Skip to main content
SpringerLink
Log in

Dual therapy with high doses of rabeprazole and amoxicillin versus triple therapy with rabeprazole, amoxicillin, and metronidazole as a rescue regimen for Helicobacter pylori infection after the standard triple therapy

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Backgrounds and Aims

Development of safe and effective rescue regimens for eradication failure of Helicobacter pylori infection by standard regimens is an urgent task. We designed the prospective study to compare the efficacy of two rescue regimens after eradication failure by the standard triple therapy.

Methods

One hundred and thirty-two patients in whom eradication of H. pylori infection failed initial triple therapy with lansoprazole 30 mg b.i.d, amoxicillin 750 mg b.i.d. and clarithromycin 400 mg b.i.d. for 1 week were randomized to either the 1–week triple therapy with rabeprazole 10 mg b.i.d., amoxicillin 750 mg b.i.d., and metronidazole 250 mg b.i.d. (RAM) or the 2–week dual therapy with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. (RA). Eradication of H. pylori was judged by 13C-urea breath test 1 month later.

Results

The intention-to-treat and per-protocol-based eradication rates were 92.4% (95% CI: 83.2–97.5) and 95.3% (95% CI: 86.9–99.0) for the RAM therapy and 90.9% (95% CI: 81.2–96.6) and 93.8% (95% CI: 84.8–98.3), respectively, for the RA therapy (P > 0.2 for both). No clinically recognizable adverse events were observed with either regimen.

Conclusion

RA as well as RAM therapy are safe and effective rescue regimens for H. pylori infection after eradication failure by the standard triple therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AUC:

area under the plasma-concentration-time curve

Cmax:

peak concentration

CYP2C19:

cytochrome P450 2C19 or S-mephenytoin 4′-hydroxylase

MIC:

minimum inhibitory concentration

PPI:

proton pump inhibitor

References

  1. Blaser MJ (1992) Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation. Gastroenterology 102(2):720–727

    PubMed  CAS  Google Scholar 

  2. Parsonnet J, Blaser MJ, Perez-Perez GI, Hargrett-Bean N, Tauxe RV (1992) Symptoms and risk factors of Helicobacter pylori infection in a cohort of epidemiologists. Gastroenterology 102(1):41–46

    PubMed  CAS  Google Scholar 

  3. Uemura N, Okamoto S, Yamamoto S et al (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345(11):784–789

    Article  PubMed  CAS  Google Scholar 

  4. Wotherspoon AC (1998) Helicobacter pylori infection and gastric lymphoma. Br Med Bull 54(1):79–85

    PubMed  CAS  Google Scholar 

  5. Malfertheiner P, Megraud F, O’Morain C et al (2002) Current concepts in the management of Helicobacter pylori infection–the Maastricht 2–2000 Consensus Report. Aliment Pharmacol Ther 16(2):167–180

    Article  PubMed  CAS  Google Scholar 

  6. Furuta T, Shirai N, Takashima M et al (2001) Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69(3):158–168

    Article  PubMed  CAS  Google Scholar 

  7. Lind T, Veldhuyzen van Zanten S, Unge P et al (1996) Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study. Helicobacter 1(3):138–144

    Article  PubMed  CAS  Google Scholar 

  8. Asaka M, Sugiyama T, Kato M et al (2001) A multicenter, double-blind study on triple therapy with lansoprazole, amoxicillin and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients. Helicobacter 6(3):254–261

    Article  PubMed  CAS  Google Scholar 

  9. Kim JM, Kim JS, Jung HC, Kim N, Kim YJ, Song IS (2004) Distribution of antibiotic MICs for Helicobacter pylori strains over a 16–year period in patients from Seoul, South Korea. Antimicrob Agents Chemother 48(12):4843–4847

    Article  PubMed  CAS  Google Scholar 

  10. Matsuhisa T, Kawai T, Masaoka T et al (2006) Efficacy of metronidazole as second-line drug for the treatment of Helicobacter pylori infection in the Japanese population: a multicenter study in the Tokyo Metropolitan Area. Helicobacter 11(3):152–158

    Article  PubMed  CAS  Google Scholar 

  11. Nagahara A, Miwa H, Kawabe M et al (2004) Second-line treatment for Helicobacter pylori infection in Japan: proton pump inhibitor-based amoxicillin and metronidazole regimen. J Gastroenterol 39(11):1051–1055

    Article  PubMed  CAS  Google Scholar 

  12. Murakami K, Sato R, Okimoto T et al (2003) Efficacy of triple therapy comprising rabeprazole, amoxicillin and metronidazole for second-line Helicobacter pylori eradication in Japan, and the influence of metronidazole resistance. Aliment Pharmacol Ther 17(1):119–123

    Article  PubMed  CAS  Google Scholar 

  13. Results of a multicentre European survey in 1991 of metronidazole resistance in Helicobacter pylori (1992) European Study Group on Antibiotic Susceptibility of Helicobacter pylori. Eur J Clin Microbiol Infect Dis 11(9):777–781

  14. Adamek RJ, Suerbaum S, Pfaffenbach B, Opferkuch W (1998) Primary and acquired Helicobacter pylori resistance to clarithromycin, metronidazole, and amoxicillin–influence on treatment outcome. Am J Gastroenterol 93(3):386–389

    PubMed  CAS  Google Scholar 

  15. Megraud F, Doermann HP (1998) Clinical relevance of resistant strains of Helicobacter pylori: a review of current data. Gut 43(Suppl 1):S61–S65

    Article  PubMed  CAS  Google Scholar 

  16. Debets-Ossenkopp YJ, Herscheid AJ, Pot RG, Kuipers EJ, Kusters JG, Vandenbroucke-Grauls CM (1999) Prevalence of Helicobacter pylori resistance to metronidazole, clarithromycin, amoxycillin, tetracycline and trovafloxacin in The Netherlands. J Antimicrob Chemother 43(4):511–515

    Article  PubMed  CAS  Google Scholar 

  17. Parsons HK, Carter MJ, Sanders DS, Winstanley T, Lobo AJ (2001) Helicobacter pylori antimicrobial resistance in the United Kingdom: the effect of age, sex and socio-economic status. Aliment Pharmacol Ther 15(9):1473–1478

    Article  PubMed  CAS  Google Scholar 

  18. Beard CM, Noller KL, O’Fallon WM, Kurland LT, Dahlin DC (1988) Cancer after exposure to metronidazole. Mayo Clin Proc 63(2):147–153

    PubMed  CAS  Google Scholar 

  19. Cavaliere A, Bacci M, Amorosi A, Del Gaudio M, Vitali R (1983) Induction of lung tumors and lymphomas in BALB/c mice by metronidazole. Tumori 69(5):379–382

    PubMed  CAS  Google Scholar 

  20. Beard CM, Noller KL, O’Fallon WM, Kurland LT, Dockerty MB (1979) Lack of evidence for cancer due to use of metronidazole. N Engl J Med 301(10):519–522

    Article  PubMed  CAS  Google Scholar 

  21. Friedman GD, Selby JV (1989) Metronidazole and cancer. JAMA 261(6):866

    Article  PubMed  CAS  Google Scholar 

  22. Furuta T, Ohashi K, Kamata T et al (1998) Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 129(12):1027–1030

    PubMed  CAS  Google Scholar 

  23. Furuta T, Ohashi K, Kosuge K et al (1999) CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 65(5):552–561

    Article  PubMed  CAS  Google Scholar 

  24. Furuta T, Shirai N, Xiao F, Ohashi K, Ishizaki T (2001) Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19. Clin Pharmacol Ther 70(5):484–492

    Article  PubMed  CAS  Google Scholar 

  25. Sugimoto M, Furuta T, Shirai N et al (2004) Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotype status. Clin Pharmacol Ther 76(4):290–301

    Article  PubMed  CAS  Google Scholar 

  26. Furuta T, Shirai N, Takashima M et al (2001) Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics 11(4):341–348

    Article  PubMed  CAS  Google Scholar 

  27. Furuta T, Shirai N, Sugimoto M, Ohashi K, Ishizaki T (2003) Retreatment of H. pylori with dual therapy using high doses of rabeprazole or lansoprazole can be effective. Aliment Pharmacol Ther 18(11–12):1175–1176

    Article  PubMed  CAS  Google Scholar 

  28. Furuta T, Shirai N, Xiao F et al (2003) High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology 50(54):2274–2278

    PubMed  CAS  Google Scholar 

  29. Furuta T, Sagehashi Y, Shirai N et al (2005) Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection. Clin Gastroenterol Hepatol 3(6):564–573

    Article  PubMed  CAS  Google Scholar 

  30. Dent JC, McNulty CA (1988) Evaluation of a new selective medium for Campylobacter pylori. Eur J Clin Microbiol Infect Dis 7(4):555–558

    Article  PubMed  CAS  Google Scholar 

  31. Clayton CL, Kleanthous H, Coates PJ, Morgan DD, Tabaqchali S (1992) Sensitive detection of Helicobacter pylori by using polymerase chain reaction. J Clin Microbiol 30(1):192–200

    PubMed  CAS  Google Scholar 

  32. Adamek RJ, Suerbaum S, Pfaffenbach B, Opferkuch W (1998) Primary and acquired Helicobacter pylori resistance to clarithromycin, metronidazole, and amoxicillin–influence on treatment outcome. Am J Gastroenterol 93(3):386–389

    PubMed  CAS  Google Scholar 

  33. Kato M, Asaka M, Ohara S, Toyota T (1998) Clinical studies of 13C-urea breath test in Japan. J Gastroenterol 33(Suppl)10:36–39

    PubMed  CAS  Google Scholar 

  34. Vakil N, Hahn B, McSorley D (1998) Clarithromycin-resistant Helicobacter pylori in patients with duodenal ulcer in the United States. Am J Gastroenterol 93(9):1432–1435

    Article  PubMed  CAS  Google Scholar 

  35. Murakami K, Fujioka T, Okimoto T, Sato R, Kodama M, Nasu M (2002) Drug combinations with amoxycillin reduce selection of clarithromycin resistance during Helicobacter pylori eradication therapy. Int J Antimicrob Agents 19(1):67–70

    Article  PubMed  CAS  Google Scholar 

  36. Wurzer H, Rodrigo L, Stamler D et al (1997) Short-course therapy with amoxycillin-clarithromycin triple therapy for 10 days (ACT–10) eradicates Helicobacter pylori and heals duodenal ulcer. ACT–10 Study Group. Aliment Pharmacol Ther 11(5):943–952

    Article  PubMed  CAS  Google Scholar 

  37. Gisbert JP, Pajares JM (2002) Review article: Helicobacter pylori “rescue” regimen when proton pump inhibitor-based triple therapies fail. Aliment Pharmacol Ther 16(6):1047–1057

    Article  PubMed  CAS  Google Scholar 

  38. Labenz J, Stolte M, Blum AL et al (1995) Intragastric acidity as a predictor of the success of Helicobacter pylori eradication: a study in peptic ulcer patients with omeprazole and amoxicillin. Gut 37(1):39–43

    Article  PubMed  CAS  Google Scholar 

  39. Grayson ML, Eliopoulos GM, Ferraro MJ, Moellering RC, Jr (1989) Effect of varying pH on the susceptibility of Campylobacter pylori to antimicrobial agents. Eur J Clin Microbiol Infect Dis 8(10):888–889

    Article  PubMed  CAS  Google Scholar 

  40. Athamna A, Athamna M, Medlej B, Bast DJ, Rubinstein E (2004) In vitro post-antibiotic effect of fluoroquinolones, macrolides, beta-lactams, tetracyclines, vancomycin, clindamycin, linezolid, chloramphenicol, quinupristin/dalfopristin and rifampicin on Bacillus anthracis. J Antimicrob Chemother 53(4):609–615

    Article  PubMed  CAS  Google Scholar 

  41. Gisbert JP, Gisbert JL, Marcos S, Moreno-Otero R, Pajares JM (2006) Third-line rescue therapy with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures. Aliment Pharmacol Ther 24(10):1469–1474

    Article  PubMed  CAS  Google Scholar 

  42. Borody TJ, Pang G, Wettstein AR et al (2006) Efficacy and safety of rifabutin-containing ‘rescue therapy’ for resistant Helicobacter pylori infection. Aliment Pharmacol Ther 23(4):481–488

    Article  PubMed  CAS  Google Scholar 

  43. Isakov V, Domareva I, Koudryavtseva L, Maev I, Ganskaya Z (2002) Furazolidone-based triple ‘rescue therapy’ vs. quadruple ‘rescue therapy’ for the eradication of Helicobacter pylori resistant to metronidazole. Aliment Pharmacol Ther 16(7):1277–1282

    Article  PubMed  CAS  Google Scholar 

  44. Sohn DR, Kobayashi K, Chiba K, Lee KH, Shin SG, Ishizaki T (1992) Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4′–hydroxylation recruited from an Oriental population. J Pharmacol Exp Ther 262(3):1195–1202

    PubMed  CAS  Google Scholar 

  45. Chiba K, Kobayashi K, Manabe K, Tani M, Kamataki T, Ishizaki T (1993) Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephenytoin 4′–hydroxylation. J Pharmacol Exp Ther 266(1):52–59

    PubMed  CAS  Google Scholar 

  46. Ishizaki T, Sohn DR, Kobayashi K et al (1994) Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals. Ther Drug Monit 16(2):214–215

    Article  PubMed  CAS  Google Scholar 

  47. Chang M, Tybring G, Dahl ML et al (1995) Interphenotype differences in disposition and effect on gastrin levels of omeprazole–suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol 39(5):511–518

    PubMed  CAS  Google Scholar 

  48. Ieiri I, Kubota T, Urae A et al (1996) Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther 59(6):647–653

    Article  PubMed  CAS  Google Scholar 

  49. Shirai N, Furuta T, Moriyama Y et al (2001) Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther 15(12):1929–1937

    Article  PubMed  CAS  Google Scholar 

  50. Shirai N, Furuta T, Xiao F et al (2002) Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups. Aliment Pharmacol Ther 16(4):837–846

    Article  PubMed  CAS  Google Scholar 

  51. Yasuda S, Horai Y, Tomono Y et al (1995) Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′–hydroxylation status. Clin Pharmacol Ther 58(2):143–154

    Article  PubMed  CAS  Google Scholar 

  52. Ishizaki T, Horai Y (1999) Review article: cytochrome P450 and the metabolism of proton pump inhibitors–emphasis on rabeprazole. Aliment Pharmacol Ther 13(Suppl 3):27–36

    Article  PubMed  CAS  Google Scholar 

  53. Williams MP, Sercombe J, Hamilton MI, Pounder RE (1998) A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24–h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 12(11):1079–1089

    Article  PubMed  CAS  Google Scholar 

  54. Stedman CA, Barclay ML (2000) Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 14(8):963–978

    Article  PubMed  CAS  Google Scholar 

  55. Furuta T, Shirai N, Xiao F et al (2004) Polymorphism of interleukin–1beta affects the eradication rates of Helicobacter pylori by triple therapy. Clin Gastroenterol Hepatol 2(1):22–30

    Article  PubMed  CAS  Google Scholar 

  56. Kubota T, Chiba K, Ishizaki T (1996) Genotyping of S-mephenytoin 4′–hydroxylation in an extended Japanese population. Clin Pharmacol Ther 60(6):661–666

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The abstract of the present study was presented at the annual meeting of American Gastroenterological Association (AGA) held in Chicago in May 2005. This study was supported by a scientific research grant from the YOKOYAMA Foundation for Clinical Pharmacology, a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (17590470), and a grant-in-aid from the Center of Excellence (COE) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The assistance of the endoscopy staff, Ms. Tazuko Nakano, Hitomi Tanaka, Satoko Takebayashi, Keiko Kikuchi, and Chieko Matsumoto, is greatly appreciated.

Conflict of Interest

The authors declared no conflict of interest.

Author information

Author notes

  1. Naohito Shirai & Masayoshi Kajimura

    Present address: Department of Gastroenterology, Enshu General Hospital, Hamamatsu, Japan

Authors and Affiliations

  1. Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Naohito Shirai

  2. First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Mitsushige Sugimoto, Chise Kodaira, Masafumi Nishino, Mutsuhiro Ikuma, Masayoshi Kajimura & Akira Hishida

  3. Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, Oita, Japan

    Kyoichi Ohashi

  4. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takashi Ishizaki

  5. Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu, 431-3192, Japan

    Takahisa Furuta

Authors
  1. Naohito Shirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsushige Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chise Kodaira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masafumi Nishino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mutsuhiro Ikuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masayoshi Kajimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kyoichi Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takashi Ishizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akira Hishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takahisa Furuta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahisa Furuta.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shirai, N., Sugimoto, M., Kodaira, C. et al. Dual therapy with high doses of rabeprazole and amoxicillin versus triple therapy with rabeprazole, amoxicillin, and metronidazole as a rescue regimen for Helicobacter pylori infection after the standard triple therapy. Eur J Clin Pharmacol 63, 743–749 (2007). https://doi.org/10.1007/s00228-007-0302-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-007-0302-8

Keywords

Search

Navigation