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Newer agents for Helicobacter pylori eradication.
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MedLine Citation:
PMID:  22767998     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Helicobacter pylori infection remains widespread internationally, with a definite morbidity and mortality. The efficacy of standard 7-14 day triple therapies is decreasing, mainly due to increasing primary bacterial resistance to antibiotics. Currently, the most effective treatments are either the sequential regimen or the concomitant therapy. Different patents have been registered showing high bactericidal effects in vitro, some of which are active against clarithromycin- and metronidazole-resistant strains, even at low pH values. Among these novel molecules, benzimidazole-derivatives, polycyclic compounds, pyloricidin, and arylthiazole analogues seem to be the more promising. The identification of essential genes for either bacterial colonization or growth represents a route for potential target therapies in the near future.
Authors:
Giulia Fiorini; Angelo Zullo; Luigi Gatta; Valentina Castelli; Chiara Ricci; Francesca Cassol; Dino Vaira
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Publication Detail:
Type:  Journal Article     Date:  2012-06-18
Journal Detail:
Title:  Clinical and experimental gastroenterology     Volume:  5     ISSN:  1178-7023     ISO Abbreviation:  Clin Exp Gastroenterol     Publication Date:  2012  
Date Detail:
Created Date:  2012-07-06     Completed Date:  2012-10-02     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  101532800     Medline TA:  Clin Exp Gastroenterol     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  109-12     Citation Subset:  -    
Affiliation:
Department of Clinical Medicine, University of Bologna, Italy.
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Journal Information
Journal ID (nlm-ta): Clin Exp Gastroenterol
Journal ID (iso-abbrev): Clin Exp Gastroenterol
Journal ID (publisher-id): Clinical and Experimental Gastroenterology
ISSN: 1178-7023
Publisher: Dove Medical Press
Article Information
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© 2012 Fiorini et al, publisher and licensee Dove Medical Press Ltd.
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collection publication date: Year: 2012
Electronic publication date: Day: 18 Month: 6 Year: 2012
Volume: 5First Page: 109 Last Page: 112
ID: 3387829
PubMed Id: 22767998
DOI: 10.2147/CEG.S25422
Publisher Id: ceg-5-109

Newer agents for Helicobacter pylori eradication
Giulia Fiorini1
Angelo Zullo2
Luigi Gatta3
Valentina Castelli1
Chiara Ricci3
Francesca Cassol4
Dino Vaira1
1Department of Clinical Medicine, University of Bologna, Italy
2Gastroenterology and Digestive Endoscopy, ‘Nuovo Regina Margherita’ Hospital, Rome, Italy
3Versilia Hospital, Lido di Camaiore, Italy
4School of Gastroenterology, University of Ferrera, Ferrera, Italy
Correspondence: Correspondence: Dino Vaira, Department of Clinical Medicine, University of Bologna, S Orsola Hospital, Via Massarenti 9, 40138 Bologna, Italy, Tel +39 51 6364140, Fax +39 51 398794, Email berardino.vaira@unibo.it

Introduction

Despite the evidence that H. pylori prevalence is declining in developed countries, the infection remains widespread internationally, with a definite morbidity and mortality.1 Indeed, H. pylori is the main cause of nonulcer dyspepsia, peptic ulcer disease, and gastric tumors, including both low-grade mucosa-associated lymphoid tissue lymphoma and adenocarcinoma.2,3 Among the extra-digestive diseases, data show a significant association between H. pylori infection and both idiopathic thrombocytopenic purpura and idiopathic iron deficiency anemia.4,5H. pylori infection is generally acquired in childhood, and it persists throughout life. Spontaneous resolution is rare, and so a targeted therapy is needed. H. pylori colonizes a kind of biological niche – ie, under the gastric mucous layer, strongly attached to epithelial cells and even within cells – where antibiotic action is impaired, and so, curing such an infection is difficult. Different antibiotic combinations, administered together with a proton pump inhibitor (PPI), have been proposed in the last decades. Unfortunately, no available therapy is able to eradicate H. pylori in all treated patients. Therefore, new drugs and novel therapeutic approaches are needed.


Current therapies

The combination of a PPI with clarithromycin and amoxicillin or metronidazole is the most common first-line therapy regimen. However, current European guidelines confirm the use of standard 7-day triple therapy only in those areas where primary clarithromycin resistance is lower than 15%–20%, whilst a prolonged 14-day regimen should be used where bacterial resistance rate is higher.6 Nevertheless, data from two large trials found that after completion of the prolonged 14-day triple therapy, the eradication rate was only 70% in nonulcer dyspepsia patients, and 81.7% in peptic ulcer patients.7,8 Therefore, different therapeutic approaches are needed. The sequential therapy was first introduced in Italy in 2000.9 This regimen is a 10-day therapy, including a simple dual therapy with a PPI plus amoxicillin 1 g (both twice daily) given for the first 5 days, followed by a triple therapy including a PPI, clarithromycin 500 mg, and tinidazole 500 mg (all given twice daily) for the remaining 5 days.

The first comprehensive, pooled-data analysis of sequential therapy, which included over 1,800 Italian patients, found an eradication rate as high as 93.5%.10 Moreover, the high efficacy of such a therapy regimen has been confirmed in several other countries, including Israel, Korea, Panama, Poland, Romania, Spain, Taiwan and Thailand, but not in Iran or Latin America.1117 Different trials compared the efficacy of sequential therapy with that of standard triple therapies. A meta-analysis showed that a sequential regimen was better than standard 7–10 day triple therapies.18 These data have been updated, and the eradication rates following the sequential therapy (2,454/2,853; 86%; 95% CI: 84.7–87.3) remained distinctly higher compared to that of triple therapies (2,320/3,079; 75.3%; 95% CI: 73.8–76.9).19

Some recent studies found that a levofloxacin- instead of clarithromycin-based sequential therapy also appears highly effective.20,21 However, such modified sequential therapy precludes the use of a levofloxacin-based second-line therapy, thereby complicating any successive therapeutic approach in patients who fail eradication therapy.22,23 Moreover, primary resistance to levofloxacin is quickly increasing worldwide, with prevalence values of 17% in Brazil, 16.8% in Belgium, 22.1% in Germany, 18% in Hong Kong, 19.1% in Italy, 14.3% in Japan, and 21.5% in Korea.22 Therefore, levofloxacin should be used with caution in a first-line therapy regimen.24

Concomitant therapy comprises a PPI plus amoxicillin, clarithromycin, and metronidazole, given all together. This therapy was first introduced as an alternative to standard triple therapies more than 10 years ago, and the original duration of therapy was only 5 days. A recent meta-analysis of 15 studies found a high efficacy of this regimen, with an eradication rate of 90%. However, it was noted that the eradication rate increased with therapy duration, being 85% at 3 days, 88% at 4 days, 89% at 5 days, 93% at 7 days, and 92% at 10 days.25 Another meta-analysis of 9 studies including only 7-day concomitant therapy calculated eradication rates of 90% at ITT and 93% at PP analysis.26 Pooled estimates of the five randomized controlled trials showed the superiority of concomitant therapy over triple therapy (OR: 2.86; 95% CI: 1.73–4.73).26


Future therapies

Although the contributing factors differ,27 therapy failure mainly depends on primary resistance to different antibiotics (eg, clarithromycin), which is increasing worldwide.28 It is thought that only new classes of antimicrobials with novel mechanisms of action can fully address the increasing drug resistance.29 In the last decade, several patents of new antibiotics have claimed potential activity against H. pylori.3032 Of note, some molecules have shown a very high bactericidal level of activity against H. pylori in vitro, including those strains with primary clarithromycin and/or metronidazole resistance. In addition, some molecules preserve antibacterial activity even at low pH values, a clear advantage for H. pylori treatment, considering that they must act in gastric acid. In particular, different benzimidazole-derivatives and polycyclic compounds have been patented, which are highly effective against H. pylori.30 Pyloricidin A, B, and C – a family of natural antibiotics – have exhibited a potent and highly selective bactericidal activity against H. pylori, with an MIC90 value of 0.013 mg/L.30 In addition, among the arylthiazole analogues, the thienylthiazole derivative 44 exhibited the strongest activity, with MIC90 values as low as 0.0065 mg/L.30 Of note, some isothiazole derivatives have been found to enable a potent inhibition of bacterial urease activity in vitro, constituting a potential “targeted” therapy for H. pylori infection.31 The list of potential useful molecules is provided in Table 1, while in Table 2 there are several plant extracts with anti-H. pylori activity in vitro.3034 Therefore, it is likely that more powerful drugs will be available in the near future to treat H. pylori infection.

Many studies have addressed the identification of novel therapeutic targets (eg, bacterial proteins, mechanisms, genes required for growth and/or colonization, etc). Further investigation of anti-H. pylori therapies have addressed the identification of essential genes required for in vitro bacterial survival, or genes essential for mucosal colonization.35,36 Indeed, several studies have shown large numbers of genes involved in cellular motility that are required for colonization or growth, demonstrating that they represent a potential target by H. pylori-specific anti-infective agents. Additional functions potentially susceptible to therapeutic intervention include cellular processes like chemotaxis, protein folding, regulation, genetic information processing, and resistance to acid and oxidative stresses.37 There are several genes that have been evaluated as potential therapeutic targets, most of them encoded for proteins which form biochemical pathways, or urease–related genes that are essential for host colonization. There are also many gene-encoding proteins required for bacterial growth that have been studied as potential therapeutic targets, but further evaluations are needed.38


Conclusion

The available antibiotics active against H. pylori in vivo are very rare, and new molecules are needed. The current most effective combination of these drugs is both sequential and concomitant therapy. Different patents have been registered showing high bactericidal effects in vitro, some of which are active against clarithromycin- and metronidazole-resistant strains, even at low pH values. Therefore, the search for novel antibacterial therapies against H. pylori is a “work in progress” driven by the goal of preventing gastric cancer, and by worldwide increasing antibiotic resistance.


Notes

fn1-ceg-5-109Disclosure

The authors reports no conflicts of interest in this work.

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Article Categories:
  • Review

Keywords: Helicobacter pylori therapy, new antibiotic agents.

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