Sequential therapy boosts H pylori eradication rates

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Antibiotics in sequence is a more formidable ally than the standard treatment regimen.



Practice changer

Prescribe sequential therapy rather than the standard (concurrent) therapy to improve H pylori eradication rates, particularly in treatment-naïve patients.1

Strength of recommendation

B: Based on a well-done meta-analysis with disease-oriented outcomes

Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Ann Intern Med. 2008;148:923-931.


A 40-year-old woman with a peptic ulcer has been diagnosed with Helicobacter pylori infection, and schedules a visit to discuss treatment. You’re aware of the declining eradication rates associated with standard therapy, and have heard that sequential therapy may be a more effective option. Should you offer it to this patient?

An estimated 30% to 40% of the US population is infected with H pylori,2 a bacterium that plays a crucial role in the pathogenesis of peptic ulcer disease, chronic gastritis, and gastric cancer.1 The triple-drug regimen (a proton-pump inhibitor [PPI] and clarithromycin with amoxicillin, tinidazole, or another imidazole) is commonly used to treat H pylori in Europe and in the United States.3 Yet the eradication rate associated with this standard 3-drug regimen in this country is <80%, and appears to be on the decline. The likely problem: the increase in antibiotic-resistant strains of H pylori.2

Put amoxicillin first

In Italy, eradication rates of >90% have been reported with a sequential therapy: a PPI and amoxicillin for 5 days, followed by the PPI, clarithromycin, and tinidazole for an additional 5 days (FIGURE).4 (Because tinidazole is a relatively new drug in the United States and physicians may use other drugs in its class instead, we refer to the drug class—imidazoles—rather than a specific medication in the FIGURE and much of the text that follows.) Using amoxicillin before the other antibiotics weakens bacterial cell walls, preventing the formation of drug efflux channels that can inhibit clarithromycin and other antibiotics, according to 1 theory.1 Thus, clarithromycin and an imidazole are more effective in the second phase of treatment.1

Should US physicians adopt the Italian protocol and prescribe tinidazole? Would metronidazole or other imidazoles be equally effective?

Sequential vs standard therapy: A comparison

STUDY SUMMARY: Sequential therapy is better on all counts

This meta-analysis found 9 randomized controlled trials (RCTs) that compared H pylori eradication rates with standard 7- to 10-day triple-drug therapy to 10-day sequential therapy; an additional small study used a 5-day triple-drug comparison group. The authors performed a thorough search and used standard meta-analysis methods for data synthesis and analysis. The patients were all H pylori treatment naïve and had not used PPIs, histamine-2 receptor antagonists, or antibiotics in the month preceding the study. All patients (n=2747) had documented H pylori infection based on fecal antigen test, histologic evaluation, biopsy urease test, or urea breath test.

All the trials were conducted in Italy, although 2 of the studies included patients from the United States. Nine RCTs compared a triple-therapy regimen with PPI to sequential therapy, 1 RCT compared a triple-drug regimen with ranitidine to sequential therapy, and 1 included only pediatric patients. Pooled eradication rates were 93.4% (95% confidence interval [CI,] 91.3%-95.5%) for sequential therapy and 76.9% (CI, 71.0%-82.8%) for standard therapy, with a relative risk reduction of 71% (CI, 64%-77%).1 The authors estimated that for every 6.3 patients (95% CI, 5.2-7.1) treated with sequential therapy, there would be 1 additional cure compared to standard therapy. Standard 7- to 10-day triple therapy remained inferior to sequential therapy in all subgroup analyses, including patients with risk factors for eradication failure.

Adherence rates were similar in both groups. Sequential therapy resulted in a median adherence rate of 97.4% (range, 90.0%-98.9%), with standard therapy at 96.8% (range, 93.0%-100%).1 Reported side effects were also similar in both treatment groups.1


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