Infection due to Helicobacter pylori (H. pylori) affects approximately 50% of the worldwide population, especially in the developing countries. It has a great impact, reaching a prevalence of up to 90% in the adult population.1–5 This bacterium has a causal relation to mucosa-associated lymphoid tissue (MALT) lymphoma and gastroduodenal ulcer, as well as an associative relation to pathologies such as functional dyspepsia, gastritis, and gastric adenocarcinoma.6–8

Among the different therapies for treating H. pylori are the standard triple therapy, which is a proton pump inhibitor (PPI) and 2 out of 3 antibiotics (amoxicillin or clarithromycin or metronidazole/tinidazole), bismuth-containing quadruple therapy (PPI, bismuth, tetracycline, and metronidazole), levofloxacin-containing triple therapy (PPI, levofloxacin, and amoxicillin), sequential therapy (PPI plus amoxicillin followed by PPI, clarithromycin and metronidazole or tinidazole), and concomitant or quadruple therapy without bismuth, which is a PPI, clarithromycin, amoxicillin, and metronidazole.7,9 The standard triple therapy currently has unacceptable H. pylori eradication levels under the 80% intention-to-treat (ITT) rate. This is mainly due to the increased resistance to clarithromycin and metronidazole.7,9 According to the Maastricht IV consensus,10 the standard triple therapy, or the bismuth-containing quadruple therapy as an alternative, have been recommended as first-line treatment in regions with a resistance to clarithromycin under 15 to 20%, while the quadruple therapy with bismuth or the triple therapy with levofloxacin are recommended as second-line therapies. On the other hand, in regions in which clarithromycin resistance is greater than 15 to 20%, the indicated first-line therapeutic regimens include the bismuth-containing quadruple therapy, the sequential therapy, and the concomitant or quadruple therapy without bismuth, while the triple therapy with levofloxacin is used as second-line therapy.11–16

Taking into account the prevalence and potential clinical consequences of this chronic infection, it is of the utmost importance to identify the ideal treatment regimens that achieve excellent eradication percentages.1 However, the success rates vary greatly worldwide and there is no consensus on their effectiveness. No ideal first-line treatment or treatment after a failed first eradication attempt has been clearly determined, and there are discrepancies in relation to optimum duration, doses, and the medication to use in each line of therapy.9,17

The aim of the present study was to provide a systematic review of the international literature that includes randomized and non-randomized clinical trials in order to evaluate the eradication effectiveness of the current first and second-line therapeutic regimens in the management of adults presenting with H. pylori infection.

The effectiveness of the different available therapeutic regimens, both first-line and second-line, included in the present systematic review for defining the ideal treatment for infection due to H. pylori varies significantly worldwide and there is currently no ideal therapeutic strategy for eradicating H. pylori infection in 100% of the cases. The proposal based on the standard triple therapy has not provided satisfactory results. Its first disadvantage is the resistance to antimicrobial drugs, especially to clarithromycin and metronidazole, and therefore many infected persons throughout the world do not benefit from these regimens. The sequential and concomitant regimens are good alternative treatments. The triple therapy with levofloxacin, as second-line treatment, is an alternative that has had excellent eradication results. Combinations that include rifabutin and furazolidone are also promising therapeutic possibilities.

Based on the observations of our review, the standard triple therapy as a first-line regimen of 1-week duration shows sub-optimal eradication rates in countries such as Turkey, Colombia, Ecuador, Japan, and the United States.24,26,41,43,50 However, in other countries such as Brazil and the United Kingdom, the eradication rates were higher;19,51 these results were similar to those obtained in the countries with low rates of resistance to clarithromycin (lower than 15 to 20%). Moreover, with therapies lasting longer than 7 days, greater eradication effectiveness was not found in countries that included the United States, Colombia, and Chile.24,41,42 These results are equivalent to those observed in the meta-analysis conducted by Fuccio et al.,62 that did not find a higher eradication rate in therapies of more than 7-day duration; likewise, in 3 randomized clinical trials conducted by Kim et al.,63 and Zagari et al.,64 the 2-week regimens did not have higher eradication rates than those of 1-week duration. Therefore, our review suggests that a duration greater than 7 days does not improve the performance of the standard triple therapy and that the resistance to antibiotics is the principal cause of eradication failure.18

On the other hand, the triple therapies with amoxicillin and the triple therapies with metronidazole for 7 days were equally effective, but the H. pylori eradication rates were unacceptable.29 Even though the triple therapies at high and low doses of metronidazole are considered effective, there were no significant differences in their effectiveness with respect to dose.33 There were also no differences in the 7-day triple therapies with clarithromycin in relation to the PPIs employed: pantoprazole and omeprazole, lansoprazole and omeprazole, or rabeprazole and omeprazole.24,25,45,50 The eradication rates, even though they were significantly higher with the triple therapy with clarithromycin, are still poor with respect to the dual therapy with clarithromycin, which achieved a better, but still unacceptable rate, according to the previously discussed criteria.26,65 Based on the results obtained from the different clinical trials included in this study, conducted in different geographic zones, it is suggested that this latter therapy reaches unacceptable eradication rates for cure (< 80%) in countries with growing rates of resistance to clarithromycin and metronidazole.12 Nevertheless, these results cannot be generalized worldwide, given that this therapeutic option is still adequate in countries that have H. pylori strains with a low resistance to clarithromycin (< 15-20%) and metronidazole (< 40%).10

In the presence of the growing increase in resistance to clarithromycin and the sub-optimum eradication rates offered by the standard triple therapy, new rescue therapies have emerged, such as the bismuth-containing quadruple therapy. In 3 studies included in our review, this therapy given for 7 days has obtained acceptable effectiveness in the ITT analyses and good effectiveness when given for 10 or 14 days.20,23,37,39,52 Our findings are adequately correlated with those of a meta-analysis conducted by Fischbach et al.66 in which they conclude that the quadruple therapies of 2-week duration improve effectiveness in relation to those of 1-week duration. In our review, the eradication rates of the quadruple therapy versus the standard triple therapy as first-line treatments were similar and there was no statistically significant difference between these 2 therapeutic regimens of 7 or 10-day duration.19–21,23 Likewise, our results are equivalent to those demonstrated in 2 meta-analyses conducted by Gene et al.,67,68 in which the quadruple therapy and the triple therapy reached similar eradication rates in the ITT analysis (79 and 80%; p=1).21 Despite the heterogeneity of the regimens included in this review, it can be concluded that the administration of treatments with a prolonged duration (greater than or equal to 10 days) and at high doses of bismuth would enable more effective eradication rates to be achieved.69

On the other hand, the standard triple therapy with metronidazole as second-line treatment, after the therapeutic failure of standard triple therapy with clarithromycin, obtained ideal eradication levels in our review; in particular, 4 clinical trials conducted in Japan show good eradication percentages in 5 days in the ITT analysis and excellent ones in 7 days.32,34,58 This therapy also shows itself to be effective as a second-line regimen at doses of metronidazole of 500 or 750mg/day, with good success rates in the ITT analyses for both regimens, even reaching up to a 93.5% eradication rate.33 The previous results could be explained by taking into account the geographic location in which the clinical experiments were carried out, given that the resistance rates to metronidazole are low in Japan (approximately 4%), whereas the resistance to clarithromycin is high (approximately 27.7%); this is above the recommended resistance limit for using clarithromycin (< 15-20%), but it is still within the accepted resistance limit for using metronidazole (< 40%).70 Nevertheless, when the standard triple therapy with clarithromycin fails, this antibiotic should not be included in the second-line treatment, because its secondary resistance would increase drastically.71

In our review, as first-line treatment the 10-day sequential therapy offers superior eradication rates with excellent effectiveness in the ITT analysis, compared with the 7-day standard triple therapy that has shown poor effectiveness.31 The sequential therapy provides good cure rates, above 90%,13 concurring with the results of 3 clinical trials conducted in Israel, Taiwan, and Italy that are included in the present review. It was used as first-line therapy and reached effective ITT eradication rates that were excellent and good in the latter two countries, respectively.53,56,61 Similar results have been reported in the systematic reviews carried out by Moayedi,72 Jafri et al.,73 and Grigorios et al.74

Another effective alternative to the standard triple therapy is concomitant or quadruple therapy without bismuth. In our review, 2 studies with concomitant therapy showed greater eradication in the PP analyses, excellent versus acceptable compared with the standard triple therapy.35,46 Likewise, meta-analyses conducted by Essa et al.75 and Georgopoulos et al.,76 obtained similar results to those of the present review.13 However, contrary to the previously obtained results, a Latin American study showed that the 14-day standard triple therapy was more effective than the 5-day concomitant therapy or the 10-day sequential therapy, with acceptable, unacceptable, and poor eradication rates, respectively.1,47 The discrepancies with the previous results could be explained by geographic variations and patterns of resistance to clarithromycin. As the authors of the Latin American study explained, the population included in the clinical experiment had a low prevalence of clarithromycin resistance and therefore achieved better results with the standard triple therapy.47,77,78

As clarithromycin replacement, therapy with quinolones associated with amoxicillin in the regular doses and a PPI twice a day has been suggested. In our review, the triple therapy with levofloxacin with a duration of 7 to 14 days was evaluated in 7 clinical trials and achieved poor to excellent eradication rates in the ITT analyses; effectiveness improved with the longer treatments.27,29,30 Additionally, as first-line therapy, this treatment was more effective than both the triple therapy with clarithromycin of 7-day duration and the triple therapy with metronidazole.29 Likewise, no significant difference was found between the doses of levofloxacin of 500mg once a day versus 500mg twice a day. Effectiveness was unacceptable in the two cases, whereas in relation to the 10-day sequential therapy, greater eradication rates in the PP and ITT analyses were obtained, excellent versus acceptable, respectively.30,56 The above results are similar to those described by Kuo et al.,13 Molina-Infante et al.,79 and Cheng et al.80 As second-line rescue therapy, the eradication rates varied from acceptable to excellent with 10-day therapies,28,56,59,60 whereas they ranged from poor to unacceptable with 7-day treatments.40,54 The least successful eradication rate was obtained in a clinical trial conducted in Turkey, and might be related to the fact that this therapy could present success failures in Asian and European populations with a high resistance to fluoroquinolones, reducing their effectiveness to rates of approximately 33%.81,82 The abovementioned studies suggest that the triple therapy with a dose of 400mg/day of levofloxacin is less effective compared with a therapy using 800mg per day, whereas better results could be obtained with more prolonged therapies.28 Finally, it is concluded that the triple therapy with levofloxacin is an effective first and second-line treatment that offers better eradication rates in relation to the standard, quadruple, and sequential therapies.

Other second-line rescue antibiotics such as rifabutin and furazolidone have been employed. In this review, we evaluated a 7-day therapy with rifabutin associated with omeprazole and amoxicillin and it had a quite unacceptable effectiveness, much lower in relation to the bismuth-containing quadruple therapy that obtained poor effectiveness in the ITT analysis.36 However, these results can most likely be explained by the fact that a 7-day duration is not sufficient, given that other studies have published more effective results with longer treatments; therapies of 10 and 12 days have offered good eradication rates and those of 7-day duration have shown poor rates.83 The latter result could be related to the doses of amoxicillin and PPI employed, taking into account the study conducted by Borody et al.,84 in which higher 12-day doses of these antibiotics were used, showing effective results as second-line rescue therapy. Nevertheless, currently there is no clear optimal therapeutic regimen with rifabutin.13 In regard to furazolidone, an additional antibiotic that has been used in rescue treatments in quadruple combination (bismuth, doxycycline, PPI, and furazolidone), had excellent success in the ITT analysis and good success in the triple combination (furazolidone, levofloxacin, and PPI).49 Upon increasing the dose of furazolidone, we observed a poor eradication rate with a dose of 200mg per day and a good rate with a dose of 400mg.48 The promising eradication rates of the therapy with furazolidone could be explained by the absence of primary resistance to this antibiotic and the absence of crossed resistance with metronidazole.85 Therefore, in the underdeveloped countries with a high resistance to metronidazole, therapies with furazolidone could be effective rescue therapies.86

The eradication of H. pylori is also a challenge in patients that are allergic to penicillin, in both first-line treatments and in cases of previous therapeutic failure. In our review, therapy with omeprazole, clarithromycin, and metronidazole of 7-day duration obtained quite unacceptable effectiveness of under 70% success in the ITT and PP analyses. On the other hand, triple therapy with levofloxacin, omeprazole, and clarithromycin of 10-day duration was a good second-line strategy, with good cure rates in the ITT and PP analyses.55 Nevertheless, these results differ from previous studies in which eradication success was poor with the use of PPI, clarithromycin, and metronidazole. Once again, these results can be correlated with the area in which the clinical trial was conducted, given that in Spain there is very high resistance to metronidazole and clarithromycin, of approximately 32.8% and 49.2%.87 In addition, different authors that have evaluated the combination of levofloxacin as second-line rescue therapy reported similar eradication rates, with excellent effectiveness in the ITT analysis.29,88 With this in mind, our suggestion for patients with a history of allergy to penicillin is the triple therapy with PPI, clarithromycin, and metronidazole; it is an adequate first-line strategy in countries where there is low resistance to these antibiotics. In other words, the regimens with levofloxacin achieve good eradication rates as a second-line alternative in this type of patient.29,58,89

In a systematic review carried out by Gisbert et al.90 that included 18 randomized clinical trials in their analysis there was a difference that was not statistically significant between the eradication rates of the triple regimens based on nitroimidazoles and amoxicillin; these results were similar to ours. According to the findings of 4 systematic reviews91–93 that compared triple regimens with different PPIs as first-line treatment, 3 of them did not show a significant difference in their eradication rates, concurring with our review. However, in contrast, an additional systematic review favored the regimens based on esomeprazole.91 Our results indicate that treatment duration above 7 days does not improve the effectiveness of the standard triple therapy, but this differs with the systematic review of Calvet et al.;94 they included 7 randomized clinical trials in their analysis and justify the use of 14-day therapies versus 7-day therapies. Nevertheless, in these 7 studies different therapeutic combinations were employed: PPI plus amoxicillin and clarithromycin, clarithromycin plus metronidazole or amoxicillin and clarithromycin and metronidazole. Because of the above, it is difficult to compare our findings with those of that study. Even so, these results would indicate that the high rates of antibiotic resistance in different geographic regions are the main cause of eradication failure, more so than the length of time of treatment.

Adamek et al., 71 support our results with a similar effectiveness between the triple and quadruple therapies as first-line regimens. This is also validated by the results obtained in the systematic review by Calvet et al., 94 analyzing 5 randomized clinical trials without finding significant differences in the eradication rates of these therapies. Likewise, the latter work indicates that the triple therapies based on nitroimidazoles and amoxicillin show similar eradication rates for H. pylori, while the triple therapies using different PPIs show equal eradication effectiveness.71 Like ours, a systematic review by Huang and Hunt95 reports similar eradication rates between clarithromycin at single and double doses. Two systematic reviews72 that include 12 clinical trials in their analysis support our results with respect to the use of the 10-day sequential regimen, compared with the 7 and 10-day triple regimens as first-line treatments. However, the Italian authors indicate that these results must be reliably corroborated by large-scale studies.

For reaching more effective eradication rates in regard to the second-line therapies, in their review Megraud and Marshall65 recommend not using clarithromycin in the case of therapeutic failures of first-line regimens based on this antibiotic, and suggest doubling the dose of metronidazole in the case of a previous eradication failure with that drug; they also state that second-line treatment should be given for a longer period of time than first-line treatment. Even though we did not find systematic reviews that compared the quadruple versus the triple regimens as second-line regimens, there is a current controversy as to which regimen is more effective, according to the results of 3 randomized clinical trials by Lee et al.,96 Magaret et al.,97 and Peitz et al.98 The results of 2 large meta-analyses 99,100 similarly corroborate that the triple therapy with levofloxacin is capable of reaching eradication rates even higher than the quadruple therapy in those patients that have had first-line standard triple therapy failure.

A limitation of the present systemic review, now proposed for a future study, was not having incorporated the antimicrobial susceptibility of the different therapeutic regimens into the search parameters; doing so would have addressed the important problem of resistance that does not allow for eradication rates above 95% to be obtained. Likewise, given today's complex regimens, treatment adherence, safety, and adverse effects, as well as the cost-benefit evaluation of therapeutic interventions should all be taken into consideration, enabling an overall approximation in the evaluation of the ideal H. pylori treatment. On the other hand, because of the high clinical heterogeneity (populations, interventions, study durations and designs) of the clinical trials evaluating the effectiveness of both first and second-line therapies, future systematic reviews should be carried out. This type of epidemiologic design is thought to be the most appropriate today for elaborating the solid knowledge that can provide the medical community with the most adequate competencies for the ideal management of this infection. The inclusion of clinical trials at the worldwide level makes this a comprehensive work in which it is possible to have representative results in different patient populations.

Infection from Helicobacter pylori should be treated as any other infectious disease, which is why a therapy must be capable of curing more than 95% of the cases in the first therapeutic attempt in order to be regarded as excellent.6 The effectiveness of the different available treatment strategies varies significantly within different geographic regions. Such is the case with the standard triple therapy, which continues to be ineffective in countries with strains that are resistant, mainly to agents such as clarithromycin and metronidazole, making this treatment unacceptable as empirical therapy. Among the first-line treatment options is the bismuth-based quadruple therapy, which did not show significant differences in its eradication rates versus those of the standard triple therapy. However, the sequential and concomitant therapies have superior eradication results, with the potential to improve their effectiveness through increasing treatment duration, whereas the triple therapy with levofloxacin offers the best results as first and second-line treatment. With this in mind, a 10-day sequential treatment could be used as first-line treatment and a 10-day levofloxacin-based regimen as retreatment. As a second-line regimen it should be administered for a longer period of time than the first-line treatment; if there is initial failure with the clarithromycin-based regimen, this antibiotic should not be used again. On the contrary, if there is initial failure with metronidazole, increased dose and treatment duration with this same drug is recommended as rescue treatment.

The order of choice of the different H. pylori eradicating regimens will depend on local studies in which the rates of resistance to the different antibiotics are determined, in order to give the appropriate initial treatment, ruling out the less effective therapies according to the experiences of each country.70 However, we consider that antimicrobial sensitivity should not be systematically evaluated after a first therapeutic failure so that effective eradication results can be achieved. 65,101

It is imperative to carry out a greater number of large-scale studies and of double-blind, randomized clinical trials with excellent methodological quality that compare current standard treatments with new therapies, so that the ideal therapeutic regimen can be established. The success rate of such beneficial treatment should be as close to 100% as possible.102

No financial support was received in relation to this article.

The authors declare there was no conflict of interest.