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.

Helicobacter pylori (H. pylori) infection is the main cause of gastritis, gastroduodenal ulcer disease, gastric adenocarcinoma and mucosa-associated tissue lymphoma. The Maastricht III Consensus Report has recommended that proton pump inhibitor (PPI)-clarithromycin-amoxicillin or metronidazole treatment for 7 to 14 d is the first choice treatment for H. pylori infection[1]. As a general rule for the treatment of other infectious diseases, clinicians should prescribe therapeutic regimens that have a per-protocol eradication rate ≥ 90% for anti-H. pylori therapy[2]. However, several large clinical trials and meta-analyses have shown that the eradication rate of the standard triple therapy has generally declined to unacceptable levels (i.e., 80% or less) recently[3,4]. In some European countries, the success rates are disappointingly low with values of only 25%-60%[5,6]. The reasons for this fall in efficacy with time are uncertain but may be related to the increasing incidence of clarithromycin-resistant strains of H. pylori [3,4,7,8]. This article will review the most recent literature in an attempt to introduce novel first-line eradication regimens with a per-protocol eradication rate exceeding 90% and rescue regimens with an eradication rate exceeding 80%.

The main reasons for eradication failure of H. pylori infection include antibiotic resistance, poor compliance and rapid metabolism of PPI[3]. Clarithromycin resistance is the major cause of eradication failure for standard triple therapy[8]. Pooled data from 20 studies involving 1975 patients treated with standard triple therapy showed an eradication rate of 88% in clarithromycin-sensitive strains vs 18% in clarithromycin-resistant strains[8]. Therefore, the background rate of clarithromycin resistance is critically important as its presence negatively impacts the efficacy of standard triple therapy. A systemic review showed that the rate of clarithromycin-resistant strains ranged from 49% (Spain) to 1% (Netherland) worldwide[9]. In areas with clarithromycin resistance of < 10% [i.e., Netherland, Sweden, Ireland, Germany, Malaysia, Taiwan (South)], it is still possible to employ a standard triple therapy to achieve a per-protocol eradication rate > 90%. However, standard triple therapies should be abandoned in areas with clarithromycin resistance ≥ 20% [i.e., Spain, Turkey, Italy (Central), Alaska, China, Japan, Cameroon] because the per-protocol eradication rates of standard therapies are often less than 85% and the intention-to-treat eradication rates are usually less than 80%[2-8,10].

Recently, several studies showed that a novel 10-d sequential therapy can achieve a promising success rate of 90%-94%[11-13]. The regimen consists of a 5-d dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) followed by a 5-d triple therapy with a PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.). Gatta et al[12] reported a rigorous systematic review that identified 13 trials evaluating 3271 patients. The data showed that sequential therapy achieved a 12% better absolute eradication rate than the standard triple therapy. A randomized, double-blind, placebo-controlled trial demonstrated that the per-protocol eradication rates of sequential therapy and standard triple therapy for clarithromycin-resistant strains were 89% and 29%, respectively[11]. However, it should be noted that most of the studies concerning sequential therapies were conducted in Italy. A recent trial in Korea showed that the per-protocol eradication rates of sequential therapy and standard triple therapy were 86% and 77%, respectively. The two therapies had comparable eradication rates[14]. There is, therefore, a clear need for well-designed randomized trials from countries other than Italy to determine the real advantages of this novel therapy.

Concomitant therapy is another novel regimen which was proved successful in the presence of clarithromycin resistance[15]. This is a 4-drug regimen containing a PPI (standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.) and metronidazole (500 mg, b.i.d.) which are all given for the entire duration of therapy. This therapy is superior to standard triple therapy for H. pylori eradication[15]. It is also less complex than sequential therapy as this regimen does not involve changing drugs halfway through. A head-to-head non-inferiority trial of 10-d sequential and 10-d concomitant therapy showed that they were equivalent (93.1% vs 93.0% by per-protocol analysis)[16].

Recently, Hsu et al[17] reported a hybrid (dual-concomitant) therapy consisting of a dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) for 7 d followed by a concomitant quadruple therapy with a PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.), clarithromcyin (500 mg, b.i.d.) and metronidazole (500 mg, b.i.d.) for 7 d. The new therapy extends the duration of amoxicillin treatment to 14 d and concomitantly employs three antibiotics in the last 7 d of the treatment course. In 117 H. pylori-infected subjects, the novel therapy provided excellent eradication rates of 99% and 97% according to per-protocol and intention-to-treat analysis, respectively. It is important to note that the new therapy has a high efficacy in the treatment of H. pylori strains harboring dual resistance to clarithromycin and metronidazole. Several studies have shown that sequential therapy is ineffective in clearing H. pylori with dual resistance[8]. The prolonged treatment duration of amoxicillin to 14 d in the hybrid therapy might account for the higher eradication rate in the face of H. pylori stains with dual resistance to clarithromycin and metronidazole. Further studies in populations with different levels of prevalence of clarithromycin and metronidazole resistance are needed to assess the efficacy of the new regimen.

Bismuth-containing quadruple therapy is an alternative first choice treatment for H. pylori infection recommended by the Maastricht III Consensus Report[1] and the Second Asia-Pacific Consensus Guidelines for H. pylori Infection[18]. Two studies each with more than 100 patients have shown eradication rates of > 90% with this combination given for 10 d[19,20]. Recently, Malfertheiner et al[21] compared the efficacy of a 10-d bismuth-containing quadruple therapy (omeprazole, bismuth, metronidazole and tetracycline) and a 7-d triple therapy (omeprazole, clarithromycin and amoxicillin). The data indicated that the former had a higher eradication rate than the latter (93% vs 70% by per-protocol analysis). Currently, the optimal treatment duration of bismuth-containing quadruple therapy remains unclear but a 10-14 d course is most commonly employed in clinical practice[22].

Based on a large body of published clinical trials, a quinolone-based triple therapy is effective in the first-line therapy of H. pylori infection. The eradication rates of levofloxacin-based triple therapy ranged from 72% to 96%[23]. The regimen might be considered in populations with clarithromycin resistance greater than 15%-20% and quinolone resistance less than 10%[23]. However, a quinolone-based triple therapy is not generally recommended as first-line therapy at the moment due to concerns about the rising prevalence of quinolone-resistant strains in the first-line and second-line anti-H. pylori therapies. Furthermore, greater use of quinolone would likely result in the development of more quinolone-resistant pathogens causing respiratory and urogenital tract infections.

The Maastricht III Consensus Report recommended a bismuth-containing quadruple therapy regimen comprising a PPI, bismuth, metronidazole and tetracycline as second-line therapy[1]. This rescue regimen fails in 5%-63% of patients with an average eradication rate of 76% on the basis of a pooled analysis[24-26]. The prevalence of metronidazole-resistant strains, dose and duration of rescue therapy seem to be important variables for the efficacy of this treatment. In bismuth-containing quadruple regimens, PPI should be prescribed in the usual dose and twice a day, colloidal bismuth subcitrate 120 mg four times a day, tetracycline 500 mg four times a day and metronidazole 500 mg three times a day. A report from Korea showed that the two-week bismuth-containing quadruple therapy was more effective than the 1-wk treatment (83% vs 64% by intention-to-treat analysis) [27].

Levofloxacin-based triple therapy consisting of levofloxacin (500 mg, q.d.), amoxicillin (1 g, b.i.d.) and a PPI (standard dose, b.i.d.) represents an encouraging strategy for second-line therapy. A meta-analysis by Saad et al[28] showed that a 10-d regimen of levofloxacin-based triple therapy was superior to a 7-d bismuth-based quadruple therapy. Another meta-analysis by Gisbert et al[29] demonstrated a borderline significance of higher H. pylori cure rates with levofloxacin-based triple regimens compared with quadruple therapies (81% vs 70%). Additionally, the study revealed fewer adverse effects with levofloxacin than with quadruple regimens (19% vs 44%). However, it is noteworthy that levofloxacin-based triple therapies seem less effective in Asia. Two randomized controlled trials from Taiwan and Hong Kong showed that levofloxacin-based triple therapy was comparable to quadruple therapy in the eradication efficacy of second-line therapy.[30,31]The second-line therapy for patients who fail to eradicate H. pylori new first-line therapies (such as sequential therapy, concomitant therapy or hybrid therapy) remains unclear. However, a recent study showed that a levofloxacin-based triple therapy with lansoprazole (30 mg, b.i.d.), levofloxacin (250 mg, b.i.d) and amoxicillin (1 g, b.i.d.) achieved a high eradication rate in patients who failed to clear H. pylori with sequential therapy[32].

Currently, a standard empirical third-line therapy is lacking. The Masstricht III Consensus Report recommended using bacterial culture with antimicrobial sensitivity tests to select antibiotics for third-line regimens[1]. Cammarota et al[33] analyzed H. pylori isolates from 94 consecutive patients in whom H. pylori infection had persisted after two eradication attempts. Ninety-four subjects (100%) were resistant to metronidazole, 89 (95%) to clarithromycin, 29 (31%) to levofloxacin and five (5%) to tetracycline. No resistance to amoxicillin was found in any of the patients. Patients were then treated with a culture-guided, third-line regimen: 89 patients with a 1-wk quadruple regimen including omeprazole, bismuth, doxycycline and amoxicillin, and five patients with a 1-wk triple regimen containing omeprazole, amoxicillin and levofloxacin or clarithromycin. Overall, H. pylori eradication was obtained in 90% of subjects treated by the culture-guided therapy.

However, it has been reported that the sensitivity of culture is less than 60%[34]. Additionally, in vitro antimicrobial sensitivity does not necessarily lead to eradication in vivo and vice versa. Recently, several empirical third-line therapies have been proposed to treat refractory H. pylori infection. A 10-d quadruple therapy comprising rabeprazole (20 mg b.i.d.), bismuth subcitrate (300 mg, q.i.d.), amoxicillin (500 mg, q.i.d.), and levofloxacin (500 mg, q.d.) achieved an eradication rate of 84% by both intention-to-treat analysis and per-protocol analysis in patients who failed to eradicate H. pylori with standard triple therapy and bismuth-based quadruple therapy[35].

Rifabutin is an antituberculous agent, which can be administered with PPI and amoxicillin for 10-14 d to eradicate H. pylori One study used rifabutin (150 mg, b.i.d.), amoxicillin (1 g, b.i.d.) and omeprazole (20 mg, b.i.d.) for 14 d as a third-line therapy[36]. Per-protocol and intention-to-treat eradication was achieved in 11/14 patients (79%). It is noteworthy that serious myelotoxicity and ocular adverse events have been reported with rifabutin therapy[37]. In addition, greater use of rifabutin would likely result in the development of more resistant strains to Myocbacterium tuberculosis and Mycobacterium avium.

Furazolidone-based therapy is another useful option to treat refractory H. pylori infection. A 7-d quadruple therapy consisting of lansoprazole (30 mg, b.i.d.), tripotassium dicitratobismuthate (240 mg, b.i.d.), furazolidone (200 mg, b.i.d.) and tetracycline (1 g, b.i.d.) has a high efficacy in third-line therapy with an eradication rate of 90% by both intention-to-treat and per-protocol analysis[38]. The recommended regimens for H. pylori therapies are summarized in Table 1.

In conclusion, with the rising prevalence of antimicrobial resistance, the treatment success of standard triple therapy has recently declined to unacceptable levels. 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 or a levofloxacin-based triple therapy can be employed as rescue treatment. 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 salvage treatment. With regard to third-line therapy of H. pylori infection, a culture-guided therapy has been recommended. If antimicrobial sensitivity data are unavailable, an empirical therapy (such as levofloxacin-based, rifabutin-based, or furazolidone-based therapies) can be employed to terminate H. pylori infection. In spite of many emerging therapies, none have been included into current major consensuses so far. Hopefully, the upcoming Maastricht IV meeting will bring a wind of change.