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Newer agents for Helicobacter pylori eradication.
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PMID:  22767998     Owner:  NLM     Status:  PubMed-not-MEDLINE    
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.
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:  -    
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
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© 2012 Fiorini et al, publisher and licensee Dove Medical Press Ltd.
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


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


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.



The authors reports no conflicts of interest in this work.

1. Sonnenberg A,Lash RH,Genta RM. National study of Helicobacter pylori infection in gastric biopsy specimensGastroenterologyYear: 201013961894190120727889
2. Alakkari A,Zullo A,O’Connor HJ. Helicobacter pylori and nonmalignant diseasesHelicobacterYear: 201116Suppl 1333721896083
3. Zullo A,Hassan C,Cristofari F,et al. Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphomaClin Gastroenterol HepatolYear: 20108210511019631287
4. Stasi R,Sarpatwari A,Segal JB,et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic reviewBloodYear: 200911361231124018945961
5. Huang X,Qu X,Yan W,et al. Iron deficiency anemia can be improved after eradication of Helicobacter pyloriPostgrad Med JYear: 201086101527227820448223
6. Malfertheiner P,Megraud F,O’Morain C,et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus ReportGutYear: 200756677278117170018
7. Zagari RM,Bianchi-Porro G,Fiocca R,et al. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER StudyGutYear: 200756447547917028126
8. Paoluzi P,Iacopini F,Crispino P,et al. 2-week triple therapy for Helicobacter pylori infection is better than 1-week in clinical practice: a large prospective single-center randomized studyHelicobacterYear: 200611656256817083378
9. Zullo A,Rinaldi V,Winn S,et al. A new highly effective short-term therapy schedule for Helicobacter pylori eradicationAliment Pharmacol TherYear: 200014671571810848654
10. Zullo A,De Francesco V,Hassan C,Morini S,Vaira D. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysisGutYear: 200756101353135717566020
11. Vaira D,Zullo A,Hassan C,Fiorini A,Vakil N. Sequential Therapy for Helicobacter pylori Eradication: The Time Is Now!Therap Adv GastroenterolYear: 200926317322
12. Kwon JH,Lee DH,Song BJ,et al. Ten-day sequential therapy as first-line treatment for Helicobacter pylori infection in Korea: a retrospective studyHelicobacterYear: 201015214815320402817
13. Sirimontaporn N,Thong-Ngam D,Tumwasorn S,Mahachai V. Ten-day sequential therapy of Helicobacter pylori infection in ThailandAm J GastroenterolYear: 201010551071107520010919
14. Schmilovitz-Weiss H,Shalev T,Chechoulin Y,et al. High eradication rates of Helicobacter pylori infection following sequential therapy: the Israeli experience treating naïve patientsHelicobacterYear: 201116322923321585609
15. Wu DC,Hsu PI,Wu JY,et al. Sequential and concomitant therapy with four drugs is equally effective for eradication of H. pylori infectionClin Gastroenterol HepatolYear: 201081364119804842
16. Greenberg ER,Anderson GL,Morgan DR,et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trialLancetYear: 2011378979050751421777974
17. Aminian K,Farsad F,Ghanbari A,Fakhreih S,Hasheminasab SM. A randomized trial comparing four Helicobacter pylori eradication regimens: standard triple therapy, ciprofloxacin based triple therapy, quadruple and sequential therapyTrop GastroenterolYear: 201031430330721568147
18. Jafri NS,Hornung CA,Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatmentAnn Intern MedYear: 20081481292393118490667
19. Gatta L,Vakil N,Leandro G,Di Mario F,Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and childrenAm J GastroenterolYear: 2009104123069307919844205
20. Romano M,Cuomo A,Gravina AG,et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trialGutYear: 201059111465147020947881
21. Molina-Infante J,Perez-Gallardo B,Fernandez-Bermejo M,et al. Clinical trial: clarithromycin vs levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradicationAliment Pharmacol TherYear: 201031101077108420180787
22. Zullo A,Hassan C,D’Ercole C,D Francesco V,Vaira D. Clarithromycin or levofloxacin in the sequential therapy for H. pylori eradication?Aliment Pharmacol TherYear: 201031111248124920518756
23. Zullo A,De Francesco V,Vaira D. Sequential therapy for Helicobacter pylori eradication: is levofloxacin better?GutYear: 20116011160421193446
24. Berning M,Krasz S,Miehlke S. Should quinolones come first in Helicobacter pylori therapy?Therap Adv GastroenterolYear: 201142103114
25. Essa AS,Kramer JR,Graham DY,Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradicationHelicobacterYear: 200914210911819298338
26. Gisbert JP,Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobater pyloriAliment Pharmacol TherYear: 201134660461721745241
27. Zullo A,De Francesco V,Hassan C. Predicting Helicobacter pylori Eradication: How to Teach an Old Dog New Tricks!J Clin GastroenterolYear: 201246425926122395061
28. De Francesco V,Giorgio F,Hassan C,et al. Worldwide H. pylori antibiotic resistance: a systematic reviewJ Gastrointestinal Liver DisYear: 2010194409414
29. Spellberg B,Powers JH,Brass EP,Miller LG,Edwards JE Jr. Trends in antimicrobial drug development: implications for the futureClin Infect DisYear: 20043891279128615127341
30. Zullo A,Hassan C,Campo SMA,Morini S. Evolving therapy for Helicobacter pylori infectionExp Opin Ther PatentsYear: 2004141014531464
31. Zullo A,Hassan C,Eramo A,Morini S. Helicobacter pylori therapy: what is coming?Expert Opin Ther PatentsYear: 200616811071112
32. Campo SM,Zullo A,Hassan C,Morini S. Antibiotic treatment strategies for Helicobacter pylori infectionRecent Pat on AntiInfect Drug DiscovYear: 2007211117
33. Kamiji MM,de Oliveira RB. Non-antibiotic therapies for Helicobacter pylori infectionEur J Gastroenterol HepatolYear: 200517997398116093876
34. Ito H,Yazawa S,Nishiyama T,Nonaka M. In vitro inhibition of Helicobacter pylori by several dietary plant agentsInt J Antimicrob AgentsYear: 2008321899818495440
35. Salama NR,Shepherd B,Falkow S. Global transposon mutagenesis and essential gene analysis of Helicobacter pyloriJ BacteriolYear: 2004186237926793515547264
36. Chalker AF,Minehart HW,Hughes NJ,et al. Systematic identification of selective essential genes in Helicobacter pylori by genome prioritization and allelic replacement mutagenesisJ BacteriolYear: 200118341259126811157938
37. Baldwin DN,Shepherd B,Kraemer P,et al. Identification of H. pylori genes contributing to stomach colonizationInfect ImmunYear: 20077521005101617101654
38. Kavermann H,Burns BP,Angermuller K,et al. Identification and characterization of Helicobacter pylori genes essential for gastric colonizationJ Exp MedYear: 2003197781382212668646

Article Categories:
  • Review

Keywords: Helicobacter pylori therapy, new antibiotic agents.

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