Comparison of sequential therapy and amoxicillin/tetracycline containing bismuth quadruple therapy for the first-line eradication of Helicobacter pylori: a prospective, multi-center, randomized clinical trial

Ju Yup Lee, Nayoung Kim, Kyung Sik Park, Hyun Jin Kim, Seon Mee Park, Gwang Ho Baik, Ki-Nam Shim, Jung Hwan Oh, Suck Chei Choi, Sung Eun Kim, Won Hee Kim, Seon-Young Park, Gwang Ha Kim, Bong Eun Lee, Yunju Jo, Su Jin Hong, Ju Yup Lee, Nayoung Kim, Kyung Sik Park, Hyun Jin Kim, Seon Mee Park, Gwang Ho Baik, Ki-Nam Shim, Jung Hwan Oh, Suck Chei Choi, Sung Eun Kim, Won Hee Kim, Seon-Young Park, Gwang Ha Kim, Bong Eun Lee, Yunju Jo, Su Jin Hong

Abstract

Background: The <80 % Helicobacter pylori eradication rate with sequential therapy is unsatisfactory. Modified bismuth quadruple therapy, replacing metronidazole with amoxicillin, could be promising because H. pylori resistance to tetracycline or to amoxicillin is relatively low. A 14-day modified bismuth quadruple protocol as first-line H. pylori treatment was compared with 10-day sequential therapy.

Methods: In total, 390 H. pylori-infected subjects participated in the randomized clinical trial: 10-day sequential therapy (40 mg pantoprazole plus 1 g amoxicillin twice a day for 5 days, then 40 mg pantoprazole and 500 mg clarithromycin twice a day and 500 mg metronidazole three times a day for 5 days) or 14-day modified bismuth quadruple therapy (40 mg pantoprazole, 600 mg bismuth subcitrate, 1 g tetracycline, and 1 g amoxicillin, twice a day). (13)C-urea breath test, rapid urease testing, or histology was performed to check for eradication.

Results: Intention-to-treat (ITT) eradication rates of 10-day sequential and 14-day quadruple therapy were 74.6 % and 68.7 %, respectively, and the per-protocol (PP) rates were 84.2 and 76.5 %, respectively. The eradication rate was higher in the sequential therapy group, but neither the ITT nor the PP analyses had a significant difference (P = 0.240 and P = 0.099, respectively). However, the adverse events were significantly lower in the modified bismuth quadruple therapy group than the sequential therapy group (36.9 vs. 47.7 %, P = 0.040).

Conclusions: Ten-day sequential therapy appears to be more effective despite frequent adverse events. However, both 10-day SQT and 14-day PBAT did not reach the excellent eradication rates that exceed 90 %. Additional trials are needed to identify a more satisfactory first-line eradication therapy.

Trial registration: ClinicalTrials.gov ( NCT02159976 ); Registration date: 2014-06-03, CRIS ( KCT0001176 ); Registration date: 2014-07-23.

Keywords: Amoxicillin; Bismuth; Eradication; Helicobacter pylori; Quadruple; Tetracycline.

Figures

Fig. 1
Fig. 1
Flowchart of participants
Fig. 2
Fig. 2
H. pylori eradication rate of 10-day SQT and 14-day PBAT according to the ITT and PP analyses. SQT, sequential therapy; PBAT, quadruple therapy consists of pantoprazole, bismuth, amoxicillin, and tetracycline; ITT, intention-to-treat; PP, per-protocol
Fig. 3
Fig. 3
H. pylori eradication rate of 10-day SQT and 14-day PBAT according to each institution. SQT, sequential therapy; PBAT, quadruple therapy consists of pantoprazole, bismuth, amoxicillin, and tetracycline; ITT, intention-to-treat

References

    1. McColl KE. Clinical practice. Helicobacter pylori infection. New Engl J Med. 2010;362:1597–1604. doi: 10.1056/NEJMcp1001110.
    1. Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter. 2007;12:275–278. doi: 10.1111/j.1523-5378.2007.00518.x.
    1. Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, Haruma K, Asaka M, Uemura N, Malfertheiner P, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015;64:1353–1367. doi: 10.1136/gutjnl-2015-309252.
    1. Lee JY, Kim N, Kim MS, Choi YJ, Lee JW, Yoon H, Shin CM, Park YS, Lee DH, Jung HC. Factors affecting first-line triple therapy of Helicobacter pylori including CYP2C19 genotype and antibiotic resistance. Dig Dis Sci. 2014;59:1235–1243. doi: 10.1007/s10620-014-3093-7.
    1. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59:1143–1153. doi: 10.1136/gut.2009.192757.
    1. Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, Gensini GF, Gisbert JP, Graham DY, Rokkas T, et al. Management of Helicobacter pylori infection--the Maastricht IV/Florence Consensus Report. Gut. 2012;61:646–664. doi: 10.1136/gutjnl-2012-302084.
    1. Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Annals Intern Med. 2008;148:923–931. doi: 10.7326/0003-4819-148-12-200806170-00226.
    1. 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 children. Am J Gastroenterol. 2009;104:3069–3079. doi: 10.1038/ajg.2009.555.
    1. Tong JL, Ran ZH, Shen J, Xiao SD. Sequential therapy vs. standard triple therapies for Helicobacter pylori infection: a meta-analysis. J Clin Pharm Ther. 2009;34:41–53. doi: 10.1111/j.1365-2710.2008.00969.x.
    1. Kim JS, Kim BW, Ham JH, Park HW, Kim YK, Lee MY, Ji JS, Lee BI, Choi H. Sequential Therapy for Helicobacter pylori Infection in Korea: Systematic Review and Meta-Analysis. Gut Liver. 2013;7:546–551. doi: 10.5009/gnl.2013.7.5.546.
    1. Zullo A, Rinaldi V, Winn S, Meddi P, Lionetti R, Hassan C, Ripani C, Tomaselli G, Attili AF. A new highly effective short-term therapy schedule for Helicobacter pylori eradication. Aliment Pharmacol Tther. 2000;14:715–718. doi: 10.1046/j.1365-2036.2000.00766.x.
    1. Yoon H, Lee DH, Kim N, Park YS, Shin CM, Kang KK, Oh DH, Jang DK, Chung JW. Meta-analysis: Is sequential therapy superior to standard triple therapy for Helicobacter pylori infection in Asian adults? J Gastroenterol Hepatol. 2013;28:1801–1809. doi: 10.1111/jgh.12397.
    1. Chung JW, Jung YK, Kim YJ, Kwon KA, Kim JH, Lee JJ, Lee SM, Hahm KB, Lee SM, Jeong JY, et al. Ten-day sequential versus triple therapy for Helicobacter pylori eradication: a prospective, open-label, randomized trial. J Gastroenterol Hepatol. 2012;27:1675–1680. doi: 10.1111/j.1440-1746.2012.07249.x.
    1. Lee JY, Kim N. Future trends of Helicobacter pylori eradication therapy in Korea. Korean J Gastroenterol. 2014;63:158–170. doi: 10.4166/kjg.2014.63.3.158.
    1. Kim SG, Jung HK, Lee HL, Jang JY, Lee H, Kim CG, Shin WG, Shin ES, Lee YC. Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition. J Gastroenterol Hepatol. 2014;29:1371–1386. doi: 10.1111/jgh.12607.
    1. Marin AC, McNicholl AG, Gisbert JP. A review of rescue regimens after clarithromycin-containing triple therapy failure (for Helicobacter pylori eradication) Exp opin Pharmacotherapy. 2013;14:843–861. doi: 10.1517/14656566.2013.782286.
    1. Venerito M, Krieger T, Ecker T, Leandro G, Malfertheiner P. Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection. Digestion. 2013;88:33–45. doi: 10.1159/000350719.
    1. Lee BH, Kim N, Hwang TJ, Lee SH, Park YS, Hwang JH, Kim JW, Jeong SH, Lee DH, Jung HC, et al. Bismuth-containing quadruple therapy as second-line treatment for Helicobacter pylori infection: effect of treatment duration and antibiotic resistance on the eradication rate in Korea. Helicobacter. 2010;15:38–45. doi: 10.1111/j.1523-5378.2009.00735.x.
    1. Lee JW, Kim N, Kim JM, Nam RH, Chang H, Kim JY, Shin CM, Park YS, Lee DH, Jung HC. Prevalence of primary and secondary antimicrobial resistance of Helicobacter pylori in Korea from 2003 through 2012. Helicobacter. 2013;18:206–214. doi: 10.1111/hel.12031.
    1. Liang X, Xu X, Zheng Q, Zhang W, Sun Q, Liu W, Xiao S, Lu H. Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study. Clin Gastroenterol Hepatol. 2013;11:802–807.e801. doi: 10.1016/j.cgh.2013.01.008.
    1. Kadayifci A, Uygun A, Polat Z, Kantarcioglu M, Kilciler G, Baser O, Ozcan A, Emer O. Comparison of bismuth-containing quadruple and concomitant therapies as a first-line treatment option for Helicobacter pylori. Turkish J Gastroenterol. 2012;23:8–13. doi: 10.4318/tjg.2012.0392.
    1. Cetinkaya ZA, Sezikli M, Guzelbulut F, Cosgun S, Duzgun S, Kurdas OO. Comparison of the efficacy of the two tetracycline-containing sequential therapy regimens for the eradication of Helicobacter pylori: 5 days versus 14 days amoxicillin. Helicobacter. 2010;15:143–147. doi: 10.1111/j.1523-5378.2010.00747.x.
    1. Chi CH, Lin CY, Sheu BS, Yang HB, Huang AH, Wu JJ. Quadruple therapy containing amoxicillin and tetracycline is an effective regimen to rescue failed triple therapy by overcoming the antimicrobial resistance of Helicobacter pylori. Aliment Pharmacol Ther. 2003;18:347–353. doi: 10.1046/j.1365-2036.2003.01653.x.
    1. Kim SE, Park YS, Kim N, Kim MS, Jo HJ, Shin CM, Lee SH, Hwang JH, Kim JW, Jeong SH, et al. Effect of Helicobacter pylori Eradication on Functional Dyspepsia. J Neurogastroenterol Motility. 2013;19:233–243. doi: 10.5056/jnm.2013.19.2.233.
    1. Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M, Hirschl AM, Andersen LP, Goossens H, Glupczynski Y. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2013;62:34–42. doi: 10.1136/gutjnl-2012-302254.
    1. Boyanova L, Mitov I. Geographic map and evolution of primary Helicobacter pylori resistance to antibacterial agents. Exp Rev Anti-infect Ther. 2010;8:59–70. doi: 10.1586/eri.09.113.
    1. Vakil N, Vaira D. Treatment for H. pylori infection: new challenges with antimicrobial resistance. J Clin Gastroenterol. 2013;47:383–388. doi: 10.1097/MCG.0b013e318277577b.
    1. Gomollon F, Sicilia B, Ducons JA, Sierra E, Revillo MJ, Ferrero M. Third line treatment for Helicobacter pylori: a prospective, culture-guided study in peptic ulcer patients. Aliment Pharmacol Ther. 2000;14:1335–1338. doi: 10.1046/j.1365-2036.2000.00833.x.
    1. Perri F, Festa V, Merla A, Quitadamo M, Clemente R, Andriulli A. Amoxicillin/tetracycline combinations are inadequate as alternative therapies for Helicobacter pylori infection. Helicobacter. 2002;7:99–104. doi: 10.1046/j.1083-4389.2002.00066.x.
    1. Lv ZF, Wang FC, Zheng HL, Wang B, Xie Y, Zhou XJ, Lv NH. Meta-analysis: is combination of tetracycline and amoxicillin suitable for Helicobacter pylori infection? World J Gastroenterol. 2015;21:2522–2533. doi: 10.3748/wjg.v21.i8.2522.
    1. Uygun A, Ozel AM, Yildiz O, Aslan M, Yesilova Z, Erdil A, Bagci S, Gunhan O. Comparison of three different second-line quadruple therapies including bismuth subcitrate in Turkish patients with non-ulcer dyspepsia who failed to eradicate Helicobacter pylori with a 14-day standard first-line therapy. J Gastroenterol Hepatol. 2008;23:42–45. doi: 10.1111/j.1440-1746.2007.05272.x.
    1. Malfertheiner P, Bazzoli F, Delchier JC, Celinski K, Giguere M, Riviere M, Megraud F. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011;377(9769):905–913. doi: 10.1016/S0140-6736(11)60020-2.
    1. Levison ME. Pharmacodynamics of antimicrobial agents. Bactericidal and postantibiotic effects. Infect Dis Clin North Am. 1995;9:483–495.
    1. Adir J, Barr WH. Dose-dependent bioavailability of tetracycline in man. J Pharmacokinet Biopharm. 1978;6:99–110. doi: 10.1007/BF01117445.
    1. Liu P, Muller M, Derendorf H. Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. Intern J Antimicrob Agents. 2002;19:285–290. doi: 10.1016/S0924-8579(02)00024-9.

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