No payoff found from higher doses in H. pylori treatment

Increasing doses of bismuth or antibiotics beyond standard levels did not improve Helicobacter pylori eradication rates across commonly used quadruple regimens, according to a large international registry analysis of more than 13,000 treatments.

The findings, drawn from the European Registry on Helicobacter pylori Management, suggest that treatment duration, adherence, and proton pump inhibitor co-therapy may play a greater role in outcomes than dose escalation.

“Key advantages of bismuth salts include the absence of known resistance and their synergistic effect with other antibiotics, both of which enhance eradication effectiveness,” corresponding author Samuel J. Martínez-Domínguez, MD, of Lozano Blesa University Hospital in Zaragoza, Spain, and colleagues wrote in the study published in Clinical Gastroenterology and Hepatology. “However, there is limited evidence on the optimal dosage required to maximize eradication success when bismuth is combined with different antibiotics.”

The researchers analyzed real-world data from 75,944 patients across 40 countries, focusing on 10,767 first line and 2,952 rescue treatments using bismuth-containing quadruple regimens.

Standard dosing achieves high cure rates

Among first-line therapies, several regimens achieved eradication rates above 90% using standard antibiotic doses, regardless of higher bismuth dosing. The most commonly used regimen — clarithromycin, amoxicillin, bismuth, and a proton pump inhibitor — accounted for 69% of first-line treatments and achieved a 94% eradication rate overall. Effectiveness exceeded 90% across all bismuth dosing strategies above 240 mg daily, with no incremental benefit at higher doses.

Similarly, the classic bismuth, metronidazole, tetracycline regimen reached about 91% effectiveness overall. Regimens using metronidazole 1,500 mg daily and tetracycline at least 1,500 mg daily consistently achieved cure rates above 90%, but increasing bismuth beyond 480 mg daily did not improve outcomes.

Other first-line regimens also performed well at standard doses. The amoxicillin, metronidazole, and bismuth regimen achieved about 91% effectiveness, while clarithromycin, metronidazole, and bismuth reached a similar rate. The amoxicillin, levofloxacin, and bismuth regimen achieved about 94% effectiveness. Across these regimens, increasing antibiotic doses — such as metronidazole above 1,000 mg daily or levofloxacin above 500 mg daily — did not improve eradication rates.

No advantage in rescue therapy

Effectiveness was lower for second- through sixth-line treatments, with overall eradication rates below 90% across regimens. For example, levofloxacin-based quadruple therapy achieved 83% effectiveness, while tetracycline-based regimens achieved 79%. Increasing bismuth or antibiotic doses in these rescue settings also failed to improve outcomes.

Multivariate analysis highlights key drivers

Multivariate models confirmed that dosing escalation was not associated with higher eradication rates in most regimens. Instead, several factors consistently predicted treatment success. Longer duration, particularly 14-day therapy, improved outcomes compared with shorter courses. Adequate adherence, defined as taking at least 90% of prescribed therapy, was strongly associated with eradication. Higher proton pump inhibitor dosing and use of therapy in the first line setting also contributed to improved effectiveness.

For example, in the clarithromycin-amoxicillin-bismuth regimen, adherence was associated with nearly eight times the odds of eradication, while 14-day therapy also improved outcomes.

Notable subgroup findings

One exception involved the amoxicillin, metronidazole, and bismuth regimen, where a dosing schedule of bismuth 120 mg four times daily showed a 2.6 times higher likelihood of eradication compared with 240 mg twice daily. However, this effect was not consistently confirmed across analyses.

Geographic variation was also observed. In Turkey, eradication rates for the tetracycline-based regimen were lower at 77% despite high antibiotic and bismuth doses, suggesting potential differences in bismuth formulation or other regional factors.

This analysis used data from a prospective, multicenter, noninterventional registry conducted since 2013. Investigators included patients with confirmed H. pylori infection treated empirically with bismuth-containing quadruple therapy. They used a modified intention-to-treat approach, including all patients who had follow-up testing at least 30 days after treatment to assess how well the therapy worked. Only regimens with at least 90 recorded cases were analyzed to ensure statistical reliability.

The authors noted several limitations. Because this was an observational registry, treatments and doses were not randomly assigned, and some regions were better represented than others. Some dosing groups were small, making the results less certain. The specific type of bismuth salt was not consistently recorded and had to be estimated by country, which may have influenced the findings.

Also, the registry included only patients treated by gastroenterologists, which may limit generalizability to primary care settings.

Clinical implications

The findings challenge the common practice of increasing antibiotic or bismuth doses to overcome treatment failure.

“Overall, when bismuth quadruple therapy was prescribed, increasing drug doses beyond the standard generally did not improve cure rates,” the authors concluded, adding that helping patients stick to treatment and complete it may have a bigger impact.

The study was funded by the European Helicobacter and Microbiota Study Group, with additional support from European Union programs and industry sponsors including Diasorin, Juvisé, and Biocodex, which were not involved in study design or analysis. Dr. Martínez-Domínguez reported that he has been a speaker for Juvisé. Several coauthors reported relationships with pharmaceutical companies; others reported no conflicts.