Frontiers in Anti-Infective Drug Discovery: Volume 8 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Anti-Infective Drug Discovery
- Sprache: Englisch
This book series brings updated reviews to readers interested in advances in the development of anti-infective drug design and discovery. The scope of the book series covers a range of topics including rational drug design and drug discovery, medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships.
Frontiers in Anti-Infective Drug Discovery is a valuable resource for pharmaceutical scientists and post-graduate students seeking updated and critically important information for developing clinical trials and devising research plans in this field.
The eighth volume of this series features 8 chapters that cover methods for antimicrobial drug discovery (with 2 chapters that focus on genomics) as well as updates on drug development against Helicobacter pylori and emerging coronaviruses, among other interesting topics:
- Eradication of Helicobacter pylori Infection with Non-Bismuth Quadruple Concomitant Therapy
- Drug Discovery Strategies Against Emerging Coronaviruses: A Global Threat
- Opportunities Offered By Fragment-Based Drug Design in Antibiotic Development
- Phage therapy as a Tool for Control of Foodborne Diseases: Advantages and Limitations
- Subtractive Genomics Approaches: Towards Anti-Bacterial Drug Discovery
- Recent Advances in the Discovery of Antimicrobials through Metagenomics
- Phyto-Nano-Antimicrobials: Synthesis, Characterization, Discovery, and Advances
- Aptamers as Anti-infective Agents
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Seitenzahl: 468
Veröffentlichungsjahr: 2020
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PREFACE
The recent COVID-19 pandemic has further highlighted our human incapacity to control infections. Pathogens of all forms and types are fast learners, and their mutations, spread and virulence can overwhelm the entire health care system within weeks. The COVID-19 pandemic has also exposed our inability to quickly come up with treatment and prevention regimes, despite the tremendous progress in pharmaceutical and biomedical sciences. In the post COVID-19 world major attention to the surveillance, prevention, and treatment of infections of all kinds is expected. Research on infections and anti-infectious drug discovery is already truly interdisciplinary in nature, and is published in journals of diverse disciplines, such as microbiology, molecular and structural biology, genomics, immunology, epidemiology, etc. It is imperative that the most exciting discoveries in this field are compiled as critically written reviews in frontier areas.
The aim of the book series “Frontiers in Anti-infectious Drug Discovery” is to focus on recent important developments. Experts in various important aspects of anti-infectious drug discovery have therefore contributed review articles on the most recent advancements. Volume 8, like the previous volumes, of this well received book series, comprises eight (8) scholarly written review articles on certain key aspects. These include genomic based identification of new drug targets and metagenomics for antimicrobials; fragment-based approach for drug designing, and of various types of antimicrobials ranging from synthetic analogs against coronaviruses, to bacterial phages against infections, nanoparticle based agents, as well as aptamers.
The chapter contributed by Gisbert and McNicholl focuses on the key advantages of concomitant non-bismuth quadruple therapy for a range of infections caused by Helicobactor pylori. Silva-Junior et al have presented an interesting review on the discovery and development of bioactive drug leads against the recent pandemic caused by SARS-CoV-2, based on analogs developed during the past SARS and MERS epidemics. Advances and challenges in fragment-based designing of new antibiotics is the key focus of the article by Kwan et al, supported by numerous examples. Foodborne bacterial infections are widespread. Ilyina et al review the recent applications of phage therapies as alternatives to antimicrobials for the treatment of food borne bacterial infections. Amjad et al have contributed a chapter on the applications of subtractive genomics to identify essential genes involved in crucial metabolic pathways of pathogens, and validating their protein products as novel drug targets. Metagonomics has emerged as a key technique for the discovery of novel antibiotics from yet uncultured microbes. The tremendous pool of new antimicrobials in unexplored microbial flora is the focus of the review by Chopra et al. Zameer has contributed a chapter on the use of nanoparticles as drug careers of synthetic and natural antimicrobial agents. In the last chapter, Syed et al have touched upon an important new field of the use of aptamers (oligonucleotides or peptide molecules) as novel diagnostic and anti-infective agents.
We would to express our sincere thanks eminent to all the authors for their excellent contributions in this vibrant, and exciting field of biomedical and pharmaceutical research. The efforts of Ms. Fariya Zulfiqar (Manager Publications) and the excellent management of Mr. Mahmood Alam (Director Publications) are also gratefully acknowledged.
Prof. Dr. Atta-ur-Rahman, FRS Honorary Life Fellow Kings College University of Cambridge Cambridge UK&Prof. Dr. M. Iqbal Choudhary H.E.J. Research Institute of Chemistry International Center for Chemical and Biological Sciences University of Karachi Karachi PakistanLIST OF CONTRIBUTORS
Eradication of Helicobacter pylori Infection with Non-Bismuth Quadruple Concomitant Therapy
Javier P. Gisbert*,Adrian G. McNichollAbstract
Background: The main recommended regimens to eradicate Helicobacter pylori infection fail in ≥20% of the cases. Several substitutes for triple therapies have been proposed, and non-bismuth quadruple therapy is one of the most widely used.
Aim: To systematically review the efficacy of non-bismuth quadruple regimen (proton pump inhibitor, clarithromycin, amoxicillin and a nitroimidazole) in the eradication of H. pylori infection.
Methods: Bibliographical searches were performed in MEDLINE/EMBASE and relevant congresses. We pooled studies evaluating the concomitant regimen, and of the randomized controlled trials comparing concomitant vs. standard triple therapy, and concomitant vs. sequential therapy.
Results: Fifty-five studies were included (6,906 patients). The meta-analysis showed that concomitant regimen offers an overall eradication rate of 87%. A sub-analysis of studies comparing one-to-one concomitant and triple therapies showed an odds ratio of 2.14 (95% CI=1.51-3.04) towards higher efficacy with concomitant regimen. This figure increased up to 2.41 (95% CI=1.80-3.24; 85% vs. 72%) when comparing arms lasting the same number of days. We also sub-analyzed the comparative efficacy between non-bismuth quadruple concomitant and sequential treatments, and concomitant achieved an odds ratio of 1.49 (95% CI=1.21-1.85) towards higher eradication results than sequential regimen.
Conclusions: Non-bismuth quadruple (concomitant) therapy achieves high efficacy in H. pylori eradication, superior to standard triple and sequential therapy. Concomitant may be more appropriate than sequential therapy for patients with clarithromycin and/or metronidazole resistance. Higher acid suppression and/or longer duration are optimizations that can increase even more its efficacy.
INTRODUCTION
Approximately fifty percent of the world population is infected by Helicobacter pylori, a bacterium linked to a broad range of upper gastrointestinal conditions such as gastritis, peptic ulcer disease, and gastric cancer [1]. The most commonly used therapy for the eradication of H. pylori, traditionally recommended by international consensus, is the proton pump inhibitor (PPI)–based, standard triple therapy, adding two antibiotics (clarithromycin plus amoxicillin or metronidazole) to a PPI [2-6]. However, the eradication rates with this regimen have fallen considerably [7, 8]. Previous meta-analyses (with more than 53,000 included patients) showed an efficacy below 80% [9, 10]. Therefore, recent debate has been raised regarding how ethical it is to continue using standard triple therapy, and alternative approaches have been recommended [11]. Although, efforts to improve eradication prolonging triple therapy’s duration have been tested, data have not consistently provided significant benefits [12, 13]. Consequently, new combinations to improve treatment of naïve patients remain as an urgent need.
Sequential treatment involving a dual regimen with a PPI plus amoxicillin for the first 5 days followed by a triple regimen including a PPI, clarithromycin, and a nitroimidazole for the following 5 days, was proposed as an alternative [14]. Several randomized clinical trials and meta-analyses have shown that the sequential regimen was more effective than the standard triple [15-19]. Therefore, some consensus conferences suggested sequential regimen as a substitute to standard triple for the first-line eradication of H. pylori [20]. Nevertheless, results obtained by a meta-analysis by the Cochrane Collaboration [21] concluded that sequential regimen outcomes were heterogeneous, and that many of the latest manuscripts were unable to show any benefit from sequential over standard triple therapy. The conclusions of the meta-analysis were clear even though the pooled eradication rate was 85%, and a potential trend towards reduced efficacy was observed in the last years [21].
Sequential treatment faced another relevant issue, whether sequential administration was really necessary or if the 4 drugs could be given concurrently [14, 22, 23]. Questions were raised regarding the risk of failure to comply with the treatment due to regimen complexity [11, 24] Moreover, the combination of amoxicillin, clarithromycin and a nitroimidazole with a PPI has previously been evaluated as a concomitant regimen in 1998: two research teams, one in Japan and the other in Germany, recommended that this drug combination should be prescribed as a concomitant 4-drug, 3-antibiotic, known as non–bismuth quadruple therapy [25, 26], providing high efficacy even in short durations (>90% by intention-to-treat in 5-day regimens).
This “non-bismuth quadruple concomitant” regimen has regained presence in recent years [27]. It is easy to convert the standard triple therapy (PPI-clarithromycin-amoxicillin) to concomitant therapy by adding of 500 mg of metronidazole (or tinidazole) twice daily [28]. Beware that “concomitant” (taking all drugs all together) may cause confusion; this term is actually a misnomer, as all H. pylori treatments, except sequential therapy, could be called concomitant therapies. Nonetheless, this will be the name used hereafter as it has been the most common denomination in the literature.
OBJECTIVE
The aim of the present chapter is to perform a critical review of published evidence on the efficacy and safety of concomitant therapy in the eradication of H. pylori infection. We will review the following aspects: 1) Efficacy of the concomitant regimen; 2) Comparison between the concomitant regimen and standard triple therapy; 3) Comparison between the concomitant and the sequential therapies; 4) Effects of different variables on the efficacy of concomitant therapy; 5) How could we increase the efficacy of the concomitant treatment? and finally; 6) What are the results with the concomitant treatment in clinical practice? (the experience of the European registry on H. pylori management).
BIBLIOGRAPHICAL SEARCHES
Bibliographical searches were performed in MEDLINE and ENDBASE using the following keywords (all fields): ((concomitant OR quadruple OR concurrent OR ((amoxicillin OR amoxycillin) AND (metronidazole OR tinidazole OR nitroimidazole) AND clarithromycin) AND (“Helicobacter pylori” OR “H. pylori”). No language restriction was applied. Bibliography from selected manuscripts and reviews were hand-searched to identify further relevant studies. Authors conducted a hand-search of communications from the American Digestive Disease Week, the International Workshop of the European Helicobacter Study Group, and the United European Gastroenterology Week. Summaries of the manuscripts selected in the different searches were reviewed, and screened for exclusion and inclusion criteria. In cases of duplicate reporting of studies or evidently based on overlapping study population, the latest valid report was considered.
EFFICACY OF THE CONCOMITANT REGIMEN
A summary of studies evaluating concomitant regimen’s efficacy is shown in Table 1 [25, 26, 29-80]. Concomitant combinations were prescribed homogenously, with only minimal alterations: the nitroimidazole (tinidazole or metronidazole) and the PPI (omeprazole, lansoprazole, rabeprazole, or esomeprazole) and. However, there was a wide duration range between three and fourteen days. The analysis of the 55 studies (6,906 patients) showed a pooled eradication percentage by intention-to-treat of 87%, with a 95% confidence interval (95% CI) ranging from 86 to 89% (Fig. 1). The data were pooled using the generic inverse variance method, which involves a weighted average of the effect estimates from the included studies. The weight for each study equals one divided by the square of the standard error (inverse of the variance) of the effect estimate. As population and regimens lengths were heterogeneous, a random effects model (DerSimonian and Laird) was applied to perform the meta-analysis (using Review Manager 5.0.25, developed by the Cochrane Collaboration).
COMPARISON BETWEEN CONCOMITANT AND STANDARD TRIPLE REGIMEN
The superiority of concomitant therapy over standard triple therapy has been confirmed in several randomized trials. A recent meta-analysis [81] evaluated 9 prospective studies treating H. pylori with a concomitant regimen for up to 7 days. Prescribed regimens generally lasted 5 days (ranging from 4 in one study to 7 in another). Overall, concomitant therapy achieved 90% intention-to-treat eradication (93% per-protocol). Moreover, the estimates of the meta-analysis of the 5 randomized controlled trials demonstrated the superiority of concomitant regimen over standard triple therapy (odds ratio of 2.86; 95% CI, 1.73-4.73).
For this chapter, we have updated these meta-analytical evaluations with more recent studies and have updated it including the new trials that have compared these two treatments. Table 2 describes the studies comparing the H. pylori eradication rate of concomitant regimen with that of standard triple therapy by intention-to-treat [25, 31, 39, 41, 42, 47, 48, 58, 60-62, 67, 68, 71, 73].
As summarized in Fig. (2), 2, 059 patients received the concomitant regimen and 2,268 the standard triple regimen. The former was more effective than the latter: 81% vs. 74% in the intention-to-treat analysis. The odds ratio for this comparison was 2.14 (95% CI, 1.51-3.04) (Fig. 2A). A sub-analysis was performed excluding those studies in which both treatments had different treatment durations between arms. This sub-analysis showed (Fig. 2B) that, when comparing both concomitant and triple therapies lasting the same number of days, concomitant achieved an odds ratio of 2.41 (95% CI= 1.80-3.24; 85% vs. 72%). If we subdivide by length of both arms the differences in efficacy between both treatments were, as expected, smaller at longer regimens due to the rapid decrease in the efficacy of standard triple therapy at shorter regimens (Fig. 2B).
Regarding tolerance, in a previously published meta-analysis [81], no severe side effects were reported in any of the manuscripts, except anaphylactic reactions to study drugs [26, 64, 70]. However, these antibiotic treatments do show a high rate of moderate or mild adverse events, in Essa et al. meta-analysis 27-51% of patients in the concomitant group suffered some discomfort with treatment (vs. 21-48% standard triple therapy group) [81], suggesting that a similar safety profile can be expected from concomitant and standard triple therapies.
COMPARISON BETWEEN CONCOMITANT AND SEQUENTIAL REGIMENS
As previously discussed, sequential therapy faces a limitation due to its complexity, as switching drugs in the middle of treatment may compromise compliance. In this situation, studies comparing sequential regiment with another regimen using the same combination of drugs but concomitantly were necessary. Such comparisons would determine whether the two phase administration of sequential regiment is actually helpful [24]. A one-to-one comparison of concomitant and sequential therapies would also answer which of these 2 candidates can eventually substitute triple therapies in first-line recommendations [82].
Fig. (2)) Meta-analysis comparing the efficacy (intention-to-treat) of the concomitant regimen with that of standard triple therapy for the eradication of H. pylori infection: A) overall; B) both arms with the same length of treatment.Studies comparing the efficacy (intention-to-treat) of the concomitant regimen with that of sequential therapy for the eradication of H. pylori infection are summarized in Table 3 [29, 33, 34, 40, 44, 45, 48, 49, 52, 53, 63, 67, 72, 74-80]. Twelve studies (Fig. 3) met the inclusion criteria (1,219 patients treated with concomitant and 1,226 with sequential), 7 of them were performed in Asia and 5 in Europe. Concomitant achieved an odds ratio of 1.49 (95% CI= 1.21-1.85; I2
The alleged superiority of concomitant therapy –compared to sequential therapy – may be due to the longer period of time each antibiotic is prescribed (10 days in the concomitant and 5 in the sequential treatments), or the expected lower impact of antibiotic resistance when the 3 antibiotics are administered concurrently, favoring synergistic effects.
EFFECTS OF DIFFERENT VARIABLES ON THE EFFICACY OF CONCOMITANT THERAPY
The eradication rate achieved with the concomitant treatment is affected by multiple factors.
Clarithromycin Resistance
Antimicrobial resistance is largely responsible for the poor eradication rates with standard triple therapy [83-85]. One meta-analysis identified an approximate 60% reduction in efficacy with standard triple therapy if strains were clarithromycin resistant [83, 86]. Taking this in consideration, the prescription of standard triple therapies may be acceptable only in regions where the rate of resistance to clarithromycin is below 15-20% [2]. Clarithromycin resistance impacts the success rate of sequential regimen, although not as markedly as in triple therapy [14, 16-19, 87-89].
The potential benefits of sequential therapy regarding resistance seem to be also applicable to concomitant regimen. The effect of H. pylori antibiotic resistance on the efficacy of first-line treatments was determined in an early meta-analysis. The data clearly identified that quadruple combinations (especially those containing both clarithromycin and metronidazole) could cure clarithromycin or metronidazole resistance [85]. That meta-analysis showed that clarithromycin resistance’s effect on concomitant regimens was minor, with 95% cure-rate in patients with clarithromycin-sensitive strains, and 96% in resistant [85].
Table 4 summarizes the studies that, up to now, have evaluated the efficacy of clarithromycin resistance on the concomitant regimen [38, 44, 55, 56, 62, 64, 70, 72]. From these data, a mean eradication rate of 83% was calculated in patients with clarithromycin resistant strains. If only studies including in the same protocol both non-bismuth quadruple regimens were considered [44, 55, 72], the eradication rate in patients with clarithromycin-resistant strains was 62% for the sequential treatment and 92% for the concomitant one.
Nitroimidazole Resistance
Experience with concomitant therapy in patients with metronidazole-resistant strains is still limited, but seems to be encouraging. Table 5 summarizes the studies that, up to now, have evaluated the efficacy of metronidazole resistance on the concomitant regimen [40, 44, 55, 56, 72]. From these data, a mean eradication rate of 98% was calculated in patients with nitroimidazole resistant strains. If only studies including in the same protocol both non-bismuth quadruple regimens were considered [40, 44, 72], the eradication rate in patients with metronidazole-resistant strains was 82% for the sequential treatment and 97% for the concomitant one.
Dual Clarithromycin and Metronidazole Resistance
Table 6 summarizes the studies that, up to now, have evaluated the efficacy of both clarithromycin and metronidazole resistance on the concomitant regimen [38, 40, 44, 55, 56, 64, 70, 72]. From these data, a mean eradication rate of 79% was calculated in patients with dual clarithromycin and nitroimidazole resistant strains. If only studies including in the same protocol both non-bismuth quadruple regimens were considered [40, 44, 55, 72], the eradication rate in patients with both clarithromycin and metronidazole-resistant strains was 47% for the sequential treatment and 79% for the concomitant one. Therefore, sequential regimen does not qualify as a good therapeutic when the prevalence of dual –clarithromycin plus metronidazole– resistant strains is greater than 5% [90]. The lower effect of antibiotic resistance on the eradication rate with concomitant therapy than with sequential therapy may be due to the longer duration of therapy with one or all of the components of the concomitant therapy.
Based on aforementioned data, it may be concluded that the main limitation of concomitant therapy is this dual resistance to metronidazole–clarithromycin [90]. Although isolated clarithromycin or metronidazole resistances by themselves did not significantly impair concomitant therapy, it is expected that dual resistance rates over 15% may cause the efficacy to fall below 90% [91]. Therefore, concomitant therapy may be the recommended therapy of choice in areas and patient groups with low risk of dual resistance, but it cannot be recommended as a first-line empirical regimen in populations expected to have high dual resistance rates (i.e. after clarithromycin or metronidazole treatment failures) or in situations when metronidazole resistance reaches 60%, such as China, the Islamic Republic of Iran, India, or Central and South America [91]. As expected from these recommendations, good/excellent reported outcomes have been published in Southern Europe and some Asian countries with relatively low metronidazole resistance regardless of the clarithromycin resistance rate (even at 40% resistance prevalence); and poor results were obtained in areas with high prevalence of clarithromycin or, specially, metronidazole resistances.
In summary, there is clear and abundant evidence pointing towards the superiority of concomitant over sequential therapy, even more in populations expected to have moderate to high dual resistances (>15%).
Duration of Treatment
The first meta-analysis including 9 manuscripts, Essa et al. [81] identified that concomitant regimen achieved excellent results, even in very short treatment durations. The results of the studies included in Table 1 and in Fig. (1) have not been able to show a clear higher eradication results with longer treatments. However, several randomized controlled trials have compared, in the same study and with the same protocol, two different durations of the concomitant therapy, and have demonstrated that the longer duration is more effective, when comparing 3 vs. 5 days (81% vs. 89% [70], 5 vs. 7 days (87% vs. 90%) [51], 5 vs. 10 days (89% vs. 96%) [50], or 5 vs. 14 days (78% vs. 86%) [36].
HOW COULD WE EVEN INCREASE THE EFFICACY OF THE CONCOMITANT TREATMENT?
It has been pointed out that we should look for “good” or even “excellent” treatments, with eradication rates higher than 90% [93]. A recent study has compared the efficacy and tolerability of the standard and the so called “optimized” concomitant regimen (using new generation PPIs at high doses and longer treatment duration) [54]. Thus, in a prospective multicenter study, H. pylori-infected patients were consecutively treated with one of these two treatments: in a first phase, 356 patients received a standard concomitant therapy with omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg and metronidazole 500 mg for 10 days b.i.d.; in a second phase, 471 patients received the same regimen but with esomeprazole 40 mg b.i.d. and lasting 14 days. Compliance with treatment was 94% and 95%, respectively (non-statistically significant differences). Per-protocol eradication rates with standard concomitant and the optimized concomitant treatments were 86% and 93% (p<0.01). Respective intention-to-treat cure rates were 86% and 91% (p<0.01). Adverse effects (mostly mild) were reported in 32% of patients in the standard concomitant group and in 44% in optimized one (p<0.05), the most common being metallic taste, diarrhea, nausea and abdominal pain. Therefore, the authors concluded that an optimized (fourteen-day and high-dose esomeprazole) non-bismuth quadruple concomitant regimen for the eradication of H. pylori is more effective than the standard concomitant one, and achieves over 90% cure rate (and also concluded that although the incidence of adverse events is higher with the optimized treatment, these are mostly mild, and do not negatively impact the compliance). However, this study does not allow drawing conclusions regarding what percentage of that improvement is due to the longer regimen or to the high acid inhibition. Different meta-analyses have proved these beneficial effects (separately for each variable) on other anti-H. pylori treatments such as triple therapies [12, 94-96]; however, only a head to head randomized trial with the different concomitant regimens (e.g., 10 vs. 14 days; and standard dose vs. high dose PPI) would be able to answer this question.
In another multicenter study −the OPTRICON Study [97], the authors compared the effectiveness and safety of two “optimized” triple and concomitant therapies. This was a prospective study performed in 16 Spanish centers using triple therapy in clinical practice. In a 3-month two-phase fashion, the first 402 patients received an optimized triple therapy [esomeprazole (40 mg b.i.d.), amoxicillin (1 g b.i.d) and clarithromycin (500 mg b.i.d) for 14 days] and the last 375 patients received an optimized concomitant treatment [optimized triple therapy plus metronidazole (500 mg b.i.d)]. The optimized concomitant therapy achieved significantly higher eradication rates in the per protocol (82.3% vs. 93.8%; P<0.001) and intention-to-treat analysis (81.3% vs. 90.4%; P<0.001]. Adverse events (97.2% mild/moderate) were significantly more common with optimized concomitant therapy (39% vs. 47%, P<0.05), but full compliance with therapy was similar between groups. In the multivariate analysis, optimized concomitant therapy was the only significant predictor of successful eradication. Therefore, the authors concluded that empiric optimized concomitant therapy achieves significantly higher cure rates (>90%) compared to optimized triple therapy; and that addition of metronidazole to optimized concomitant therapy increased eradication rates by 10%, resulting in more mild adverse effects, but without impairing compliance with therapy.
WHAT ARE THE RESULTS WITH THE CONCOMITANT TREATMENT IN CLINICAL PRACTICE? THE EXPERIENCE OF THE EUROPEAN REGISTRY ON H. pylori MANAGEMENT
Aiming to evaluate the results from the clinical practice of European gastroenterologists regarding the management of H. pylori, the European Helicobacter Study Group organized a project to register the daily clinical practice of 300 researchers from 30 European Countries: The European Registry on H. pylori Management (Hp-EuReg). This project has been ongoing for less than two years but it has already included 10.000 patients, and it is expected to last for 10 years. The results from clinical practice presented during the International Workshop on Helicobacter (Rome, 2014) [98] correlate with the meta-analytical estimation: for example the overall eradication rate estimated for concomitant regimen is 87% while the observed efficacy in the Registry for the standard commonly used concomitant treatment is also 87%, although the coadjuvation with esomeprazole and lengthening the regimen to 14 days is able to increase the efficacy up to 92%.
The Hp-EuReg also includes data on other treatment options such as standard triple therapies, bismuth quadruple and sequential, all of them both in regular and optimized regimens (longer and double dose PPIs). The registry shows a clear superiority of concomitant regimen over standard triple therapies (76%). However, so far it has not been able to obtain statistically significant differences between concomitant, sequential and bismuth quadruple (at identical durations). The discordance with the meta-analytical estimation when comparing concomitant and sequential in the registry may be explained to the fact that many of the sequential prescriptions have used esomeprazole and probiotic coadjuvation, which may have indirectly increased the efficacy of sequential treatment.
The preliminary results presented in Rome in 2014 concluded that the use of standard triple therapies (still the most frequently prescribed) offers sub-optimal results in Europe, and that quadruple therapies achieved higher eradication rates, especially in longer treatment durations and/or with the coadjuvation of esomeprazole.
CONCLUSIONS
Standard triple therapy is still the most widely used treatment in clinical practice in many countries. However, the prevalence of clarithromycin resistance has increased substantially in recent years, and there has been a corresponding decrease in the eradication rate for H. pylori infection. Eradication rates are at their lowest levels since a decade ago and are likely to fall further as antimicrobial resistance becomes more prevalent worldwide [92]. It is clear that alternative treatment regimens are urgently needed, particularly for patients with clarithromycin-resistant strains of H. pylori [99].
In the present chapter, we have critically reviewed the evidence on the role of non-bismuth quadruple −concomitant− therapy in the treatment of H. pylori infection. Our meta-analysis of the 55 studies (including 6,906 patients) that up to now have evaluated the efficacy of the concomitant treatment revealed a mean H. pylori cure rate (intention-to-treat) of approximately 90%. In addition, based on the results of several randomized controlled trials comparing concomitant vs.
