Treatment options for Helicobacter pylori infection when proton pump inhibitor-based triple therapy fails in clinical practice

BACKGROUND: The effectiveness of Helicobacter pylori eradication regimens has not been extensively investigated in the clinical practice setting. The optimal treatment choice after an initial failed eradication attempt has not been determined. AIMS: To evaluate proton pump inhibitor-based triple therapies as first-line eradication regimens in clinical practice, and to establish the efficacy of second-line regimens in the context of an initial failed eradication attempt. METHODS: Three hundred and eight patients with dyspepsia and evidence of H. pylori at endoscopy were recruited. As first-line therapy, 116 patients received omeprazole 20 mg b.d. in combination with amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. (OAC) while 192 patients received omeprazole 20 mg b.d. in combination with metronidazole 400 mg b.d. and clarithromycin 250 mg b.d. (OMC). H. pylori status was reassessed at least 4 weeks after therapy (25 patients failed to attend for further testing). Of 52 patients with an initial failed eradication attempt, 20 patients received a 1 week quadruple therapy regimen incorporating omeprazole 20 mg b.d., tripotassium dicitrato bismuthate 120 mg q.d.s., tetracycline 500 mg q.d.s. and metronidazole 400 mg t.d.s., 20 patients received a 2-week proton pump inhibitor-based triple therapy regimen as described, and 12 patients received a further 1-week proton pump inhibitor-based triple therapy regimen. RESULTS: Including 308 patients, the intention-to-treat (ITT) eradication rates for OAC and OMC as first-line regimens were 72% (95% CI: 63-80%) and 73% (95% CI: 67-79%) respectively. A per protocol (PP) analysis on the 283 patients who completed follow-up gives an initial eradication rate of 78% (95% CI: 69-86%) for OAC and 79% (95% CI: 73-85%) for OMC. There were 60 patients (21%; 95% CI: 17-26%) in whom the initial eradication attempt was unsuccessful. With second-line therapy, H. pylori was successfully eradicated in a further 35/52 (67%; 95% CI: 58-73%) patients. The eradication rates with the quadruple regimen and 2-week triple therapy regimens were 75% (95% CI: 56-94%) and 80% (95% CI: 63-98%) respectively (P = 0. 71). The eradication rate with a repeat 1-week regimen was 33% (95% CI: 7-60%). CONCLUSIONS: The eradication rates achieved in this 'in practice' study with recommended first-line 1-week proton pump inhibitor-based triple therapy regimens were lower than the rates achieved with similar regimens in the clinical trial setting. A repeat 1-week proton pump inhibitor-based triple therapy regimen was not successful as a salvage therapy. Both the 2-week proton pump inhibitor-based triple therapy regimen and the 1-week quadruple therapy regimen were successful second-line treatments in >/=75% of patients.     

Review article: Helicobacter pylori "rescue" regimen when proton pump inhibitor-based triple therapies fail

Even with the currently most effective treatment regimens, about 10-20% of patients will fail to obtain eradication of Helicobacter pylori infection. Therefore, in designing a treatment strategy, we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of second-line treatment depends on which treatment was used initially, as re-treatment with the same regimen is not recommended. Therefore, it is not necessary to perform culture after the first eradication failure. Assessment of the sensitivity of H. pylori to antibiotics only after failure of the second treatment is suggested in clinical practice. Different possibilities of empirical treatment have been suggested. After failure of proton pump inhibitor-amoxicillin-clarithromycin, quadruple therapy has generally been used. More recently, replacement of the proton pump inhibitor and the bismuth compound by ranitidine bismuth citrate has also achieved good results. After proton pump inhibitor-amoxicillin-nitroimidazole failure, re-treatment with proton pump inhibitor-amoxicillin-clarithromycin has been proven to be effective. Finally, first-line treatment should not combine clarithromycin and metronidazole in the same regimen, because of the problem of resistance to both antibiotics. Recently, rifabutin-based rescue therapies have been shown to constitute an encouraging strategy for eradication failures, as they are effective against H. pylori strains resistant to antibiotics.     

Pantoprazole-based 10-day triple therapy is effective in Helicobacter pylori eradication

Aim:

To investigate the efficacy of a short course of pantoprazole-based triple therapy in Helicobater pylori eradication in a single-centre pilot study.

Methods:

Patients with active or healed duodenal ulcer or with gastric erosions or gastritis, all of whom were H. pylori-positive, received 10 days of twice-daily open treatment with pantoprazole 40 mg, plus clarithromycin 250 mg and tinidazole 500 mg. H. pylori was assessed at entry and 28–35 days after the end of treatment by rapid urease test (at entry only), culture and antimicrobial sensitivity, histology and ¹³ C urea breath test. The criterion for eradication was a negative result in all three tests.

Results:

Seventy patients were treated, of whom four were excluded from analysis due to major deviations from the study protocol. Eradication of H. pylori was achieved in 57/66 patients (per protocol analysis 86% (95% CI: 78–95%)) and was higher in patients with organisms sensitive to nitroimidazole before treatment (sensitive: 47/53 (89%), insensitive: 10/13 (77%)). There was marked reduction in acute gastritis throughout the stomach while chronic gastritis decreased only in the corpus. Healing was achieved in all 24 patients with active duodenal ulcer. Treatment was complied with; only one patient missed one of the 20 doses. Adverse events were of mild or moderate intensity and did not require withdrawal from treatment.

Conclusion:

A short course of pantoprazole-based triple therapy is well tolerated and effective in eradicating H. pylori.

     

Helicobacter pylori eradication with proton pump inhibitor-based triple therapies and re-treatment with ranitidine bismuth citrate-based triple therapy

BACKGROUND: It has been suggested that short-term triple therapy comprising a proton pump inhibitor, plus clarithromycin and amoxycillin be used as first choice in treating H. pylori infection, while eradication failure patients should be further treated with a quadruple therapy. Nevertheless, conflicting results have been reported using these treatment regimens in different countries. METHODS: A total of 278 patients with H. pylori infection were randomised to receive one-week triple therapy, comprising clarithromycin 500 mg b.d., amoxycillin 1 g b.d., and either omeprazole 20 mg b.d. (OAC; 90 patients), or pantoprazole 40 mg b.d. (PAC; 95 patients), or lansoprazole 30 mg b.d. (LAC; 93 patients). H. pylori infection at entry, and eradication 4-6 weeks after therapy had ended, were assessed by rapid urease test and histology on biopsies from the antrum and the corpus. When eradication did not occur, patients were given a 2-week treatment comprising ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s. and tinidazole 500 mg b.d. (RBTT). Eradication in these patients was assessed 4-6 weeks after conclusion of treatment by a further endoscopy. RESULTS: Six patients were lost to the follow-up. At the end of the first course of treatment, the overall H. pylori eradication rate was 78% (95% CI: 73-83) and 79% (95% CI: 75-84) at 'intention-to-treat' (ITT) and 'per protocol' (PP) analysis, respectively, without any statistically significant difference between treatment regimens, although a trend for better results with the omeprazole combination was observed. Moreover, H. pylori eradication was achieved in 82% (95% CI: 75-97) (ITT) and 86% (95% CI: 69-94) (PP) of 38 patients re-treated with RBTT regimen. CONCLUSIONS: Our data found that this short-term triple therapy is not a satisfactory treatment (< 80% eradication rate) for H. pylori infection. The 2-week triple therapy used as re-treatment in eradication failure patients yielded more promising results.     

Rabeprazole-based 3-day and 7-day triple therapy vs. omeprazole-based 7-day triple therapy for the treatment of Helicobacter pylori infection

BACKGROUND: Rabeprazole is a new proton pump inhibitor with more potent acid suppressive and anti-Helicobacter effects. AIM: To compare two different regimens of rabeprazole-based triple therapy vs. 7-day omeprazole-based triple therapy for the eradication of Helicobacter pylori infection. METHOD: Patients with proven H. pylori infection were randomized to receive: (i) 7-day rabeprazole, 10 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily; (ii) 3-day rabeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily; or (iii) 7-day omeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily. Endoscopy (CLO test, histology) was performed before randomization and 6 weeks after drug treatment. RESULTS: One hundred and seventy-three patients were randomized. H. pylori eradication rates (intention-to-treat, n=173/per protocol, n=167) were 88%/91% for 7-day rabeprazole-based therapy, 72%/72% for 3-day rabeprazole-based therapy and 82%/89% for 7-day omeprazole-based therapy, respectively. The per protocol eradication rate was significantly better in the 7-day rabeprazole-based therapy and 7-day omeprazole-based therapy groups when compared to the 3-day rabeprazole-based therapy group (P=0.01 and P=0.04, respectively). Compliance was excellent and all three regimens were well tolerated. CONCLUSIONS: The efficacy of seven-day rabeprazole-based triple therapy is similar to 7-day omeprazole-based triple therapy for the eradication of H. pylori infection.     

Randomised clinical trial: the efficacy of a 10-day sequential therapy vs. a 14-day standard proton pump inhibitor-based triple therapy for Helicobacter pylori in Korea

Aliment Pharmacol Ther 2011; 34: 1098–1105

Summary

Background The eradication rates of Helicobacter pylori (H. pylori) using a proton pump inhibitor (PPI)‐based triple therapy have declined due to antibiotic resistance worldwide. Aim To compare the eradication rate of the 10‐day sequential therapy for H. pylori infection with that of the 14‐day standard PPI‐based triple therapy. Methods This was a prospective, randomised, controlled study. A total of 409 patients with H. pylori infection were randomly assigned to receive either the 10‐day sequential therapy regimen, which consisted of pantoprazole (40 mg) plus amoxicillin (1000 mg) twice a day for 5 days, then pantoprazole (40 mg) with clarithromycin (500 mg) and metronidazole (500 mg) twice a day for another five consecutive days or the 14‐day PPI‐based triple therapy regimen, which consisted of pantoprazole (40 mg) with amoxicillin (1000 mg) and clarithromycin (500 mg) twice a day for 14 days. The pre‐ and post‐treatment H. pylori status were assessed by rapid urease test, urea breath test, or histology. Successful eradication was confirmed at least 4 weeks after finishing the treatment. Results In the intention‐to‐treat analysis, the eradication rates of the 10‐day sequential therapy and of the 14‐day PPI‐based triple therapy were 85.9% (176/205) and 75.0% (153/205), respectively (P = 0.006). In the per‐protocol analysis, the eradication rates were 92.6% (175/205) and 85% (153/204), respectively (P = 0.019). There was no statistically significant difference between the two investigated groups regarding the occurrence of adverse event rates (18.9% vs. 13.3%, P = 0.143). Conclusion The 10‐day sequential therapy achieved significantly higher eradication rates than the 14‐day standard PPI‐based triple therapy in Korea.     

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.     

Seven-day is more effective than 4-day ranitidine bismuth citrate-based triple therapy in eradication of Helicobacter pylori in children: a prospective randomized study

BACKGROUND: Helicobacter pylori infection is common in paediatric population. To date, there is still no universally accepted recommendation on the treatment of this infection in children. Ranitidine bismuth citrate-based triple therapy has been shown to be effective in H. pylori eradication in adults but its use has rarely been validated in children. AIM: To investigate the efficacy of ranitidine bismuth citrate-based triple therapy in eradication of H. pylori in children and to determine the shortest duration of treatment required. PATIENTS AND METHODS: We conducted a prospective randomized study comparing ranitidine bismuth citrate plus amoxicillin plus clarithromycin given for 4 days vs. 7 days in H. pylori-infected children diagnosed by (13)C-urea breath test. Eradication was evaluated by repeat (13)C-urea breath test at 6 weeks after treatment. RESULTS: A total of 206 children were recruited (median age 12 years, 97 boys and 109 girls). Ninety-eight (47.6%) and 108 (52.4%) children were randomized to receive 7-day and 4-day regimen respectively. The eradication rate of 4-day treatment arm was 77.8% (both intention-to-treat and per protocol) compared with 88.8% (intention-to-treat, P = 0.036) and 89.7% (per protocol, P = 0.022) of 7-day regimen. There was no statistical difference in terms of side effects between the two groups. CONCLUSIONS: Seven-day ranitidine bismuth citrate-based triple therapy is an effective and well-tolerated treatment for eradication of H. pylori in children.     

Third-line rescue therapy with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures

BACKGROUND: In patients with a first eradication failure, a second (rescue) therapy still fails in > 20% of cases. AIM: To compare rifabutin and levofloxacin rescue regimens in patients with two consecutive Helicobacter pylori eradication failures. METHODS: Patients, in whom first treatment with omeprazole-clarithromycin-amoxicillin and a second trial with omeprazole-bismuth-tetracycline-metronidazole (or ranitidine bismuth citrate with these antibiotics) had failed, received 10 days of treatment with either rifabutin (150 mg b.d.) or levofloxacin (500 mg b.d.), plus amoxicillin (1 g b.d.) and omeprazole (20 mg b.d.). Cure rates were evaluated by the (13)C-urea breath test. RESULTS: Twenty patients received rifabutin, and 20 levofloxacin. All the patients returned for follow-up. Compliance in the rifabutin group was 100%. Four patients in the levofloxacin group did not take the medication correctly (in two cases due to adverse effects: myalgia and rash). Side effects in the rifabutin and levofloxacin groups were reported in 60% and 50% of the cases, respectively. Five patients (25%) treated with rifabutin presented with leucopenia, and six (30%) treated with levofloxacin presented with myalgias. Per-protocol cure rates were 45% (95% confidence interval, 26-66%) in the rifabutin group, and 81% (57-93%) in the levofloxacin group (P < 0.05). Intention-to-treat cure rates were, 45% (26-66%) and 85% (64-95%), respectively (P < 0.01). CONCLUSIONS: After two previous H. pylori eradication failures, a 10-day triple levofloxacin-based rescue regimen is more effective than the same regimen with rifabutin.     

Failure of a 1-day high-dose quadruple therapy for cure of Helicobacter pylori infection

BACKGROUND: The optimal duration of treatment for eradication of Helicobacter pylori has still to be defined. A 1-day high-dose quadruple therapy with a combination of amoxycillin (or tetracycline), metronidazole, a bismuth salt and a proton pump inhibitor has led to eradication rates of 57-77%. In view of the high frequency of metronidazole-resistant strains of H. pylori in Europe, we hypothesized that by using clarithromycin in place of metronidazole and by increasing the dose of proton pump inhibitor, the efficacy of a 1-day high-dose quadruple therapy could be improved. METHODS: Patients were randomized to receive either amoxycillin 1000 mg b.d., clarithromycin 500 mg b.d. and lansoprazole 30 mg b.d. for 7 days, or amoxycillin 2000 mg q.d.s., clarithromycin 500 mg q.d.s., lansoprazole 30 mg t.d.s. and bismuth subcitrate 240 mg q.d.s. for 1 day. RESULTS: It was originally intended to include 100 patients. The first planned interim analysis performed after follow-up was completed for 30 patients revealed H. pylori eradication rates of 80% (12/15) in the 7-day triple therapy group and 20% (3/15) in the 1-day quadruple therapy group, the difference being highly significant (P = 0.003). Because the efficacy of the 1-day treatment was so low, the study was stopped for ethical reasons. Eleven patients who failed with the 1-day treatment were re-treated with the 7-day triple therapy: the eradication rate was 91% (10/11). CONCLUSIONS: One-day high-dose quadruple therapy with amoxycillin, clarithromycin, lansoprazole and bismuth subcitrate is dramatically less effective than the classic 7-day triple therapy with the same antibiotics.     

One-week triple vs. quadruple therapy for Helicobacter pylori infection - a randomized trial

BACKGROUND: Seven-day triple therapy including omeprazole, clarithromycin and amoxicillin has become the treatment of choice for Helicobacter pylori infection. However, 7 days of classical quadruple therapy combining omeprazole, tetracycline, metronidazole and bismuth may be an alternative to triple therapy. AIM: To compare triple vs. quadruple therapy for H.pylori eradication. METHODS: Three hundred and thirty-nine patients with peptic ulcer and H. pylori infection were included in the study. Patients were randomized to receive omeprazole, 20 mg, amoxicillin, 1 g, and clarithromycin, 500 mg, all b.d., or omeprazole, 20 mg b.d., tetracycline chloride, 500 mg, metronidazole, 500 mg, and bismuth subcitrate, 120 mg, all t.d.s. Cure was defined as a negative urea breath test at least 2 months after treatment. RESULTS: Per protocol and intention-to-treat cure rates were 86%[95% confidence interval (CI), 80-91%] and 77% (95% CI, 70-83%) for triple therapy, and 89% (95% CI, 82-93%) and 83% (95% CI, 76-88%) for quadruple therapy. No significant differences between the groups were found in the cure rates, compliance or side-effects. CONCLUSION: One-week triple and quadruple therapy show similar results when used as first-line eradication treatment.     

Therapeutic impact of CYP2C19 pharmacogenetics on proton pump inhibitor-based eradication therapy for Helicobacter pylori

Current regimens for the eradication of Helicobacter pylori consist of a proton pump inhibitor (PPI) plus one or two antibacterial agents, such as amoxicillin (AMPC), clarithromycin (CAM) or metronidazole (MNZ). PPIs are mainly metabolized by S-mephenytoin 4'-hydroxylase (CYP2C19) in the liver. The polymorphism of CYP2C19 is associated with the pharmacokinetics and pharmacodynamics of PPIs. Eradication rates by PPI-based therapies are also affected by this genotype, as well as bacterial resistance to antibiotics. An individualized treatment strategy based on CYP2C19-related pharmacogenetics or pharmacogenomics and bacterial resistance is expected to increase the cure rate of the initial treatment. It is also necessary to recognize that there is a possible drug-drug interaction between some of the drugs used in this treatment regimen.     

艾普拉唑7d三联疗法及10d序贯疗法根除幽门螺杆菌的临床疗效

目的观察艾普拉唑7 d三联疗法及10 d序贯疗法根除幽门螺杆菌（Hp）的临床疗效。方法 142例经电子胃镜、RUT检查证实Hp阳性的慢性胃炎患者,随机分成3组。A组予艾普拉唑5 mg+阿莫西林克拉维酸钾0.914 g+呋喃唑酮0.1g,bid,疗程7 d;B组予艾普拉唑5 mg+阿莫西林克拉维酸钾0.914 g,疗程5 d,继之艾普拉唑5 mg+克拉霉素0.5 g+呋喃唑酮0.1g,疗程5 d,共计10 d,每天均给药2次;C组予埃索美拉唑20 mg+阿莫西林克拉维酸钾0.914 g+呋喃唑酮0.1 g,bid,疗程7 d。疗程结束4周后行¹⁴C-尿素呼气试验(¹⁴C-UBT),观察Hp根除率、症状缓解率及不良反应发生情况。结果 A、B、C组患者症状缓解率比较差异无统计学意义（P>0.05）;Hp根除率分别为60%、58.54%和55.26%,经检验P均>0.05。3组患者均无明显不良反应发生。结论 3组用药方案虽能达到良好的症状缓解率,但Hp根除率均未超过60%,低于理想标准。     

低剂量新三联疗法根除血透患者幽门螺杆菌的疗效及安全性研究

目的研究以低剂量奥美拉唑为基本药物联合低剂量阿莫西林胶囊和克拉霉素片的7日新三联疗法治疗维持性血液透析患者幽门螺杆菌的疗效及安全性。方法选取22例合并幽门螺杆菌感染的血透患者为研究对象,同时选取30例各脏器功能正常的合并幽门螺杆菌患者为对照组,血透患者和对照组的服药剂量为：奥美拉唑胶囊20mg qd、阿莫西林胶囊500mg bid、克拉霉素片250mg qd,疗程均为1周,停药4周后通过组织学及碳呼气试验检测幽门螺杆菌的感染情况,比较两组的幽门螺杆菌根除率。结果血透患者幽门螺杆菌的清除率为81.8%,而非尿毒症患者为80%（P〉0.05）。所有研究对象均未发生严重的不良反应。结论低剂量新三联疗法对根除血透患者幽门螺杆菌是有效及安全的。     

5-day vs. 7-day triple therapy with rabeprazole, clarithromycin and amoxicillin for Helicobacter pylori eradication

AIM: To determine whether a 5-day regimen with rabeprazole, clarithromycin and amoxicillin (RCA) was as effective as a 7-day regimen. METHODS: A total of 139 H. pylori-infected patients were randomized to receive either a 5-day or 7-day course of rabeprazole 10 mg b.d., clarithromycin 400 mg b.d. and amoxicillin 750 mg b.d. Eradication was assessed by CLO test, histology and 13C-urea breath test. RESULTS: On the intention-to-treat basis, eradication rates were 66% (46 out of 70) and 84% (58 out of 69) for the 5- and 7-day regimens, respectively (P < 0.05). Using per protocol analysis, eradication rates were 70% (46 out of 66) and 91% (58 out of 64) for the 5- and 7-day regimens, respectively (P < 0.01). Adverse events, which were observed in 14 patients from each group, caused discontinuation of treatment in only two patients, resulting in excellent compliance. CONCLUSIONS: Our 5-day regimen of RCA yielded inferior results, whereas the 7-day regimen achieved an eradication rate exceeding 90% on the per protocol basis. Therefore, treatment regimens of less than 7 days for proton pump inhibitor-clarithromycin-amoxicillin therapies cannot be recommended.     

A triple therapy regimen after failed Helicobacter pylori treatments

BACKGROUND: Following standard triple therapy, up to 20% of patients require further Helicobacter pylori eradication treatment. Data regarding the efficacy of re-treatment in these patients are scarce. AIM: To evaluate the efficacy of a triple therapy after one or more consecutive treatment failures. METHODS: A total of 51 patients with persistent H. pylori infection after at least one unsuccessful standard 1-week regimen were enrolled in the study. H. pylori infection at entry was assessed by rapid urease test and histology on biopsies from the antrum and the corpus. Patients were given a 2-week triple therapy, comprising ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s., and tinidazole 500 mg b.d. Ranitidine bismuth citrate was given during meals, whilst tetracycline and tinidazole was given after meals. Bacterial eradication was assessed by endoscopy (36 patients) or 13C-urea breath test (15 patients) 4-6 weeks after therapy had ended. RESULTS: All 51 patients completed the study and H. pylori eradication was achieved in 46, with an eradication rate of 90% (95% CI: 82-98). In detail, bacterial eradication was obtained in 96% of patients who had previously failed one course of clarithromycin-amoxicillin based triple therapy, in 88% patients who had failed a clarithromycin-tinidazole based triple therapy, in 83% patients who had failed both treatment schedules, and in the only patient who had failed three consecutive therapeutic attempts. Two patients took the therapy for 9 and 10 days instead of the full 14 day-course. No major side-effects were reported, whilst six (12%) patients complained of mild side-effects. CONCLUSION: This study demonstrates that this triple therapy regimen is effective for re-treatment of H. pylori infection.