Alternative and rescue treatment regimens for Helicobacter pylori eradication

Eradication therapy has been incorporated into clinical practice. The regimens currently recommended for first-line treatment include a 2-week bismuth-based triple therapy (mainly in developing countries), a 1 - 2 week proton pump inhibitor (PPI)-based triple therapy and a 1-week ranitidine bismuth citrate (RBC)-based triple therapy. However, these regimens fail to eradicate Helicobacter pylori in up to 20% of patients due to poor compliance, inadequate treatment duration, smoking, old age and bacterial resistance to nitroimidazoles and/or macrolides in particular. Therefore, alternative regimens that avoid nitroimidazoles and/or macrolides or overcome bacterial resistance to these drugs, improve compliance, minimise side effects and/or reduce costs have been evaluated. One-week quadruple therapy, which adds a PPI or histamine receptor 2-blocker to bismuth-based triple therapy, usually achieves an eradication rate of 90% when used as an alternative first-line therapy but the efficacy decreases when used as a rescue therapy. Several new triple therapies that may be used as alternative and/or rescue therapies have been evaluated. Among these are furazolidone-based (furazolidone plus an antibiotic and a bismuth salt, a PPI or RBC), fluoroquinolone-based (levofloxacin or moxifloxacin plus an antibiotic and a PPI) and ecabet sodium-based (ecabet plus two antibiotics) triple therapies. Recently, rifabutin has been used in combination with a PPI and amoxycillin as a rescue therapy, with satisfactory eradication rates. In addition, a number of new antimicrobial agents are currently under investigation in in vitro studies but the clinical values of these agents needs to be confirmed.     

Alternative and rescue treatment regimens for Helicobacter pylori eradication

Eradication therapy has been incorporated into clinical practice. The regimens currently recommended for first-line treatment include a 2-week bismuth-based triple therapy (mainly in developing countries), a 1 – 2 week proton pump inhibitor (PPI)-based triple therapy and a 1-week ranitidine bismuth citrate (RBC)-based triple therapy. However, these regimens fail to eradicate Helicobacter pylori in up to 20% of patients due to poor compliance, inadequate treatment duration, smoking, old age and bacterial resistance to nitroimidazoles and/or macrolides in particular. Therefore, alternative regimens that avoid nitroimidazoles and/or macrolides or overcome bacterial resistance to these drugs, improve compliance, minimise side effects and/or reduce costs have been evaluated. One-week quadruple therapy, which adds a PPI or histamine receptor 2-blocker to bismuth-based triple therapy, usually achieves an eradication rate of 90% when used as an alternative first-line therapy but the efficacy decreases when used as a rescue therapy. Several new triple therapies that may be used as alternative and/or rescue therapies have been evaluated. Among these are furazolidone-based (furazolidone plus an antibiotic and a bismuth salt, a PPI or RBC), fluoroquinolone-based (levofloxacin or moxifloxacin plus an antibiotic and a PPI) and ecabet sodium-based (ecabet plus two antibiotics) triple therapies. Recently, rifabutin has been used in combination with a PPI and amoxycillin as a rescue therapy, with satisfactory eradication rates. In addition, a number of new antimicrobial agents are currently under investigation in in vitro studies but the clinical values of these agents needs to be confirmed.     

Moxifloxacin-based strategies for first-line treatment of Helicobacter pylori infection

BACKGROUND: Standard anti-Helicobacter pylori therapy may not achieve a satisfactory eradication rate. Fluoroquinolones, such as moxifloxacin, are safe and promising agents for H. pylori eradication. AIM: To compare the efficacy of two 1-week moxifloxacin-based H. pylori eradication regimens with two standard treatments. METHODS: Three hundred and twenty H. pylori-positive subjects were randomized into four groups to receive: moxifloxacin, amoxicillin, esomeprazole (Group MAE); moxifloxacin, tinidazole and esomeprazole (Group MTE); standard triple therapies with clarithromycin, amoxicillin and esomeprazole (Group CAE) or tinidazole (Group CTE) for 7 days. H. pylori status was re-assessed 6 weeks after the end of therapy by 13C urea breath test. RESULTS: Three hundred and twenty patients completed the efficacy analysis per protocol; H. pylori eradication rate in group MTE was 90% (72 of 80) and 92% (72 of 78), in group MAE was 88% (70 of 80) and 89%, (70 of 79) in Group CAE was 73% (58 of 80) and 78% (58 of 74), and in Group CTE was 75% (60 of 80) and 79% (60 of 76), respectively, in intention-to-treat and in per protocol analyses. Eradication rates of moxifloxacin-based triple therapies were significantly higher than that observed using standard triple schemes. The incidence of side effects was significantly lower in moxifloxacin groups than in control groups. CONCLUSIONS: Seven-day moxifloxacin-based triple therapies provide optimal eradication rates with a good compliance when compared with the standard triple therapy schemes.     

Resistance of Helicobacter pylori to antibiotics and its impact on treatment options.

The treatment of Helicobacter pylori infection is jeopardized by resistance to the antibiotics used, which turns out to be the main risk factor for failure. Resistance is due to point mutations. For clarithromycin only two sites in the 23S rRNA sequence are concerned and can be easily detected by molecular methods, while for metronidazole several mutations on rdxA and other genes can be responsible and so do not allow such detection. The situation for the rare cases of amoxicillin resistance is not fully determined. The impact of resistance on the clinical outcome is dramatic for clarithromycin while it only decreases the success by 20% for metronidazole.     

Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure

BACKGROUND: A quadruple therapy has been generally recommended as rescue regimen for Helicobacter pylori eradication failures. AIMS: To systematically review the efficacy and tolerance of levofloxacin-based rescue regimens, and to conduct a meta-analysis of studies comparing these regimens with quadruple therapy for H. pylori eradication failures. METHODS: Selection of studies -- levofloxacin-based rescue regimens. For the meta-analysis, randomized-controlled trials comparing levofloxacin-based and quadruple regimens. Search strategy -- electronic and manual. Assessment of study quality -- independently by two reviewers. Data synthesis --'intention-to-treat' eradication rate. RESULTS: Mean eradication rate with levofloxacin-based regimens was 80%. Ten-day regimens were more effective than 7-day combinations (81% vs. 73%; P < 0.01). The meta-analysis showed better results with levofloxacin than with the quadruple combination (81% vs. 70%; OR = 1.80; 95% CI = 0.94-3.46). This difference reached statistical significance and heterogeneity markedly decreased when a single outlier study was excluded or when only high-quality studies were considered. Meta-analysis showed less adverse effects with levofloxacin than with quadruple regimen, both overall (19% vs. 44%; OR = 0.27; 95% CI = 0.16-0.46) and regarding severe adverse effects (0.8% vs. 8.4%; OR = 0.20; 95% CI =0.06-0.67). CONCLUSIONS: After H. pylori eradication failure, levofloxacin-based rescue regimen is more effective and better tolerated than the generally recommended quadruple therapy. A 10-day combination of levofloxacin-amoxicillin-proton pump inhibitor constitutes an encouraging second-line alternative.     

Empirical rescue therapy after Helicobacter pylori treatment failure: a 10-year single-centre study of 500 patients

Background Several ‘rescue’ therapies have been recommended to eradicate Helicobacter pylori, but they still fail in >20% of the cases, and these patients constitute a therapeutic dilemma. Aim To evaluate the efficacy of different ‘rescue’ therapies empirically prescribed during 10 years to 500 patients in whom at least one eradication regimen had failed to cure H. pylori infection. Methods Design : Prospective single‐centre study. Patients : Consecutive patients in whom at least one eradication regimen had failed. Intervention : Rescue regimens included: (i) quadruple therapy with omeprazole–bismuth–tetracycline–metronidazole; (ii) ranitidine bismuth citrate–tetracycline–metronidazole; (iii) omeprazole–amoxicillin–levofloxacin; and (iv) omeprazole–amoxicillin‐rifabutin. Antibiotic susceptibility was unknown (rescue regimens were chosen empirically). Outcome : Eradication was defined as a negative ¹³C‐urea breath test 4–8 weeks after completing therapy. Results Five hundred patients were included (76% functional dyspepsia, 24% peptic ulcer). Compliance rates with first‐, second‐ and third‐line regimens were 92%, 92%, and 95%, respectively. Adverse effects were reported by 30%, 37%, and 55% of the patients receiving second‐, third‐, and fourth‐line regimens. Overall, H. pylori cure rates with the second‐, third‐, and fourth‐line rescue regimens were 70%, 74%, and 76%, respectively. Cumulative H. pylori eradication rate with four successive treatments was 99.5%. Conclusion It is possible to construct an overall treatment strategy to maximize H. pylori eradication, on the basis of administration of four consecutive empirical regimens; thus, performing bacterial culture even after a second or third eradication failure may not be necessary.     

7-day rescue therapy with ranitidine bismuth citrate after Helicobacter pylori treatment failure

BACKGROUND: Quadruple rescue therapy requires a complex scheme with four drugs. AIM: To evaluate the efficacy of ranitidine bismuth citrate-tetracycline-metronidazole rescue regimen, and to compare two different metronidazole dose schemes. METHODS: Prospective multicentre study including proton-pump inhibitor + clarithromycin + amoxicillin failures. Rescue regimen included two 7-day treatment: (i) ranitidine bismuth citrate (400 mg b.d.)-tetracycline (500 mg q.d.s.)-metronidazole (500 mg t.d.s.; RTM1); or (ii) the same regimen but with metronidazole 250 mg q.d.s. (RTM2). Eradication was confirmed with (13)C-urea breath test. RESULTS: A total of 150 patients were included (58 RTM1, 92 RTM2). All patients but two (one in each group) returned after treatment. About 86% in group RTM1 and 95% in RTM2 correctly took all the medications (P = 0.076). Per-protocol eradication rates with RTM1 and RTM2 were 74 (95% CI: 60-84) and 69% (59-78). The intention-to-treat eradication rates were 64 (51-75) and 70% (59-78; P > 0.05). The type of regimen was not associated with eradication in the multivariate analysis. Adverse effects were more frequent with RTM1 (41%) than with RTM2 (30%; P > 0.05). CONCLUSION: Seven-day triple rescue therapy with ranitidine bismuth citrate-tetracycline-metronidazole is effective for Helicobacter pylori eradication, and represents an encouraging alternative to quadruple therapy, with the advantage of simplicity. The administration of metronidazole every 6 h (together with tetracycline), and at a low dose (250 mg), achieves similar efficacy and is probably associated with a better compliance and a lower incidence of adverse effects.     

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.     

Role of antibiotic sensitivity testing before first-line Helicobacter pylori eradication treatments

BACKGROUND: The resistance of Helicobacter pylori to antibiotics has been advocated as a major cause of treatment failure, and antimicrobial sensitivity testing has been proposed to improve efficacy; however, its role before first-line therapy has not been investigated in detail. AIM: To assess whether antimicrobial sensitivity testing improves the eradication rate of first-line anti-Helicobacter treatments and to compare the effectiveness of ranitidine bismuth citrate and omeprazole in the presence of H. pylori resistance to antibiotics. METHODS: Two hundred and forty-two patients were assigned to either empirical or antimicrobial sensitivity testing-based treatment; within each group, subjects were further randomized to receive ranitidine bismuth citrate, 400 mg b.d., tinidazole, 500 mg b.d., and clarithromycin, 500 mg b.d., or omeprazole, 20 mg b.d., clarithromycin, 500 mg b.d., and amoxicillin, 1 g b.d., for 1 week, with substitution of the resistant antibiotic in the antimicrobial sensitivity testing-based treatment group. RESULTS: Eradication rates were 67% [confidence interval (CI), 55-79%] in the empirical treatment group and 76% (CI, 65-87%) in the antimicrobial sensitivity testing-based group (P=N.S.). The overall success rate was 60% (CI, 51-69%) with omeprazole and 82% (CI, 73-91%) with ranitidine bismuth citrate (P<0.03); the latter overcame antibiotic resistance in 12 of 15 strains vs. zero of eight strains by omeprazole. CONCLUSIONS: Antimicrobial sensitivity testing before first-line treatment does not improve the eradication rate, which is greater when ranitidine bismuth citrate is included in the treatment.     

Helicobacter pylori infection--current treatment practice

Helicobacter pylori infection, which is present in 30 - 60% of the population in developed countries and in more than 60% in developing countries, is established to be a major cause of gastritis, peptic ulcer disease and gastric cancer. Eradication therapy has been incorporated into clinical practice over the past 15 years. Treatment regimens include a 2 week bismuth-based triple therapy (a bismuth compound plus metronidazole, tetracycline or amoxycillin), a 1 week proton-pump inhibitor (PPI)-based triple therapy and a 1 week ranitidine bismuth citrate (RBC)-based triple therapy (a PPI or RBC plus any two of the three antibiotics, metronidazole, amoxycillin and clarithromycin). These regimens achieve eradication rates of > 80%. H. pylori resistance to metronidazole and clarithromycin decreases the clinical efficacy of most regimens, despite the high eradication rates for resistant strains achieved by the RBC-triple therapy in some recent trials. The dose of antibiotics (especially clarithromycin) and the duration of treatment may also influence the eradication rate. Doctors' beliefs impact on clinical practice and, thus, influence the clinical application of eradication therapy. Whereas peptic ulcer disease and primary gastric low-grade B-cell mucosa-associated lymphoid tissue lymphoma (MALToma) have become established as definite indications for eradication therapy, there remain controversies surrounding non-ulcer dyspepsia, gastro-oesophageal reflux disease, atrophic gastritis, intestinal metaplasia, use of non-steroidal anti-inflammatory drugs (NSAIDs) and H. pylori-related extradigestive diseases.     

含四环素和甲硝唑四联疗法对青霉素过敏患者幽门螺杆菌感染的疗效分析

目的:分析含四环素和甲硝唑四联疗法一线治疗青霉素过敏患者Hp(幽门螺杆菌)感染的疗效及安全性。方法:纳入2016年4月—2019年4月收治的82例青霉素过敏Hp感染患者,随机平均分为对照组和观察组,各41例。对照组采用阿莫西林、克拉霉素、埃索美拉唑三联治疗,观察组采用甲硝唑、四环素、枸橼酸铋钾、埃索美拉唑四联治疗,对比两组Hp根除率、临床疗效、不良反应发生情况。结果:观察组Hp根除率(68.29%,28/41)以及临床总有效率(95.12%,39/41)高于对照组(39.02%,16/41、68.29%,28/41),差异有统计学意义P<0.05;观察组不良反应发生率(7.32%,3/41)低于对照组(9.76%,4/41),差异无统计学意义P>0.05。结论:含四环素、甲硝唑四联疗法可显著提高青霉素过敏Hp感染患者Hp根除率,促进嗳气等症状消退,且不良反应较少,值得推广。     

左氧氟沙星对幽门螺杆菌感染补救治疗疗效观察

目的探讨左氧氟沙星三联方案对幽门螺杆菌感染进行补救治疗的疗效。方法64例患者经胃镜以及病理检查证实为消化性溃疡,并且经一线治疗方案根除失败,给予雷贝拉唑10mg,左氧氟沙星200mg,阿莫西林1000mg,2次／d,疗程7d。治疗4周后行^14C呼气试验。结果64例患者中56例HP阴性,根除率为87．5％,其中仅有2例出现轻度不良反应。结论对HP根除治疗失败的患者左氧氟沙星为安全有效的补救治疗方案。     

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.     

Helicobacter pylori infection and eradication in paediatric patients

Helicobacter pylori is now recognised to be typically acquired during childhood. Studies also indicate that the infection is frequently lost in childhood; however, it is still unclear whether this is related to the use of antibacterials, the natural history of the infection, or both. H. pylori colonises gastric mucosa and is causally related to chronic gastritis and peptic ulcer disease in both children and adults. Successful eradication of H. pylori has resulted in the healing of duodenal ulcers and the lowering of the ulcer relapse rate in children. Therapy to cure the infection should be started in all children with peptic (duodenal or gastric) ulcer who are still infected. The ideal anti-H. pylori regimen should be safe, cheap, easy to comply with, well tolerated by children and able to achieve a high cure rate. Although US data are lacking, it is anticipated that the treatment regimen for children should be similar to that in adults (a triple therapy regimen that combines a proton pump inhibitor with 2 antimicrobial agents for 14 days). It is inappropriate to prescribe anti-H. pylori therapy without a firm diagnosis. The use of multiple antibacterials in a paediatric patient with an ulcer but without H. pylori infection cannot provide any benefit to the patient or the community. Such an approach only provides the possibility for adverse effects, for example development of antibacterial resistance among bystander bacteria. It is very important to confirm the diagnosis of H. pylori infection. The [13C]urea breath test is the noninvasive method of choice to determine H. pylori status in children and the ideal test for post-therapy testing. There is a need for post-therapy confirmation because of the likelihood of poor outcome for some treatment regimens, which is why post-therapy testing should be the standard of care. There is weak and inconsistent evidence of an association between H. pylori infection and recurrent abdominal pain (RAP) in children, in part because of the unclear definition of RAP in the literature. Therefore, there is still considerable debate regarding the treatment of infected children with RAP.     

The treatment of Helicobacter pylori infection

Indications for eradication of Helicobacter pylori infection have widened since the National Institutes of Health consensus conference in 1994. It is argued that they should now include infected patients with non-ulcer dyspepsia, those concerned about the risk of gastric cancer, patients with gastric lymphoma, and those requiring long-term treatment with a proton pump inhibitor. Problems with existing clinical trials are discussed, and the results of different treatment regimens are discussed. It is proposed that future eradication trials should investigate H. pylori -infected subjects identified by serology, rather than ulcer patients, and that eradication is proved only by a pair of ¹³C-urea breath tests.     

Randomized trial of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of Helicobacter pylori resistant to both metronidazole and clarithromycin

BACKGROUND: The clinical management of Helicobacter pylori infected patients who failed standard eradication therapies remains a challenge. AIM: To investigate the efficacy of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of H. pylori, and the correlation between cytochrome P450 2C19 (CYP2C19) polymorphisms and treatment outcome. METHODS: Patients infected with H. pylori resistant to both metronidazole and clarithromycin (n = 145) were randomized to either esomeprazole 20 mg, rifabutin 150 mg and amoxicillin 1 g, each given b.d. for 7 days (ERA), or to omeprazole 40 mg and amoxicillin 1000 mg, each given t.d.s. for 14 days (OA). Crossover therapy was offered in cases of persistent infection. CYP2C19 polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphism. RESULTS: Intention-to-treat and per-protocol eradication rates were: ERA 74% (62.4-83.6) and 78% (66.7-87.3); high-dose OA 70% (57.5-79.7) and 75% (62.5-84.5). Crossover therapy was successful in seven of 10 patients with ERA and in eight of 10 patients with OA. Premature discontinuation of treatment occurred in 2% and 5% of patients, respectively. There was only a non-significant trend to lower eradication rates in homozygous extensive metabolizers. CONCLUSIONS: Triple therapy with esomeprazole, rifabutin and amoxicillin and high-dose omeprazole/amoxicillin are comparable and effective and safe for rescue therapy of H. pylori regardless of the patient's CYP2C19 genotype.     

Helicobacter pylori: strategies for treatment

Helicobacter pylori (Hp) is a Gram-negative bacteria able to live in the human stomach, a very surprising fact considering the acid environment of gastric mucosa. Identified by Marshall and Warren in 1982 [1,2], this bacterium seems aetiologically related to many gastric diseases, previously known as ‘acid related diseases’. Compelling evidence demonstrates that Hp is the most important aetiological agent of gastritis [3], the principal causal factor in peptic ulcer [4], contributes to the genesis of gastric cancer [5] and has a critical role in the development of many mucosa-associated lymphoid tissue (MALT) lymphomas [6]. Although experimental data have recently provided hard evidence to support the role of Hp in the genesis of gastritis, ulcer and carcinoma [7], a critical argument for Hp generating peptic ulcer disease has been, in fact, the change in the natural history of peptic ulcer that follows the cure of the infection.     

Strategies to treat patients with antibiotic resistant Helicobacter pylori

Increased resistance to clarithomycin and metronidazole, the two main antibiotics used to treat Helicobacter pylori infection, has led to a search for alternatives to the proton pump inhibitor based triple therapies commonly used. The main rescuse therapy is a bismuth-based quadruple therapy. However, triple therapies with tetracycline and metronidazole or amoxicillin and metronidazole can be considered in the case of clarithomycin resistance. They can also be used in the case of metronidazole resistance by increasing the dose and duration of metronidazole. The only therapy without clarithomycin and metronidazole includes rifabutin and amoxicillin. Dual therapies with amoxicillin and a proton pump inhibitor at high dose can also be used.