Rewievs : Historical therapy and current treatment

Helicobacter pylori – dotychczasowa terapia i leczenie współczesne

Sebastian Adrian Fedorowicz1,A–F, Karolina Julia Radzikowska1,A–F, Karolina Mende1,A–F, Stanisław Ferenc1,2,A,E,F, Jan Gnus1,2,A,E,F

1 Faculty of Medicine, Wroclaw Medical University, Wrocław, Poland 2 Research and Development Centre, Voivodeship Specialist Hospital in Wroclaw, Wrocław, Poland

A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation; D – writing the article; E – critical revision of the article; F – final approval of the article

Pielęgniarstwo i Zdrowie Publiczne, ISSN 2082-9876 (print), ISSN 2451-1870 (online) Piel Zdr Publ. 2020;10(1):49–55

Address for correspondence Abstract Sebastian Adrian Fedorowicz e-mail: [email protected] Helicobacter pylori (H. pylori) infection is a cause of gastritis, which in consequence may lead to gastric ulcers, mucosa-associated lymphoid tissue (MALT) lymphoma or a cancerous process. It is estimated that this bac- Funding sources teria, being an oncogenic factor, exists in the gastrointestinal tract in more than half of the world population. None declared This proportion varies according to the level of economic development of a given country; in highly develo- ped countries it can be only 24%, while in developing countries it reaches even 70%. The maximal efficacy Conflict of interest None declared of H. pylori eradication is up to 90% and the issue of antibiotic resistance is a major clinical problem. There are 56.7% strains with metronidazole resistance and 55.2% strains with clarithromycin resistance in Lower Silesia. The latest guidelines of the Maastricht V/Florence 2016 Consensus confirm that probiotics containing Received on December 3, 2019 Reviewed on January 16, 2020 Saccharomyces boulardii, Lactobacillus or Bifidobacterium may increase the percentage of eradication. Mo- Accepted on February 10, 2020 reover, the intake of broccoli sprouts in the diet may support the treatment of H. pylori infection. The aim of this study is to present and compare the historical methods of therapy to the current treatment. This pa- per presents invasive and non-invasive methods of diagnosis. Moreover, the way of discovering H. pylori, the characteristics of this with its pathogenicity and basic epidemiological information are covered. Key words: Helicobacter pylori infection, probiotics, Helicobacter pylori eradication, antibiotic resistance

This is a translated article. Please cite the original Polish-language version as Fedorowicz SA, Radzikowska KJ Mende K, Ferenc S, Gnus J. Helicobacter pylori – dotychczasowa terapia i leczenie współczesne. Piel Zdr Publ. 2020;10(1):49–55. doi:10.17219/pzp/118082

DOI 10.17219/pzp/118082

Copyright © 2020 by Wroclaw Medical University This is an article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/) 50 S.A. Fedorowicz, et al. H. pylori: Historical and current treatment

Streszczenie Zakażenie Helicobacter pylori jest przyczyną zapalenia błony śluzowej żołądka, którego konsekwencją mogą być wrzody żołądka, chłoniak MALT lub proces nowotwo- rowy. Szacuje się, że ta bakteria, będąca potwierdzonym czynnikiem onkogennym, bytuje w przewodzie pokarmowym u ponad połowy ludzi na świecie. Odsetek ten waha się w zależności od stopnia rozwoju ekonomicznego danego państwa – w krajach rozwiniętych może wynosić tylko 24%, natomiast w krajach rozwija- jących się sięgać nawet 70%. Skuteczność eradykacji H. pylori wynosi maksymalnie 90%, a dużym problemem klinicznym jest kwestia oporności bakterii na anty- biotyki. Na Dolnym Śląsku 56,7% szczepów tej bakterii jest opornych na metronidazol, a 55,2% na klarytromycynę. Najnowsze wytyczne Konsensusu Maastricht V/ Florencja 2016 potwierdzają, że preparaty probiotyczne ze szczepami Saccharomyces boulardii, Lactobacillus lub Bifidobacterium mogą zwiększyć odsetek eradyka- cji. Także podaż kiełków brokułów w diecie może wspomagać leczenie zakażenia H. pylori. Celem pracy jest przedstawienie i porównanie dotychczasowych metod terapii z leczeniem współczesnym. Omówiono inwazyjne oraz nieinwazyjne metody diagnostyczne. Przybliżono również sposób odkrycia H. pylori, charakterystykę mikroorganizmu wraz z jego chorobotwórczością oraz podano podstawowe informacje epidemiologiczne. Słowa kluczowe: zakażenie Helicobacter pylori, probiotyki, eradykacja Helicobacter pylori, antybiotykooporność

Introduction later he complained about nausea and unpleasant smell from his mouth, and then vomiting appeared. Endosco- The history of Helicobacter pylori (H. pylori) is insepa- py results on the 8th day of the experiment were obvious rable from the history of Homo sapiens. This is proven by – advanced gastritis, and from the biopsy H. pylori was genetic analyses, according to which the bacterium prob- cultured, which thus became a confirmed etiological ably originates from East Africa and spread around the factor of gastritis.6 In 2005, Marshall and Warren were world about 58,000 years ago with the expansion of mod- awarded the Nobel Prize in Physiology and Medicine.5 ern human. Studies show a correlation between strain diversity and human genetic diversity and geographical distribution.1 Characteristics of H. pylori The first mention of spiral bacteria existing in the stomach dates back to 1875. Georg Bottcher and Michel Helicobacter pylori is a Gram-negative, catalase- and Letulle observed these microorganisms back then, but oxidase-positive, helical-shaped bacillus bacterium. It were unable to culture them and probably because of that has 4–6 flagella at the pole, which allow it to move. It is they did not conquer the scientific world with this dis- a facultative anaerobe and needs carbon dioxide (CO2) to covery.2 The author of subsequent descriptions from 1893 grow. There is a layer of glycocalyx on its surface, which is Giulio Bizzozero, who discovered bacteria that exist determines its hydrophobicity and negative charge. In in the acidic environment of a dog’s stomach.3 Another the acidic environment of the stomach, this layer is par- milestone was in 1889, when Polish professor Walery Ja- tially removed, exposing hydrophobic spots that allow worski first described in detail the presence of “cochlear”, adhesion to the cells of stomach epithelium.7 The outer “spiral” bacterium in human gastric fluids. He called it membrane of the microorganism contains a lipopolysac- Vibrio rugula and concluded that it could be an etiologi- charide (LPS) composed of lipid A, an oligosaccharide cal agent of gastritis.4 core and side-chain O. Compared to other bacteria, lipid Jaworski’s discovery did not have a significant impact A shows little biological activity and side-chain O can on the scientific world at that time for 2 reasons: first- “mimic” Lewis blood groups, making it easier for the bac- ly, it was published only in Polish in Podręcznik chorób teria to avoid reactions from the host immune system. żołądka i dyetetyki szczegółowej, and secondly, it met The LPS has the capacity for genetic variability, which with considerable criticism from the scientific commu- makes it possible to adapt to the conditions of the gas- nity. Franz Boas (authority in the area of gastrointestinal tric mucosa and also ensures population diversity. The diseases and discoverer of Boas–Oppler bacillus) showed genome encodes a number of outer membrane proteins, that he was able to obtain morphologically similar shapes such as porines, adhesines, iron transporters, or a set of as by-products of a chemical reaction between the gastric proteins with previously unknown functions. mucosa and hydrochloric acid.4 Helicobacter pylori also has the ability to respond However, the real breakthrough came only in 1982, quickly to changes in the environment, which results in over 90 years after Jaworski’s discovery, when H. pylori changes in the transcription of specific genes responsible in vitro culture started.5 It was a success of 2 Austra- for coping with stress. The response of bacteria to envi- lians – Barry James Marshall and Robin Warren. In 2018, ronmental stress is multi-factorial and can be initiated by Marshall drank the bacterial suspension himself after using multiple interconnected regulatory systems.8 a control endoscopy to prove the role of bacteria in the An important role in pathogenesis is played by the vacA pathogenesis of gastric ulcers and gastritis. Just a few days genes encoding the vacuolating toxin secreted by the bac- Piel Zdr Publ. 2020;10(1):49–55 51

terium, which is responsible for the destruction of epithe- According to the studies conducted in the USA, Europe lial cells. In culture, it causes the formation of vacuoles and Japan, the number of infection cases decreases by in stomach cells and leads to their destruction. The vacA 25% per decade.14 gene consists of 2 variable parts – the s region present in the form of s1 and s2 alleles, and the m region in the form of m1 and m2 alleles. The combination of alleles of the Diseases induced by H. pylori s and m regions determines the production of cytotoxin by a given strain. The s1a variant of the vacA gene shows Chronic gastritis a higher pathogenicity than s1b, while the s2 variant is more commonly found in connection with the diagnosis Chronic gastritis is a condition in which a chronic in- of gastric ulcer disease. Moreover, the m1 variant causes flammatory infiltration is present in the gastric mucosa, much greater damage to the gastric mucosa than the m2 leading to metaplasia and its gradual disappearance. variant. Additionally, the cagA gene (cytotoxin-associated Colonization of the gastric and duodenal mucosa with gene) is used as a marker to detect the presence of cag H. pylori bacteria is considered to be the main cause of pathogenicity islands. Several cag island genes are re- their chronic inflammation. The bacteria can be found sponsible for encoding proteins increasing the virulence in the mucus covering the membrane. The characteris- of a strain.9 The microorganism produces urease, which tic histological picture in the course of this disease is in- is important in the diagnosis of infections and also pro- testinal metaplasia, atrophy and neutrophil infiltration. vides protection against gastric acid.10 Inflammation develops as the sum of the influence of toxins and enzymes secreted by bacteria and chemical compounds released by the activated neutrophils. Epidemiology of H. pylori The course of the disease is usually subclinical and sometimes even asymptomatic. Usually, the symptoms Heliobacter pylori is a widespread pathogen that has of dyspepsia are found: nausea, vomiting and a feeling of been living in human bodies for many thousands of years. discomfort in the abdomen. Sometimes, when there is an It is the first formally recognized bacterial carcinogen and extensive loss of gastric mucosa cells, hypochlorhydria or the main etiological agent of gastric ulcers and other gas- achlorhydria can be diagnosed. trointestinal diseases. The infection affects all parts of the The final clinical outcome depends on the extent and world and studies show the presence of this bacterium in location of the infection. When an effective treatment is more than half of the living population, although there are applied, the health condition improves significantly, but differences in infection frequency among countries. the cessation of inflammatory infiltration may take much Man is the main reservoir of this microorganism and longer. Chronic gastritis has a considerable bearing on the infection is spread through secretions (saliva, vomit) the occurrence of peptic ulcers and the development of and excretions through oral–oral and fecal–oral routes. stomach cancer.15 Young children are particularly exposed to the infection, Infection with H. pylori always leads to active chronic most often the patients under the age of 12. gastritis, which then causes gastric or duodenal ulcers in Bacteria excreted with feces may be present in the 1–10% of cases.16 aquatic environment in the form of endospores, so it is assumed that water is an important route for the patho- gen to spread. This mainly concerns countries with a low socio-economic status. The regions with the highest in- A peptic ulcer is defined as a cavity in the mucous mem- fection rate include Africa (approx. 70%), South America brane that reaches beyond its muscularis mucosae. The (69%) and Western Asia (65%), while in highly developed presence of inflammatory infiltration in its surroundings countries, the infection rate is much lower and reaches is characteristic. Peptic ulcer disease is one of the most 37% in North America, 34% in Western Europe and 24% common gastrointestinal diseases. The incidence rate in Oceania.11 Poland is one of the countries with a high among men is twice as high as among women. infection rate. According to the research, the percentage Infection with H. pylori together with the abuse of non- of people infected in our country reaches approx. 84% in steroidal anti-inflammatory drugs are the main causes of adults and approx. 32% in people up to 18 years of age.12 the peptic ulcer development. In most cases, it is located Childhood is a particularly important period in the in the duodenum. process of H. pylori infection. It has been shown that the The bacterium has the ability to produce urease, which invasion takes place at an early age, and that poor socio- decomposes urea. As a result of this reaction, ammonium economic conditions are most conducive to it. Contact ions are formed in the stomach to neutralize hydrochloric with infected individuals appears to be the main route for acid. The pH in the stomach is lowered, which activates the the spread of the pathogen.13 As urbanization increases, pathological secretion of gastrin, a hormone that increases the number of H. pylori infections decreases in the West. the secretion of hydrochloric acid by the stomach. The gas- 52 S.A. Fedorowicz, et al. H. pylori: Historical and current treatment

tric mucosa is irritated, and a peptic ulcer develops at the betes mellitus type 2, and fibromyalgia, are still under sites of contact with hydrochloric acid. The penetration of study, and the results to date are not conclusive.23 strongly acidified gastric contents into the duodenum in- duces the development of the ulcer in this place. Whether the infection with H. pylori will cause the Diagnosis of H. pylori infection development of the disease is also determined by the genetic characteristics of the bacteria. In the vast major- The diagnostic methods can be divided into invasive ity of patients with peptic ulcer symptoms, an infection and non-invasive. Invasive methods require gastrosco- with the cagA gene strain was found. It constitutes one py with biopsy. It is recommended to perform them in of many genes determining the pathogenicity of bacteria. the presence of dyspeptic signs and symptoms (pyrosis, Genetic predispositions are also important factors in bloating, belching). The section should be taken from the the development of gastric ulcer disease, as well as other pars prepylorica region, where bacteria may be present. agents, such as smoking, alcohol consumption and diet, Cardia, fundus and corpus are the regions where bacteria which may increase the risk of the disease. may be present in patients taking proton-pump inhibitors Helicobacter pylori is responsible for the formation of (PPIs).24 The material collected may be tested for urease more than 75% of duodenal ulcers and 70% of stomach ul- production, or be subject to histopathological evaluation cers; therefore, the eradication of bacteria is a very impor- for early detection of possible neoplastic changes or cul- tant step during treatment. Moreover, pathogen removal ture establishment. Unexplained iron-deficiency anemia, reduces the risk of recurrence of ulcers and bleeding from idiopathic thrombocytopenic erythrema and vitamin B12 the ulcer by 10–15 times. In patients who have not under- deficiency are the reasons to search for an infection. gone antimicrobial treatment, the recurrence of bleeding Non-invasive methods include: urease production test during the year occurs in 25% of cases, and after success- (respiratory test, urine test), stool test detecting anti- ful eradication, the risk decreases completely.17 gens that are produced by live H. pylori bacteria, sero- logical test, and polymerase chain reaction testing (PCR) Stomach cancer (stool or saliva sample). The gold standard of diagnosis is the urease breathing test (UBT), which does not require Chronic atrophic gastritis in H. pylori infection may gastroscopy. The patient is administered orally a dose of cause gastric cancer.18 The eradication of bacteria in as- 13C-labelled urea, or less commonly 14C radioisotope, ymptomatic infected persons, and in persons after endo- which is broken down in the stomach by bacterial urease scopic gastric cancer resection, reduces the risk of gastric into ammonia and CO2. The amount of labelled CO2 in cancer.19 the exhaled air correlates with the presence of H. pylori in the stomach. The measurement is made after 15–30 min; MALT lymphoma the test is characterized by high sensitivity (90–95%) and specificity (90–98%). The selection of the method depends Mucosa-associated lymphoid tissue (MALT) lympho- on the current clinical situation of the patient and the need ma is a lymphatic tissue cancer of the digestive tract. It to perform endoscopy of the upper gastrointestinal tract.24 is usually located in the stomach. Long-term gastric mu- Test-and-treat strategy consists in conducting a non- cositis caused by H. pylori is found in 90% cases of this invasive test and performing eradication in case of a posi- tumor.20 Scientific studies have shown that H. pylori is tive result. In Poland, it is used exclusively in younger involved in the initiation and progression of MALT lym- patients (under 45 years of age) due to a higher risk of phoma.21 The eradication of bacteria has been shown to developing stomach cancer without alarming symptoms, cause complete histological regression of low-grade ma- such as weight loss, dysphagia, overt gastrointestinal lignant lymphoma.22 bleeding, tumor in the abdominal cavity, or iron-defi- ciency anemia. In the elderly, or when alarming symp- The effect ofH. pylori on diseases toms occur, an endoscopic examination of the upper gas- outside the gastrointestinal tract trointestinal tract is necessary.25 According to the Kyoto Global Consensus, H. pylori in- Helicobacter pylori has been shown to be associated fection has been identified as an infectious disease that with unexplained iron-deficiency anemia, idiopathic requires treatment regardless of whether the infection is 26 thrombocytopenic erythrema and vitamin B12 deficiency. clinically symptomatic or asymptomatic. The eradication of H. pylori in chronic hives and rosacea also brings beneficial effects. The effects of bacteria on asthma, chronic obstructive Treatment methods used to date pulmonary disease, coronary arterial disease, ischemic stroke, Raynaud syndrome, Parkinson’s and Alzheimer’s The first treatment method of H. pylori infection was diseases, Sjögren’s syndrome, metabolic syndrome, dia- created in 1987 by Thomas Borody, an Australian gastro- Piel Zdr Publ. 2020;10(1):49–55 53

enterologist born in Cracow. He worked then with Mar- any new cure, the studies on using different combina- shall and Warren. It was a triple therapy consisting of tions of drugs used so far were analyzed. The sequential bismuth, metronidazole and tetracycline. It soon became treatment, which consists in 5-day PPIs with amoxicillin common in the USA. therapy, and then 5-day PPIs, clarithromycin and met- Over the years, the number of new reports on the ronidazole therapy, has gained recognition. It was also infection and treatment regimens has been increas- proposed to take 3 antibiotics simultaneously with PPIs ing. Therefore, in 1997, the European Helicobacter py- (the quadruple therapy without bismuth). An old formula lori Study Group organized a meeting in Maastricht for consisting in the quadruple therapy with bismuth has H. pylori specialists, primary care physicians and rep- been renewed due to developing galenical formula con- resentatives from national gastroenterological societ- taining bismuth salts, tetracycline and metronidazole in ies. The Maastricht consensus meeting was attended 1 pill.30 by 63 participants from 19 European countries, as well as observers from Canada, Japan and the USA. During the meeting, it was concluded that the treatment should Contemporary treatment be simple, well-tolerated, easy to implement, and cost- effective. Additionally, some modifications concerning Nowadays, in accordance with the guidelines of the the drugs used in eradication therapy were established. Maastricht V/Florence 2016 Consensus Report,25 the fol- A classic triple therapy based on bismuth was replaced lowing treatment regimen for H. pylori infection is applied: by triple therapy consisting of PPIs and 2 antibiotics (op- ––triple therapy – consists in the application of PPIs and tionally: clarithromycin, metronidazole and amoxicil- 2 out of 3 antibiotics listed below: amoxicillin, clarith- lin). The literature and clinical experience of that time romycin and 5-nitroimidazole derivative (metronidazo- indicated a higher efficiency, a lower number of adverse le or tinidazole); effects and patients’ better amenability to this treat- ––bismuth quadruple therapy – based on a bismuth com- ment regimen.27 pound, PPIs and 2 antibiotics (usually tometronidazole Another meeting was held in Maastricht in 2000. Then in combination with tetracycline). It is also possible to the therapy was modified. New guidelines recommended administer levofloxacin, amoxicillin, rifabutin, or fura- using PPIs or bismuth along with clarithromycin and zolidone; amoxicillin or metronidazole in the therapy of the first ––non-bismuth quadruple therapy – has 3 possible va- choice. Numerous studies proved the same efficiency of riants. The st1 one is simultaneous therapy, which con- bismuth regimens and PPIs regimens. The therapy of the sists in the application of PPIs, amoxicillin, clarithro- second choice should be quadruple and consists of PPIs, mycin, and nitroimidazole derivative for 10–14 days. bismuth, metronidazole, and tetracycline. If bismuth is The 2nd variant – sequential therapy – consists in the not available, the therapy of the second choice can be application of PPIs and amoxicillin for 5–7 days, and triple therapy based on PPIs.28 then clarithromycin and nitroimidazole derivative. The Maastricht III Consensus Report of 2005 indicates 3rd variant of non-bismuth quadruple therapy is a hy- that the guidelines concerning the treatment of the first brid therapy – during the first 7 days only PPIs and choice have remained unchanged: it is still PPIs, clarithro- amoxicillin are administered, then clarithromycin and mycin and amoxicillin or metronidazole if the immunity nitroimidazole derivative; to clarithromycin in a given area is less than 15–20%. In ––fluoroquinolone therapy – can be quadruple or triple. addition, there were indicated the advantages of using The former consists of PPIs, amoxicillin, fluoroquinolo- metronidazole instead of amoxicillin in the areas where ne (mainly levofloxacin, sometimes moxifloxacin), and the immunity is lower than 40%. Also, 14-day treatment bismuth compound. Triple fluoroquinolone therapy was found superior to 7-day treatment. The quadruple consists of the same elements as the quadruple one, but bismuth therapy was recognized as an alternative treat- without bismuth compound.25 ment to the therapy of the first choice and remained the main therapy of the second choice. If not available, PPIs, amoxicillin or tetracycline were recommended as the Resistance therapy of the second choice.29 The triple PPIs, clarithromycin and amoxicillin or met- The main reason for the failure of H. pylori eradication ronidazole treatment has become widespread because it is the development of resistance by the bacteria. Current- was recommended by all conferences held up-to-date. ly, there is a high level of resistance of bacteria in Poland. However, as years passed, its efficiency lowered and al- The research conducted in Lower Silesia in 2011–2013 lowed up to 70% of patients to be cured. This resulted showed the existence of 56.7% of strains resistant to met- mainly from increasing antibiotic resistance in bacteria ronidazole, 55.2% – to clarithromycin and 5.9% – to levo- against clarithromycin. In 2012, during the Maastricht floxacin. Double resistance was detected in 32.8% of cas- IV/Florence Consensus meeting, despite not developing es. Resistance to amoxicillin has not been detected yet.31 54 S.A. Fedorowicz, et al. H. pylori: Historical and current treatment

If treatment regimen fails, an antibiotic susceptibility test Portion of vegetables should be performed and the therapy should be adjusted to antibiogram. Sulforaphane is a sulfur-containing organic substance that enhances the removal of toxic substances from the body and has an anticancer effect.38 In nature, it is found Probiotics primarily in vegetables, such as Brussels sprouts, kale, kohlrabi, rucola, and cauliflower, while the largest quan- Probiotics, as defined by the Food and Agriculture Or- tities are found in broccoli. It has been proven that eating ganization of the United Nations (FAO) and the World broccoli sprouts can inhibit the growth of H. pylori.39 The Health Organization (WHO), are living microorganisms such studies was carried out on a small group of respon- which, when administered in a sufficient amount, have dents and does not provide strong evidence, but shows a beneficial effect on the health of the host.32 Can they possible treatment options or treatment support. help in H. pylori eradication? It turns out that probiotics have both direct and indi- rect inhibitory effects against H. pylori, indicated both in Summary animal models and in clinical trials.33 Their application as adjuvant therapy for the traditional treatment of H. py- Reviewing the history of discoveries and treatments of lori increases the eradication level while reducing adverse H. pylori, one can see the great impact of this bacterium effects.34 So why is there controversy over their routine on gastrointestinal disorders. Detection of H. pylori and use? Dozens of various probiotic preparations are avail- its eradication facilitate the treatment of chronic gastri- able in Poland, but not all of them have been tested for tis, gastric mucosal erosion, gastric and duodenal ulcers, efficacy, and only a few are registered as medicinal pro- stomach cancer, MALT lymphoma as well as unexplained ducts.35 They are often multi-component, heterogeneous iron-deficiency anemia, idiopathic thrombocytopenia, preparations differing in bacterial strains and their doses, and vitamin B12 deficiency. The indications regarding the so they are difficult to compare. eradication have changed, especially those concerning Official guidelines of the 2016 Maastricht V/Florence bismuth. The first therapies were based on this element, Consensus indicate that preparations with strains of and then it was replaced with PPIs in 2000. In the follow- Saccharomyces boulardii (S. boulardii), Lactobacillus or ing years, the same efficacy of treatment regimen based Bifidobacterium can increase H. pylori eradication rates on bismuth and PPIs was proven, so bismuth was again by improving therapy tolerance, mainly by reducing diar- used in the therapy. The main problem of eradication fail- 25 rhea incidence. ure is the increasing resistance of bacteria to antibiotics. Among the probiotic preparations, a preparation To the medicines used in recent years – apart from clar- with S. boulardii strain, whose efficiency is well docu- ithromycin, amoxicillin and metronidazole – fluoroqui- 36 mented, deserves special attention. A meta-analysis of nolones have been included. 11 randomized clinical trials, involving a total of 2,200 subjects (including 330 children), showed that patients ORCID iDs belonging to the S. boulardii group are likely to achieve Sebastian Adrian Fedorowicz  https://orcid.org/0000-0002-3207-9353 H. pylori eradication (79.6% instead of 71% observed pa- Karolina Julia Radzikowska  https://orcid.org/0000-0002-1718-7540 tients in the control group) and less likely to experience Karolina Mende  https://orcid.org/0000-0003-4516-6648 Stanisław Ferenc  https://orcid.org/0000-0003-3669-4748 any therapy-related adverse effects, especially diarrhea Jan Gnus  https://orcid.org/0000-0002-6220-950X and nausea.36 The authors conclude, however, that de- spite a significant increase in the eradication rate, it is References still unsatisfactory. 1. Linz B, Balloux F, Moodley Y, et al. 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