Review article: Helicobacter pylori eradication–understandable caution but no excuse for inertia

The long-term management of patients with peptic ulcer disease is unsatisfactory, as judged by the persistently high levels of haemorrhage, perforation and death from this condition in Western countries. Although ulcer recurrence and complications can be prevented, many patients with peptic ulcer disease fail to receive the benefits of modern therapeutic regimens. In recent years, eradication of Helicobactor pylori has been promoted as a‘cure’for peptic ulcer disease and, while such claims are premature, there can be little doubt that this treatment–when successful– dramatically improves the medium-term prognosis of ulcer patients. However, in general, clinicians have given this promising therapeutic advance a lukewarm welcome. The aim of this detailed review of the literature is to remove the uncertainty and confusion surrounding many aspects of eradication therapy. Estimates are provided of the eradication rates after either triple therapy or the combination of omeprazole plus amoxycillin, and the sources of variation in published studies are discussed. Problems associated with eradication therapy, including side effects, compliance and re-infection, are addressed in order to ascertain the extent and clinical significance of each factor. In addition, studies reporting the outcome of patients with peptic ulcer disease after eradication are assessed with reference to both ulcer recurrence and complications. The result of the review is to dissipate much of the scepticism concerning eradication therapy. However, whilst acknowledging the efficacy of eradication therapy, its limitations have also to be recognized. By itself, it does not provide the complete answer to peptic ulcer disease. For some ulcer patients, eradication therapy is the preferred option; for others, prophylactic therapy with H2-receptor antagonists is more suitable. Guidelines are proposed for the selection of patients for each alternative therapy. The crucial point is that patients with peptic ulcer–excluding the small proportion with a mild form of the disease—require positive, long-term management consisting of either continuous prophylaxis with H2-receptor antagonists or the eradication of Helicobacter pylori.     

序贯疗法与标准三联疗法治疗幽门螺杆菌的临床疗效比较

目的：研究序贯疗法与标准三联疗法治疗幽门螺杆菌的临床疗效。方法选取幽门螺杆菌阳性患者120例,按照数字表法将患者分为A组和B组,每组60例。 A组给予序贯疗法（奥美拉唑＋阿莫西林治疗5 d以后继续以奥美拉唑＋克拉霉素＋替硝唑治疗5 d）治疗,B组给予标准三联疗法（奥美拉唑＋阿莫西林＋克拉霉素）治疗,比较两组幽门螺杆菌根除率、溃疡愈合总有效率以及不良反应。结果 A组幽门螺杆菌的根除率91．7％（55／60）,显著高于对照组的71．7％（43／60）（χ^2＝11．915,P＝0．023）;A组溃疡愈合总有效率96．7％（58／60）,显著高于B组的88．3％（53／60）（χ^2＝9．915,P＝0．038）;两组不良反应发生率差异无统计学意义（χ^2＝4．735,P＝0．072）。结论序贯疗法相比标准三联疗法治疗幽门螺杆菌具有较好的效果,能显著提高幽门螺杆菌的根除率,且无严重不良反应。     

Review article: the treatment of Helicobacter pylori infection

The discovery of Helicobacter pylori has stimulated great interest in its role in gastritis, non-ulcer dyspepsia and peptic ulceration. Treatment regimens to eradicate this organism from gastric mucosa have also received considerable attention. Current recommendations limit the use of triple drug combinations only to specific patient groups.     

布拉氏酵母菌联合标准三联疗法根治幽门螺杆菌感染的meta分析

目的 系统评价布拉氏酵母菌联合标准三联疗法根治幽门螺杆菌感染的疗效与安全性.方法 通过检索PubMed、EMBASE、Cochrane Central Register of Controlled Trials、MEDLINE等数据库1982年1月至2011年12月相关文献,全面收集应用布拉氏酵母菌联合标准三联疗法治疗Hp感染的随机对照试验,并用RevMan 5.0.2软件进行meta分析.结果 纳入5个试验包括1307例患者.其中4项试验的数据显示,与对照组相比,布拉氏酵母菌联合标准三联疗法能显著提高Hp根除率(n=915,OR=1.66,95％C1:1.22～1.26,P=0.001);有效降低三联疗法相关性不良反应(n=1305,OR=0.32,95％CI:0.17～0.63,P=0.008),特别是腹泻的发生率(4项试验,n=1215,OR=0.42,95％CI:0.27～0.64,P＜0.0001);但2组间的其他不良反应发生率无显著性差异.结论 布拉氏酵母菌联合标准三联疗法可显著性提高Hp感染的根治率,降低三联疗法总体相关性不良反应,特别是腹泻发生率.     

Review article: esomeprazole in the treatment of Helicobacter pylori

Proton pump inhibitor-based triple therapy is the most commonly used treatment for eradication of Helicobacter pylori, with pooled eradication rates of approximately 90%. In the USA, per protocol eradication rates with 10-day proton pump inhibitor-based triple therapy are approximately 85%. Esomeprazole, a new proton pump inhibitor that is the S-isomer of omeprazole and produces a greater inhibition of acid secretion than omeprazole, has recently been evaluated in the treatment of H. pylori. Seven-day twice daily triple therapy with esomeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg provided intention-to-treat eradication rates of 86-90% and per protocol eradication rates of 90-91% in duodenal ulcer patients in Europe and Canada. Ten-day triple therapy with esomeprazole 40 mg q.d.s., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. achieved intention-to-treat eradication rates of 77-78% and per protocol eradication rates of 84-85% in USA duodenal ulcer patients. Thus, esomeprazole triple therapy with amoxicillin and clarithromycin is effective in the treatment of H. pylori, with eradication rates comparable to previously studied proton pump inhibitor-based triple therapies.     

Review article: the cost of diagnosing Helicobacter pylori infection

Non-invasive testing and treatment for Helicobacter pylori has been recommended for dyspeptic patients in primary care and a number of recent studies have demonstrated the cost-effectiveness of this approach. As the prevalence of H. pylori infection declines, the positive and negative predictive values of individual tests will change. Cost-effectiveness is important in determining the appropriate test in individual populations. Recent studies have shown that the stool antigen test and the urea breath test have high sensitivity and specificity in the detection of H. pylori infection before and after therapy. Cost-effectiveness studies have shown that when the prevalence of H. pylori infection is low or intermediate, serological tests have relatively poor accuracy compared with the stool test or the urea breath test. In populations with low or intermediate prevalence (<60%) these tests should be preferred to ELISA serology or office-based whole-blood test or serology. This is particularly true when the prevalence of H. pylori infection is less than 30% as is seen in many developed countries. When the prevalence of H. pylori infection is high (>60%), low-cost antibody tests are cost-effective.     

Review article: the treatment of refractory Helicobacter pylori infection

The occurrence of refractory Helicobacter pylori infection is increasing. When the bacteria are not eradicated it means that the antibiotics have not reached the gastric mucosa at a sufficient concentration and over a sufficient time lapse to kill them. The main reasons for this are poor patient compliance, resistant bacteria, low gastric pH and a high bacterial load. Therefore, when administering a new treatment, it is important to choose antibiotics which do not face resistance problems and which increase the dosage of antisecretory drugs and the duration of treatment and, if possible, to add a topical agent such as bismuth salt. The recommended empirical strategy is to prescribe quadruple therapy or, alternatively, 2-week triple therapy including amoxicillin-metronidazole, tetracycline-metronidazole or amoxicillin-rifabutin. However, when H. pylori is susceptible, clarithromycin can still be used. In the case of a high level of metronidazole resistance, furazolidone can be employed. In each case, it is important to ensure good patient compliance, and counselling is helpful in this regard. However, the best approach remains the prevention of refractory H. pylori infection and, for this purpose, antimicrobial susceptibility testing before first-line therapy is important and should be encouraged.     

Sequential treatment for Helicobacter pylori does not share the risk factors of triple therapy failure

BACKGROUND: Predicting factors for the outcome of conventional Helicobacter pylori triple therapy have been identified. Of these, the presence of the CagA gene is a strong predictor of successful treatment. Our preliminary data show that this factor becomes irrelevant when sequential therapy is used. AIM: To identify predicting factors for the outcome of H. pylori eradication using two therapeutic schemes (triple and sequential) of equal duration (10 days). METHODS: Ninety-six patients with H. pylori infection were randomly assigned to receive one of the following therapeutic schemes: group A: rabeprazole (20 mg b.d.) plus amoxicillin (1 g b.d.) for 5 days, followed by rabeprazole (20 mg b.d.) plus tinidazole (500 mg b.d.) and clarithromycin (500 mg b.d.) for a further 5 days; group B: rabeprazole (20 mg b.d.) plus amoxicillin (1 g b.d.) and clarithromycin (500 mg b.d.) for 10 days. Age, sex, smoking, endoscopic and histological findings, and CagA and VacA status were considered as candidates for a model of multivariate analysis which used therapeutic outcome as the dependent variable. CagA and VacA status were assessed by polymerase chain reaction on DNA isolated from gastric antral specimens. RESULTS: The sequential scheme was significantly more effective than prolonged triple therapy (P < 0.05). Smoking (P < 0.001) and the absence of the CagA gene (P < 0.05) were significantly associated with the failure of triple therapy, but the effectiveness of sequential treatment was not predicted by these factors. CONCLUSION: Our data suggest that sequential therapy is not affected by bacterial and host factors which have, until now, predicted the outcome of conventional eradication treatments.     

Meta-analysis: high-dose proton pump inhibitors vs. standard dose in triple therapy for Helicobacter pylori eradication

Background The evidence on whether high‐dose proton pump inhibitors (PPIs) increase cure rates of Helicobacter pylori treatment has not been previously assessed. Aim To evaluate the evidence on the usefulness of high‐dose PPI in standard triple therapy by performing a systematic review and a meta‐analysis. Methods A systematic search was performed in multiple databases and in the abstracts submitted to the Digestive Diseases Week, the European Helicobacter Study Group congress and the United European Gastroenterology Week. Randomized trials comparing a standard dose of a PPI with high‐dose PPI both twice a day in triple therapy combining a PPI plus clarithromycin and either amoxicillin or metronidazole were selected. Relative risk (RR) and 95% confidence intervals (95% CIs) for all comparisons were calculated using Review Manager. Results Six studies fulfilled the inclusion criteria. All used triple therapy for 7 days. A mean intention‐to‐treat cure rate of 82% was achieved with high‐dose PPI and one of 74% with standard dose (RR: 1.09; 95% CI: 1.01–1.17). Subgroup analysis showed that the maximum increase was observed when the PPI compared were omeprazole 20 mg or pantoprazole 40 mg vs. esomeprazole 40 mg. Conclusion High‐dose PPI seems more effective than standard‐dose for curing H. pylori infection in 7‐day triple therapy.     

Three-day intravenous triple therapy is not effective for the eradication of Helicobacter pylori infection in patients with bleeding gastro-duodenal ulcer

AIM: To test the efficacy of an ultra-short intravenous triple therapy against Helicobacter pylori infection in patients with bleeding peptic ulcer against standard oral 1-week triple therapy in a randomised, double-blind prospective trial. METHODS: PATIENTS: (n = 75) with haemorrhagic peptic ulcer and H. pylori infection were randomised into: an Intravenous Group to receive omeprazole, clarithromycin and amoxicillin-clavulanic acid intravenously b.d. for 3 days followed by 7 days of oral omeprazole plus placebo of clarithromycin and amoxicillin; an Oral Group to receive intravenous omeprazole plus placebo of clarithromycin and amoxicillin-clavulanic acid followed by 7 days of oral omeprazole, clarithromycin and amoxicillin b.d. Gastric biopsies were obtained for urease test. A 13C-urea breath test was performed to check for H. pylori eradication. RESULTS: Intention-to-treat eradication was 50% (19/38) in the Intravenous Group and 78% (29/37) in the Oral Group (odds ratio 3.63; 95% confidence interval 1.32-9.94; P < 0.01; number needed to treat (NNT) = 4). Per protocol eradication was 50% (14/28) in the Intravenous Group and 86% (24/28) in the Oral Group (P < 0.005). There were no statistically significant differences in adverse events between the two treatment groups. CONCLUSIONS: An ultra-short, 3-day, intravenous, triple therapy containing omeprazole, clarithromycin and amoxicillin-clavulanic acid cannot be recommended as an effective eradication regimen for H. pylori infection related to haemorrhagic gastro-duodenal ulcer.     

Review article: treatment of Helicobacter pylori infection with ranitidine bismuth citrate- or proton pump inhibitor-based triple therapies

Triple therapy, combining a proton pump inhibitor with clarithromycin (C) and either amoxycillin (A) or a nitro-imidazole (I) is the standard in Helicobacter pylori eradication therapy. Recently, triple therapies based on ranitidine bismuth citrate (RBC) have emerged as an alternative. This review examines the current literature for studies directly comparing proton pump inhibitor- with RBC-based triple therapies. Seventeen studies were identified, of which three have been published as a full paper. Eradication rates in an intention-to-treat analysis ranged from 51 to 98%. No large difference in cure rates between the different regimens was demonstrated, although the RBC-I-C combination was somewhat superior. No definite conclusions could be made about the impact of metronidazole or clarithromycin resistance since only three studies performed a formal resistance analysis. No serious side-effects were reported, and dropout rates were equal for the two regimens. Both RBC- and proton pump inhibitor-based triple therapies are highly effective. If one prefers a imidazole/clarithromycin combination the evidence presented here suggests that RBC should be used instead of a proton pump inhibitor. Larger studies comparing both forms of triple therapy, using proper resistance analysis, are needed before final conclusions can be reached regarding efficacy in the setting of bacterial resistance.     

Review article: rifabutin in the treatment of refractory Helicobacter pylori infection

Aliment Pharmacol Ther 2012; 35: 209–221

Summary

Background Even with the current most effective treatment regimens, a relevant proportion of patients will fail to eradicate Helicobacter pylori infection. Aim To evaluate the role of rifabutin in the treatment of H. pylori infection. Methods Bibliographical searches were performed in MEDLINE. Data on the efficacy of rifabutin‐containing regimens on H. pylori eradication were combined and meta‐analysed using the generic inverse variance method. Results Rifabutin shows good in vitro activity against H. pylori. Mean H. pylori rifabutin resistance rate (calculated from 11 studies including 2982 patients) was 1.3% (95% confidence interval = 0.9–1.7%). When only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%). On the other hand, higher values of rifabutin resistance were calculated (1.59%) when only post‐treatment patients were considered. Overall, mean H. pylori eradication rate (intention‐to‐treat analysis) with rifabutin‐containing regimens (1008 patients) was 73% (67–79%). Respective cure rates for second‐line (223 patients), third‐line (342 patients) and fourth/fifth‐line (95 patients) rifabutin therapies were 79% (67–92%), 66% (55–77%) and 70% (60–79%) respectively. For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day; this dose seems to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10‐ to 12‐day regimens are generally recommended. The mean rate of adverse effects was 22% (19–25%). Myelotoxicity is the most significant, although this complication was rare. Until now, all patients have recovered of leucopenia uneventfully in a few days, and there have been no reports of infection or other adverse outcomes related to it. Conclusion Rifabutin‐containing rescue therapy constitutes an encouraging strategy after multiple (usually three) previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin.     

Review article: the control of gastric acid and Helicobacter pylori eradication

This review focuses on the gastric acid pump as a therapeutic target for the control of acid secretion in peptic ulcer and gastro-oesophageal reflux disease. The mechanism of the proton pump inhibitors is discussed as well as their clinical use. The biology of Helicobacter pylori as a gastric denizen is then discussed, with special regard to its mechanisms of acid resistance. Here the properties of the products of the urease gene clusters, ureA, B and ureI, E, F, G and H are explored in order to explain the unique location of this pathogen. The dominant requirement for acid resistance is the presence of a proton gated urea transporter, UreI, which increases access of gastric juice urea to the intrabacterial urease 300-fold. This enables rapid and continuous buffering of the bacterial periplasm to approximately pH 6.0, allowing acid resistance and growth at acidic pH in the presence of 1 mM urea. A hypothesis for the basis of combination therapy for eradication is also presented.     

Review article: the transmission of Helicobacter pylori from stomach to stomach

The mode of transmission of Helicobacter pylori is largely unknown and is a matter of circumstantial evidence and speculation rather than fact. However, the principle evidence is of two sorts: the epidemiological data, providing evidence of possible risk factors associated with transmission, and the identification of potential sources from which H. pylori could be acquired. Evidence exists for several potential sources of infection and several possible modes of transmission, and it is feasible that the transmission of H. pylori varies according to the cultural and demographic circumstances. However, the most likely recognized source for H. pylori is the human stomach, although it is not known by what route the organism is transmitted to the stomach. Evidence suggests close personal contact is important and that acquisition occurs mainly in childhood. This article reviews the evidence for the source of infection and the route of transmission of H. pylori.     

标准三联疗法四联疗法及序贯疗法根除幽门螺杆菌的疗效观察

目的比较标准三联疗法、四联疗法及序贯疗法根除幽门螺杆菌(Hp)的疗效及安全性。方法300例非溃疡性消化不良者随机入选三联、四联及序贯疗法组,三联疗法组予兰索拉唑+阿莫西林+克拉霉素治疗10d。四联疗法组予兰索拉唑+胶体次枸橼酸铋+阿莫西林+克拉霉素治疗10d。序贯疗法组前5d予兰索拉唑+阿莫西林治疗,后5d予兰索拉唑+克拉霉素+甲硝唑治疗。治疗结束至少停药4周后复查14 C尿素呼气试验,结果阴性表示根除成功。同时评估疗效及安全性。对Hp根除率进行意向性分析和符合方案分析比较。结果意向性分析显示三联疗法组、四联疗法组及序贯疗法组的Hp根除率分别是66%(66/100)、82%(82/100)及84%(84/100)。符合方案分析显示三联疗法组、四联疗法组及序贯疗法组的Hp根除率分别是72%(66/92)、91%(82/90)及89%(84/94)。意向性分析及符合方案分析均表明三联疗法组Hp根除率明显低于四联疗法组或序贯疗法组,差异有统计学意义(P均<0.05),而四联疗法组与序贯疗法组间差异无统计学意义(P>0.05)。结论四联疗法或序贯疗法可作为临床根治Hp的一线治疗方案。