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.
Subjects: Children aged 5 (>15 kg) -18 years, diagnosed with H. pylori infection during upper
endoscopy with a positive culture and results for antibiotic susceptibility testing for
clarithromycin and metronidazole and without resistance to both antibiotics who meet all
inclusion and none of the exclusion criteria.
Symptoms (abdominal pain, bloating, nausea, vomiting, bad metallic taste) on the diary are
scored from 0-3 (0=none; 1=mild, not interfering with normal activity; 2=moderate,
interfering with normal activity; 3=severe, daily activity not possible). Stool pattern are
monitored for frequency and consistency (0=no stool, 1=hard (Bristol stool scale 1-2),
2=formed (BSS 3-4), 3=soft (BSS 5-6), 4=watery (BSS 7). A number for each stool must be
filled. We defined diarrhoea as more than two soft stools (Bristol stool scale 5 or 6) per
day and/or one or more stools of watery consistency (BSS 7), and constipation as less than 3
bowel movements per week and/or stools of hard consistency. The intake drugs of the triple
therapy, the study product and concomitant drugs are recorded on the diary. In addition,
special events of interest will be recorded.
Randomization will be performed in two groups with sealed envelopes: group with 7-day therapy
plus BS and group of patients with 14-days therapy without BS. The therapy will otherwise be
prescribed according to the antibiotic susceptibility testing. Patients susceptible for
clarithromycin will receive amoxicillin and clarithromycin, if resistant to clarithromycin
they will receive amoxicillin and metronidazole. Double-resistant patients (not susceptible
to neither Clarithromycin nor to Metronidazole) are excluded as mentioned above.
Once allocated, the children randomization numbers will be used to identify the participant
during the study period. A child who, for whatever reason, withdraws or is withdrawn from the
study after having been allocated a randomization number (R-code), will be classified as drop
out and identified as such in the relevant report.
The patient will record the intake of study product and triple therapy in a diary on a daily
basis. The adherence to the prescribed treatment will be checked at visit 2 and expressed in
percent of doses taken. An adherence of >80 % will be considered as per protocol, an
adherence <80 % is considered as protocol violation and these patients will be considered for
ITT analysis.