Primary antibiotic resistance of Helicobacter pylori in the Asia-Pacific region between 1990 and 2022: an updated systematic review and meta-analysis.

BACKGROUND: We previously showed rising primary antibiotic resistance of Helicobacter pylori during 1990-2015 in the Asia-Pacific region. However, whether primary antibiotic resistance continues to rise is unknown. Therefore, we aimed to assess the latest prevalence of H pylori antibiotic resistance in this region. METHODS: We did an updated systematic review and meta-analysis of observational studies and randomised controlled trials published in PubMed, Embase, and Cochrane Library between Jan 1, 1990, and July 12, 2023. Studies investigating primary H pylori resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, or tetracycline in individuals naive to eradication therapy in the Asia-Pacific region (as defined by the UN geoscheme) were eligible for inclusion. There were no language restrictions. Studies that focused on specific subpopulations (eg, children) were excluded. Using a standardised extraction form, two authors independently reviewed and extracted summary data from all eligible articles. The updated prevalence of antibiotic resistance was generated by meta-analysis under a random-effects model and subgroup analyses were done by countries and periods of study. Between-study variability was assessed by use of I2. The study is registered in PROSPERO, CRD42022339956. FINDINGS: A total of 351 studies, including 175 new studies and 176 studies from our previous analysis, were included in this meta-analysis. The overall prevalence of primary antibiotic resistance of H pylori between 1990 and 2022 was 22% (95% CI 20-23; I2=96%) for clarithromycin, 52% (49-55; I2=99%) for metronidazole, 26% (24-29; I2=96%) for levofloxacin, 4% (3-5; I2=95%) for tetracycline, and 4% (3-5; I2=95%) for amoxicillin. Prevalence varied considerably between countries and across study periods. From 1990 to 2022, the prevalence of primary resistance increased for clarithromycin, metronidazole, and levofloxacin but remained stable for amoxicillin and tetracycline. The latest primary resistance prevalences were 30% (95% CI 28-33; I2=93%) for clarithromycin, 61% (55-66; I2=99%) for metronidazole, 35% (31-39; I2=95%) for levofloxacin, 4% (2-6; I2=96%) for tetracycline, and 6% (4-8; I2=96%) for amoxicillin in the Asia-Pacific region. INTERPRETATION: Treatment guidelines should be adapted in response to the rising primary resistance of key antibiotics for H pylori eradication. A global policy to control and monitor the antibiotic resistance of H pylori is urgently needed. FUNDING: Ministry of Health and Welfare of Taiwan, National Science and Technology Council of Taiwan, and National Taiwan University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Second-line levofloxacin-based quadruple therapy versus bismuth-based quadruple therapy for Helicobacter pylori eradication and long-term changes to the gut microbiota and antibiotic resistome: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Levofloxacin-based therapy or bismuth-based quadruple therapy are the recommended second-line regimens for Helicobacter pylori eradication after failure of clarithromycin-based therapy. However, resistance to levofloxacin has increased in the past decade. Furthermore, little is known about the long-term effects of H pylori eradication on the antibiotic resistome. In this study, we compared these second-line eradication therapies for efficacy, tolerability, and short-term and long-term effects on the gut microbiota, antibiotic resistome, and metabolic parameters. METHODS: We did a multicentre, open-label, parallel group, randomised controlled trial at eight hospitals in Taiwan. Adult patients (age ≥20 years) with persistent H pylori infection after first-line clarithromycin-based therapy were randomly assigned (1:1, permuted block sizes of four) to receive levofloxacin-based sequential quadruple therapy for 14 days (EAML14; esomeprazole 40 mg and amoxicillin 1 g for 7 days, followed by esomeprazole 40 mg, metronidazole 500 mg, and levofloxacin 250 mg for 7 days, all twice-daily) or bismuth-based quadruple therapy for 10 days (BQ10; esomeprazole 40 mg twice daily, bismuth tripotassium dicitrate 300 mg four times a day, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). All investigators were masked to the randomisation sequence. The primary endpoint was H pylori eradication rate measured by 13C urea breath test 6 weeks after second-line treatment according to both intention-to-treat (ITT) and per-protocol analysis. The microbiota composition and antibiotic resistome of faecal samples collected at baseline (before treatment) and at 2 weeks, 8 weeks, and 1 year after eradication therapy was profiled by shotgun metagenomic sequencing and 16S rRNA gene sequencing. The frequency of adverse effects and changes in the gut microbiota and antibiotic resistome were assessed in all participants with available data. The trial is complete and registered with ClinicalTrails.gov, NCT03148366. FINDINGS: Between Feb 25, 2015, and Dec 11, 2020, 560 patients were randomly assigned to receive EAML14 or BQ10 (n=280 per group; 261 [47%] men and 299 [53%] women). Mean age was 55·9 years (SD 12·7) in the EAML14 group and 54·9 years (12·3) in the BQ10 group. Eradication of H pylori was achieved in 246 (88%) of 280 participants in the EAML14 group and 245 (88%) of 280 in the BQ10 group according to ITT analysis (risk difference -0·4%, 95% CI -5·8 to 5·1; p=0·90). In the per-protocol analysis, 246 (90%) of 273 participants in the EAML14 group and 245 (93%) of 264 participants in the BQ10 group achieved H pylori eradication (risk difference 2·7%, 95% CI -0·2 to 7·4; p=0·27). Transient perturbation of faecal microbiota diversity at week 2 was largely restored to basal state 1 year after EAML14 or BQ10. Diversity recovery was slower with BQ10, and recovery in species abundance was partial after both therapies. On shotgun sequencing, we observed significant increases in total resistome after EAML14 (p=0·0002) and BQ10 (p=4·3 × 10-10) at week 2, which were restored to pretreatment level by week 8. The resistance rates of Escherichia coli and Klebsiella pneumonia to levofloxacin, ciprofloxacin, ampicillin (ampicillin-sulbactam for K pneumonia), and various cephalosporins were significantly increased in the EAML14 group compared with in the BQ10 group at week 2, which were restored to pretreatment levels and showed no significant differences at week 8 and 1 year. The frequency of any adverse effects was significantly higher after BQ10 therapy (211 [77%] of 273 participants) than after EAML14 therapy (134 [48%] of 277; p<0·0001). INTERPRETATION: We found no evidence of superiority between levofloxacin-based quadruple therapy and bismuth-based quadruple therapy in the second-line treatment of H pylori infection. The transient increase in the antibiotic resistome and perturbation of faecal microbiota diversity were largely restored to pretreatment state from 2 months to 1 year after eradication therapy. FUNDING: The Ministry of Science and Technology of Taiwan, the Ministry of Health and Welfare of Taiwan, National Taiwan University Hospital, Taipei Veteran General Hospital, and the Australian Federal Government through the St George and Sutherland Medical Research Foundation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Bismuth salts with versus without acid suppression for Helicobacter pylori infection: A transmission electron microscope study.

BACKGROUND: Bismuth oxychloride produced by interaction of bismuth compounds with gastric acid is believed to damage Helicobacter pylori. The effect of bismuth salts on H. pylori in the presence of strong acid suppression is unknown. This randomized trial aimed to determine effects of bismuth subcitrate on H. pylori with and without acid suppression. METHODS: H. pylori -positive participants were allocated (1:1:1) to receive (a) no treatment (control), (b) colloidal bismuth subcitrate (CBS, 125 mg/tab), or (c) CBS plus high-dose proton-pump inhibitor (PPI), esomeprazole 40 mg q.i.d. for 3 days. In the treatment groups, CBS was given: 1 dose, 1 hour before endoscopy, 1 dose, 4 hours before endoscopy, or q.i.d. 24 hours before endoscopy. The study end-points were evaluated using transmission electron microscopy to observe the morphological changes of H. pylori in antral and corpus biopsies. RESULTS: Twenty-seven H. pylori carriers were enrolled in this trial with qualitative end-points. In the no treatment group, active budding and replication of H. pylori were observed. In the CBS group, cellular swelling, vacuolization, structural degradation, and cell wall eruption of H. pylori were observed, with no apparent association with when the CBS was given. Among those receiving high-dose PPI-plus CBS or CBS only, there were no differences in number of H. pylori present or severity of bacterial damage whether CBS was given 1, 4, or 24 hours before endoscopy. CONCLUSIONS: Based on direct morphological evaluation, the toxic effect of CBS treatment on H. pylori was demonstrated independent of acid suppression with PPI.

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial.

Background: Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown. Objectives: To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy. Methods: We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855. Results: The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%-94.1%) and 91.6% (284 of 310, 95% CI 87.8%-94.3%) in the ITT analysis, respectively (difference -0.3%, 95% CI -4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001). Conclusions: Optimized 14 day sequential therapy was non-inferior to, but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance.

Treatment of Helicobacter pylori infection: Where are we now?

Gastric cancer and Helicobacter pylori infection remain a burden in many Asian countries. In the face of rising antibiotic resistance, the eradication rate of standard triple therapy is declining in many Asian countries. We reviewed the updated epidemiology of gastric cancer, prevalence of H. pylori infection, and antibiotic resistance in Asia. We also reviewed the strategies to improve the efficacy of H. pylori eradication therapies, including the use of high dose proton pump inhibitor, four drug therapies (including bismuth quadruple, concomitant, and sequential therapy), susceptibility guided therapy, extending the treatment duration to 14 days, and development of effective rescue therapy. Four drug therapies are usually more effective than triple therapy when given in the same duration, except in areas with concomitantly high metronidazole resistance and low clarithromycin resistance. The efficacies of different four drug regimens appeared to be similar. However, trials from different geographic areas showed contradictory results, indicating that the optimal therapy should be decided according to the local prevalence of antibiotic resistance. We proposed a prediction model to calculate the efficacy of different regimens according to the prevalence of antibiotic resistance. More large randomized trials which provide information on the antibiotic resistance are urgently needed to build a more accurate and reliable model. It is hoped that we will be able to decide the optimal regimens by routine surveillance of antibiotic resistance.

Development of bacterial transglycosylase inhibitors as new antibiotics: moenomycin A treatment for drug-resistant Helicobacter pylori.

The problem of multidrug-resistant Helicobacter pylori requires new antibiotics development. We have evaluated a potential antibiotics, moenomycin A, which is classified as a phosphoglycolipid antibiotics that targets transglycosylase and is previously thought to be limited in Gram-positive bacteria. Herein, we report the activity of moenomycin A against multidrug-resistant H. pylori and the isolates from patients with different gastrointestinal diseases.

Efficacy of genotypic resistance-guided sequential therapy in the third-line treatment of refractory Helicobacter pylori infection: a multicentre clinical trial.

OBJECTIVES: The efficacy of sequential therapy and the applicability of genotypic resistance to guide the selection of antibiotics in the third-line treatment of Helicobacter pylori have not been reported. We aimed to assess the efficacy of genotypic resistance-guided sequential therapy in third-line treatment. METHODS: Genotypic and phenotypic resistances were determined in patients who failed at least two eradication therapies by PCR with direct sequencing and agar dilution test, respectively. The patients were retreated with sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole plus clarithromycin, levofloxacin or tetracycline for another 7 days (all twice daily), according to genotypic resistance determined using gastric biopsy specimens. Eradication status was determined by the (13)C-urea breath test. Trial registered at clinicaltrials.gov (identifier: NCT01032655). RESULTS: The overall eradication rate was 80.7% (109/135, 95% CI 73.3%-86.5%) in the intention-to-treat analysis. The presence of amoxicillin resistance (OR 6.83, 95% CI 1.62-28.86, P = 0.009) and prior sequential therapy (OR 4.77, 95% CI 1.315-17.3, P = 0.017), but not tetracycline resistance (tetracycline group), were associated with treatment failure. The eradication rates in patients who received clarithromycin-, levofloxacin- and tetracycline-based sequential therapies were 78.9% (15/19), 92.2% (47/51) and 71.4% (25/35) in strains susceptible to clarithromycin, levofloxacin and tetracycline, respectively. CONCLUSIONS: A simple molecular method guiding sequential therapy can achieve a high eradication rate in the third-line treatment of refractory H. pylori infection.

Empirical modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy for Helicobacter pylori infection: a multicentre clinical trial.

OBJECTIVES: Sequential therapy appears to achieve a higher Helicobacter pylori eradication rate than triple therapy. We assessed the efficacy and tolerability of modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy. METHODS: Patients who failed first-line triple therapy with clarithromycin, amoxicillin and a proton pump inhibitor were eligible in this multicentre trial. Eligible patients were treated with esomeprazole 40 mg and amoxicillin 1 g for the first 5 days, followed by esomeprazole 40 mg, levofloxacin 250 mg and metronidazole 500 mg for another 5 days (all given twice daily). Eradication was confirmed with a (13)C-urea breath test 6 weeks after therapy. Drug susceptibility, presence/absence of gyrA mutation and CYP2C19 genotype were also determined. RESULTS: A total of 142 patients were enrolled. The eradication rate was 95.1% [135/142, 95% confidence interval (CI) 91.5%-98.6%] in the intention-to-treat analysis and 96.4% (133/138, 95% CI 93.3%-99.5%) in the per protocol analysis. Four patients (2.8%) failed to take at least 80% of the drugs due to adverse effects. The eradication rates were 50% (4/8) and 97.7% (43/44) in patients with and without metronidazole resistance, respectively (P = 0.001). The eradication rates were 84.6% (11/13) and 95.1% (58/61) in patients with and without gyrA mutation, respectively (P = 0.210). The eradication rates were not affected by the CYP2C19 polymorphism (P = 0.421). CONCLUSIONS: This modified sequential therapy achieved an excellent eradication rate (>95%) in second-line treatment and the eradication rate appeared to be affected by metronidazole resistance.

Genotypic resistance in Helicobacter pylori strains correlates with susceptibility test and treatment outcomes after levofloxacin- and clarithromycin-based therapies.

The accuracy of genotypic resistance to levofloxacin (gyrA mutations) and its agreement with treatment outcomes after levofloxacin-based therapy have not been reported. We aimed to assess the correlation. Helicobacter pylori strains isolated from patients who received levofloxacin-based and clarithromycin-based triple therapies in a previous randomized trial were analyzed for point mutations in gyrA and 23S rRNA. PCR followed by direct sequencing was used to assess the gyrA and 23S rRNA mutations. An agar dilution test was used to determine the MICs of clarithromycin and levofloxacin. We found that the agreement between genotypic and phenotypic resistance to levofloxacin was best when the MIC breakpoint was >1 µg/ml (kappa coefficient, 0.754). The eradication rates in patients with and without gyrA mutations were 41.7% and 82.7%, respectively (P = 0.003). The agreement between genotypic and phenotypic resistance to clarithromycin was best when the MIC breakpoint was >2 µg/ml (kappa, 0.694). The eradication rates in patients with and without 23S rRNA mutations were 7.7% and 93.5%, respectively (P < 0.001). The agreements (kappa coefficient) between therapeutic outcomes after clarithromycin-based triple therapy and genotypic and phenotypic resistance were 0.671 and 0.356, respectively. The agreements (kappa coefficient) between therapeutic outcomes after levofloxacin-based triple therapy and genotypic and phenotypic resistance were 0.244 and 0.190, respectively. In conclusion, gyrA and 23S rRNA mutations in H. pylori strains appeared to be better markers than phenotypic resistance in the prediction of treatment outcomes. The optimal breakpoints for levofloxacin and clarithromycin resistance appeared to be >1 µg/ml and >2 µg/ml, respectively.

Levofloxacin-based and clarithromycin-based triple therapies as first-line and second-line treatments for Helicobacter pylori infection: a randomised comparative trial with crossover design.

BACKGROUND: The efficacy of a levofloxacin-based regimen as the first-line treatment and a clarithromycin-based regimen as the second-line treatment for Helicobacter pylori infection remains unknown. The aim of this study was to assess the eradication rates of these two regimens using different administration sequences. METHODS: Eligible patients were randomised to receive LAL: levofloxacin (750 mg once a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days, or CAL: clarithromycin (500 mg twice a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days. Patients with positive [(13)C]urea breath test after treatment were retreated with the rescue regimen in a crossover manner for 10 days. RESULT: When used as first-line treatment (n=432), the eradication rates of LAL (n=217) and CAL (n=215) were 74.2 and 83.7% (p=0.015) in the intent-to-treat (ITT) analysis, and 80.1 and 87.4% (p=0.046) in the per-protocol (PP) analysis, respectively. When used as second-line treatment, the eradication rates of LAL (n=26) and CAL (n=40) were 76.9 and 60% (p=0.154) in the ITT analysis, and 80 and 61.5% (p=0.120) in the PP analysis, respectively. The overall eradication rates of CAL followed by LAL were better than the reverse sequence in both the ITT analysis (93% vs 85.3%, p=0.01) and the PP analysis (97.6% vs 92.5%, p=0.019). The eradication rate was significantly lower in the presence of levofloxacin resistance in the LAL group (50% vs 84.4%, p=0.018) and clarithromycin resistance in the CAL group (44.4% vs 90.7%, p=0.002). CONCLUSION: CAL achieved a higher eradication rate than LAL as the first-line treatment, but not as the second-line treatment. The strategy of using CAL as the initial treatment and LAL as the rescue regimen achieved higher eradication rates than the reverse sequence.

Asia-Pacific consensus guidelines on gastric cancer prevention.

BACKGROUND AND AIM: Gastric cancer is a major health burden in the Asia-Pacific region but consensus on prevention strategies has been lacking. We aimed to critically evaluate strategies for preventing gastric cancer. METHODS: A multidisciplinary group developed consensus statements using a Delphi approach. Relevant data were presented, and the quality of evidence, strength of recommendation, and level of consensus were graded. RESULTS: Helicobacter pylori infection is a necessary but not sufficient causal factor for non-cardia gastric adenocarcinoma. A high intake of salt is strongly associated with gastric cancer. Fresh fruits and vegetables are protective but the use of vitamins and other dietary supplements does not prevent gastric cancer. Host-bacterial interaction in H. pylori infection results in different patterns of gastritis and differences in gastric acid secretion which determine disease outcome. A positive family history of gastric cancer is an important risk factor. Low serum pepsinogens reflect gastric atrophy and may be useful as a marker to identify populations at high risk for gastric cancer. H. pylori screening and treatment is a recommended gastric cancer risk reduction strategy in high-risk populations. H. pylori screening and treatment is most effective before atrophic gastritis has developed. It does not exclude the existing practice of gastric cancer surveillance in high-risk populations. In populations at low risk for gastric cancer, H. pylori screening is not recommended. First-line treatment of H. pylori infection should be in accordance with national treatment guidelines. CONCLUSION: A strategy of H. pylori screening and eradication in high-risk populations will probably reduce gastric cancer incidence, and based on current evidence is recommended by consensus.