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Effect of Antibiotic Susceptibility and CYP3A4/5 and CYP2C19 Genotype on the Outcome of Vonoprazan-Containing Helicobacter pylori Eradication Therapy.

ABSTRACT: BACKGROUND:Helicobacter pylori eradication containing the potassium-competitive acid blocker, vonoprazan, achieves a higher eradication rate than therapy with proton pump inhibitors (PPIs). Because vonoprazan is mainly metabolized by CYP3A4/5, CYP genotype may affect the eradication rate. We investigated the influence of antibiotic susceptibility and CYP3A4/5 and CYP2C19 genotypes on the eradication rates. METHODS:A total of 307 Japanese who were genotyped for CYP3A4 *1/*22, CYP3A5 *1/*3 and CYP2C19 *1/*2/*3/*17, and investigated for susceptibility to antimicrobial agents, received vonoprazan-containing regimens: (1) With amoxicillin and clarithromycin as the first-line treatment; (2) with amoxicillin and metronidazole as the second-line treatment; or (3) with amoxicillin and sitafloxacin as the third-line treatment. RESULTS:The eradication rate was 84.5% (95% confidence interval [CI]: 78.9-89.1%) using first-line, 92.6% (95% CI: 82.1-97.9%) using second-line and 87.5% (95% CI: 73.1-95.8%) using third-line treatment. Infection with clarithromycin-resistant strains was a predictive factor for failed eradication (odds ratio: 5.788, 95% CI: 1.916-17.485, p = 0.002) in multivariate analysis. No significant differences were observed in the eradication rate of regimens among CYP3A4, CYP3A5 and CYP2C19 genotypes. CONCLUSIONS:Genotyping for CYP3A4 *1/*22, CYP3A5 *1/*3 and CYP2C19 *1/*2/*3/*17 before vonoprazan-containing eradication treatment may not be useful for predicting clinical outcomes.

SUBMITTER: Sugimoto M

PROVIDER: S-EPMC7599771 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Effect of Antibiotic Susceptibility and <i>CYP3A4/5</i> and <i>CYP2C19</i> Genotype on the Outcome of Vonoprazan-Containing <i>Helicobacter pylori</i> Eradication Therapy.

Sugimoto Mitsushige M Hira Daiki D Murata Masaki M Kawai Takashi T Terada Tomohiro T

Antibiotics (Basel, Switzerland) 20200926 10

<h4>Background</h4><i>Helicobacter pylori</i> eradication containing the potassium-competitive acid blocker, vonoprazan, achieves a higher eradication rate than therapy with proton pump inhibitors (PPIs). Because vonoprazan is mainly metabolized by CYP3A4/5, CYP genotype may affect the eradication rate. We investigated the influence of antibiotic susceptibility and <i>CYP3A4/5</i> and <i>CYP2C19</i> genotypes on the eradication rates.<h4>Methods</h4>A total of 307 Japanese who were genotyped for ...[more]

PMID: 32993151

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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:Antibiotics resistance in Helicobacter pylori (H. pylori) is the major factor for eradication failure. Molecular tests including fluorescence in situ hybridization, PCR-restriction fragment length polymorphism, and dual priming oligonucleotide-PCR (DPO-PCR) play critical roles in the detection of antibiotic susceptibility; however, limited knowledge is known about application of multiple genetic analysis system (MGAS) in the area of H. pylori identification and antibiotics resistance detection.The aim of this study is to determine the antibiotics resistance using different molecular tests and evaluate the treatment outcomes of E-test-based genotypic resistance.A total of 297 patients with dyspepsia complaint were recruited for gastroscopies. Ninety patients with H. pylori culture positive were randomly divided into 2 groups (test group and control group). E-test, general PCR, and MGAS assay were performed in test group. Patients in control group were treated with empirical therapy (rabeprazole + bismuth potassium citrate + amoxicillin [AMX] + clarithromycin [CLR]), whereas patients in test group received quadruple therapy based on E-test results twice daily for 14 consecutive days. The eradication effect of H. pylori was confirmed by C-urea breath test after at least 4 weeks when treatment was finished.Rapid urease test showed 46.5% (128/297) patients with H. pylori infection, whereas 30.3% (90/297) patients were H. pylori culture positive. E-test showed that H. pylori primary resistance rate to CLR, AMX, metronidazole, tetracycline, and levofloxacin (LVX) was 40.0% (18/45), 4.4% (2/45), 53.3% (24/45), 0% (0/45), and 55.6% (25/45), respectively. In addition, there are many multidrug resistant (MDR) phenotypes, and the MDR strains have higher minimum inhibitory concentration than their single-drug resistant counterparts. Considering E-test as the reference test, the sensitivities of general PCR and MGAS in detecting CLR resistance were 83.3% (15/18) and 94.4% (17/18), whereas in detecting LVX resistance were 100% (25/25) and 83.3% (15/18), respectively. Finally, the eradication rate in test group was significantly higher than that in control group as demonstrated by intention-to-treat analysis and per-protocol analysis.MGAS is a promising assay for H. pylori identification and antibiotic susceptibility testing. Phenotypic resistance-guided quadruple therapy showed a high efficacy in treating patients with H. pylori infection.

Project description:BACKGROUND The effects of PPI are variable owing to the CYP2C19 polymorphisms. However, whether the polymorphisms could affect the Hp eradication efficacy of triple therapy is still not clear. The present study aimed to assess the effects of CYP2C19 gene polymorphisms on proton pump inhibitor (PPI), amoxicillin, and levofloxacin triple therapy for Helicobacter pylori (Hp) eradication. MATERIAL AND METHODS We randomly assigned 160 Hp-positive patients with chronic gastritis to 2 groups to receive either 20 mg bid omeprazole (OAL group, n=80) or 10 mg bid rabeprazole (RAL group, n=80), combined with 1000 mg bid amoxicillin and 500 mg qd levofloxacin. The 2 groups were treated for 10 days. The CYP2C19 genotypes included wild-type, M1 mutant gene (*2, the mutation of exon 5), and M2 mutant gene (*3, the mutation of exon 4) identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFIP). According to CYP2C19 genotype combinations, the patients were divided into extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) subgroups. The eradication efficacy of Hp was evaluated by 14C-UBT at 28 days after treatment. RESULTS The trial was completed by 155 patients. Hp eradication rates in OAL and RAL groups were 78.2% and 88.3%, respectively, on per-protocol (PP) analysis, indicating no significant difference (P>0.05). Regarding CYP2C19 genotypes, eradication rates of 60.7%, 84.2%, and 100% were obtained for EM, IM, and PM subgroups, respectively, of the OAL group. EM group eradication rates were significantly lower than IM and PM group values (P<0.05). In the RAL group, no such difference was observed (P>0.05). Hp eradication rates were significantly lower in the EM subgroup of the OAL group compared with that of the RAL group. CONCLUSIONS Hp eradication rates were higher in the RAL group than in OAL-treated patients. Interestingly, omeprazole-based therapy was significantly affected by the CYP2C19 genotype, unlike the rabeprazole-based therapy.

Project description:Summary of Trial Design.Lengthy exposure to quinolone-containing triple therapy in Helicobacter pylori eradication leads to the development of drug resistance. Sequential therapy with a quinolone and metronidazole -containing regimen appears to be an effective treatment option. This randomized controlled trial aimed to compare the efficacy of 5-plus 5 days' levofloxacin and metronidazole-containing sequential therapy (EALM) with that of 10-day levofloxacin-containing triple therapy (EAL) in second-line H pylori eradication treatment.One hundred and sixty-four patients who had failed the H pylori eradication attempts using the standard triple therapy (proton pump inhibitor bid, clarithromycin 500 mg bid, amoxicillin 1 g bid × 7 days) were randomly assigned to either an EALM therapy group (n = 82; esomeprazole 40 mg bid and amoxicillin 1 g bid for 5 days, followed by esomeprazole 40 mg bid, levofloxacin 500 mg qd, and metronidazole 500 mg tid, for 5 days) or a 10-day EAL therapy group (n = 82; levofloxacin 500 mg qd, amoxicillin 1 g bid, and esomeprazole 40 mg bid). One patient was lost to follow-up in each group. Follow-up for H pylori status was performed 4 to 8 weeks later.Eradication rates for the EALM and EAL groups were 90.2% (74/82, 95% confidence interval [CI] = 83.7%-96.8%) and 80.5% (66/82, 95% CI = 71.7%-89.2%, P = 0.077) in the intention-to-treat analysis; and 91.4% (74/81, 95% CI = 85.1%-97.6%) and 81.5% (66/81, 95% CI = 72.8%-90.1%, P = 0.067) in the per-protocol analysis. The adverse events for the EALM and EAL groups were 23.5% versus 11.1%, P = 0.038 but were all very mild and were well tolerated except for 1 patient with poor compliance. The compliances were 98.8% and 100%, respectively, between the 2 groups. An antibiotic resistance to levofloxacin was the clinical factor influencing the efficacy of H. pylori eradication therapy in the EAL group, and dual resistance to levofloxacin and metronidazole in the EALM group.Levofloxacin and metronidazole-containing sequential therapy achieved a >90% eradication rate as a second-line H pylori therapy. Dual antibiotic resistance to levofloxacin and metronidazole was the clinical factor influencing the efficacy of H pylori eradication therapy in the sequential therapy (ClinicalTrials.gov number: NCT02596620).

Dataset Information

Effect of Antibiotic Susceptibility and CYP3A4/5 and CYP2C19 Genotype on the Outcome of Vonoprazan-Containing Helicobacter pylori Eradication Therapy.

Publications

Effect of Antibiotic Susceptibility and <i>CYP3A4/5</i> and <i>CYP2C19</i> Genotype on the Outcome of Vonoprazan-Containing <i>Helicobacter pylori</i> Eradication Therapy.

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