Helicobacter pylori Eradication Therapy

Hidekazu Suzuki; Toshihiro Nishizawa; Toshifumi Hibi

Future Virology. 2010;5(4):639-648.

Abstract and Introduction

Abstract

Helicobacter pylori infection is the main cause of gastritis, gastroduodenal ulcers and gastric cancer. H. pylori eradication has been shown to have a prophylactic effect against gastric cancer. According to several international guidelines, the first-line therapy for treating H. pylori infection consists of a proton pump inhibitor (PPI) or ranitidine bismuth citrate, with any two antibiotics among amoxicillin, clarithromycin and metronidazole, given for 7–14 days. However, even with these recommended regimens, H. pylori eradication failure is still seen in more than 20% of patients. The failure rate for first-line therapy may be higher in actual clinical practice, owing to the indiscriminate use of antibiotics. The recommended second-line therapy is a quadruple regimen composed of tetracycline, metronidazole, a bismuth salt and a PPI. The combination of PPI–amoxicillin–levofloxacin is a good option as second-line therapy. In the case of failure of second-line therapy, the patients should be evaluated using a case-by-case approach. European guidelines recommend culture before the selection of a third-line treatment based on the microbial antibiotic sensitivity. H. pylori isolates after two eradication failures are often resistant to both metronidazole and clarithromycin. The alternative candidates for third-line therapy are quinolones, tetracycline, rifabutin and furazolidone; high-dose PPI/amoxicillin therapy might also be promising.

Introduction

Helicobacter pylori infection is one of the most prevalent infectious diseases worldwide, affecting an estimated 40–50% of the world population. H. pylori has been identified as a group 1 carcinogen by the WHO and is associated with the development of gastric cancer. In experimental studies, H. pylori eradication has been demonstrated to have a prophylactic effect against gastric cancer.^[1–4] In human beings, the beneficial effect of H. pylori eradication in reducing gastric cancer incidence has been reported.^[5–7] The indications for H. pylori eradication as proposed by an international consensus of experts (Maastricht III Consensus Report) are listed in Box 1 .^[8,9] The revised Maastricht guidelines endorsed all the previous indications for H. pylori treatment.

First-line therapy for H. pylori infection is generally accepted to consist of a proton pump inhibitor (PPI; standard dose twice daily [b.i.d.]) or ranitidine bismuth citrate, plus two antibiotics, namely clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.), administered for 7–14 days. Metronidazole (500 mg b.i.d.) has also been used as an alternative to amoxicillin.^[8,10] However, according to a number of recent meta-analyses, even with the recommended regimens, H. pylori eradication failure is still seen in approximately 20% of patients. This issue is becoming a cause for concern owing to the indiscriminate use of antibiotics.

Zullo et al. assessed the eradication rate of a new sequential treatment regimen compared with conventional triple therapy for the eradication of H. pylori infection. A total of 1049 dyspeptic patients were studied prospectively. H. pylori-infected patients were randomized to receive 10-day sequential therapy (rabeprazole [20 mg b.i.d.] plus amoxicillin [1 g b.i.d.] for the first 5 days, followed by rabeprazole [20 mg b.i.d.], clarithromycin [500 mg b.i.d.] and tinidazole [500 mg b.i.d.] for the remaining 5 days) or standard 7-day therapy (rabeprazole [20 mg b.i.d.], clarithromycin [500 mg b.i.d.] and amoxicillin [1 g b.i.d.]). Higher eradication rates were found with the sequential regimen compared with the standard regimen (intention to treat [ITT]: 92 vs 74%, p < 0.0001; per protocol: 95 vs 77%, p < 0.0001). Higher eradication rates were also evident in patients with peptic ulcer disease and nonulcer dyspepsia. In both treatments, compliance was similar (>90%), as was the rate of side effects, which were mild.^[11] A pooled-data analysis of all studies on the sequential regimen was performed by Zullo et al.^[12] Overall, more than 1800 patients have been treated with the sequential regimen. Such a therapy was superior to 7–10-day triple therapies in pediatric, adult and elderly patients, achieving an eradication rate constantly higher than 90% at ITT analysis. The sequential regimen is a novel, promising therapeutic approach.

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Table 1. Third-line *Helicobacter pylori* eradication therapy.
Patients (n)	Regimen	Duration of therapy days	Eradication rate (%)		Ref.
Patients (n)	Regimen	Duration of therapy days	ITT	PP	Ref.
100	Omeprazole 20 mg b.i.d. Levofloxacin 500 mg b.i.d. Amoxicillin 1 g b.i.d.	10	60	66	^[44]
37	Rabeprazole 20 mg b.i.d. Levofloxacin 500 mg q.d. Bismuth 300 mg q.i.d. Amoxicillin 500 mg q.i.d.	10	84	84	^[47]
67	PPI b.i.d. Rifabutin 150 mg b.i.d. Amoxicillin 1 g b.i.d.	10	72	76	^[52]
20	Omeprazole 20 mg b.i.d. Rifabutin 150 mg b.i.d. Amoxicillin 1 g b.i.d.	10	45	45	^[45]
10	PPI b.i.d. Furazolidone 200 mg b.i.d. Amoxicillin 1 g b.i.d.	7	60	60	^[53]
42	Omeprazole 40 mg q.i.d. Amoxicillin 750 mg q.i.d.	14	75.6	83.8	^[56]
89 (culture guided)	Omeprazole 20 mg b.i.d. Bismuth 120 mg b.i.d. Doxycycline 100 mg b.i.d. Amoxicillin 1 g b.i.d.	7	91	92	^[59]

b.i.d.: Twice daily; ITT: Intention to treat; PP: Per protocol; PPI: Proton pump inhibitor; q.d.: Once daily; q.i.d.: Four-times daily.

Box 1. Indications for *Helicobacter pylori* eradication.
Duodenal ulcer Gastric ulcer Atrophic gastritis Gastric mucosa-associated lymphoid tissue lymphoma Nonulcer dyspepsia (functional dyspepsia) Uninvestigated dyspepsia (in areas with a prevalence of >10%) Following resection of gastric cancer First-degree relatives of patients with gastric cancer Unexplained iron-deficiency anemia Idiopathic thrombocytopenic purpura Before the commencement nonsteroidal anti-inflammatory drug therapy Patients receiving long-term aspirin therapy At the patient's request (after a discussion of the risk and benefits)

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