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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Background:

Azithromycin is an acid-stable macrolide that achieves remarkably high concentrations in gastric tissue, persisting above the MIC90 for Helicobacter pylori over a period of 5-days, after a single 500 mg oral dose.

Aim:

To evaluate and compare the efficacy, safety, and tolerability of two eradicating regimens of pantoprazole, azithromycin and tinidazole.

Methods:

A total of 100 consecutive symptomatic H. pylori-positive patients received pantoprazole 40 mg b.d. for 1 week, and were randomly assigned to either azithromycin 500 mg o.m. and tinidazole 500 mg b.d. during the first 3 days (early group, n=50) or during the last 3 days of therapy with pantoprazole (late group, n=50). H. pylori status was assessed by histology and rapid urease test at entry and by histology and 13C-urea breath test 1 month after the end of the therapy.

Results:

Ninety-nine patients completed the study. H. pylori was eradicated in 86% of patients in the early group (intention-to-treat 86%) and in 88% of patients in the late group (intention-to-treat 88%).

Conclusions:

This short triple therapy is effective for H. pylori eradication. The compliance was excellent and side-effects negligible. Moreover, the pantoprazole pre-treatment did not modify the efficacy of the therapy.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Helicobacter pylori is an important cause of peptic ulcer disease and chronic gastritis and has been linked to the pathogenesis of gastric malignancy. For these reasons, anti-H. pylori regimens are being investigated with increasing frequency, with about 1500 reports being published between 1984 and 1999.1 Many combinations of antibiotics and antisecretory drugs have been tested in an attempt to find the optimal regimen. The regimen of choice should be cheap, simple, of short-duration, associated with few side-effects, and with an efficacy of 90% or greater.2 The most popular strategies for producing a high rate (80–95%) of H. pylori eradication entail the use of two antibiotics given for at least 1-week.3 The use of antibiotics for shorter periods has been investigated infrequently, as the increased daily dose considered necessary is thought to be associated with an increase in side-effects.4

Currently, clarithromycin provides the backbone for several therapeutic regimens for H. pylori. Azithromycin is a potentially attractive therapeutic agent for H. pylori, given its excellent mean inhibitory concentration for this organism and long biological half-life.5, 6 However, the available published trials utilizing azithromycin have yielded conflicting results.7[8][9][10][11][12][13][14][15]–16 Moreover, some data suggest that pre-treating patients with proton pump inhibitors before starting the antibiotics could decrease the efficacy of the antimicrobial treatment.17[18][19]–20

We thus evaluated two regimens consisting of 7 days of pantoprazole in combination with azithromycin and tinidazole given for the first or the last 3 days. We also assessed the frequency and severity of side-effects and compliance associated with each regimen.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

We prospectively investigated unselected out-patients complaining of dyspeptic symptoms, who were referred to our department to undergo upper gastrointestinal endoscopy for the first time. The study was conducted according to good clinical practice and the Declaration of Helsinki. All patients were informed verbally and by a written information sheet about the basic concepts of H. pylori infection and the role of its eradication in cure of the disease. The demographic and endoscopic data of our study population are reported in Table 1.

Table 1.  Demographic data and endoscopic features of the study groupThumbnail image of

Subjects excluded from the study included: patients affected by serious concomitant illnesses or who had previously undergone gastric surgery; pregnant women; patients who had been treated in the preceding 2 months with antibiotics, H2-blockers, bismuth or proton pump inhibitors; patients with known allergy to macrolides; and patients who had previously undergone eradication therapy.

During the pre-treatment upper gastrointestinal endoscopy, a total of 10 biopsies were taken using fenestrated-needle forceps. Five of the biopsies were collected from the lesser curvature, greater curvature, anterior and posterior stomach wall within 2–3 cm of the pylorus, with the remainder being collected from the middle portion of the greater curvature of the corpus, approximately 8 cm from the cardia, and from the incisura angularis. From antral and gastric corpus four biopsies were used for the histological evaluation (haematoxylin-eosin and Giemsa stain) and one for rapid urease test (CP-test, Yamanouchi Pharma), respectively. H. pylori infection was defined when positive results in both the rapid urease test and histology were obtained.

A further gastroscopy was carried out 1 month after completing proton pump inhibitor therapy, during which eight biopsies were taken from the antrum and corpus. Eradication was defined as negative results from both the 13C-urea breath test.

Treatment (PAzT)

After the initial assessment for H. pylori infection, the H. pylori-positive patients were assigned to one of the two following treatments, by a computer generated list.

1 Pantoprazole 40 mg b.d. (before breakfast and dinner) for 7 days; after 4 days, the addition of tinidazole 500 mg b.d. (before breakfast and dinner) and azithromycin 500 mg o.m. (2 h after breakfast) for 3 days (late group).

2 Pantoprazole 40 mg b.d. (before breakfast and dinner) for 7 days, plus tinidazole 500 mg b.d. (before breakfast and dinner) and azithromycin 500 mg o.m. (2 h after breakfast) for the first 3 days (early group).

The overall number of pills consumed by each patient in both regimens was 23.

At the end of this period each patient was interviewed by telephone to assess any adverse events and compliance. Side-effects were rated using a scale of 0, none; 1, mild; 2, moderate; 3, severe; 4, intolerable. Compliance was considered excellent if patients used 100% of their medication; good > 90% and fair < 90% of their medication.

Patients with endoscopic findings of active gastric or duodenal ulcers received pantoprazole 40 mg o.m. for an additional 4 weeks following the antibiotics therapy.

Statistical analysis

The demographic and clinical characteristics of the study groups were compared statistically by χ2-test. The results of treatment were compared by χ2-test or Fisher’s exact test for comparison of proportions with a 95% confidence interval (CI). All statistical analyses were two-tailed, and significance was accepted at a P-value < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

The two groups were comparable in terms of common clinical variables (Table 1), and the overall results of the study are summarized in Table 2. Only one patient dropped out of the study, refusing the follow-up endoscopy.

Table 2.  Results of treatmentThumbnail image of

A total of 99 patients (50 from late group and 49 from early group) were therefore suitable for evaluation. One month after treatment, 87 of the 99 patients were H. pylori-negative, with no statistically significant differences being evident between the two treatment groups or between the various subgroups defined by the pre-treatment endoscopic findings (Table 2). Only six patients in each group were still H. pylori-positive. Complete ulcer healing was endoscopically observed at follow-up in all patients.

Only one patient missed the follow-up endoscopy and was considered a dropout. The remaining 99 patients completed the study without contravening the protocol.

Compliance was excellent in all treated patients. Side-effects of nausea and abdominal pain were recorded in two patients (4%) of both the early and late groups, with no statistically significant difference being found between the groups. In all cases the symptoms were mild and short-lived, and no treatment was necessary. Thus the therapy was not discontinued.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

During the last few years, intensive research has been carried out to identify simpler and better-tolerated anti-H. pylori regimens. The ideal anti-H. pylori therapy should be a simple, short course of medication which is well-tolerated and has a high eradication rate but few side-effects. The Working Party of the European Helicobacter pylori Study Group advised that short-term triple therapy, consisting of a proton pump inhibitor plus clarithromycin and either amoxicillin or metronidazole should be used as first choice in treatment of H. pylori infection.21 However, because of the frequency of side-effects and the relatively complicated schedule, poor compliance is often reported during such triple therapy.4, 22 Moreover, the prevalence of metronidazole or clarithromycin-resistant H. pylori strains in the industrialized countries is increasing, and varies considerably amongst populations studied.23[24]–25 In a recent large multicentre, double-blind study, conducted in north-central Italy, primary resistance to macrolides and metronidazole was seen in 11% and 15% of patients, respectively. The resistance to macrolides was similar to that reported in other European countries, whilst metronidazole resistance was lower than expected.30

Although the role of azithromycin treatment has not been clearly defined, it has favourable pharmacokinetic characteristics, and was therefore considered to be an appropriate alternative to clarithromycin. The median concentration of azithromycin in gastric tissue following therapy in a dosage of 500 mg/day for 3 days amounted to 7.5 μg/g on day 2 to 9.7 μg/g on day 5. In all tissue samples, azithromycin levels were well above the MIC90 for H. pylori (0.24 μg/mL). The well-known tissue affinity of azithromycin, highlighted by the lack of detectable levels in gastric juice and the absorption of the drug after oral administration is greatly reduced when it is given during or after a meal.26, 27 The long half-life of this drug could allow a shorter duration of treatment, which in turn could improve patient compliance and reduce the overall cost of therapy. Until now, 11 of the available studies that contained azithromycin for the triple therapy have utilized different treatment regimens, and reported eradication rates have varied considerably between 28% and 93% (Table 3).7[8][9][10][11][12][13][14][15]–16, 28

Table 3.  Published trials evaluating therapies containing azithromycin for H. pylori infectionThumbnail image of

In six studies, the azithromycin was administrated with meals and the cure rate observed ranged from 28% to 85%.7, 8, 12[13]–14, 16 Since administration at this time can reduce the intestinal absorption of the antibiotic by approximately 50%, lower anti-H. pylori gastric tissue concentrations of the drug was a possible explanation for the lower cure rate.27 Another study tested azithromycin 500 mg/day for 3 days in combination with metronidazole 1 g/day plus omeprazole 40 mg/day or colloidal bismuth subcitrate 480 mg/day, and achieved eradication rates of 80% and 60%, respectively.15 Four trials have tested azithromycin 500 mg/day for 3 days administered in fasting patients, in combination with a proton pump inhibitor and tinidazole or amoxicillin.9[10]–11, 28 The cure rates reached in these studies vary from 86–93%. The present study is the first trial evaluating the efficacy of pantoprazole combined with azithromycin and tinidazole for only 3 days. In our experience this triple therapy resulted in an intention-to-treat eradication rate of 87% of patients. Some data have suggested that treating patients with omeprazole before starting antibiotics decreases the efficacy of the antimicrobial therapy.17[18][19]–20 Only one prospective study has evaluated this possibility and did not find a statistical difference in patients pre-treated or concomitantly treated with omeprazole.29 Moreover, this possibility also has practical implications, because patients are often already on antisecretory therapy at the time that H. pylori infection is diagnosed, and thus the physician may be uncertain as to whether to withdraw therapy or not. In our study there was no significant difference between the two regimens; therefore the 4 days of proton pump inhibitor pre-treatment did not modify the efficacy of the therapy in eradicating the H. pylori infection.

In conclusion, our results suggest that short duration triple therapy with pantoprazole, tinidazole and azithromycin at usual dosage, if administrated in fasting patients, is a valid alternative to the better-known and widely used 1-week triple therapies. In fact, it achieves a high cure rate with a low number of pills, compared to standard triple therapy (23 vs. 35). Compliance to treatment was excellent and side-effects were infrequent, transient and usually slight and short-lived.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

We thank Monica Gallamini for preparation of manuscript and Arturo Terranova and Francesca Bonifazi for expert technical assistance.

Bibliography

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography
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