Antibiotic Resistance and Therapy Outcome in H. pylori Eradication Failure Patients.
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.
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).
Project description:Helicobacter pylori (H. pylori) eradication regimen has not been standardized for patients with penicillin allergy. We investigated the association between the efficacy of a 10-day sitafloxacin, metronidazole, and esomeprazole triple regimen and antibiotic resistance, in patients with penicillin allergy.Penicillin-allergic patients infected with H. pylori were enrolled between March 2014 and November 2015. The minimum inhibitory concentrations (MICs) of sitafloxacin and metronidazole, and the gyrA mutation status of the H. pylori strains were determined before treatment. The cut-off points for antimicrobial resistance were defined as 8.0?µg/ml for metronidazole and 0.12?µg/ml for sitafloxacin. The patients received the triple therapy (20?mg esomeprazole, bid; 250?mg metronidazole, bid; and 100?mg sitafloxacin, bid) for 10 days. Successful eradication was evaluated using the [13C] urea breath test or the H. pylori stool antigen test.Fifty-seven patients were analyzed, and the overall eradication rate was 89.5%. The eradication rate in cases of double antibiotic resistance to metronidazole and sitafloxacin was 40.0%, whereas for other combinations of resistance, this was above 90.0%. Finally, the eradication rate of gyrA mutation-negative strains was 96.2%, whereas for gyrA mutation-positive strains, it was 83.9%. Adverse events were reported in 31.6% of cases, all of which were mild and tolerable.Ten days of sitafloxacin and metronidazole triple therapy was safe and highly effective in eradicating H. pylori in penicillin-allergic patients. Double resistance to metronidazole and sitafloxacin was an important predicting factor for eradication failure. However, 10 days of the sitafloxacin and metronidazole triple therapy was highly effective if the strain was susceptible to either sitafloxacin or metronidazole.
Project description:Sequential therapy with a proton pump inhibitor (PPI) and amoxicillin followed by a PPI, clarithromycin, and an imidazole agent reportedly have a better rate of curing Helicobacter pylori infection than PPI, amoxicillin, and clarithromycin triple therapy. The concomitant administration of these 4 drugs (concomitant therapy) is also an effective treatment strategy. We compared the efficacies of sequential and concomitant therapy and analyzed the effects of antibiotic resistance in patients with H pylori infection.In a randomized trial of 232 H pylori-infected patients from 3 hospitals in Kaohsiung, Taiwan, patients were given 10 days of sequential (n = 115) or concomitant (n = 117) therapy. H pylori status was confirmed by endoscopy or urea breath test.Intention-to-treat analysis demonstrated similar eradication rates for sequential (92.3%; 95% confidence interval [CI], 87.5%-97.1%) and concomitant therapy (93.0%; 95% CI, 88.3%-97.7%)(P = .83). Per-protocol eradication results were similar for sequential (93.1%; 95% CI, 90.7%-95.5%) and concomitant therapy (93.0%; 95% CI, 88.3%-97.7%) (P = .99). Univariate analysis showed that compliance and resistance to clarithromycin were independent determinants of eradication. Dual resistance did not influence the level of eradication in the concomitant group, but significantly affected that of the sequential therapy group. Clarithromycin resistance was less frequent than expected.Sequential or concomitant therapy with a PPI, amoxicillin, clarithromycin, and an imidazole agent are equally effective and safe for eradication of H pylori infection. Resistance to clarithromycin, compliance, and adverse events reduced the level of eradication. Concomitant therapy may be more suitable for patients with dual resistance to antibiotics.
Project description:BACKGROUND/AIMS:The eradication failure rate of standard triple therapy (proton pump inhibitor, clarithromycin, and amoxicillin) for Helicobacter pylori infection has increased owing to antibiotic resistance in Korea. We assessed whether Saccharomyces boulardii probiotic or broccoli sprout extract sulforaphane supplementation could increase the H. pylori eradication rate and/or reduce antibiotic-associated adverse events. METHODS:A total of 217 patients with H. pylori-positive chronic gastritis or peptic ulcer disease were recruited. Clarithromycin resistance was assessed in all patients by testing for A2142G and A2143G point mutations in H. pylori 23S rRNA using a dual-priming polymerase chain reaction (PCR) oligonucleotide. Thirty-four patients (17.3%) were clarithromycin-resistant and were excluded from the study. Finally, 183 patients with infections not resistant to clarithromycin were randomly assigned to triple therapy only (group A, n = 61), triple therapy plus probiotics (group B, n = 61), or triple therapy plus sulforaphane (group C, n = 61) groups. CYP2C19 polymorphisms were examined at position G681A of exon 5 and G636A of exon 4 by PCR with restriction fragment length polymorphism (PCR-RFLP) analysis. H. pylori eradication was assessed by 13C-urea breath test 4 weeks after treatment completion. RESULTS:The eradication rates were similar among the groups both in the intention- to-treat (A = 85.2%, B = 89.6%, and C = 81.6%) and per-protocol (A = 89.2%, B = 86.8%, and C = 96.3%) analyses. The frequencies of overall adverse events in the groups also did not differ (A vs. B: p = 0.574; A vs. C: p = 1.000). CONCLUSION:Probiotic or sulforaphane with triple therapy for H. pylori infection neither increased the eradication rate nor reduced the occurrence of adverse events.
Project description:BACKGROUND:Smectite can serve as a drug delivery system and gentamicin-intercalated smectite hybrids are expected to supersede the standard therapy for Helicobacter pylori eradication. The aim of this study was to confirm whether the minimum inhibitory concentration (MIC) of aminoglycosides applied as smectite hybrids remained low against recently isolated H. pylori strains. MATERIALS AND METHODS:A total of 140 strains were collected for a minimum period of 3 years. Antimicrobial susceptibility tests were performed, and the MICs of eight antibiotics (amoxicillin, clarithromycin, metronidazole, tetracycline, levofloxacin, gentamicin, netilmicin, and tobramycin) were determined by using the Epsilometer test and following the European Committee on Antimicrobial Susceptibility Testing recommendations. RESULTS:The resistance rate of clarithromycin was high, up to 30.7%, although it is a major antimicrobial agent used in standard therapy. The MIC₅₀ and MIC₉₀ of gentamicin (0.25 mg/L and 0.75 mg/L) and netilmicin (0.19 mg/L and 0.75 mg/L) were lower than other alternative therapies for H. pylori eradication. In clarithromycin-resistant strains, the MIC₅₀ was 0.25 mg/L and the MIC₉₀ was 1 mg/L for gentamicin; for netilmicin, the values were 0.25 mg/L and 0.75 mg/L, respectively. CONCLUSION:Through the use of gentamicin and netilmicin, which have low MICs for H. pylori, aminoglycoside-intercalated smectite hybrids are expected to emerge as a new standard therapy for H. pylori eradication.
Project description: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.
Project description:In the face of rising prevalence of antibiotic resistance, susceptibility testing to provide personalized treatment is recommended prior to eradication therapy for Helicobacter pylori (H. pylori). Yet, population specific treatment according to the local prevalence of antibiotic resistance may be an alternative if susceptibility testing is not available. In this article, we reviewed the global prevalence of primary antibiotic resistance and the efficacies of commonly used regimens in antibiotic susceptible and resistance strains. We then constructed a model to predict the efficacies of these regimens and proposed an algorithm to choose the optimal first-line and rescue therapies according to the prevalence of antibiotic resistance. Clarithromycin-based therapy (triple, sequential, concomitant, and hybrid therapies) for 14 days remains the treatment of choice in regions with low clarithromycin resistance (?15%) and bismuth quadruple therapy may be an alternative therapy. In regions with high clarithromycin resistance (>?15%), bismuth quadruple therapy is the treatment of choice and non-bismuth quadruple therapy may be an alternative. Either levofloxacin-based therapy or bismuth quadruple therapy may be used as second-line rescue therapy for patients fail after clarithromycin-based therapies, whereas levofloxacin-based therapy may be used for patients fail after bismuth quadruple therapy. Susceptibility testing or genotypic resistance should be determined after two or more eradication failures. However, empirical therapy according to prior medication history to avoid the empirical reuse of levofloxacin and clarithromycin may be an acceptable alternative after consideration of cost, patient preference, and accessibility. Rifabutin-based therapy for 14 days may serve as the fourth-line therapy. New antibiotics specific for H. pylori are highly anticipated.
Project description:Antimicrobial resistance is one of the major factors determining the efficacy of Helicobacter pylori eradication therapy. This study aimed to estimate the recent prevalence of multidrug resistance of H. pylori and its impact on eradication in Korea. A total of 174 patients were prospectively enrolled at Chung-Ang University Hospital from 2017 to 2019. H. pylori strains were isolated from the gastric body and antrum. The minimum inhibitory concentrations of antibiotics were determined by the serial twofold agar dilution method. Eradication results were reviewed and analyzed in connection with antibiotic resistance. The prevalence of H. pylori infection was 51.7% (90/174). The culture success rate was 77.8% (70/90). The resistance rates for clarithromycin, metronidazole, amoxicillin, tetracycline, levofloxacin, and moxifloxacin were 28.6% (20/70), 27.1% (19/70), 20.0% (14/70), 18.6% (13/70), 42.9% (30/70), and 42.9% (30/70), respectively. The multidrug resistance (resistance to two or more classes of antimicrobials) rate was 42.9% (30/70). Dual resistance to clarithromycin and metronidazole was confirmed in 8.6% (6/70). Eradication with a first-line treatment was successful in 75% (36/48), and those who received second-line treatment all achieved successful eradication. The rate of multidrug resistance is increasing, and standard triple therapy (STT) is no longer an acceptable first-line option for H. pylori eradication in Korea.
Project description:The gram-negative bacterium Helicobacter pylori (H. pylori) causes chronic gastritis, gastric and duodenal ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma. Treatment is recommended in all symptomatic patients. The current treatment options for H. pylori infection are outlined in this review in light of the recent challenges in eradication success, largely due to the rapid emergence of antibiotic resistant strains of H. pylori. Antibiotic resistance is a constantly evolving process and numerous studies have shown that the prevalence of H. pylori antibiotic resistance varies significantly from country to country, and even between regions within the same country. In addition, recent data has shown that previous antibiotic use is associated with harbouring antibiotic resistant H. pylori. Local surveillance of antibiotic resistance is warranted to guide clinicians in their choice of therapy. Antimicrobial resistance is assessed by H. pylori culture and antimicrobial susceptibility testing. Recently developed molecular tests offer an attractive alternative to culture and allow for the rapid molecular genetic identification of H. pylori and resistance-associated mutations directly from biopsy samples or bacterial culture material. Accumulating evidence indicates that surveillance of antimicrobial resistance by susceptibility testing is feasible and necessary to inform clinicians in their choice of therapy for management of H. pylori infection.
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.