Despite the number of studies, the optimal treatment for H. pylori infection has not been found and routine clinical treatments are usually triple or quadruple antibiotic therapies[13].

Prevalence of antibiotic resistance to various antimicrobials varies in different geographical regions, and is associated with the consumption of antibiotics in those areas[14]. The most commonly used antibiotics are imidazole (metronidazole or tinidazol), macrolide (clarithromycin or azithromycin), tetracycline, amoxicillin, rifabutin and furazolidon[9,15]. Bismuth, a heavy metal with anti-H. pylori activity is used in bismuth-based quadruple therapy and seems almost totally maintains high eradication rates, independent of antibiotic resistance[16,17].

A survey of antibiotic resistance to the four commonly used antibiotics against H. pylori in Vietnam from July 2012 to January 2014 showed that 42.4% were resistant to clarithromycin, 41.3% to levofloxacin, 76.1% to metronidazole, and 1.1% to amoxicillin[18].

A cross-sectional study with collection of gastric biopsies in the United States from 2009 through 2013 showed the prevalence of H. pylori resistance to levofloxacin was 31.3%, to metronidazole it was 20.3%, to clarithromycin it was 16.4%, and to tetracycline it was 0.8%. No isolate exhibited amoxicillin resistance, but clarithromycin resistance increased from 9.1% in 2009-2010 to 24.2% in 2011-2013[19].

Results on antibiotic resistance in two time, the first time period (2000) and the second period (2010) in Greece revealed during the first time period 30% and 0% of patients were infected with clarithromycin or quinolone-resistant strains but, in the second time period (2010), the resistance rate to clarythromycin or quinolone increased to 42% and 5.3%, respectively[20].

A systematic review of literatures on H. pylori antibiotic resistance carried out in Iran within the time span of 1997 to 2013. The incidance of H. pylori resistance to various antibiotics, including metronidazole, clarithromycin, furazolidone, amoxicillin, tetracycline, ciprofloxacin, levofloxacin was 61.6%, 22.4%, 21.6%, 16.0%, 12.2%, 21.0% and 5.3%, respectively[21]. Compared the results from different countries showed prevalence of H. pylori resistance to various antibiotics is not the same and may be changed in time even in the same population.

Overwhelming evidence indicates that in order to determine an appropriate antibiotic in drug regimen against H. pylori infections, information on antibiotic susceptibility of the bacterium within different geographical areas of world is required.

H. pylori treatment involves combination of antimicrobial and anti-secretory agents for 7 to 14 d. PPIs inhibit the parietal cell H⁺/K⁺ adenosine triphosphatase (ATPase), the enzyme of canalicular membrane of gastric parietal cells which is responsible for the last step in gastric acid secretion[22,23]. Inhibition of this enzyme is more efficient than H2-receptor antagonists in suppressing gastric acid secretion[24].

At low pH, gastric PPIs as acid-activated pro drug transform to a spiro intermediate of dihydrobenzimidazole, then undergoes aromatization to a sulfenic acid followed by dehydration to form a tetracyclic sulfonamide[25]. PPIs bind to different cysteines in the α subunit of the H⁺/K⁺ ATPase and inhibits the enzyme[26,27].

PPI with anti-secretory effect declines the acid production from stomach, which allows the tissues damaged by the infection to heal. PPI can also make acid-labile antibiotics more stable by elevation of the gastric pH, and also may alter luminal concentrations of antibiotics by transporting of antibiotics from plasma to gastric juices and elevating the success rate of eradication[28,29].

The differences in pharmacokinetics for example elimination half-life, bioavailability and metabolism of currently available PPIs may translate into differences in clinical outcomes[30]. All PPIs have good oral bioavailability and all PPIs except tenatoprazole undergo hepatic metabolism via the CYP isoforms CYP2C19 and CYP3A4, therefore with the elimination half-lives ranging from 1 to 1.5 h have the short elimination rate[31,22]. Genetic polymorphism in CYP2C19 plays an important role in the metabolism of individual PPIs to different amounts, thereby affecting therapeutic effectiveness[32].

Several studies have produced conflicting data on eradication rates of H. pylori among CYP2C19 genotypes taking PPI based regimens[33]. Some examples of the CYP2C19 pathway’s relative impact on the PPI metabolism have been demonstrated. The lansoprazole-based or omeprazole-based triple therapies were affected by CYP2C19 genotype status, whereas esomeprazole-based or rabeprazole-based triple therapies were not[30,33,34]. The dosage and duration of treatment of PPIs for adults correspond to those that are able to suppress gastric acid secretion. Long-term omeprazole therapy in H. pylori positive patients induced changes in mucosal inflammation and glandular atrophy[35]. Hyper gastrinemia induced by PPI administration and corpus atrophic gastritis in patients with H. pylori infection might promote the development of gastric cancer[36].

Dual treatments including a PPI with either clarithromycin or amoxicillin or metronidazole were popular during the previous decades. Dual therapy is now obsolete due to lack of efficacy of clarithromycin and metronidazole[37]. On the contrary, worldwide primary and secondary resistance to amoxicillin of H. pylori is generally low and rare respectively, although it is a usual medication in standard triple therapy and therefore it is suitable for use in the dual therapy of H. pylori infection[9].

Amoxicillin is effective at high (> 5.5) pH environments. According to some controversial data, PPI in standard doses wouldn't be able in rapid metabolizers to achieved enough pH inhibition for effective antibiotic activity in mucus of gastric, determining lower eradication rates after therapy with regimens containing standard dose of PPI[38,39].

Several studies assumed that there is direct and indirect demonstration which stated high-dose PPI, above the common standards, could ameliorate H. pylori treatment cure rates. The general idea in the back of high-dose PPI plus amoxicillin treatment is to overcoming resistance by altering the environment in which dormant H. pylori settled, thus inciting the bacteria to get in the replicative state and become sensitive to the antibiotics[40,41]. In spite of the advantage of the low resistance rate to amoxicillin and theoretical advantages of high-dose PPI, it has been shown that the efficacy of high dose dual treatment is vary in different reports[9].

A number of recently different regiments for the H. pylori treatments are described in Table 1.

An open-label, prospective, single-center pilot study evaluated the effectiveness of amoxicillin plus high-dose PPI dual therapy for H. pylori eradication. The intention-to-treat (ITT) cure was achieved in 72.2% and in per protocol (PP) 74.2%, respectively[42].

In an open-labelled and single-center prospective study, the overall success at eradication of H. pylori by two planned consecutive rescue therapies was tested. The first rescue therapy including high-dose PPI dual therapy with amoxicillin or rabeprazole for 2 wk was highly tolerable and the PP and ITT success rate was 75.4% and 71.8% which was less than the second rescue therapy with amoxicillin and rabeprazole and levofloxacin[43].

In the study of Ince et al[44], dual therapy containing high-dose PPI (omeprazole) and amoxicillin was more cost-effective, successful and safe compared to standard triple therapy in patients with dyspepsia.

A prospective, open-label pilot study of H. pylori eradication revealed that 2-wk dual regimen of twice a day high-dose long acting lansoprazole plus amoxicillin treatment success was not acceptable[41].

Based on a large-scale multihospital trial study, high-dose dual therapy containing rabeprazole and amoxicillin is superior to standard regimens as sequential therapy or triple therapy for H. pylori infection, with similar safety profiles and tolerability[45].

If the theory, that consistently high intra gastric pH is required to reliably achieve more than 90% H. pylori eradication, the some mentioned studies results do not confirmed this theory. It seems many regiments were not sufficient to eradicate H. pylori.

Triple H. pylori therapy comprising a PPI, amoxicillin and clarithromycin is used as the firstline therapy. Clarithromycin or metronidazole resistance has been related to a reduction of success rates, making it a significant reason leading to treatment failure of H. pylori[46]. The other factors such as rapid metabolism of PPIs by CYP2C19, poor patient compliance, high acidity of stomach and bacterial load seem to be the main causes of eradication failure[33,42]. One hundred and thirty-six patients enrolled in the study of 10-d triple therapy comprising esomeprazole plus amoxicillin and metronidazole. Cure rates of patients were 82.4% by ITT analysis and 88.2% by PP analysis[47]. Based on several available clinical trials, it seems that a quinolone-based triple therapy will be operative as the first-line therapy in H. pylori infection[11]. The use of levofloxacin as an alternative of clarithromycin in triple and sequential therapies has been investigated by Qian et al[48] 7-d levofloxacin based triple therapy (levofloxacin, amoxicillin, esomeprazole) generated unsatisfactorily therapeutic efficiency, only levofloxacin-containing sequential therapy reached adequate outcome.

The effectiveness of a triple bismuth-consisting regimen along with amoxicillin and nifuratel used for eradication of H. pylori in patients were evaluated. The results of this study revealed the therapy containing bismuth subcitrate, amoxicillin and nifuratel yielded a success rate of 86% in childhood[49].

Standard dose (amoxicillin 1 g, clarithromycin 500 mg and rabeprazole 20 mg, all two times per day for 10 d) vs half dose regimen in therapy of H. pylori infected subjects was equally efficient and better tolerated[50].

The results of triple therapy containing clarithromycin, amoxicillin and esomeprazole 40 mg or omeprazole 20 mg in different genotypes of CYP2C19 showed that esomeprazole containing regimen increased eradication rate in comparison with the triple therapy based on omeprazole in extensive metabolizers of CYP2C19. Regardless to genotyping of CYP2C19 the H. pylori, eradication rates remained similarly comparable among the omeprazole and the esomeprazole group[51].

One thousand four hundred and sixty-three H. pylori infected participated in a study to compare 10-d sequential, 14-d triple and 5-d concomitant therapies. The best eradication efficacy has been reported by standard 14-d triple therapy followed by sequential 10-d therapy[52].

Quadruple therapy comprising bismuth subcitrate, PPI, metronidazole and tetracycline has been accepted better than standard triple therapy in several studies[53-55]. Ten-days quadruple therapy containing bismuthate dicitrate, esomeprazole, levofloxacin and tetracycline showed success rate of 95.8% after the failure of sequential therapy. This regimen could be used as a good choice in high clarithromycin resistance areas[56]. In a similar study 14-d therapy with esomeprazole, amoxicillin, levofloxacin, and bismuth achieved more than 90% eradiation rate after the failed sequential or concomitant therapies[10].

Four hundred and twenty-four patients (96.8% metronidazole resistance) did not respond to standard therapies treated by lansoprazole, bismuth potassium citrate plus (tetracycline and metronidazole or tetracycline and furazolidone or amoxicillin and tetracycline or amoxicillin and furazolidone) which all bismuth-containing quadruple therapies reached higher than 90% success rate[57].

The efficiency of quadruple H. pylori therapy has been confirmed as the first-line regimen in a randomized trial. During this study, 14-d quadruple therapy was compared with 7-d standard therapy. Fourteen-days quadruple therapy comprising bismuth, PPI, amoxicillin and clarithromycin exhibited acceptable success rate and could be prescribed as the first line therapy[58].

An open alabel, randomized, phase 3 trial compared 10-d quadruple therapy with 7-d standard therapy in 440 patients. The quadruple therapy produced higher success rates (80%) in comparison with standard triple therapy (55%). Quadruple therapy could be accepted as the first line of treatment because of increased incidence of clarithromycin-resistant. In addition, quadruple therapy showed higher eradication rate but comparable side effects with standard therapy[59].

One hundred and six Iranian duodenal ulcer patients participated in the study of furazolidone in comparison with metronidazole during a quadruple therapy for eradication of H. pylori infection. In furazolidone group eradication rate was 75% and 82% (in ITT and PP analysis) but in metronidazole group 55% and 56% respectively[60].

Sixty-four patients who failed previous clarithromycin, amoxicillin and omeprazole, (standard triple treatment) eradication treatment were treated for 10 d with tetracycline, bismuth subcitrate potassium and metronidazole four times per day and omeprazole two times per day. According to results, H. pylori eradication rates were between 93.2% to 95.0%[61].

One hundred and fifty patients in high resistance area were enrolled in a study to evaluate levofloxacin-containing quadruple therapy or high dose metronidazole plus bismuth subcitrate, esomeprazole, and tetracycline. Eradication rates were similar in both groups. Thus, metronidazole is a good choice because it is cheaper and more feasible[62].

Concomitant quadruple therapy is a non-bismuth quadruple based therapy comprising omeprazole, metronidazole, amoxicillin, and clarithromycin during 5 to 7 d[63,64]. The consequence of a meta-analysis of several randomized trials exhibited that concomitant quadruple therapy has been better than standard triple therapy[65] in addition, another meta-analysis of 2070 patients also confirmed this result[66].

Resistance to both metronidazole and clarithromycin considerably influence sequential therapy but did not affect the success rate of concomitant quadruple therapy. In addition, concomitant regimen has been confirmed to be safe and similarly active like sequential therapy in eradication of H. pylori[67]. In an area that 23.5% of subjects had clarithromycin resistant H. pylori strains, (33% resistant to metronidazole and 8.8% resistant to both drugs), the efficacy of 2 different optimized nonbismuth quadruple regimens was compared. According to the results, concomitant quadruple therapy with omeprazole, amoxicillin, clarithromycin and nitro imidazole two times a day for 14 d showed more than 90% cure rate of H. pylori[68].

An Italian innovation in the quadruple therapy leads to sequential therapy comprising dual therapy for 5 d with amoxicillin and PPI and 5 more days with tinidazole, clarithromycin and PPI[69]. This regimen was studied among 52 patients suffering from H. pylori infection and eradication rate around 98% was achieved with ITT analysis[70]. The other study which assessed the success rate of treatment by sequential therapy in compare with standard triple therapy showed that 10-d sequential therapy was better than standard triple therapy in children, that is confirmed by the researches done on adults[71].

A retrospective study compared eradication treatment in subjects that underwent triple treatment consisting of clarithromycin, PPI and amoxicillin or sequential treatment involving a clarithromycin, PPI and amoxicillin, and metronidazole in a high anti-microbial resistance setting. Eradication rate of H. pylori was comparable between the two treatment groups[72].

Two recently meta-analysis studies established above mentioned data, according to Jafri et al[73], review H. pylori treatment in 2747 patients. Success rates were 93.4% in sequential regimen where as 76.9% in common triple therapy.

The influence of different factors on success rate of H. pylori eradication assessed using two therapy regimens (sequential and triple therapy) for equal 10-d period of study. The data suggested that traditional factors such as smoking and CagA gene change efficacy of triple therapies but did not affect sequential therapy[74].

Ten-days sequential regime consisted of amoxicillin plus a PPI for 5 d, was continued by clarithromycin, metronidazole and a PPI for more 5 d demonstrated higher efficacy of triple therapy[75]. In another study 900 patients were examined for sequential therapy comprising amoxicillin and lansoprazole for 7 d continued by metronidazole, lansoprazole, and clarithromycin vs standard triple therapy. In the outcome, success rate was 90.7% in sequential therapy but 82.3% in triple therapy[76].

Cure rate of the sequential therapy was altered based on the type of used nitro imidazole, on the other hand, a therapy program with metronidazole provided results which were not as good as tinidazole[69]. Certainly, the results of Choi et al[77], study showed that H. pylori eradication rate was 77.9% of subjects treated by a metronidazole-based 10-d sequential regimen[77] compared to the results of the other study which indicated 97.4% of treatment by a tinidazole-based regimen. Eradication rate was 84.2% in the other metronidazole-based sequential therapy which was less than tinidazole-based therapy[75]. Most likely, such occurrence is because of longer half-life of tinidazole vs metronidazole[78].

In high clarithromycin resistance areas, clarithromycin substitution by levofloxacin has been investigated. Levofloxacin sequential therapy showed eradication rate more than 96% in comparison with 80.8% clarithromycin sequential therapy[79]. Levofloxacin-based sequential regimen is better than usual triple therapy as the first line in the sites with high incidence of resistance to clarithromycin[80].

Recently a retrospective study has been done among subjects that underwent triple treatment consisting of clarithromycin, amoxicillin and a PPI or sequential treatment involving amoxicillin, a PPI, clarithromycin, and metronidazole eradication treatment in a high anti-microbial resistance setting. The H. pylori eradication rate was not statistically different between the 2 treatment groups[72].