Bismuth Quadruple Therapy Versus Standard Triple Therapy for the First-line Treatment of Helicobacter Pylori Infection in Children: Efficacy and Safety

Infection with Helicobacter pylori (H. pylori) is still a very common bacterial infection in humans, despite the worldwide significant decrease in incidence and prevalence recorded in recent years. Infection with H. pylori is mostly acquired during early childhood, and in low prevalence countries such as European countries, infected family members, particularly the mothers, are the main source of infection. Chronic inflammation of the gastric mucosa can cause peptic erosions and ulcerations, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. In addition, extra gastric complications, such as iron-deficiency anemia, may be induced by H. pylori infection. The first line treatments currently available for children infected with H. pylori are various combinations of proton pump inhibitors (PPI) with antibiotics including amoxicillin, clarithromycin and/or imidazoles. While previously 7 days treatment had been recommended, the low eradication rate demanded longer treatment duration of 10-14 days increasing the chance for adverse effects and lower compliance to therapy.

In the last decade, the eradication rates using these schemes have declined and have led to recommendation for higher dosages, longer duration of therapy or regimens including three instead of two different antibiotics, either sequentially or concomitantly. The low success rates are essentially due to the increasing resistance rates to macrolides and to lesser extent imidazole. Koletzko et al. detected very high primary resistance rates to metronidazole and clarithromycin in Europe (23% and 20%, respectively), whereas resistance after failed eradication therapy was even higher (35% and 42%, respectively). Children born to mothers from developing countries and Asia have extremely high primary resistance rates to metronidazole due to the frequent usage of this drug for parasitic infection in Africa and Asia. The high resistance rate to clarithromycin is caused by the frequent use of macrolides in children for respiratory tract infections resulting in a higher primary clarithromycin resistance rates in paediatric patients compared to adults. The newest guidelines of the European and North American societies of Gastroenterology, Hepatology and Nutrition (ESPGHAN and NASPGHAN) recommend in anti - H. pylori infected children to perform culture and antibiotic susceptibility testing prior first therapy and to tailor the therapy according to the results, and give higher doses as previously suggested with a treatment duration of 14 days.

Adverse events such as diarrhoea, nausea, taste disturbance, and abdominal pain are frequent during eradication therapy and mainly due to antibiotics, with diarrhoea being the most common one. Higher doses and longer treatment duration recommended in the newest guidelines may augment this problem and may result in discontinuation of the therapy. Since non- compliance to therapy is the second most frequent cause for treatment failure improving compliance by decreasing adverse effects may result in better clearance rates with a lower risk for the development of antibiotic-resistance strains.

Therefore, new therapeutic protocols are needed to decrease side effects and improve compliance for H. pylori treatment protocols and hopefully to raise the eradication rates.

The Bismuth salicylate is an option as part of first line therapy in children for H. pylori eradication already at the two latest paediatric guidelines NASPGHAN/ESPGHAN published in 2011 and 2017. BS is not used more in praxis due to the fact that is not available in the drugstores in many European countries. In Slovenia is it on the market in the form of Bizmut oksid 120 mg produced by Krka pharmaceutical company. It is officially registered for H. pylori eradication. There is a lot of data in adults, but very little prospective data in children available on the treatment protocols with BS and eradication rates in an anti-H. pylori therapy in a paediatric population. It is an investigator initiated single center, randomized, study to compare the effectiveness of triple therapy (PPI, two antibiotics (tailored to antibiotic susceptibility testing)) given for 2 weeks with the same eradication protocol (PPI, two antibiotics (tailored to antibiotic susceptibility testing)) lasting only for one week with Bismuth subcitrate in H. pylori infected children. The study included a pre-screening, an intervention (1-2 weeks) and a post-intervention time (8 weeks), with total of 2 visits and 2 phone calls after inclusion. The total duration of the study will be 8 weeks.