Pylori Antimicrobial Resistance Research Articles

Antimicrobial Resistance Molecular Mechanisms of Helicobacter pylori in Jordanian Children: A Cross-Sectional Observational Study

H. pylori antimicrobial resistance causes increasing treatment failure rates among H. pylori gastritis in children. This study investigates the molecular mechanisms of H. pylori antimicrobial resistance among Jordanian children. Demographic, clinical, and laboratory data were recorded for children referred to Prince Hamzah Hospital. Clarithromycin, Metronidazole, and Levofloxacin susceptibility were tested via E-test. Clarithromycin-related mutations were investigated using Real-Time (RT)-PCR and Levofloxacin resistance was analyzed with DNA sequencing of the gyrA gene. 116 children were recruited, including 55.2% females and 55.2% in the age range of 10.1 to 14 years. A total of 82.7% were naïve to eradication therapy. H. pylori positivity was 93.9%, 89.6%, 61.7%, and 84.3% according to Rapid Urease Test, histology, culture, and RT-PCR, respectively. Resistance rates were 25.9% for Clarithromycin, 50% for Metronidazole, and 6.9% for Levofloxacin via E-test. A2142G or A2143G or a combination of both mutations concerning Clarithromycin resistance were documented in 26.1% of samples, while mutations in gyrA gen-related to Levofloxacin resistance were reported in 5.3% of samples. Antibiotic resistance was significantly affected by abdominal pain, anemia, hematemesis, and histological findings (p < 0.05). H. pylori resistance was documented for Metronidazole and Clarithromycin. RT-PCR for H. pylori identification and microbial resistance determination are valuable alternatives for cultures in determining antimicrobial susceptibility.

Clinical Implication of Drug Resistance for H. pylori Management.

Rates of antimicrobial-resistance among H. pylori strains are increasing worldwide, resulting in declining eradication rates with current therapies, especially those containing clarithromycin or levofloxacin. To improve H. pylori management, a paradigm shift is needed, from the empiric approaches formerly employed, to regimen selection based upon knowledge of local and patient-level antimicrobial susceptibility data. We review the mechanisms of H. pylori antimicrobial resistance and the available worldwide pattern of resistance to key antimicrobials used in H. pylori therapy. The practicalities and challenges of measuring susceptibility in clinical practice is discussed, including not only conventional culture-based techniques but also novel sequencing-based methods performed on gastric tissue and stool samples. Though clinical trials of "tailored" (susceptibility-based) treatments have yet to show the clear superiority of tailored over empiric regimen selection, the ability to measure and modify treatment based upon antimicrobial susceptibility testing is likely to become more frequent in clinical practice and should lead to improved H. pylori management in the near future.

How We Approach Difficult to Eradicate Helicobacter pylori

How We Approach Difficult to Eradicate Helicobacter pylori

Comprehensive Integration of Genome-Wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter pylori-Induced Gastric Disease.

Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa and can lead to gastric inflammation, ulcers, and stomach cancer. Due to the increase in H. pylori antimicrobial resistance new methods to identify the molecular mechanisms of H. pylori-induced pathology are urgently needed. Here we utilized a computational biology approach, harnessing genome-wide association and gene expression studies to identify genes and pathways determining disease development. We mined gene expression data related to H. pylori-infection and its complications from publicly available databases to identify four human datasets as discovery datasets and used two different multi-cohort analysis pipelines to define a H. pylori-induced gene signature. An initial Helicobacter-signature was curated using the MetaIntegrator pipeline and validated in cell line model datasets. With this approach we identified cell line models that best match gene regulation in human pathology. A second analysis pipeline through NetworkAnalyst was used to refine our initial signature. This approach defined a 55-gene signature that is stably deregulated in disease conditions. The 55-gene signature was validated in datasets from human gastric adenocarcinomas and could separate tumor from normal tissue. As only a small number of H. pylori patients develop cancer, this gene-signature must interact with other host and environmental factors to initiate tumorigenesis. We tested for possible interactions between our curated gene signature and host genomic background mutations and polymorphisms by integrating genome-wide association studies (GWAS) and known oncogenes. We analyzed public databases to identify genes harboring single nucleotide polymorphisms (SNPs) associated with gastric pathologies and driver genes in gastric cancers. Using this approach, we identified 37 genes from GWA studies and 61 oncogenes, which were used with our 55-gene signature to map gene-gene interaction networks. In conclusion, our analysis defines a unique gene signature driven by H. pylori-infection at early phases and that remains relevant through different stages of pathology up to gastric cancer, a stage where H. pylori itself is rarely detectable. Furthermore, this signature elucidates many factors of host gene and pathway regulation in infection and can be used as a target for drug repurposing and testing of infection models suitability to investigate human infection.

Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: a multicentre randomised trial in Japan

ObjectiveTo date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for Helicobacter pylori treatment. This study aimed to investigate the efficacy...

Empirical or susceptibility-guided treatment for Helicobacter pylori infection? A comprehensive review.

Although susceptibility-guided therapy is frequently recommended for Helicobacter pylori infection, the evidence available to date supporting this strategy is limited. The aim of the present article is to review the advantages and limitations of the susceptibility-guided and the empirical strategies to treat this infection. We performed a bibliographic search to identify studies investigating H. pylori susceptibility-guided therapy. Culture is not the only way to assess antibiotic resistance, as different polymerase chain reaction-based approaches have been developed as alternative methods. For detecting H. pylori antimicrobial resistance, a molecular approach based on a stool sample might enable more convenient, time-saving methods. Unfortunately, the antimicrobial susceptibility cannot be obtained in all cases. Furthermore, antibiotic susceptibility testing in clinical practice yields useful information only for a few antibiotics: clarithromycin, metronidazole, and quinolones. In addition, susceptibility towards clarithromycin and metronidazole in vitro does not necessarily lead to eradication in vivo. In the case of H. pylori therapy failure, we should not re-administer any of the antibiotics against which H. pylori has probably become resistant. Our updated meta-analysis showed that susceptibility-guided treatment is not better than empirical treatment of H. pylori infection in first-line therapy if the most updated quadruple regimens are empirically prescribed, and similar efficacy results were also demonstrated with the two strategies for second-line therapy. Cumulative H. pylori eradication rate with several successive rescue therapies empirically prescribed reaches almost 100%. Finally, the studies that have evaluated the cost-effectiveness of the susceptibility-guided treatment have achieved contradictory results. In summary, we can conclude that the evidence is too limited to support the generalized use of susceptibility-guided therapy for H. pylori treatment in routine clinical practice, either as first-line or as rescue treatment. Nevertheless, it would be recommended that susceptibility tests are performed routinely, even before prescribing first-line treatment, in specialized centers with an interest in H. pylori management.

1239 Clinical Safety of RHB-105: A Novel Rifabutin Based Triple Therapy for the Treatment of Helicobacter pylori Infection

INTRODUCTION: Increasing H. pylori antimicrobial resistance has resulted in a need for new, improved therapies and recognition by the World Health Organization as a high priority for development of safe and effective treatment options. Rifabutin is an approved antibiotic whose most commonly reported adverse event (AE) is chromaturia. However, daily dosing of 300 mg rifabutin has historically demonstrated some safety concerns including neutropenia, leukopenia and thrombocytopenia. Our research suggests that a lower divided rifabutin dose is effective in H. pylori eradication without concerns of myelotoxicity. METHODS: This phase 3 data review is a safety assessment of RHB-105 (all-in-one fixed oral capsule formulation: rifabutin 50 mg, amoxicillin 1000 mg, omeprazole 40 mg) Q8H in treatment naive H. pylori infected patients. In two phase 3 studies, 573 US subjects were randomized to receive RHB-105 (n = 305), placebo (n = 41), or active comparator (n = 227) for 14 days. The first study compared RHB-105 with placebo (77:41 subjects) while the second study compared RHB-105 with active comparator (amoxicillin 1000 mg, omeprazole 40 mg, without rifabutin) 228:227 subjects. RESULTS: RHB-105 was well tolerated compared to either placebo or active comparator and the proportion of subjects reporting AEs were generally similar (41.0%, 46.3% vs 34.8%, respectively). AEs occurring in ≥1% of RHB-105 patients vs active comparator were diarrhea (9.5% vs 7.5%), chromaturia (3.0% vs 0.0%), abdominal pain (2.8% vs 1.8%) and vomiting (1.3% vs 0.9%). AEs occurring in ≥1% RHB-105 patients vs placebo were nausea (3.6% vs 2.4%), and chromaturia (3.0% vs 2.4%). Myelotoxicity was not reported in either study. Four SAEs (RHB-105: 2, Placebo: 1, Active comparator: 1) were reported but no deaths were reported. The two SAEs in RHB-105 patients included anemia and diabetic ketoacidosis with neither considered treatment related. Treatment discontinuation due to AE occurred in 4 patients (1.3%) receiving RHB-105, 1 (2.4%) placebo and 1 (0.4%) active comparator. AEs leading to discontinuation of RHB-105 were nausea (occurring in 2 patients), vomiting, and nasal congestion with cold-like symptoms occurring in 1 patient each, respectively. CONCLUSION: RHB-105, a low-dose rifabutin based regimen appears to be a generally well-tolerated treatment option for patients with H. pylori infection. As expected, chromaturia was reported more frequently in RHB-105. Importantly myelotoxicity was not reported.

Appropriate first-line regimens to combat Helicobacter pylori antibiotic resistance: an Asian perspective.

Asia has the largest population of any continent and the highest incidence of gastric cancer in the world, making it very important in the context of Helicobacter pylori infection. According to current guidelines, standard triple therapy containing a proton pump inhibitor (PPI) and two antibiotics; amoxicillin (AMX) and clarithromycin (CAM) or metronidazole (MNZ), is still the preferred first-line regimen for treatment of H. pylori infection. However, the efficacy of legacy triple regimens has been seriously challenged, and they are gradually becoming ineffective. Moreover, some regions in Asia show patterns of emerging antimicrobial resistance. More effective regimens including the bismuth and non-bismuth quadruple, sequential, and dual-concomitant (hybrid) regimens are now replacing standard triple therapies as empirical first-line treatments on the basis of the understanding of the local prevalence of H. pylori antimicrobial resistance. Selection of PPI metabolized by the non-enzymatic pathway or minimal first pass metabolism and/or increasing dose of PPI are important to increase H. pylori eradication rates. Therefore, local antibiotic resistance surveillance updates, selection of appropriate first-line regimens with non-enzymatic PPI and/or increased doses of PPI, and detailed evaluation of patients’ prior antibiotic usage are all essential information to combat H. pylori antibiotic resistance in Asia.

Strategy for the Treatment of Helicobacter pylori Infection

The eradication of Helicobacter pylori not only heals peptic ulcers but also prevents their recurrence and reduces the risk of development of gastric cancer and other H. pylori-associated disorders. H. pylori eradication heals gastritis and may prevent the spread of infection, reducing the future costs required for the treatment of subsequent H. pylori-associated diseases. There are various guidelines for the management of H. pylori infection worldwide, such as the guidelines of the American College of Gastroenterology, Maastricht IV, the Second Asia-Pacific Consensus Conference, and Japan. The Japanese health insurance system approved H. pylori eradication therapy for H. pylori-related chronic gastritis in 2013. Triple therapy regimens comprising 1 proton pump inhibitor and 2 antimicrobial agents such as amoxicillin, clarithromycin, metronidazole, levofloxacin, or tetracycline have been widely used to eradicate this bacterium. The rate of successful eradication has declined owing to the increased rate of drug resistance stemming from the wide usage of antibiotics. This issue is of particular relevance with regard to clarithromycin. In worldwide, clarithromycin-based triple therapy should be abandoned, as it is no longer effective. Quadruple therapy and sequential therapy are reasonable alternatives for initial therapy. First-line treatment should be recommended on the basis of an understanding of the local prevalence of H. pylori antimicrobial resistance.

Cholesterol Enhances Helicobacter pylori Resistance to Antibiotics and LL-37

The human gastric pathogen Helicobacter pylori steals host cholesterol, modifies it by glycosylation, and incorporates the glycosylated cholesterol onto its surface via a cholesterol glucosyltransferase, encoded by cgt. The impact of cholesterol on H. pylori antimicrobial resistance is unknown. H. pylori strain 26695 was cultured in Ham's F12 chemically defined medium in the presence or absence of cholesterol. The two cultures were subjected to overnight incubations with serial 2-fold dilutions of 12 antibiotics, six antifungals, and seven antimicrobial peptides (including LL-37 cathelicidin and human alpha and beta defensins). Of 25 agents tested, cholesterol-grown H. pylori cells were substantially more resistant (over 100-fold) to nine agents than were H. pylori cells grown without cholesterol. These nine agents included eight antibiotics and LL-37. H. pylori was susceptible to the antifungal drug pimaricin regardless of cholesterol presence in the culture medium. A cgt mutant retained cholesterol-dependent resistance to most antimicrobials but displayed increased susceptibility to colistin, suggesting an involvement of lipid A. Mutation of lpxE, encoding lipid A1-phosphatase, led to loss of cholesterol-dependent resistance to polymyxin B and colistin but not other antimicrobials tested. The cgt mutant was severely attenuated in gerbils, indicating that glycosylation is essential in vivo. These findings suggest that cholesterol plays a vital role in virulence and contributes to the intrinsic antibiotic resistance of H. pylori.

An overview of antimicrobial resistance and the future of medicinal plants in the treatment of Helicobacter pylori infections

Helicobacter pylori, a gram negative helical bacillus that inhabits the human stomach is now recognised as the causative agent of chronic gastritis, peptic ulcer, duodenal ulcer and mucosa associated lymphoid tissue (MALT) lymphoma. The treatment of H. pylori infection typically employs a triple drug regimen using two antibiotics and a proton pump inhibitor (PPI) or bismuth with a success rate of 80 - 90%. However, resistance to the most commonly used antibiotics is a growing global concern. With an alarming H. pylori prevalence of 90% reported in some African countries and 90 100% Metronidazole (MTZ)-resistance, one of the drugs used in the treatment regimen, the need for alternative treatment regimens is imperative. Medicinal plants seem to provide an alternative source of treatment and are among the attractive sources of new drugs shown to produce promising results against H. pylori in-vitro. Researchers have been testing crude extracts of a wide variety of plants used in folklore medicine for the identification of potential anti- H. pylori agents. This review appraises the current state of H. pylori antimicrobial resistance, medicinal plant constituents ranging from extracts commonly in use, by the lay community, to substances being prospected and tested by researchers as possible substitutes to treat H. pylori infection. There is a need to continue to monitor resistance and revolutionize the search for alternative treatment regimens against H. pylori particularly as the life span of any drug is limited.

Helicobacter pylori culture and antimicrobial resistance in Iran

Helicobacter pylori is considered as an important etiologic factor in pathogenesis of peptic ulcer disease, chronic gastritis and gastric cancer. To eradicate this micro-organism, numerous regimens containing various antimicrobial agents have been suggested. However, H pylori antimicrobial resistance is a leading factor to treatment failure and recurrence of the disease. The aim of the study was to evaluate the prevalence of H pylori resistance to metronidazole, clarithromycin, tetracycline, amoxicillin, erythromycin and furazolidone in authors pediatric patients. Antral biopsy of all pediatric patients with negative history of receiving anti-H pylori regimen and endoscopic findings of nodular gastritis or peptic ulcer without previous history of NSAID consumption, burning and trauma were performed for H pylori histology, urease test and culture. All positive cultures were tested for antimicrobial susceptibility. Twenty four patients (14 male and 10 female) between 3.5 and 14 years of age were culture positive. 54.16% of the isolates were resistant to metronidazole, 8.33% to amoxicillin, 4.16% to erythromycin and 4.16% to clarithromycin. None of authors patients were resistant to tetracycline and furazolidone. H. pylori antimicrobial resistance could be a major contributor to failure of H pylori eradication. Continuous prospective surveillance of H. Pylori is essential. Moreover, culture and antimicrobial susceptibility test is recommended for resistant cases after the first failure to therapy.

Resistencia antimicrobiana en Helicobacter pylori: aspectos clínicos y moleculares

Helicobacter pylori is a relevant pathogen for gastroduodenal diseases in human beings. Although its eradication often improves gastroduodenal diseases, H pylori is acquiring an elevated rate of resistance to various antimicrobials, such as metronidazole, clarithromycin, tetracycline and amoxicillin. Multi-drug resistance is a major problem to select the appropriate treatment of infectious diseases. To improve our understanding on the complexity of the problem, in this article we review the resistance mechanisms and give an update on H pylori antimicrobial resistance.

H. pylori antimicrobial resistance in the united states: Preliminary results of a 9-center study

H. pylori antimicrobial resistance in the united states: Preliminary results of a 9-center study

Treatment of Helicobacter pylori

Overwhelming evidence implicates Helicobacter pylori as a significant causative factor in many gastroduodenal diseases. Effective multidrug antimicrobial regimens are available for cure of the infection, so investigative efforts are focusing on cost-effectiveness and treatment outcome in various populations. Potential associations between H. pylori and nongastric disorders are being examined. Recognition that infection is largely acquired during childhood has emphasized the need to study pediatric issues. Posttreatment studies confirm the importance of the bacterium in pathogenesis and relapse of peptic ulcer disease. Antimicrobial resistance has a negative impact on cure of the infection and healing of gastroduodenal lesions. Methodology to evaluate H. pylori antimicrobial susceptibility has been standardized by the National Committee for Clinical Laboratory Standards, and minimum inhibitory concentration breakpoints to standardize resistance assays are being established. Surveillance of H. pylori antimicrobial resistance is underway in a Centers for Disease Control and Prevention multisite project in the United States.