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Helicobacter pylori Virulence Factors and Antibiotic Susceptibility

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A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 42485

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Dr. Natale Figura

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Guest Editor

Medical and -surgical Sciences and Neurosciences, Università degli Studi di Siena, Siena, Italy
Interests: Gastroenterology; Helicobacter pylori; H. pylori virulence factors; host response to H. pylori infection; H. pylori-related extra-digestive diseases

Dr. Antonio Ponzetto

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Guest Editor

Università degli Studi di Torino, Torino, Italy
Interests: gastroenterology; clinical and basic aspects of H. pylori; proteomics for dissecting the molecular basis of gastrointestinal diseases; clinical and basic aspects of Hepatitis C virus and B virus

Special Issue Information

Dear Colleagues,

Helicobacter pylori is a spiral organism that colonizes the human gastric and gastric-type mucosa. It is an agent of chronic gastritis (CG), the pabulum on which peptic ulceration, gastric mucosa atrophy and cancer may develop. Despite H. pylori being a primary pathogen, most infected individuals do not show any sign or symptom of infection throughout their lifetime. This prompted researchers to investigate the different isolates to ascertain which virulence factors (VFs) could enable the various strains to cause the most severe outcomes of infection. VF CagA and VacA are currently being investigated in depth, but other VFs may warrant being investigated more thoroughly. Some VFs show a stronger immune response and a more substantial local and systemic inflammatory status; they may also modify the gastric microbiome, and this activity may not be confined to the stomach. Some observations suggest that strains expressing CagA are more susceptible to antibiotics (An) and chemotherapeutic agents used to cure infection. In addition, some natural substances, used together with An, might help doctors to get rid of these organisms from the gastric mucosa. The aim of the present Special Issue is to publish state of art research regarding H. pylori VFs and chemo-susceptibility that may help physicians and researchers to select patients most suited for treatment and which drugs should be administered.

Dr. Natale Figura
Dr. Antonio Ponzetto
Guest Editors

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Keywords

Antimicrobial drugs and therapies
virulence factors
CagA
VacA
pathogenesis
host response
extra-digestive diseases
gastric microbioma
pro-inflammatory cytokines
chemosusceptibility

Published Papers (9 papers)

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Research

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16 pages, 2374 KiB

Open AccessArticle

Searching for New Tools to Counteract the Helicobacter pylori Resistance: The Positive Action of Resveratrol Derivatives

by Paola Di Fermo, Silvia Di Lodovico, Rosa Amoroso, Barbara De Filippis, Simonetta D’Ercole, Emanuela Di Campli, Luigina Cellini and Mara Di Giulio

Antibiotics 2020, 9(12), 891; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9120891 - 10 Dec 2020

Cited by 15 | Viewed by 2442

Abstract

The drug-resistance phenomenon in Helicobacter pylori underlines the need of novel strategies to improve the eradication rate including alternative treatments combining antibiotic and non-antibiotic compounds with synergistic action. In this study, the antibacterial (MIC/MBC) and anti-virulence effects (biofilm reduction and swarming motility inhibition) of resveratrol-RSV and new synthetized RSV-phenol derivatives, with a higher bioavailability, alone and combined with levofloxacin-LVX were evaluated against resistant H. pylori clinical strains. The experiments were confirmed in vivo using the Galleria mellonella model. Among the studied RSV derivatives, RSV-3 and RSV-4 possessed higher antibacterial activity with respect to RSV (MICs from 6.25 to 200 µg/mL and from 3.12 to 200 µg/mL, respectively). RSV, RSV-3, and RSV-4 were able to synergize with LVX restoring its effect in two out of seven clinical resistant strains tested for the study. RSV, RSV-3, and RSV-4, alone and with LVX at sub-MIC and sub-synergistic concentrations, significantly reduced the biofilm formation. Moreover, RSV-3 and RSV-4 reduced the H. pylori swarming motility on soft agar. RSV, RSV-3, and RSV-4 were non-toxic for G. mellonella larvae and displayed a protective effect against H. pylori infection. Overall, RSV–phenol derivatives should be considered interesting candidates for innovative therapeutic schemes to tackle the H. pylori antibiotic resistance. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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11 pages, 500 KiB

Open AccessArticle

Discovery of a Novel Mutation in DNA Gyrase and Changes in the Fluoroquinolone Resistance of Helicobacter pylori over a 14-Year Period: A Single Center Study in Korea

by Su Yeon Rhie, Jae Yong Park, Tae-Seop Shin, Jeong Wook Kim, Beom Jin Kim and Jae Gyu Kim

Antibiotics 2020, 9(6), 287; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9060287 - 27 May 2020

Cited by 3 | Viewed by 2793

Abstract

The efficacy of fluoroquinolone-based eradication therapy largely depends on the fluoroquinolone resistance of H. pylori. The aim of this study was to investigate the changes in the primary resistance rate of H. pylori to fluoroquinolone and the mechanism of resistance in Korea. A total of 153 strains and 48 strains of H. pylori were isolated at a tertiary hospital in 2005/2006 and 2017/2018, respectively. The minimum inhibitory concentrations (MICs) of fluoroquinolone were determined by the serial 2-fold agar dilution method. DNA sequences in the quinolone resistance-determining regions of gyrA/gyrB were analyzed in resistant strains. Subsequent natural transformation study was performed to determine the association between gyrase mutation and resistance. The resistance rates increased from 19.0% (29/153) to 43.8% (21/48) both for levofloxacin and moxifloxacin. The MIC values for resistant strains increased from 2–8 µg/mL to 4–16 µg/mL over time. Mutation of gyrA was detected in 93.1% (27/29) and 100% (21/21) among the resistant strains in both periods, respectively. A novel Gly-85 mutation of gyrA was found and confirmed to be associated with fluoroquinolone resistance. Fluoroquinolone resistance rate of H. pylori has markedly increased over time in Korea. The resistance is mostly due to the point mutation of gyrA. Fluoroquinolone-containing regimens should be carefully selected in Korea, considering the increasing fluoroquinolone resistance. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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10 pages, 3297 KiB

Open AccessFeature PaperArticle

Antimicrobial Efficacy of Five Probiotic Strains Against Helicobacter pylori

by Ilaria Maria Saracino, Matteo Pavoni, Laura Saccomanno, Giulia Fiorini, Valeria Pesci, Claudio Foschi, Giulia Piccirilli, Giulia Bernardini, John Holton, Natale Figura, Tiziana Lazzarotto, Claudio Borghi and Berardino Vaira

Antibiotics 2020, 9(5), 244; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9050244 - 11 May 2020

Cited by 17 | Viewed by 5297

Abstract

Treatment of Helicobacter pylori (H. pylori) infection is a challenge for clinicians. The large increase in drug-resistant strains makes the formulation of new therapeutic strategies fundamental. The frequent onset of side effects during antibiotic treatment (mainly due to intestinal dysbiosis) should not be underestimated as it may cause the interruption of treatment, failure of H. pylori eradication and clonal selection of resistant bacteria. Probiotic integration during antibiotic treatment can exert a dual function: a direct antagonistic effect on H. pylori and a balancing effect on dysbiosis. Therefore, it fulfills the definition of a new therapeutic strategy to successfully treat H. pylori infection. Data reported in literature give promising but discrepant results. Aim: To assess in vitro bacteriostatic and bactericidal activity of probiotic strains against H. pylori. Materials and methods: L. casei, L. paracasei, L. acidophilus, B. lactis and S. thermophilus strains were used. Agar well diffusion and time-kill curves were carried out to detect bacteriostatic and bactericidal activity, respectively. Results: All probiotic strains showed both bacteriostatic and bactericidal activity vs. H. pylori. Conclusions: Such findings prompted us to plan a protocol of treatment in which probiotics are given to infected patients in association with antibiotic therapy. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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7 pages, 394 KiB

Open AccessArticle

Antibiotic Resistance and Therapy Outcome in H. pylori Eradication Failure Patients

by Saracino I.M., Pavoni M., Zullo A., Fiorini G., Saccomanno L., Lazzarotto T., Cavallo R., Antonelli G. and Vaira D.

Antibiotics 2020, 9(3), 121; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9030121 - 13 Mar 2020

Cited by 18 | Viewed by 3152

Abstract

Helicobacter pylori (H. pylori) eradication fails in a definite amount of patients despite one or more therapeutic attempts. Curing these patients is progressively more difficult, due to development of antibiotic resistance. Current guidelines suggest testing antibiotic susceptibility in H. pylori isolates following two therapeutic attempts. Aim: to evaluate the development of antibiotic resistance, MIC values trends and therapeutic outcomes in patients who failed at least one H. pylori eradication therapy. Methods: consecutive patients, referred to perform upper gastrointestinal endoscopy (UGIE) to our Unit from January 2009 to January 2019 following at least one therapeutic attempt were considered. Bacterial resistance towards clarithromycin, metronidazole and levofloxacin was tested. Patients received either a susceptibility-guided therapy or Pylera^®. Results: a total of 1223 patients were H. pylori positive, and antibiotic susceptibility was available for 1037. The rate of antibiotic resistance and MIC values significantly increased paralleling the number of previous therapeutic attempts. Eradication rates of antibiogram-tailored therapies remained stable, except for the sequential therapy if used as a third line. As a rescue treatment, the Pylera^® therapy achieved cure rates comparable to those of the other culture-guided therapies. Conclusions: A significant increase in the secondary resistance towards the three tested antibiotics was observed, both as rate and MIC values, in correlation with the number of therapy failures. These findings should be considered when administering an empirical second-line therapy. Pylera^® therapy eradication rates are comparable to culture-tailored therapies. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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10 pages, 689 KiB

Open AccessArticle

Trends in Primary Antibiotic Resistance in H. pylori Strains Isolated in Italy between 2009 and 2019

by Ilaria Maria Saracino, Giulia Fiorini, Angelo Zullo, Matteo Pavoni, Laura Saccomanno and Dino Vaira

Antibiotics 2020, 9(1), 26; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9010026 - 13 Jan 2020

Cited by 26 | Viewed by 3984

Abstract

Background and aims: the increasing prevalence of strains resistant to antimicrobial agents is a critical issue for the management of Helicobacter pylori infection. This study aimed to evaluate, in Italian naïve patients, H. pylori antibiotic resistance trends and their potential predictive factors during the last decade. Methods: consecutive Italian naïve H. pylori positive patients, referred from General Practitioners to our Unit from January 2009 to January 2019 to perform an upper gastrointestinal endoscopy (UGIE), were considered. Each patient underwent ¹³C-urea breath test (¹³C-UBT) and UGIE with multiple biopsies to perform rapid urease test (RUT), culture/susceptibility test (vs. clarithromycin, metronidazole, levofloxacin), and histopathological examination. H. pylori status was assessed through CRM (composite reference method: at least two tests positive or only culture positive). Results: between 2009 and 2014, 1763 patients were diagnosed as H. pylori positive, 907 were naïve with antibiogram available. Between 2015 and 2019, 1415 patients were diagnosed as H. pylori positive, antibiotic susceptibility test was available in 739 naïve patients. H. pylori primary antibiotic resistance rates in the first and second five-year period were, respectively, clarithromycin 30.2% (95% CI 27.2–33.3), 37.8% (95% CI 34.2–41.4); metronidazole 33.3% (95% CI 30.2–36.5), 33.6% (95% CI 30.2–37.1); levofloxacin 25.6% (95% CI 22.8–28.5), 33.8% (95% CI 37.4–47.4), double resistance clarithromycin-metronidazole 18.9% (95% CI 16.4–21.6), 20.7% (95% CI 17.8–23.8). The increase of the resistance rates to clarithromycin and levofloxacin in naïve patients was statistically significant (p < 0.05). Although eradication rates for sequential therapy in the 10 years considered were 93.4% (95% CI 92–94.6) and 87.5% (95% CI 85.7–89) at per-protocol (PP) and intention-to-treat (ITT) analysis, respectively, they showed a significant decrease in the second five-year period. Conclusions: this data highlights an increase in primary H. pylori antibiotic resistance and strongly suggests the importance of drug susceptibility testing also in naïve patients. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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13 pages, 1152 KiB

Open AccessArticle

Helicobacter pylori Infection and Autoimmune Thyroid Diseases: The Role of Virulent Strains

by Natale Figura, Giovanni Di Cairano, Elena Moretti, Francesca Iacoponi, Annalisa Santucci, Giulia Bernardini, Stefano Gonnelli, Nicola Giordano and Antonio Ponzetto

Antibiotics 2020, 9(1), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9010012 - 30 Dec 2019

Cited by 27 | Viewed by 4353

Abstract

Aim: To verify a possible association between overall H. pylori and CagA+ H. pylori infection and autoimmune thyroid diseases (AITDs). Methods: Consecutive patients with AITDs admitted to one single centre of Endocrinology during one solar year were examined. The diagnoses were Hashimoto thyroiditis (HT) in 76, Graves’ Disease (GD) in 39, and aspecific thyroiditis (AT) in 44 patients. Controls were 136 individuals without AITDs. Median values of fT3, fT4, anti-thyreoglobulin (Tg) antibodies, IL-1β, IL-6, and TNF-α in patients were compared with those in controls. H. pylori infection and CagA status were determined serologically. Structural homology of some thyroid proteins with H. pylori antigens was investigated. Results: H. pylori infection prevalence was significantly increased in GD (66.6%) and HT (64.4%) patients, vs. 29.4% of controls and 34.0% of AT. CagA seropositivity was significantly more frequent in GD (46.1%) and HT (46.9%) infected patients, vs. infected controls (20%). fT3 and fT4 median values were significantly decreased in infected CagA+ GD patients vs. uninfected GD patients. IL-1β median values were increased in patients respect to controls, independently of the clinical form of AITD. Median values of IL-6, TNF-α and anti-Tg autoantibodies in CagA infected patients were significantly higher than those measured in infected CagA− and uninfected patients and in infected CagA+ controls. The examined thyroid proteins shared putative conserved domains with numerous bacterial antigens. Conclusions: Overall H. pylori and CagA+ H. pylori infection were associated with GD and HT, putatively through an increased inflammatory status and molecular mimicry. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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Review

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16 pages, 483 KiB

Open AccessReview

Best Helicobacter pylori Eradication Strategy in the Era of Antibiotic Resistance

by Su Young Kim and Jun-Won Chung

Antibiotics 2020, 9(8), 436; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9080436 - 23 Jul 2020

Cited by 24 | Viewed by 11031

Abstract

Antibiotic resistance is the major reason for Helicobacter pylori treatment failure, and the increasing frequency of antibiotic resistance is a challenge for clinicians. Resistance to clarithromycin and metronidazole is a particular problem. The standard triple therapy (proton pump inhibitor, amoxicillin, and clarithromycin) is no longer appropriate as the first-line treatment in most areas. Recent guidelines for the treatment of H. pylori infection recommend a quadruple regimen (bismuth or non-bismuth) as the first-line therapy. This treatment strategy is effective for areas with high resistance to clarithromycin or metronidazole, but the resistance rate inevitably increases as a result of prolonged therapy with multiple antibiotics. Novel potassium-competitive acid blocker-based therapy may be effective, but the data are limited. Tailored therapy based on antimicrobial susceptibility test results is ideal. This review discussed the current important regimens for H. pylori treatment and the optimum H. pylori eradication strategy. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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14 pages, 803 KiB

Open AccessReview

The Puzzle of Coccoid Forms of Helicobacter pylori: Beyond Basic Science

by Enzo Ierardi, Giuseppe Losurdo, Alessia Mileti, Rosa Paolillo, Floriana Giorgio, Mariabeatrice Principi and Alfredo Di Leo

Antibiotics 2020, 9(6), 293; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9060293 - 31 May 2020

Cited by 32 | Viewed by 5737

Abstract

Helicobacter pylori (H. pylori) may enter a non-replicative, non-culturable, low metabolically active state, the so-called coccoid form, to survive in extreme environmental conditions. Since coccoid forms are not susceptible to antibiotics, they could represent a cause of therapy failure even in the absence of antibiotic resistance, i.e., relapse within one year. Furthermore, coccoid forms may colonize and infect the gastric mucosa in animal models and induce specific antibodies in animals and humans. Their detection is hard, since they are not culturable. Techniques, such as electron microscopy, polymerase chain reaction, loop-mediated isothermal amplification, flow cytometry and metagenomics, are promising even if current evidence is limited. Among the options for the treatment, some strategies have been suggested, such as a very high proton pump inhibitor dose, high-dose dual therapy, N-acetycysteine, linolenic acid and vonoprazan. These clinical, diagnostic and therapeutic uncertainties will represent fascinating challenges in the future. Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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Other

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8 pages, 2043 KiB

Open AccessBrief Report

High Primary Antibiotic Resistance of Helicobacter pylori Strains Isolated from Pediatric and Adult Patients in Poland during 2016–2018

by Paweł Krzyżek, Dorota Pawełka, Barbara Iwańczak, Radosław Kempiński, Konrad Leśniakowski, Francis Mégraud, Łukasz Łaczmański, Monika Biernat and Grażyna Gościniak

Antibiotics 2020, 9(5), 228; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9050228 - 02 May 2020

Cited by 11 | Viewed by 3022

Abstract

Monitoring the antibiotic resistance of H. pylori is an important step in the effective treatment of this bacterium, thus the aim of the present study was to assess the prevalence of antimicrobial resistance of H. pylori strains isolated from pediatric and adult patients with primary infections in 2016–2018. Antral biopsies from 334 treatment-naïve patients (126 children and 208 adults) were obtained. A total of 71 clinical H. pylori strains (22 from children and 49 from adults) were isolated and examined for amoxicillin (AMX), clarithromycin (CLR), metronidazole (MTZ), tetracycline (TET), and levofloxacin (LEV) susceptibility. The activity of the antibiotics was measured by E-tests. Strains were considered as resistant to antibiotics with minimum inhibitory concentrations (MICs) equal to ≥0.125 μg/mL (AMX), ≥0.5 μg/mL (CLR), ≥8 μg/mL (MTZ), and ≥1 μg/mL (TET and LEV). The highest prevalence of antibiotic resistance in H. pylori strains was observed for CLR and MTZ, at frequencies of 54.5% and 31.8% vs. 30.6% and 46.9% for children and adults, respectively. A much lower frequency of isolation of resistant strains was demonstrated for LEV and TET, this being 9.1% and 4.5% vs. 18.4% and 4.1% for pediatric and adult patients, respectively. The presence of AMX-resistant strains was not observed. The H. pylori strains isolated from Polish patients with primary infections showed a high level of antibiotic resistance to CLR and MTZ (>30%). Full article

(This article belongs to the Special Issue Helicobacter pylori Virulence Factors and Antibiotic Susceptibility)

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