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Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection.

ABSTRACT: Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against Helicobacter pylori. In this scenario, repurposing drugs could be a valuable strategy to fast-track novel antimicrobial agents. In the present study, we analyzed the inhibitory capability of 1,4-dihydropyridine (DHP) antihypertensive drugs on the essential function of the H. pylori response regulator HsrA and investigated both the in vitro antimicrobial activities and the in vivo efficacy of DHP treatments against H. pylori. Six different commercially available and highly prescribed DHP drugs-namely, Nifedipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine, and Lercanidipine-noticeably inhibited the DNA binding activity of HsrA and exhibited potent bactericidal activities against both metronidazole- and clarithromycin-resistant strains of H. pylori, with minimal inhibitory concentration (MIC) values in the range of 4 to 32 mg/L. The dynamics of the decline in the bacterial counts at 2 × MIC appeared to be correlated with the lipophilicity of the drugs, suggesting different translocation efficiencies of DHPs across the bacterial membrane. Oral treatments with 100 mg/kg/day of marketed formulations of Nimodipine or Nitrendipine in combination with omeprazole significantly reduced the H. pylori gastric colonization in mice. The results presented here support a novel therapeutic solution for treatment of antibiotic-resistant H. pylori infections.

SUBMITTER: Gonzalez A

PROVIDER: S-EPMC6969910 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection.

González Andrés A Casado Javier J Chueca Eduardo E Salillas Sandra S Velázquez-Campoy Adrián A Espinosa Angarica Vladimir V Bénejat Lucie L Guignard Jérome J Giese Alban A Sancho Javier J Lehours Philippe P Lanas Ángel Á

Pharmaceutics 20191215 12

Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against Helicobacter pylori. In this scenario, repurposing drugs could be a valuable strategy to fast-track novel antimicrobial agents. In the present study, we analyzed the inhibitory capability of 1,4-dihydropyridine (DHP) antihypertensive drugs on the essential function of the H. pylori response regulator HsrA and investigated both the in vitro antimicrobial activities and the ...[more]

PMID: 31847484

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Project description:Background:Empirical therapy of Helicobacter pylori frequently results in treatment failure due to unrecognized antimicrobial resistance. The aim of this study was to investigate the effectiveness of susceptibility-guided therapy for rescue treatment of H. pylori infection in China. Methods:This was a prospective study of consecutive 200 patients infected with H. pylori with one or more treatment failures. The therapy chosen was susceptibility based using the most effective, best-tolerated regimens first and a locally proven, reliably effective regimen for multidrug-resistant infections. All patients received 14-day triple therapy, i.e. esomeprazole 20?mg and amoxicillin 1?g twice a day plus clarithromycin 500?mg twice a day, metronidazole 400?mg twice a day, or levofloxacin 500?mg daily, or, for multidrug-resistant infections, amoxicillin-containing bismuth quadruple therapy with esomeprazole 20?mg twice a day, bismuth 220?mg twice a day, amoxicillin 1?g three times a day, and metronidazole 400?mg four times a day. Antibiotic resistance was determined by agar dilution. Results:The eradication rate of susceptibility-guided therapy overall was 94.5% (189/200, 95% confidence interval: 90.4-97.2%). Around 28% (56/200) of patients carried strains susceptible to one of the tested antibiotics and were prescribed the triple therapy. A total of 144 multidrug-resistant patients received bismuth quadruple therapy. The eradication rates were all greater than 90%, i.e. 91.7% (11/12), 92.3% (12/13), and 93.5% (29/31) in those who received clarithromycin, metronidazole, and levofloxacin-containing triple therapy and 95.1% (137/144) for the bismuth quadruple therapy. There were no differences in eradication rates between the subgroups. Conclusions:Although susceptibility-guided therapy proved high efficacious despite the high proportion of multidrug-resistant strains, the strategy suggested the best approach for this population would be empirical amoxicillin-containing bismuth quadruple therapy. ClinicalTrials.gov identifier: NCT03413020.

Project description:In this review, we discuss the problem of antibiotic resistance, heteroresistance, the utility of cultures and antibiotic susceptibility tests in Helicobacter pylori (Hp) eradication, as well as the updated treatment strategies for this infection. The prevalence of antibiotic resistance is increasing all over the world, especially for metronidazole and clarithromycin, because of their heavy use in some geographical areas. Heteroresistance (simultaneous presence of both susceptible and resistant strains in different sites of a single stomach) is another important issue, as an isolate could be mistakenly considered susceptible if a single biopsy is used for antimicrobial tests. We also examined literature data regarding eradication success rates of culture-guided and empiric therapies. The empiric therapy and the one based on susceptibility testing, in Hp eradication, may depend on several factors such as concomitant diseases, the number of previous antibiotic treatments, differences in bacterial virulence in individuals with positive or negative cultures, together with local antibiotic resistance patterns in real-world settings. Updated treatment strategies in Hp infection presented in the guidelines of the Toronto Consensus Group (2016) are reported. These suggest to prolong eradication therapy up to 14 days, replacing the old triple therapy with a quadruple therapy based on proton pump inhibitor (PPI), bismuth, metronidazole, and tetracycline for most of the patients, or as an alternative quadruple therapy without bismuth, based on the use of PPI, amoxicillin, metronidazole, and clarithromycin. The new drug vonoprazan, a first-in-class potassium-competitive acid blocker recently approved in Japan, is also considered to be a promising solution for Hp eradication, even for clarithromycin-resistant strains. Furthermore, there is growing interest in finding new therapeutic strategies, such as the development of vaccines or the use of natural resources, including probiotics, plants, or nutraceuticals.

Project description:IntroductionHelicobacter pylori (HP) infection is associated with many gastrointestinal disorders, including gastric cancer, and consensus guidelines recommend eradication after detection. There is a theoretical, yet uninvestigated, concern that HP treatment could increase the risk of Clostridium difficile infection (CDI). Using the data from a large cohort of patients with HP, we investigated whether HP eradication is associated with CDI.MethodsA retrospective cohort study within the Veterans Health Administration on 38,535 patients (median age 61.8 years; 91.8% men) with detected HP between January 1, 1994, and December 31, 2018 was conducted. Primary outcome was a positive laboratory test for CDI within 3 months of HP detection. Multivariable logistic regression evaluated the following: patient demographics, previous CDI, recent hospitalization, and whether the patient received HP eradication therapy (by antibiotic and regimen, and including proton pump therapy). Secondary analysis of those treated evaluated whether eradication of HP was associated with CDI.ResultsAmong 38,535 patients, 28,818 (74.8%) were treated for HP and 284 (0.74%) developed CDI. In multivariable analysis, prominent factors included hospital discharge within 12 weeks (odds ratio [OR] 2.15; 95% confidence interval [CI]: 1.22-3.77) and 4 weeks (OR 3.46; 95% CI: 2.18-5.48), P < 0.001, and previous CDI (OR 12.5; 95% CI: 9.21-17.0, P < 0.001). Treatment of HP was not associated with future CDI. In secondary analysis of those treated, confirmation of eradication was not associated with future CDI (OR 1.49; 95% CI: 0.67-3.29).DiscussionIn a large study of US patients with HP, we demonstrate that neither treatment nor eradication of HP is associated with CDI. Previous C. difficile infection and recent hospital discharge, established risk factors for CDI, are strongly associated. These findings suggest that treatment should be continued to be prescribed when HP is detected (http://links.lww.com/AJG/B507).

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Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection.

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Repurposing Dihydropyridines for Treatment of <i>Helicobacter pylori</i> Infection.

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