Recent Insights into Antibiotic Resistance inHelicobacter pyloriEradication

Antibiotics have been useful in the treatment ofH. pylori-related benign and malignant gastroduodenal diseases. However, emergence of antibiotic resistance often decreases the eradication rates ofH. pyloriinfections. Many factors have been implicated as causes of treatment failure, but the main antibiotic resistance mechanisms described to date are due to point mutations on the bacterial chromosome, a consequence of a significantly phenotypic variation inH. pylori. The prevalence of antibiotic (e.g., clarithromycin, metronidazole, tetracycline, amoxicillin, and furazolidone) resistance varies among different countries; it appears to be partly determined by geographical factors. Since the worldwide increase in the rate of antibiotic resistance represents a problem of relevance, some studies have been performed in order to identify highly active and well-tolerated anti-H. pyloritherapies including sequential, concomitant quadruple, hybrid, and quadruple therapy. These represent a promising alternatives in the effort to overcome the problem of resistance. The aim of this paper is to review the current status of antibiotic resistance inH. pylorieradication, highlighting the evolutionary processes in detail at alternative approaches to treatment in the past decade. The underlying resistance mechanisms will be also followed.

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Reduced Vancomycin Susceptibility in Staphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

Clinical Microbiology Reviews ◽

10.1128/cmr.00042-09 ◽

2010 ◽

Vol 23 (1) ◽

pp. 99-139 ◽

Cited By ~ 541

Author(s):

Benjamin P. Howden ◽

John K. Davies ◽

Paul D. R. Johnson ◽

Timothy P. Stinear ◽

M. Lindsay Grayson

Keyword(s):

Staphylococcus Aureus ◽

Cell Wall ◽

Treatment Failure ◽

Treatment Outcomes ◽

Susceptibility Testing ◽

Point Mutations ◽

Resistance Mechanisms ◽

Wall Thickening ◽

Clinical Implications ◽

The Past

SUMMARY The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) over the past decade has provided a challenge to diagnostic microbiologists to detect these strains, clinicians treating patients with infections due to these strains, and researchers attempting to understand the resistance mechanisms. Recent data show that these strains have been detected globally and in many cases are associated with glycopeptide treatment failure; however, more rigorous clinical studies are required to clearly define the contribution of hVISA to glycopeptide treatment outcomes. It is now becoming clear that sequential point mutations in key global regulatory genes contribute to the hVISA and VISA phenotypes, which are associated predominately with cell wall thickening and restricted vancomycin access to its site of activity in the division septum; however, the phenotypic features of these strains can vary because the mutations leading to resistance can vary. Interestingly, changes in the staphylococcal surface and expression of agr are likely to impact host-pathogen interactions in hVISA and VISA infections. Given the subtleties of vancomycin susceptibility testing against S. aureus, it is imperative that diagnostic laboratories use well-standardized methods and have a framework for detecting reduced vancomycin susceptibility in S. aureus.

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Sorting out the Superbugs: Potential of Sortase A Inhibitors among Other Antimicrobial Strategies to Tackle the Problem of Antibiotic Resistance

Antibiotics ◽

10.3390/antibiotics10020164 ◽

2021 ◽

Vol 10 (2) ◽

pp. 164 ◽

Cited By ~ 1

Author(s):

Nikita Zrelovs ◽

Viktorija Kurbatska ◽

Zhanna Rudevica ◽

Ainars Leonchiks ◽

Davids Fridmanis

Keyword(s):

Cell Wall ◽

Antibiotic Resistance ◽

Pathogenic Bacteria ◽

Resistance Mechanisms ◽

Surface Proteins ◽

Sortase A ◽

Inhibitory Compounds ◽

Alternative Means ◽

Alternative Approaches ◽

Conventional Antibiotics

Rapid spread of antibiotic resistance throughout the kingdom bacteria is inevitably bringing humanity towards the “post-antibiotic” era. The emergence of so-called “superbugs”—pathogen strains that develop resistance to multiple conventional antibiotics—is urging researchers around the globe to work on the development or perfecting of alternative means of tackling the pathogenic bacteria infections. Although various conceptually different approaches are being considered, each comes with its advantages and drawbacks. While drug-resistant pathogens are undoubtedly represented by both Gram(+) and Gram(−) bacteria, possible target spectrum across the proposed alternative approaches of tackling them is variable. Numerous anti-virulence strategies aimed at reducing the pathogenicity of target bacteria rather than eliminating them are being considered among such alternative approaches. Sortase A (SrtA) is a membrane-associated cysteine protease that catalyzes a cell wall sorting reaction by which surface proteins, including virulence factors, are anchored to the bacterial cell wall of Gram(+) bacteria. Although SrtA inhibition seems perspective among the Gram-positive pathogen-targeted antivirulence strategies, it still remains less popular than other alternatives. A decrease in virulence due to inactivation of SrtA activity has been extensively studied in Staphylococcus aureus, but it has also been demonstrated in other Gram(+) species. In this manuscript, results of past studies on the discovery of novel SrtA inhibitory compounds and evaluation of their potency were summarized and commented on. Here, we discussed the rationale behind the inhibition of SrtA, raised some concerns on the comparability of the results from different studies, and touched upon the possible resistance mechanisms as a response to implementation of such therapy in practice. The goal of this article is to encourage further studies of SrtA inhibitory compounds.

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Phenotypic and Genotypic Analysis of Resistant Helicobacter pylori Strains Isolated from Children with Gastrointestinal Diseases

Diagnostics ◽

10.3390/diagnostics10100759 ◽

2020 ◽

Vol 10 (10) ◽

pp. 759

Author(s):

Monika Maria Biernat ◽

Aldona Bińkowska ◽

Łukasz Łaczmański ◽

Paweł Biernat ◽

Paweł Krzyżek ◽

...

Keyword(s):

Helicobacter Pylori ◽

Antibiotic Resistance ◽

Point Mutations ◽

Gastrointestinal Diseases ◽

Drug Susceptibility Testing ◽

Test Method ◽

Ulcer Disease ◽

Genotypic Analysis ◽

Clinical Diagnoses ◽

H Pylori

Antibiotic resistance of Helicobacter pylori is currently a global issue. The aim of this study was to analyze actual antibiotic resistance rates of H. pylori strains isolated from children with primary infections and to compare the incidence of mutations that determine resistance to clarithromycin (CH) and metronidazole (MET) in children with different clinical diagnoses. A total of 91 H. pylori strains were isolated from 108 children with primary infections. Drug susceptibility testing of the strains was performed using E-test method. Classical sequencing of DNA fragments was used to detect point mutations for CH and MET resistance. Resistance to CH was detected in 31% of isolated strains (28/91), while resistance to MET and CH was detected in 35% (32/91) of strains. A2143G was the most frequently detected mutation and was dominant among strains isolated from children with peptic ulcer disease (80%). Mutations in the rdxA gene were found significantly more frequently among MET-resistant strains than MET-sensitive strains (p = 0.03, Chi2 = 4.3909). In children, a higher frequency of H. pylori multiresistant strains was observed compared with the previous study in the same area. Differences were found in the occurrence of point mutations among H. pylori strains resistant to CH isolated from children with different clinical diagnoses.

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Effectiveness of Second through Sixth Line SalvageHelicobacter pyloriTreatment: Bismuth Quadruple Therapy is Almost Always a Reasonable Choice

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2016/7321574 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Tahir Shaikh ◽

Carlo A. Fallone

Keyword(s):

Salvage Therapy ◽

Absolute Risk ◽

Absolute Risk Reduction ◽

Lower Proportion ◽

Antibiotic Exposure ◽

Quadruple Therapy ◽

Multiple Treatment ◽

The Past ◽

Reasonable Choice ◽

H Pylori

Aim.There is a paucity of data on the efficacy of empiricH. pyloritreatment after multiple treatment failures. The aim of this study is to examine the efficacy of empiric salvage therapy as a second through sixth line treatment.Methods.In this single gastroenterology center prospective study in Montreal, Canada, patients with failedH. pyloritreatment were offered empiric salvage therapy based on the patients’ previous antibiotic exposure. Enrollment occurred after 1–5 previous failed attempts and eradication determined at least 4 weeks after completion of treatment.Results.205 treatments were attempted in 175 patients using 7 different regimens. Eradication was achieved in 154 attempts (PP = 81% (154/191), ITT = 75% (154/205)). Bismuth quadruple therapy (BQT) had higher eradication success (PP = 91% (102/112), ITT = 84% (102/121)) when compared to all PPI triple therapies combined (PP = 66% (49/74), absolute risk reduction (ARR): 25% (95% CI: 13–37), ITT = 62% (49/79), ARR: 22% (95% CI: 10–35), andp<0.001) and when compared to levofloxacin triple therapy (PP = 66% (40/61), ARR: 26% (95% CI: 13–39), ITT = 61% (40/66), and ARR: 24% (95% CI: 10–37)). Eradication was achieved in a high proportion with BQT on attempt two (PP = 94% (67/71), ITT = 91% (67/74)), three (PP = 85% (17/20), ITT = 71% (17/24)), four (PP = 100% (11/11), ITT = 92% (11/12)), and five (PP = 86% (6/7), ITT = 75% (6/8)). Patients with previous combined bismuth and tetracycline exposure had a lower proportion of eradication compared to patients without such an exposure (PP: 60% (6/10) versus 95% (94/99), ARR: 35% (95% CI: 11–64), andp<0.001; ITT: 55% (6/11) versus 90% (94/105), ARR: 35% (95% CI: 10–62), andp<0.01).Conclusions.Salvage therapy with a bismuth quadruple regimen is superior to triple therapies and is effective for second through fifth line empirical treatment (≥85% PP, ≥70% ITT). Successful eradication is significantly lower with BQT if a similar bismuth based regimen was used in the past.

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Antimicrobial Susceptibility of Canadian Isolates ofHelicobacter pyloriin Northeastern Ontario

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2015/853287 ◽

2015 ◽

Vol 26 (3) ◽

pp. 137-144 ◽

Cited By ~ 8

Author(s):

Nelson F Eng ◽

Gustavo Ybazeta ◽

Katrina Chapman ◽

Nya L Fraleigh ◽

Rebecca Letto ◽

...

Keyword(s):

Antibiotic Resistance ◽

Antimicrobial Resistance ◽

Ribosomal Rna ◽

Antimicrobial Susceptibility ◽

Point Mutations ◽

Test Methods ◽

Surveillance Programs ◽

Resistant Strains ◽

H Pylori ◽

23S Ribosomal Rna

BACKGROUND:Helicobacter pyloriplays a significant role in gastritis and ulcers. It is a carcinogen as defined by the WHO, and infection can result in adenocarcinomas and mucosa-associated lymphoid tissue lymphomas. In Canada, rates of antimicrobial resistance are relatively unknown, with very few studies conducted in the past 15 years.OBJECTIVE: To examine rates of resistance in Sudbury, Ontario, compare antimicrobial susceptibility methods and attempt to determine the molecular basis of antibiotic resistance.METHODS: Patients attending scheduled visits at Health Sciences North (Sudbury, Ontario) provided gastric biopsy samples on a volunteer basis. In total, 20H pyloriisolates were collected, and antimicrobial susceptibility testing (on amoxicillin, tetracycline, metronidazole, ciprofloxacin, levofloxacin and clarithromycin) was conducted using disk diffusion and E-test methods. Subsequently, genomic DNA from these isolates was sequenced to detect mutations associated with antimicrobial resistance.RESULTS: Sixty-five percent of the isolates were found to be resistant to at least one of the listed antibiotics according to E-test. Three isolates were found to be resistant to ≥3 of the above-mentioned antibiotics. Notably, 25% of the isolates were found to be resistant to both metronidazole and clarithromycin, two antibiotics that are normally prescribed as part of first-line regimens in the treatment ofH pyloriinfections in Canada and most of the world. Among the resistant strains, the sequences of 23S ribosomal RNA andgyrA, which are linked to clarithromycin and ciprofloxacin/levofloxacin resistance, respectively, revealed the presence of known point mutations associated with antimicrobial resistance.CONCLUSIONS: In general, resistance to metronidazole, ciprofloxacin/levofloxacin and clarithromycin has increased since the studies in the early 2000s. These results suggest that surveillance programs ofH pyloriantibiotic resistance may need to be revisited or improved to prevent antimicrobial therapy failure.

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DRUG RESISTANCE IN HELICOBACTER PYLORI

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032016000400002 ◽

2016 ◽

Vol 53 (4) ◽

pp. 215-223 ◽

Cited By ~ 19

Author(s):

Júlia Silveira VIANNA ◽

Ivy Bastos RAMIS ◽

Daniela Fernandes RAMOS ◽

Andrea VON GROLL ◽

Pedro Eduardo Almeida da SILVA

Keyword(s):

Helicobacter Pylori ◽

Digestive System ◽

Point Mutations ◽

Resistance Mechanisms ◽

High Rate ◽

Current Therapy ◽

Genetic Characteristics ◽

Inappropriate Use ◽

Worldwide Distribution ◽

H Pylori

ABSTRACT Background Helicobacter pylori has a worldwide distribution and is associated with the pathogenesis of various diseases of the digestive system. Treatment to eradicate this microorganism involves the use of a combination of antimicrobials, such as amoxicillin, metronidazole, clarithromycin, and levofloxacin, combined with proton pump inhibitors. Although the current therapy is effective, a high rate of treatment failure has been observed, mainly because of the acquisition of point mutations, one of the major resistance mechanisms developed by H. pylori. This phenomenon is related to frequent and/or inappropriate use of antibiotics. Conclusion This review reported an overview of the resistance to the main drugs used in the treatment of H. pylori, confirming the hypothesis that antibacterial resistance is a highly local phenomenon and genetic characteristics of a given population can influence which therapy is the most appropriate.

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A Randomized Controlled Trial Shows that both 14-Day Hybrid and Bismuth Quadruple Therapies Cure Most Patients with Helicobacter pylori Infection in Populations with Moderate Antibiotic Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00140-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 9

Author(s):

Feng-Woei Tsay ◽

Deng-Chyang Wu ◽

Hsien-Chung Yu ◽

Sung-Shuo Kao ◽

Kung-Hung Lin ◽

...

Keyword(s):

Helicobacter Pylori ◽

Antibiotic Resistance ◽

Eradication Rate ◽

Therapy Group ◽

Controlled Trial ◽

Hybrid Therapy ◽

Content Type ◽

Quadruple Therapy ◽

H Pylori ◽

To Receive

ABSTRACT Hybrid therapy is a novel two-step treatment achieving a high eradication rate for Helicobacter pylori infection. Currently, whether this new therapy achieves a higher eradication rate than bismuth quadruple therapy remains an unanswered question. The aim of this prospective, randomized comparative study was to investigate the efficacies of 14-day hybrid therapy and bismuth quadruple therapy in the treatment of H. pylori infection. From July 2013 to June 2015, eligible H. pylori-infected subjects were randomly assigned to receive either 14-day bismuth quadruple therapy (pantoprazole, bismuth subcitrate, tetracycline, and metronidazole for 14 days) or 14-day hybrid therapy (a 7-day dual therapy with pantoprazole plus amoxicillin, followed by a 7-day quadruple therapy with pantoprazole plus amoxicillin, clarithromycin, and metronidazole). H. pylori status was examined 6 weeks after the end of treatment. Three hundred thirty H. pylori-infected participants were randomized to receive 14-day bismuth quadruple therapy (n = 164) or 14-day hybrid therapy (n = 166). The eradication rates by intention-to-treat analysis were similar: 93.9% versus 92.8%, respectively (95% confidence interval [CI], −4.3% to 5.4%; P = 0.68). Per-protocol analysis yielded similar results (96.7% versus 94.9%, respectively; P = 0.44). However, bismuth quadruple therapy had a higher frequency of adverse events than hybrid therapy (55.5% versus 15.7%, respectively; 95% CI, 30.4% to 49.2%; P < 0.001). The two treatments exhibited comparable drug adherence (93.9% versus 97%, respectively). The resistance rates of antibiotics were: clarithromycin, 16.7% of patients; amoxicillin, 1.3%; metronidazole, 25%; and tetracycline, 0%. In the bismuth quadruple therapy group, the eradication rate of metronidazole-resistant strains was lower than that of metronidazole-susceptible strains (70.0% versus 96.4%, respectively; P = 0.04). In the hybrid therapy group, no significant impact of clarithromycin or metronidazole resistance on eradication rates was identified. Both 14-day hybrid and bismuth quadruple therapies cure most patients with H. pylori infection in populations with moderate antibiotic resistance. However, the 14-day hybrid therapy has fewer adverse effects than the bismuth quadruple therapy. (This study has been registered at ClinicalTrials.gov under identifier NCT02541864.)

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Antibiotic Resistance Mechanisms ofHelicobacter pylori

Canadian Journal of Gastroenterology ◽

10.1155/1999/838072 ◽

1999 ◽

Vol 13 (3) ◽

pp. 243-249 ◽

Cited By ~ 11

Author(s):

Paul S Hoffman

Keyword(s):

Antibiotic Resistance ◽

Ribosomal Rna ◽

Resistance Mechanisms ◽

Reductive Activation ◽

Ulcer Disease ◽

Drug Products ◽

Clarithromycin Resistance ◽

H Pylori ◽

Antimicrobial Intervention ◽

23S Ribosomal Rna

Infection withHelicobacter pyloriis most frequently associated with gastritis and peptic ulcer disease. Antimicrobial intervention, together with proton pump inhibitors, has become the standard therapy for treating this disease. Resistance to clarithromycin and metronidazole, two of the most commonly used antimicrobials for treatment ofH pyloriinfections, is often associated with treatment failures and relapse of infection. Clarithromycin resistance arises through mutations leading to base changes in 23S ribosomal RNA subunits, while resistance to metronidazole is due to mutations in therdxAgene, which encodes a novel nitroreductase that is responsible for reductive activation of the drug. Products of metronidazole activation are mutagenic and can be demonstrated to increase both the mutation frequency and the frequency at which antibiotic resistance arises inH pylori.

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Analysis of the primary and post-treatment antibiotic resistance of Helico-bacter pylori in Nanjing area

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200722162613 ◽

2020 ◽

Vol 21 ◽

Author(s):

Zong-Dan Jiang ◽

Bang-Shun He ◽

Zhen-Yu Zhang ◽

Shu-Kui Wang ◽

Dan Ran ◽

...

Keyword(s):

Antibiotic Resistance ◽

Post Treatment ◽

Current Status ◽

Antibiotics Resistance ◽

Dilution Method ◽

Agar Dilution Method ◽

Rapid Urease Test ◽

Urease Test ◽

H Pylori ◽

Resistance Rates

Background: Resistance of Helicobacter pylori（H. pylori） to antibiotics is increasing worldwide. In order to understand the current situation of antibiotic resistance in Nanjing and provide a reasonable basis for clinical selection of antibiotics to cure H. Pylori. Objective: To investigate the current status of H. Pylori antibiotics resistance in Nanjing area, and analyze the primary and post-treatment antibiotic resistance of H. pylori in this area. Methods: During the period from July 2017 to December 2019, 1533 gastric mucosal specimens from patients with positive H. pylori confirmed by breath test or rapid urease test were collected for isolation and identify H. pylori. The agar dilution method was used for antibiotic resistance test. Results: The result showed that the resistance rates of H. pylori to amoxicillin, clarithromycin, levofloxacin, furazolidone, tetracycline and metronidazole were 2.74%, 47.03%, 33.59%, 0.91%, 0.52% and 80.76%, respectively in the period of July 2017 to December 2019. The resistance rates of H. pylori (primary Vs post-treatment) to amoxicillin, clarithromycin, levofloxacin, furazolidone, tetracycline and metronidazole were 1.83% Vs 6.08%, 38.62% Vs 77.81%, 27.41% Vs 56.23%, 0.58% Vs 2.13%, 0.33% Vs 1.22%, 78.57% Vs 88.75%, respectively. Conclusions: Antibiotic resistance of H. pylori remained a problem for the effective eradication of this pathogen and its associated diseases in Nanjing area. For post-treatment eradication patients, clinicians should took into account regional antibiotic resistance rate, personal antibiotic exposure history, economic benefit ratio, adverse antibiotic reactions, antibiotic availability and other aspects．

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Application of Visual Gene Clip-Based Tailored Therapy for the Eradication of Helicobacter pylori

BioMed Research International ◽

10.1155/2021/6150628 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Lili Yang ◽

Ao Zou ◽

Huihua Wu ◽

Hai Guo ◽

Fangting Zhang ◽

...

Keyword(s):

Helicobacter Pylori ◽

Antibiotic Resistance ◽

Confidence Interval ◽

Acid Secretion ◽

Antimicrobial Agents ◽

Point Mutations ◽

Eradication Therapy ◽

23S Rrna ◽

Tailored Therapy ◽

H Pylori

Background. Helicobacter pylori eradication with therapies employing a proton pump inhibitor (PPI) and antimicrobial agents is mainly achieved via bacterial susceptibility to antimicrobial agents and the magnitude of acid secretion inhibition. However, annual eradication rates have greatly declined in Mainland China, and therefore, tailored H. pylori eradication regimens that inhibit acid secretion and employ optimal antimicrobial agents determined based on gene clip testing may improve eradication rates. This study was aimed at evaluating the efficacy of tailored H. pylori eradication therapy guided by visual gene clip testing for antibiotic resistance and PPI metabolism genotypes. Methods. This prospective study included 244 patients (141 men and 103 women aged 20–79 years) receiving initial treatment for H. pylori infection. Visual gene clip testing using gastric mucosal specimens was performed to detect antibiotic resistance to clarithromycin conferred by the A2142G and A2143G point mutations of the H. pylori 23S rRNA gene and to levofloxacin conferred by the Asn87 and Asp91 point mutations of the H. pylori gyrA gene. Patients received a 14-day bismuth quadruple therapy regimen guided by testing for antibiotic resistance and CYP2C19 polymorphisms, and primary H. pylori eradication was assessed at least 4 weeks after therapy. Results. H. pylori strains were successfully isolated from the gastric mucosa tissues of 244 patients. Antibiotic resistant isolates were identified in 63 patients, with clarithromycin resistance observed in 50 patients, levofloxacin resistance in 7 patients, and dual resistance in 6 patients. The PPI metabolic genotype of CYP2C19 was detected in 242 of 244 cases, and 97 cases were categorized as extensive metabolizers, 141 as intermediate metabolizers, and 4 as poor metabolizers. Among the 242 patients who received tailored therapy, the H. pylori eradication rate was 90.9% (95% confidence interval 87.3%~94.6%) in the intention-to-treat analysis and 96.9% (95% confidence interval 94.7%~99.2%) in the per protocol analysis. Conclusions. Tailored therapy for H. pylori infection guided by determination of antibiotic resistance and CYP2C19 polymorphism using visual gene chip technology may provide high clinical effectiveness as initial H. pylori eradication therapy.

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