Quadruple Therapy Containing Amoxicillin and Tetracycline is an Effective Regimen to Rescue Failed Triple Therapy by Overcoming the Antimicrobial Resistance of Helicobacter pylori

C.- H. Chi, C.- Y. Lin, B.- S. Sheu, H.- B. Yang, A.- H. Huang, J.- J. Wu

Abstract and Introduction

Abstract

Aim: To identify optimal antibiotics for second-line quadruple therapy of Helicobacter pylori after failed 1-week triple therapy.
Methods: One hundred patients were enrolled in this study after the failure of 1-week triple therapy. They were randomized to receive 1-week quadruple therapy consisting of amoxicillin, omeprazole and bismuth salts, plus either metronidazole or tetracycline. Before quadruple therapy, the H. pylori culture of each patient was tested for metronidazole resistance or clarithromycin resistance by E-test. Six weeks later, an endoscopy or 13C-urea breath test was used to define the success of H. pylori eradication.
Results: The H. pylori eradication rates by intention-to-treat and per protocol analysis were higher in the tetracycline group than in the metronidazole group (intention-to-treat: 78% vs. 58%, P < 0.05; per protocol: 89% vs. 67%, P < 0.05). In the metronidazole group, but not in the tetracycline group, the per protocol eradication rate of quadruple therapy was lower for the infected isolates with metronidazole resistance than for those without metronidazole resistance (77% vs. 33%, P < 0.05).
Conclusion: Quadruple therapy, including tetracycline and amoxicillin, improves the H. pylori eradication rate after failed triple therapy.Introduction

To eradicate Helicobacter pylori, the current standard treatment is triple therapy, combining a proton pump inhibitor with two antibiotics. This is the standard treatment because of its high tolerability and simplicity of administration.[1-7] The rates of successful eradication vary widely, however, ranging from 70% to 95%.[3-10] Treatment failure occurs because of poor patient compliance or bacterial resistance.[6, 8, 10] Patients for whom 1-week proton pump inhibitor-based triple therapy fails require an effective rescue regimen, such as quadruple therapy.

Many clinical studies have applied versatile regimens of quadruple therapy to eradicate primary H. pylori infection, with eradication rates of 75-90%.[11-14] The most common regimen of quadruple therapy, consisting of a proton pump inhibitor, bismuth salt, metronidazole and tetracycline, is tentatively recommended by the Maastricht 2-2000 Consensus to rescue patients with failure of first-line therapy.[15]

In a randomized trial, proton pump inhibitor-bismuth salt-metronidazole-tetracycline second-line therapy achieved an eradication rate of 84% after the failure of amoxicillin-omeprazole-clarithromycin triple therapy.[16] Georgopoulos et al. also showed that proton pump inhibitor-bismuth salt-metronidazole-tetracycline was significantly superior to a similar regimen using clarithromycin instead of tetracycline.[17] The presence of tetracycline in the quadruple therapy regimen was considered to be important to overcome the existing antimicrobial resistance.[17] In contrast, another novel trial by Peitz et al. found an unsatisfactory eradication rate of 65% for the proton pump inhibitor-bismuth salt-metronidazole-tetracycline regimen after failed triple therapy with metronidazole-omeprazole-clarithromycin.[18] Peitz et al. reported that the antimicrobial resistance of H. pylori, to either metronidazole or clarithromycin, should have led clinicians to expect a strong negative impact on the outcome of the proton pump inhibitor-bismuth salt-metronidazole-tetracyc-line regimen.[18] This novel trial, despite the negative efficacy of the selected regimens, implied that, for second-line quadruple therapy, it is best to select antibiotics without H. pylori resistance. Moreover, the influence of the antimicrobial resistance of H. pylori on quadruple therapy requires further validation, especially in endemic areas of metronidazole resistance of H. pylori infection.

Clarithromycin is generally not recommended for repetitive use after the failure of anti-H. pylori therapy containing this antibiotic.[17, 18] In contrast, tetracycline and amoxicillin have rarely been reported to lead to antimicrobial resistance of H. pylori world-wide. We conducted this prospective study to test whether quadruple therapy, including a proton pump inhibitor, bismuth salt, amoxicillin and tetracycline, could be used to rescue failed proton pump inhibitor-based triple therapy containing strong antibiotics such as clarithromycin. The inclusion of amoxicillin in quadruple therapy has rarely been reported in the published literature. Therefore, we also determined whether the concurrent usage of amoxicillin, with either tetracycline in the proton pump inhibitor-bismuth salt-amoxicillin- tetracycline regimen or metronidazole in the proton pump inhibitor-bismuth salt-amoxicillin-metronidazole regimen, was effective in improving the eradication efficacy by overcoming the high endemic metronidazole resistance of H. pylori in Taiwan.

Section 1 of 4 C.- H. Chi*,†, C.- Y. Lin‡, B.- S. Sheu*, H.- B. Yang§, A.- H. Huang§ and J.- J. Wu¶

Departments of *Internal Medicine and †Emergency, National Cheng Kung University, Tainan, Taiwan; ‡Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan; Departments of §Pathology and ¶Medical Technology, National Cheng Kung University, Tainan, Taiwan
Aliment Pharmacol Ther 18(3):347-353, 2003. © 2003 Blackwell Publishing
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