【作者】 刘静；

【导师】 左秀丽；

【作者基本信息】 山东大学 ， 内科学（消化系病）（专业学位）， 2020， 硕士

【摘要】 研究背景:目前全世界有近50%人口感染了幽门螺杆菌(Helicobacter pylori,H.pylori),我国H.pylori感染率达50%。已证明H.pylori感染可导致包含慢性胃炎、消化性溃疡、胃癌和胃粘膜相关组织淋巴瘤在内的多种消化系统疾病;同时H.pylori感染也与不明原因的缺铁性贫血、代谢综合征、心脑血管疾病、免疫性血小板减少性紫癜等胃肠外疾病相关。根除H.pylori可延缓慢性萎缩性胃炎的发展,降低早期胃癌患者异时性胃癌的发生率,或可有效减轻我国胃癌疾病负担。全球范围内H.pylori根除失败现象越来越普遍,其主要原因包括H.pylori对抗生素耐药率逐渐升高,患者对根除治疗方案依从性不佳,临床用药方案不规范等;反复的根除治疗失败继而加剧了补救根除治疗的困难,造成部分H.pylori感染迁延难治。有学者提出患者接受共识推荐的四联方案根除治疗失败3次及以上考虑为难治性幽门螺杆菌感染。针对难治性幽门螺杆菌感染,目前指南和共识尚缺乏推荐的根除治疗方案。研究目的:本研究旨在探求14天改良序贯疗法对难治性幽门螺杆菌感染的根除疗效,分析其难治性幽门螺杆菌抗生素耐药性特点,并结合相关血液学检查,评估改良方案的患者依从性及安全性。研究方法:前瞻性纳入2018年10月1日至2019年12月31日于山东大学齐鲁医院消化内科门诊经13C尿素呼气试验、快速尿素酶试验或组织学检查证实H pylori感染的患者且经Maastricht V共识或第五次全国幽门螺杆菌感染处理共识报告推荐的14天不同抗生素组合的四联方案治疗失败3次及以上的患者共60人。入组患者均接受胃镜检查并行幽门螺杆菌培养及抗生素敏感性检测试验,患者均接受14天改良序贯方案:前7天为埃索美拉唑40mg bid/雷贝拉唑20mg bid、阿莫西林1000mgbid、四环素500mgqid、呋喃唑酮100mgtid,后7天为埃索美拉唑40mg bid/雷贝拉唑20mgbid、胶体果胶铋200mgbid、阿莫西林1000mgbid、四环素500mg qid。停药1-3天评估患者的依从性及不良反应。停药8周复查13C尿素呼气试验并评估H.pylori根除率、患者症状改善情况。研究结果:共60例受试者被纳入本研究,56例最终完成试验。14天改良序贯方案对难治性幽门螺杆菌的根除率在意向性分析分析、改良的意向性分析、符合方案集分析中分别为 83.3%(53/60)、93.0%(53/57)、94.6%(53/56)。42.4%的患者发生不良反应,未发生严重不良反应,3.4%的受试者因不耐受药物不良反应而停药。依从性好的受试者占94.9%。幽门螺杆菌培养阳性率83.3%(50/60)。克拉霉素、甲硝唑、左氧氟沙星、阿莫西林的单药耐药率分别为60.0%、100.0%、70.0%、2.0%,未发现呋喃唑酮及四环素耐药菌株。克拉霉素和甲硝唑双重耐药率为4.0%,左氧氟沙星和甲硝唑的双重耐药率为14.0%。三重耐药率(克拉霉素、甲硝唑及左氧氟沙星均耐药)为54.0%。研究结论:我们通过初步研究发现14天改良序贯疗法可有效根除(根除率>90%)难治性幽门螺杆菌感染,具有良好的安全性及患者依从性,或可成为根除难治性幽门螺杆菌感染的新方案。更多还原

【Abstract】 Background:Helicobacter pylori colonizes the stomachs of approximately 50%of the global population,which had a prevalence of 50%in China.Helicobacter pylori is a main pathogen for chronic gastritis,peptic ulcer disease,gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma.Meanwhile,it is associated with many extra-gastric diseases,such as unexplained iron deficiency anemia,metabolic syndrome and immune thrombocytopenic purpura.Helicobacter pylori eradicating reduces the severity of chronic atrophic gastritis and prevent metachronous gastric cancer in patients with early gastric cancer,which may effectively reduce the burden of gastric cancer in China.The eradication failure of Helicobacter pylori has been becoming more and more common worldwide.The main causes of this phenomenon include the increasing antibiotic resistance,poor patient compliance and non-standard regimen.The failure of eradication exacerbates the difficulty of rescue therapies.Difficult-to-treat Helicobacter pylori infection usually refers to patients who fail after 3 or more eradication therapies.Therefore,novel rescue regimen has been urgently required for solving the therapeutic dilemma.Aims:The aim of this pilot study was to evaluate the effectiveness and tolerability of the modified sequential regimen in patients with difficult-to-treat Helicobacter pylori infection.The characteristics of antibiotic resistance of Helicrobacter pylori were analyzed.Methods:A total of 60 patients proven Helicobacter pylori infection by’3C-urea breath test(13C-UBT),rapid urease test or histological examination were involved in this study from October 2018 to December 2019 in Qilu Hospital of Shandong University.Patients with persistent Helicobacter pylori infection after at least 3 failed standard quadruple eradication therapies were eligible for enrollment.Patients were scheduled to undergo blood routine examination,hepatic and renal function test,esophagogastroduodenoscopy and Helicobacter pylori culture before enrolled in this research.Patients were treated with modified sequential therapy containing esomeprazole 40 mg/rabeprazole 20 mg,amoxicillin 1 g,furazolidone 100mg and tetracycline 500mg for the first 7 days,followed by esomeprazole 40 mg/rabeprazole 20 mg,amoxicillin 1 g,tetracycline 500mg and colloidal bismuth pectin 220mg for another 7 days(PPI and amoxicillin were given twice daily,tetracycline was given four times per day,furazolidone was given three times per day).Helicobacter pylori eradication was defined as a negative result in 13C-UBT performed at least 8 weeks after the end of treatment.All subjects were asked to stop histamine 2 blocker and proton pump inhibitor for at least four weeks before 13C-UBT.Compliance was assessed by standardized interview at the end of treatment,as well as by pill count in the medication boxes returned at the interview.Compliance was considered low when<90%of pills were taken.The patients were asked to record the adverse events throughout the trial.A standardized interview and case report form were used to assess the adverse events and compliance at the end of treatment.Results:A total of 60 patients participated in this study,and 56 patients completed the whole study.The eradication rate in the intention-to-treat analysis,modified intention-to-treat analysis and per-protocol analysis were 83.3%,93.0%and 94.6%,respectively.42.4%of enrolled patients had adverse events and all of them were mild to moderate.Only 3.4%of patients discontinued medication due to the intolerance of adverse effect.Patients with good compliance accounted for 94.9%.Among 50 culture positive specimens,the resistance rate of clarithromycin,metronidazole,levofloxacin and amoxicillin were 60.0%,100.0%,70.0%and 2.0%.Helicobacter pylori existence of multiple drug resistance to metronidazole,levofloxacin and clarithromycin-resistant strains was 54.0%。Conclusion:Modified sequential therapy could achieve good eradication rate(>90%)for difficult-to-treat Helicobacter pylori infection with safety and good compliance.更多还原