Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Cancer Center, Taipei, Taiwan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Lancet Infect Dis. 2019 Oct;19(10):1109-1120. doi: 10.1016/S1473-3099(19)30272-5.
In first-line treatment of Helicobacter pylori, we have previously shown that the eradication frequency was 83·7% (95% CI 80·4-86·6) for triple therapy for 14 days (T14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily), 85·9% (82·7-88·6) for concomitant therapy for 10 days (C10; lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily), and 90·4% (87·6-92·6) for bismuth quadruple therapy for 10 days (BQ10; bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). In this follow-up study, we assess short-term and long-term effects of these therapies on the gut microbiota, antibiotic resistance, and metabolic parameters.
This was a multicentre, open-label, randomised trial done at nine medical centres in Taiwan. Adult patients (>20 years) with documented H pylori infection were randomly assigned (1:1:1, with block sizes of six) to receive T14, C10, or BQ10. We assessed long-term outcomes (reinfection frequency, changes in the gut microbiota, antibiotic resistance, and metabolic parameters) in patients with available data, excluding all protocol violators and those with unknown post-treatment H pylori status. Faecal samples were collected before treatment and 2 weeks, 2 months, and at least 1 year after eradication therapy. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was done followed by high-throughput sequencing. Susceptibility testing for faecal Escherichia coli and Klebsiella pneumoniae was done. This trial is complete and registered with ClinicalTrials.gov, NCT01906879.
Between July 17, 2013, and April 20, 2016, 1620 participants were randomly assigned to the three treatment groups (540 [33%] per group). 1214 (75%) attended 1-year follow-up and are included in this analysis. Compared with baseline, alpha diversity was significantly reduced 2 weeks after T14 (p=0·0002), C10 (p<0·0001), and BQ10 (p<0·0001) treatment. Beta diversity was also significantly altered 2 weeks after T14 (p=0·0010), C10 (p=0·0001), and BQ10 (p=0·0001). Alpha diversity and beta diversity were restored at week 8 (p=0·14 and p=0·918, respectively) and 1 year (p=0·14 and p=0·918) after T14, but were not fully recovered at week 8 and after 1 year in patients treated with C10 (p=0·0001 and p=0·013 at week 8; p=0·019 and p=0·064 at 1 year) and BQ10 (p<0·0001 and p=0·0002; p=0·001 and p=0·029). A transient increase at week 2 after T14 and C10 of the resistance rates of E coli to ampicillin-sulbactam (12% [15/127] to 66% [38/58] for T14, 7% [10/135] to 64% [28/44] for C10), cefazolin (13% [16/127] to 43% [25/58] for T14, 10% [13/135] to 41% [18/44] for C10), cefmetazole (8% [10/127] to 26% [15/58] for T14, 4% [5/135] to 18% [8/44] for C10), levofloxacin (8% [10/127] to 35% [20/58] for T14, 7% [10/135] to 32% [14/44] for C10), gentamicin (13% [19/146] to 47% [27/58] for T14, 15% [22/149] to 45% [20/44] for C10), and trimethoprim-sulfamethoxazole (33% [48/146] to 86% [50/58] for T14, 28% [42/148] to 86% [38/44] for C10; p<0·05 in paired samples in the above analyses) returned to basal state at week 8 and after 1 year. Although bodyweight and body-mass index slightly increased, there were significant improvements in metabolic parameters, with a decrease in insulin resistance, triglycerides, and LDL and an increase in HDL. Overall, there was no significant change in the prevalence of metabolic syndrome at week 8 and 1 year after T14, C10, and BQ10.
Eradication of H pylori infection has minimal disruption of the microbiota, no effect on antibiotic resistance of E coli, and some positive effects on metabolic parameters. Collectively, these results lend support to the long-term safety of H pylori eradication therapy.
National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.
在幽门螺杆菌的一线治疗中，我们之前的研究表明，三联疗法（14 天疗程：兰索拉唑 30mg，阿莫西林 1g，克拉霉素 500mg，每日两次）的根除率为 83.7%（95%CI 80.4-86.6），三联疗法（10 天疗程：兰索拉唑 30mg，阿莫西林 1g，克拉霉素 500mg，甲硝唑 500mg，每日两次）的根除率为 85.9%（82.7-88.6），铋四联疗法（10 天疗程：枸橼酸铋钾 300mg，每日 4 次，兰索拉唑 30mg，每日 2 次，四环素 500mg，每日 4 次，甲硝唑 500mg，每日 3 次）的根除率为 90.4%（87.6-92.6）。在这项随访研究中，我们评估了这些疗法对肠道微生物群、抗生素耐药性和代谢参数的短期和长期影响。
这是一项在台湾九家医疗中心进行的多中心、开放标签、随机试验。>20 岁且有明确幽门螺杆菌感染的成年患者被随机分为三组（1:1:1，每组 6 个块），分别接受三联疗法（T14）、三联疗法（C10）或铋四联疗法（BQ10）。我们对有可用数据的患者进行了长期结局（再感染率、肠道微生物群变化、抗生素耐药性和代谢参数）评估，排除了所有违反方案的患者和治疗后幽门螺杆菌状态不明的患者。在治疗前和治疗后 2 周、2 个月和至少 1 年后收集粪便样本。对 16S rRNA 的 V3 和 V4 高变区进行扩增，然后进行高通量测序。对粪便大肠杆菌和肺炎克雷伯菌进行药敏试验。本试验已完成并在 ClinicalTrials.gov 注册，注册号为 NCT01906879。
2013 年 7 月 17 日至 2016 年 4 月 20 日，共有 1620 名患者被随机分为三组（每组 540 名）。1214 名（75%）患者参加了 1 年随访，包括在本分析中。与基线相比，T14（p=0.0002）、C10（p<0.0001）和 BQ10（p<0.0001）治疗后 2 周时 alpha 多样性显著降低。T14（p=0.0010）、C10（p=0.0001）和 BQ10（p=0.0001）治疗后 2 周时 beta 多样性也发生了显著改变。T14 治疗后第 8 周（p=0.14）和 1 年（p=0.14）时 alpha 多样性和 beta 多样性恢复，但 C10（第 8 周 p=0.0001，第 1 年 p=0.013）和 BQ10（第 8 周 p<0.0001，第 1 年 p=0.0002）治疗后第 8 周和 1 年时并未完全恢复。T14 和 C10 治疗后 2 周时大肠杆菌对氨苄西林-舒巴坦（T14：12%[15/127]至 66%[38/58]，C10：7%[10/135]至 64%[28/44]）、头孢唑林（T14：13%[16/127]至 43%[25/58]，C10：10%[13/135]至 41%[18/44]）、头孢美唑（T14：8%[10/127]至 26%[15/58]，C10：4%[5/135]至 18%[8/44]）、左氧氟沙星（T14：8%[10/127]至 35%[20/58]，C10：7%[10/135]至 32%[14/44]）、庆大霉素（T14：13%[19/146]至 47%[27/58]，C10：15%[22/149]至 45%[20/44]）和复方磺胺甲噁唑（T14：33%[48/146]至 86%[50/58]，C10：28%[42/148]至 86%[38/44]）的耐药率增加，但在配对样本中均显著降低（上述分析中的 p<0.05）。尽管体重和体重指数略有增加，但代谢参数有显著改善，胰岛素抵抗、甘油三酯和 LDL 降低，HDL 升高。总体而言，T14、C10 和 BQ10 治疗后 8 周和 1 年时，代谢综合征的患病率没有显著变化。
幽门螺杆菌感染的根除对微生物群的破坏很小，对大肠杆菌的抗生素耐药性没有影响，对代谢参数有一些积极影响。这些结果共同支持幽门螺杆菌根除治疗的长期安全性。
台湾大学附属医院和台湾科技部。
