Professor El-Omar has selected Professor Xavier Calvet to do the next #GUTBlog. He is Consultant at the Servei d’Aparell Digestiu, Parc Taulí, Hospital Universitari, Barcelona, Spain (the full biography of first and senior authors are below).

The #GUTBlog focusses on the paper “Bismuth quadruple three-in-one single capsule three times a day increases effectiveness compared with the usual four times a day schedule: results from the European Registry on Helicobacter pylori Management (Hp-EuReg)” which was published in paper copy in GUT in November 2023.

Professors Xavier Calvet writes:

“Treatment of Helicobacter pylori (H. pylori) gastric infection has been a challenge for gastroenterologists since its first description in 1983. The bacterium showed remarkable resilience, and infection persisted after most antibiotic monotherapies. Seven-day triple therapies combining a proton pump inhibitor (PPI), clarithromycin and either amoxicillin or metronidazole were the first effective standard treatments. However, the rapid rise of antibiotic bacterial resistance – especially to macrolides – brought down the effectiveness rate of triple therapy to unacceptably low figures. After this, multiple trial and error assays led to highly effective new standard therapies designed in accordance with the currently accepted H. pylori treatment principles:

a) Use of four drugs
b) Length of treatment at least 10 days
c) Use of PPI at high doses as one of the four drugs
d) Avoidance of macrolides or quinolones, especially after a treatment failure. The primary resistance rate to these drugs is generally high, and the secondary resistance rate after the failure of a schedule containing these same drugs approaches 100%

Bismuth quadruple therapy (BQT) combining tetracycline, metronidazole and a bismuth salt plus a PPI fulfills all these H. pylori treatment principles. BQT is not new; early studies in the 1990s already showed that ten to fourteen-day BQT achieved cure rates close to 100%. Additionally, BQT offers two important advantages: first, it requires only two antibiotics, tetracycline and metronidazole, thus reducing the antibiotic load; second, it is not affected by bacterial antibiotic resistance. H. pylori resistance to tetracycline or bismuth salts is exceptional and H. pylori resistance to metronidazole can be overcome by giving high doses for ten days or more. Nonetheless, BQT has never been very popular, because it presents several disadvantages as well: a) the complexity of administering four drugs at different daily schedules; b) the very high number of pills required: from 192 to 304 for a standard fourteen-day treatment, depending on the local presentations of bismuth, tetracycline and metronidazole; c) the frequent unavailability of some of the treatment components, especially tetracycline and bismuth and, finally d) the side effects, in particular of metronidazole. For all these reasons, adherence has been an important issue, and has reduced the effectiveness of the treatment in clinical practice.

The launch of a single capsule containing bismuth, tetracycline and metronidazole in 2007, marketed as Pylera®, offered a partial solution to some of the weaknesses of BQT. When associated with a PPI, this single capsule bismuth quadruple therapy (ScBQT) achieved cure rates above 90% with a treatment of only ten days and notably simplified the ScBQT schedule. This new drug combination was superior to triple therapy in pivotal randomized controlled trials (RCTs). After its launch in several countries, data from RCTs, clinical series and registers have consistently suggested that this ScBQT is equally or even more effective than 14-day schedules of bismuth and non-bismuth quadruple therapies.

Our study goes one step further, by simplifying and improving the results of ScBQT. The study reports clinical practice data from 3,712 Spanish patients included in the European Registry on H. pylori management (Hp-EuReg) who underwent treatment with ScBQT. We compared data from 1,196 patients receiving a modified schedule of ScBQT – four pills three times a day with meals – versus 2,516 patients treated with the schedule recommended in the summary of product characteristics (three pills, four times a day). Many patients in both treatment groups also received esomeprazole or omeprazole 40 mg twice a day as concomitant PPI, instead of the recommended dose of omeprazole 20 mg twice a day. Cure rates were significantly higher with the new approach (94% vs. 91%, p=0.002). Furthermore, the use of a three times a day schedule with meals (OR:1.58; 95%CI:107-2.33) and the use of medium to high PPI doses (OR:2.08; 95%CI:1.37-3.14) were statistically significant predictors of the cure of the infection in the multivariate analysis.

The main conclusions of the study are not just that the “new” three times a day schedule improves ScBQT effectiveness, but also that, whatever the schedule, ScBQT achieves very high cure rates in a geographical area where H. pylori shows a very high antibiotic resistance rate to macrolides, quinolones and metronidazole. So, our results support the widespread use of ScBQT, in particular in areas with high prevalence of antibiotic resistant H. pylori strains.

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