metronidazole exposure, regardless of the interval from exposure. BQT 7 days can achieve high eradication rates with fewer side effects in areas with low metronidazole resistance or in patients without metronidazole exposure.

A three-in-one formulation (Pylera®) of three drugs, bismuth subcitrate, metronidazole, and tetracycline, is frequently prescribed in the United States and Europe. This formulation is preferred to BQT because of its small number of capsules but consists of 10 days. Few studies have compared the BQT eradication rates for 10 and 14 days (Dore et al., 2011). According to our study, 10-day BQT may not be sufficient in patients with past metronidazole exposure, suggesting that 10-day regimens should be avoided in areas with high metronidazole resistance.

Our study has several limitations. First, our study is a retrospective study which inevitably includes inherent limitations due to its study design. Most importantly, the baseline characteristics of patients with and without exposure were different. Specifically, BQT was prescribed as first-line regimens more often in patients without past metronidazole exposure. Second, patients classified as unexposed in this study might have been prescribed metronidazole at other hospitals. However, it is essential to note that metronidazole is not commonly prescribed in primary clinics in Korea (Park et al., 2017; Health Insurance Review and Assessment Service, 2021). Also, reclassification of these patients into the exposed group is expected to strengthen our findings further. Third, the follow-up loss rate was high in patients who were prescribed BQT. However, our study was retrospective, and the high follow-up loss rate reflects the reality of actual clinics. Another study reported that only 34.9% of those prescribed H. pylori eradication regimens visited the hospital to check their eradication results (Kumar et al., 2021). Finally, this study was conducted in a region with high metronidazole resistance. Our results may not be applicable in areas with different metronidazole.

In conclusion, past metronidazole exposure lowered the H. pylori eradication rate of BQT regimens, and longer exposure duration was associated with lower eradication rates. Prolonging the BQT duration to 14 days should be considered in patients with past metronidazole exposure.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Institutional Review Board (IRB) of Catholic Medical Center (IRB approval number, XC20WIDI0119). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

YC designed the study, reviewed the literature, acquired and analyzed data, administrated the project, performed statistical analyses, wrote the original draft, and reviewed and edited the manuscript. JK supervised the study and was responsible for paper conception and manuscript review, and editing. JP acquired data and reviewed and edited the manuscript. HC, DK, JO, TK, and DC acquired data and edited the manuscript. WC, B-WK, and SK analyzed data and edited the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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