High-dose, Ten-day Esomeprazole, Amoxicillin and Metronidazole Triple Therapy Achieves High Helicobacter Pylori Eradication Rates

J. Sánchez-Delgado; P. García-Iglesias; M. Castro-Fernández; F. Bory§, M. Barenys; L. Bujanda; J. Lisozain; M. M. Calvo; S. Torra; J. P. Gisbert; X. Calvet

Disclosures

Aliment Pharmacol Ther. 2012;36(2):190-196. 

In This Article

Abstract and Introduction

Abstract

Background Strong acid inhibition using esomeprazole increases cure rates with triple therapy and 10-day treatments are more effective than 7-day ones. The combination of amoxicillin plus metronidazole at full doses, and using a physiologically-correct schedule three times a day, and has been shown to overcome metronidazole resistance and to achieve good eradication rates.
Aims To assess the eradication rate of a new first-line treatment regimen associating strong acid inhibition, amoxicillin and metronidazole and to evaluate tolerance.
Methods Patients from eight hospitals were included. Helicobacter pylori status was assessed by at least one of the following: histology, culture, rapid urease test or urea breath test (UBT). Ten-day treatment was prescribed comprising esomeprazole 40 mg twice a day plus amoxicillin 1 g and metronidazol 500 mg both three times a day. Helicobacter pylori cure was assessed by UBT.
Results A hundred and thirty-six patients were enrolled. Mean age was 52.6 ± 16 years and 59.6% of patients were men. Main indications for treatment were: uninvestigated dyspepsia (13.6%); functional dyspepsia (18.2%); gastric ulcer (21.8%); and duodenal ulcer (39.8%). Helicobacter pylori eradication was achieved in 112 of the 127 patients who returned for follow-up. Eradication rates were 82.4% (95% CI: 74.7–88.1) by intention-to-treat analysis and 88.2% (95% CI: 81.2–92.8) by per protocol. Treatment was well tolerated and no major side effects were reported. Nine patients complained of mild side effects.
Conclusions Cure rates of the combination of esomeprazole, amoxicillin and metronidazole are high and the treatment was well tolerated. This pilot study warrants the comparison of this schedule with current standards.

Introduction

The standard, recommended first-line treatment for Helicobacter pylori infection is triple therapy, using the combination of two antibiotics (clarithromycin plus either amoxicillin or metronidazole) and a proton pump inhibitor (PPI) for at least 7 days.[1] Currently, however, eradication rates with triple therapy are at the lowest levels seen in the past decade. As clarithromycin resistance is the strongest predictor of treatment failure, cure rates are likely to fall further as antimicrobial resistance becomes more prevalent worldwide. When the prevalence of clarithromycin resistance in the population reaches 15–20%, eradication rates of clarithromycin-containing triple therapy decrease below the recommended threshold of 80%.[2,3]

The current recommendations for first-line therapy in areas where triple therapy fails are either classical, quadruple therapy containing bismuth or quadruple therapies containing clarithromycin. Although superior to triple therapy, these approaches have clear shortcomings. 'Classical' bismuth-containing quadruple therapy combines a PPI twice a day, metronidazole three times a day and tetracycline and bismuth four times a day for 10–14 days: a complicated schedule requiring a large number of daily pills. A single-pill compound combining tetracycline, metronidazole and bismuth given every 6 hours has recently been shown to be superior to a 7-day standard triple therapy; however, although this single-pill compound probably facilitates adherence to treatment, the intention-to-treat cure rate was only 80%.[4]

Clarithromycin-containing quadruple therapies combine a PPI plus amoxicillin, metronidazole and clarithromycin: Sequential schedules consist of a PPI for 10 days plus amoxicillin for the first 5 days followed by five additional days of clarithromycin plus metronidazole, whereas 'concomitant' treatments give the PPI plus the three antibiotics for 10 days. Whatever the schedule, using clarithromycin in quadruple therapy to counteract increasing clarithromycin resistance does not seem a very reasonable approach. In fact, the usefulness of sequential quadruple therapy is reduced in patients harbouring clarithromycin-resistant strains.[5,6] In addition, the efficacy of sequential therapy has been reported to be low in some studies. For example, in a large, recent study in Latin America, 1416 H. pylori-infected patients were randomised to receive 14-day 'classical' triple therapy, 10-day sequential therapy or 5-day concomitant therapy; cure rates with triple therapy were superior to those of both competing treatments (82% vs.77% vs. 74% respectively).[7]

In this context of increasing resistance rates and the lack of a defined standard for first-line H. pylori treatment, using a triple therapy with high doses of a PPI plus amoxicillin and metronidazole in a pharmacologically adequate schedule may be a useful alternative. The choice of amoxicillin and metronidazole in a setting of increasing antibiotic resistance is strategically sound: resistance to amoxicillin is extremely unusual, due to the need for more than one mutation in the bacteria genome.[8] Previous studies have also demonstrated that metronidazole resistance can be overcome using high doses of this antibiotic for 10 days or more.[9,10]

The combination of a PPI, amoxicillin and metronidazole has not been widely used, possibly because of a feeling that its efficacy may be lower. The initial MACH studies showed it to be less effective than clarithromycin-containing triple therapy.[11] Subsequently, the efficacy of the amoxicillin–metronidazole combination in triple therapy was found to be similar or only slightly lower than clarithromycin-containing therapies.[12,13] A probable reason for the reduced efficacy of the amoxicillin–metronidazole combination is that the initial MACH studies and most of the later analysis scheduled these antibiotics twice a day, a dosage that is clearly inadequate in view of the short half-life of both drugs. In contrast, the few studies that used these drugs three times a day have shown notably higher cure rates.[14]

In addition to using an antibiotic combination that is efficacious in the setting of increasing resistances, a second useful measure for raising cure rates of H. pylori treatment is to increase the level of acid suppression. Maximum increase in eradication was observed with very strong acid inhibition: that is, when the PPI used was esomeprazole and this drug was given at a 40 mg dose twice a day.[15]

Finally, in addition to antibiotic resistances, poor adherence is the other important predictor of treatment failure.[16] This is especially important in multidrug H. pylori treatment. Although data on H. pylori treatment are scarce, reviews of antibiotic treatment show that once-a-day treatments have the best adherence rates, from 80% to nearly 100%. If a single daily dose is not feasible, twice-a-day and three times-a-day schedules achieve similar and reasonably good adherence rates of around 70%, especially when given with meals.[17]

To overcome the current low cure rates with triple therapy, we used a four-point strategy: (i) avoidance of clarithromycin; (ii) use of metronidazole and amoxicillin in pharmacologically correct schedules; (iii) administration of drugs with meals in an attempt to improve adherence; and (iv) use of strong acid inhibition.

The aim of the present study was, thus, to evaluate the efficacy of a triple schedule combining esomeprazole 40 mg twice a day plus amoxicillin 1 g and metronidazole 500 mg three times a day, all given with meals over a 10-day period, as an empirical first-line approach for curing H. pylori infection.

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