Third-line and rescue therapy for refractory Helicobacter pylori infection: A systematic review

BACKGROUND Due to increasing resistance rates of Helicobacter pylori(H.pylori)to different antibiotics,failures in eradication therapies are becoming more frequent.Even though eradication criteria and treatment algorithms for first-line and second-line therapy against H.pylori infection are well-established,there is no clear recommendation for third-line and rescue therapy in refractory H.pylori infection.AIM To perform a systematic review evaluating the efficacy and safety of rescue therapies against refractory H.pylori infection.METHODS A systematic search of available rescue treatments for refractory H.pylori infection was conducted on the National Library of Medicine’s PubMed search platform based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Randomized or non-randomized clinical trials and observational studies evaluating the effectiveness of H.pylori infection rescue therapies were included.RESULTS Twenty-eight studies were included in the analysis of mean eradication rates as rescue therapy,and 21 of these were selected for analysis of mean eradication rate as third-line treatment.For rifabutin-,sitafloxacin-,levofloxacin-,or metronidazole-based triple-therapy as third-line treatment,mean eradication rates of 81.6%and 84.4%,79.4%and 81.5%,55.7%and 60.6%,and 62.0%and 63.0%were found in intention-to-treat(ITT)and per-protocol(PP)analysis,respectively.For third-line quadruple therapy,mean eradication rates of 69.2%and 72.1%were found for bismuth quadruple therapy(BQT),88.9%and 90.9%for bismuth quadruple therapy,three-in-one,Pylera®(BQT-Pylera),and 61.3%and 64.2%for non-BQT)in ITT and PP analysis,respectively.For rifabutin-,sitafloxacin-,levofloxacin-,or metronidazole-based triple therapy as rescue therapy,mean eradication rates of 75.4%and 78.8%,79.4 and 81.5%,55.7%and 60.6%,and 62.0%and 63.0%were found in ITT and PP analysis,respectively.For quadruple therapy as rescue treatment,mean eradication rates of 76.7%and 79.2%for BQT,84.9%and 87.8%for BQT-Pylera,and 61.3%and 64.2%for non-BQT were found in ITT and PP analysis,respectively.For susceptibility-guided therapy,mean eradication rates as third-line and rescue treatment were 75.0%in ITT and 79.2%in PP analysis.CONCLUSION We recommend sitafloxacin-based triple therapy containing vonoprazan in regions with low macrolide resistance profile.In regions with known resistance to macrolides or unavailability of bismuth,rifabutin-based triple therapy is recommended.

Second-line rescue treatment of Helicobacter pylori infection: Where are we now?

At present, the best rescue therapy for Helicobacter pylori(H. pylori) infection following failure of firstline eradication remains unclear. The Maastricht Ⅴ/Florence Consensus Report recommends bismuth quadruple therapy, or fluoroquinolone-amoxicillin triple/quadruple therapy as the second-line therapy for H. pylori infection. Meta-analyses have shown that bismuth quadruple therapy and levofloxacin-amoxicillin triple therapy have comparable eradication rates, while the former has more adverse effects than the latter. There are no significant differences between the eradication rates of levofloxacin-amoxicillin triple and quadruple therapies. However, the eradication rates of both levofloxacin-containing treatments are suboptimal. An important caveat of levofloxacin-amoxicillin triple or quadruple therapy is poor eradication efficacy in the presence of fluoroquinolone resistance. High-dose dual therapy is an emerging second-line therapy and has an eradication efficacy comparable with levofloxacinamoxicillin triple therapy. Recently, a 10-d tetracyclinelevofloxacin(TL) quadruple therapy comprised of a proton pump inhibitor, bismuth, tetracycline and levofloxacin has been developed, which achieves a markedly higher eradication rate compared with levofloxacin-amoxicillin triple therapy(98% vs 69%) in patients with failure of standard triple, bismuth quadruple or non-bismuth quadruple therapy. The present article reviews current second-line anti-H. pylori regimens and treatment algorisms. In conclusion, bismuth quadruple therapy, levofloxacin-amoxicillin triple/quadruple therapy, high-dose dual therapy and TL quadruple therapy can be used as second-line treatment for H. pylori infection. Current evidence suggests that 10-d TL quadruple therapy is a simple and effective regimen, and has the potential to become a universal rescue treatment following eradication failure by all firstline eradication regimens for H. pylori infection.

A new look at anti-Helicobacter pylori therapy

With the rising prevalence of antimicrobial resistance,the treatment success of standard triple therapy has recently declined to unacceptable levels (i.e.,80% or less) in most countries.Therefore,several treatment regimens have emerged to cure Helicobacter pylori (H.pylori) infection.Novel first-line anti-H.pylori therapies in 2011 include sequential therapy,concomitant quadruple therapy,hybrid (dual-concomitant) therapy and bismuth-containing quadruple therapy.After the failure of standard triple therapy,a bismuth-containing quadruple therapy comprising a proton pump inhibitor (PPI),bismuth,tetracycline and metronidazole can be employed as rescue treatment.Recently,triple therapy combining a PPI,levofloxacin and amoxicillin has been proposed as an alternative to the standard rescue therapy.This salvage regimen can achieve a higher eradication rate than bismuth-containing quadruple therapy in some regions and has less adverse effects.The best second-line therapy for patients who fail to eradicate H.pylori with first-line therapies containing clarithromycin,amoxicillin and metronidazole is unclear.However,a levofloxacin-based triple therapy is an accepted rescue treatment.Most guidelines suggest that patients requiring third-line therapy should be referred to a medical center and treated according to the antibiotic susceptibility test.Nonetheless,an empirical therapy (such as levofloxacin-based or furazolidone-based therapies) can be employed to terminate H.pylori infection if antimicrobial sensitivity data are unavailable.

Efficacy and safety of high-dose esomeprazole–amoxicillin dual therapy for Helicobacter pylori rescue treatment:a multicenter,prospective,randomized,controlled trial

Background:High-dose dual therapy(HDDT)with proton pump inhibitors(PPIs)and amoxicillin has attracted widespread attention due to its favorable efficacy in eradicating Helicobacter pylori(H.pylori).This study aimed to compare the efficacy and safety of high-dose PPI-amoxicillin dual therapy and bismuth-containing quadruple therapy for H.pylori rescue treatment.Methods:This was a prospective,randomized,multicenter,non-inferiority trial.Patients recruited from eight centers who had failed previous treatment were randomly(1:1)allocated to two eradication groups:HDDT(esomeprazole 40 mg and amoxicillin 1000 mg three times daily;theHDDTgroup)and bismuth-containing quadruple therapy(esomeprazole 40 mg,bismuth potassium citrate 220 mg,and furazolidone 100 mg twice daily,combined with tetracycline 500 mg three times daily;the tetracycline,furazolidone,esomeprazole,and bismuth[TFEB]group)for 14 days.The primary endpoint was the H.pylori eradication rate.The secondary endpoints were adverse effects,symptom improvement rates,and patient compliance.Results:A total of 658 patients who met the criteria were enrolled in this study.The HDDT group achieved eradication rates of 75.4%(248/329),81.0%(248/306),and 81.3%(248/305)asdetermined by the intention-to-treat(ITT),modified intention-totreat(MITT),and per-protocol(PP)analyses,respectively.The eradication rates were similar to those in the TFEB group:78.1%(257/329),84.2%(257/305),and 85.1%(257/302).The lower 95%confidence interval boundary(9.19%in the ITT analysis,9.21%in the MITT analysis,and9.73%in the PP analysis)was greater than the predefined non-inferiority margin of10%,establishing a non-inferiority of the HDDT group vs.the TFEB group.The incidence of adverse events in the HDDT group was significantly lower than that in the TFEB group(11.1%vs.26.8%,P<0.001).Symptom improvement rates and patients’compliance were similar between the two groups.Conclusions:Fourteen-day HDDT is non-inferior to bismuth-containing quadruple therapy,with fewer adverse effects and good treatment compliance,suggesting HDDT as an alternative for H.pylori rescue treatment in the local region.Trial registration:Clinicaltrials.gov,NCT04678492.

Efficacy of a therapeutic strategy for eradication of Helicobacter pylori infection

AIM: To determine the efficacy of our therapeutic strategy for Helicobacter pylori (H. pylori) eradication and to identify predictive factors for successful eradication. METHODS: From April 2006 to June 2010, we retrospectively assessed 2428 consecutive patients (1025 men, 1403 women; mean age 55 years, age range 18-92 years) with gastric histology positive for H. pylori infection referred to our unit for 13-C urea breath test(UBT), after first-line therapy with proton pump inhibitor (PPI) b.i.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d. for 7 d. Patients who were still positive to UBT were recommended a second-line therapy (PPI b.i.d. + amoxicillin 1 g b.i.d. + tinidazole 500 mg b.i.d. for 14 d). Third choice treatment was empirical with PPI b.i.d. + amoxicillin 1 g b.i.d. + levofloxacin 250 mg b.i.d. for 14 d. RESULTS: Out of 614 patients, still H. pylori-positive after first-line therapy, only 326 and 19 patients respectively rechecked their H. pylori status by UBT after the suggested second and third-line regimens. "Per protocol" eradication rates for first, second and thirdline therapy were 74.7% (95% CI: 72.7%-76.4%), 85.3% (95% CI: 81.1%-89.1%) and 89.5% (95% CI: 74.9%-103%) respectively. The overall percentage of patients with H. pylori eradicated after two treatments was 97.8% (95% CI: 97.1%-98.4%), vs 99.9% (95% CI: 99.8%-100%) after three treatments. The study found that eradication therapy was most effective in patients with ulcer disease (P < 0.05, P = 0.028), especially in those with duodenal ulcer. Smoking habits did not significantly affect the eradication rate. CONCLUSION: First-line therapy with amoxicillin and clarithromycin produces an H. pylori eradication rate comparable or superior to other studies and secondline treatment can still be triple therapy with amoxicillin and tinidazole.

Quinolone-based first, second and third-line therapies for Helicobacter pylori

Helicobacter pylori(H. pylori) is a very common bacterium that infects about 50% of the world population in urban areas and over 90% of people living in rural and developing countries. Fluoroquinolones, a class of antimicrobials, have been extensively used in eradication regimens for H. pylori. Levofloxacin is the most commonly used, and in second-line regimens, is one of the most effective options. However, an increasing resistance rate of H. pylori to fluoroquinolones is being observed, that will likely affect their effectiveness in the near future. Other novel fluoroquinolone molecules, such as moxifloxacin, sitafloxacin, gatifloxacin and gemifloxacin, have been proposed and showed encouraging results in vitro, although data on their clinical use are still limited. Further studies in large sample trials are needed to confirm their safety and efficacy profile in clinical practice.

Rifabutin as salvage therapy for Helicobacter pylori eradication:Cornerstones and novelties

When several Helicobacter pylori eradication treatments fail,guidelines recommend a cultured guided approach;however,culture is not widely available.Therefore,a rifabutin based regimen could be the best solution.Rifabutin indeed shows a low rate of antibiotic resistance.Rifabutin is generally used in combination with amoxicillin in a triple therapy,with eradication rates about 80%in third-line regimens.The ideal duration of this therapy should range between 10 and 12 d.Combinations with antibiotics other than amoxicillin have demonstrated even better results,such as vonoprazan,which is a type of novel acid suppressor drug.Finally,a new formulation of triple therapy in a single capsule is under investigation,which is a field that deserves further investigation.Some notes of caution about rifabutin should be mentioned.This drug is used to treat tuberculosis or atypical mycobacteria;therefore,before starting a rifabutin-based eradication regimen,Mycobacterium tuberculosis infection should be thoroughly tested,since its use could promote the development of antibiotic resistance,thus affecting its effectiveness against Koch’s bacillus.Additionally,some serious side effects must be evaluated before starting any rifabutin-based therapy.Adverse effects include fever,nausea,vomiting and bone marrow suppression.For this reason,full blood count surveillance is required.

左氧氟沙星三联方案与常规四联补救方案治疗幽门螺杆菌感染的荟萃分析

目的:系统性评价含左氧氟沙星的三联方案与常规四联补救方案治疗幽门螺杆菌(Hpylori)感染的疗效和不良反应发生率.方法:从常用电子数据库检索含左氧氟沙星的三联方案与四联补救方案根除Hpylori的随机临床试验,荟萃分析各项研究的根除率和不良反应发生率的合并OR值;进行敏感性分析;以漏斗图检测发表偏倚.结果:共13项随机临床试验(1181例)符合纳入标准.含左氧氟沙星的三联方案和四联补救方案按意向治疗(ITT)分析的Hpylori的根除率分别为77.5%(95%CI74.1%-80.9%)和70.5%(95%CI66.8%-74.2%),合并OR值为1.51(95%CI0.91-2.53);总不良反应发生率分别为21.3%(95%CI17.7%-24.9%)和36.0%(95%CI31.8%-40.2%),合并OR值0.45(95%CI0.29-0.71).结论:含左氧氟沙星的三联方案具有与常规四联补救方案相似的根除Hpylori疗效,而且可以显著降低根除过程中的不良反应发生率.

7天与10天莫西沙星三联疗法根除幽门螺杆菌的疗效比较

目的:随着含铋剂四联疗法根除幽门螺杆菌(Helicobacter pylori,Hp)疗效的下降,临床上需要新的补救治疗方案,本研究比较了不同疗程的莫西沙星三联疗法补救治疗Hp的疗效和安全性。方法:将Hp感染经常规三联疗法治疗失败的89例患者随机分为A组(45例)和B组(44例)。两组患者均给予含莫西沙星的三联疗法(莫西沙星+雷贝拉唑钠肠溶片+阿莫西林),A组患者疗程为7天,B组患者疗程10天,治疗结束后4周做^(13)C尿素酶呼气试验进行比较。结果:A组41例完成治疗及随访,其中33例补救治疗成功;B组38例完成治疗及随访,32例根除治疗成功,A、B两组的ITT根除率分别为73.3%和72.7%,其PP根除率分别为80.5%和84.2%。两组根除率比较无统计学差异(P>0.05)。结论:7天与10天莫西沙星三联疗法根除率无明显差异,Hp补救治疗可选用7天莫西沙星三联方案。

含呋喃唑酮四联疗法对幽门螺杆菌多次根除失败患者的效果

目的 评价含呋喃唑酮的四联疗法对既往多次根除幽门螺杆菌（H.pylori）失败患者的效果和安全性.方法 采用前瞻性随机对照临床研究,对象为既往H.pylori感染根除治疗2次或以上的患者,2011年7月至2013年6月北京医院消化科门诊156例符合入选标准的患者被纳入,其中男91例、女65例.将入选患者按随机数字表法随机分为呋喃唑酮组（80例）和左氧氟沙星组（76例）,分别给予含呋喃唑酮的四联疗法（埃索美拉唑镁20 mg 2次/d＋呋喃唑酮100 mg 2次/d＋阿莫西林1000 mg 2次/d＋胶体果胶铋150 mg 3次/d）和含左氧氟沙星的四联疗法（埃索美拉唑镁20 mg 2次/d＋左氧氟沙星500 mg 1次/d＋阿莫西林1000 mg 2次/d＋胶体果胶铋150 mg 3次/d）,疗程均为10d,治疗结束后4周做13C尿素酶呼气试验比较H.pylori根除疗效.结果 呋喃唑酮组76例完成治疗及随访,其中67例补救治疗成功,其按意向治疗（ITT）和按符合方案（PP）H.pylori根除率分别为83.8％ （67/80）和88.2％（67/76）;左氧氟沙星组72例完成治疗及随访,53例根除治疗成功,其ITT和PP H.pylori根除率分别为69.7％（53/76）和73.6％ （53/72）;呋喃唑酮组H.pylori根除率高于左氧氟沙星组,差异均有统计学意义（x2 =4.311、5.100,P=0.038、0.024）.结论 对既往多次H.pylori根除治疗失败的患者,埃索美拉唑＋呋喃唑酮＋阿莫西林＋胶体果胶铋10 d疗法是疗效较好的补救治疗方案.

含利福布汀的三联或四联疗法在幽门螺杆菌根除失败后的应用

根除幽门螺杆菌(Hp)是防治消化性溃疡、慢性活动性胃炎等疾病的主要措施,作为一线治疗的三联或四联方案的根除率逐年降低。抗分枝杆菌药物利福布汀有较强的抗Hp活性,国内外陆续有将含利福布汀方案作为Hp感染一线治疗失败后的补救或三/四线方案的报道。本文对利福布汀的作用机制、药动学特点及含利福布汀方案的疗效和安全性作一综述。