Proton Pump Inhibitor-based Triple Therapy Research Articles

Appropriate timing of the 14C-urea breath test to establish eradication of Helicobacter pylori infection.

The aim of this study was to determine the performance characteristics of the 14C-urea breath test (UBT) performed 2 wk after the completion of therapy for Helicobacter pylori using a 4 to 6 wk study as the gold standard. Patients with active Helicobacter pylori infection at four medical centers received proton pump inhibitor-based triple or quadruple therapy for 10-14 days. Patients underwent the 14C-UBT 2 and 4-6 wk after the completion of therapy. A positive test was defined as 14CO2 excretion of >200 dpm, a negative test as <50 dpm, and an equivocal test as >50 but <200 dpm. Performance characteristics of the 2-wk UBT were calculated using the 4 to 6-wk result as a gold standard. Eighty-five patients were enrolled and 82 patients (mean +/- SD age, 62 +/- 15 yr; 15 women) completed the protocol. Four patients had equivocal UBT results and were excluded from the analysis. Of the 78 patients, 68 (87%) had a negative 4 to 6-wk UBT. The 2-week UBT yielded a sensitivity of 90% (95% confidence interval 72-100%), specificity of 99% (97-100%), and accuracy of 97% (93-100%). In patients with a persistently positive UBT, 14CO2 excretion at 2 wk was significantly lower than at 4-6 wk after therapy (p = 0.03). A UBT performed 2 wk after therapy yielded results comparable to 4 to 6 wk testing. Further studies to evaluate the optimal time of confirmatory testing in the age of more effective proton pump inhibitor-based triple therapies are warranted.

A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxycillin for treating Helicobacter pylori infection.

Although triple therapies with a proton pump inhibitor, clarithromycin and either amoxycillin or metronidazole are the most widely accepted treatment for Helicobacter pylori infection, there is no consensus on how long treatment should be maintained for. To evaluate whether increasing the length of triple therapies beyond 7 days improves treatment efficacy. An extensive search of the literature was performed. Reports of randomized trials comparing different lengths of therapy were selected. Short (7-day) vs. long (10/14-day) therapies were compared, and three-way comparison of 7-day vs. 10-day, 10-day vs. 14-day and 7-day vs. 14-day therapies was performed. Meta-analysis was conducted using conventional shareware (Review Manager 4.0). The Peto Odds Ratio using a fixed model analysis was calculated for each comparison. Thirteen studies were identified. Pooled 10- to 14-day therapies achieved better results than 7-day schedules. In head-to-head comparisons, only 14-day therapies were significantly better than 7-day treatments. Improvement in cure rates ranged from 7 to 9%. Comparisons of 7-day vs. 10-day and 10-day vs. 14-day also showed a non-significant trend towards better cure rates with longer therapies. Fourteen-day, proton pump inhibitor-based triple therapy achieves better results than 7-day schedules. Additional data are necessary to evaluate 10-day therapies.

Rifabutin-based 'rescue therapy' for Helicobacter pylori infected patients after failure of standard regimens.

The ideal treatment for patients who have failed eradication of Helicobacter pylori infection after standard proton pump inhibitor-based triple therapies has still to be determined. Although either a second course of triple therapy or a quadruple therapy (proton pump inhibitor plus bismuth-based triple therapy) has been proposed, the efficacy of these second-line therapies is relatively unknown. Therefore, alternative strategies are needed. To assess the efficacy and tolerability of rifabutin, a derivative of rifamycin-S, in patients who were still H. pylori infected after two or more courses of 1-week triple therapies. Patients were given a 1-week regimen of pantoprazole 40 mg b.d. + amoxycillin 1 g b.d. + rifabutin 300 mg daily. Side-effects and compliance were determined at the end of therapy. Eradication rate was assessed with a 13C-urea breath test performed at 4 and 12 weeks after treatment. Forty-one patients (mean age 47 +/- 15 years) were studied. All patients took medications according to the proposed schedule. Side-effects were infrequent and mild. The eradication rates were 71% (95% CI: 57-85%) on intention-to-treat analysis and 74% (95% CI: 61-88%) on per protocol analysis. Rifabutin, in combination with pantoprazole and amoxycillin, is an effective and well tolerated regimen in patients who failed standard eradication treatments.

Triple therapy for Helicobacter pylori eradication: a comparison of pantoprazole once versus twice daily

Proton pump inhibitor-based triple therapy is recommended as treatment for Helicobacter pylori eradication. The proton pump inhibitor may be given once or twice daily. However, little information is available on how these two treatment strategies compare. H. pylori-positive patients (two positive test results) with endoscopy-proven healed duodenal ulcer or non-ulcer dyspesia were randomly allocated to 1 week of double-blind treatment with pantoprazole 40 mg once or twice daily, plus clarithromycin 250 mg and metronidazole 400 mg twice daily. Eradication was defined as a negative 13C-urea breath test (13C-UBT) and histology, 4-5 weeks post-treatment. The follow-up phase comprised 12 months off therapy, with 13C-UBT at 6 and 12 months. Two hundred and four patients received treatment: pantoprazole once daily (x1), n=104; twice daily (x2), n=100. Eradication rates were 84% in both the pantoprazole x1 and pantoprazole x2 groups by modified intention-to-treat analysis and 89% and 87%, respectively, by per protocol analysis. Metronidazole resistance was found in 44% of pre-treatment cultures of H. pylori. Eradication rates were similar in susceptible (72%) and resistant (75%) strains. During follow-up, recrudescence of infection occurred in 3/118 patients. When using pantoprazole plus clarithromycin and metronidazole, the proton pump inhibitor can be used once daily without loss of efficacy.

Selection of lower cutoff point of [13C]urea breath test is helpful to monitor H. pylori eradication after proton pump inhibitor-based triple therapy.

Our objectives were to test the efficacy of [13C] urea breath test (UBT) for H. pylori infection in patients before and after proton pump inhibitor (PPI) based triple therapy, and thus to trace the optimal cutoff value of UBT to monitor H. pylori eradication; and to analyze the histologic bacterial density and distribution of H. pylori in patients with equivocal UBT. A total of 441 dyspeptic cases patients enrolled and completed the study design, including 120 noninfected and 321 H. pylori-infected patients. All 441 cases had received the same protocol of UBT. in which the baseline and 15-min gas samples after ingestion of 100 mg 13C-labeled urea were analyzed for excess 13CO2/12CO2 ratio (ECR). In addition, a first endoscopy was performed in each patient to evaluate the initial status of H. pylori by culture and histology. Of the 321 H. pylori-infected patients, 286 received a second endoscopy and a second UBT six weeks after completing any one of four regimens of the PPI-based triple therapy to document the success of H. pylori eradication. During both sessions of endoscopy, topographic gastric biopsies for histology were sampled to evaluate the distribution and density of H. pylori. Based on the diagnostic standard by culture and histology, the sensitivity and specificity of the first UBT achieved most optimally was 97.5% and 96.7%, respectively, by setting the cutoff point of ECR at 4.0. In contrast, using the same cutoff point of 4.0, the sensitivity and specificity of the second UBT in patients after therapy achieved just 80% and 97.6%, respectively. By applying cutoff points downward of 4.0, 3.5, 3, and 2.5 for the second UBT, the sensitivity was elevated to 80%, 82.8%, 88.6%, and 94.3%, respectively, while the specificity was preserved at more than 95.2%. The overall eradication rate of H. pylori was 87.8% (251/286). Seven of 35 patients with failure of therapy had equivocal ECR at the second UBT (range 2-5), and this accounted for the false negative result. All seven patients had low bacterial densities, and three patients had bacteria distributed only in high body near the cardia. In conclusion, selection of a lower cutoff value of ECR at 2.5 is helpful to maintain the diagnostic accuracy of UBT for monitoring the H. pylori eradication. The equivocal ECR of UBT after therapy would be related to the low bacterial load and its distribution.

Proton pump inhibitor-based triple therapy is the preferred treatment among general practitioners (GPs) in Italy for patients with Helicobacter pylori infection,

Proton pump inhibitor-based triple therapy is the preferred treatment among general practitioners (GPs) in Italy for patients with Helicobacter pylori infection,

Management of Helicobacter pylori-related gastrointestinal diseases by general practitioners in Italy.

To investigate the diagnostic approach to and management of Helicobacter pylori infection at primary care level in Italy 2 years after the Maastricht consensus report. A total of 100 randomly selected general practitioners (GPs) answered a 12-item multiple-choice questionnaire, personally delivered and collected by non-medical staff. In 25% of cases, GPs preferred a prompt referral of dyspeptic patients to the specialist. The favourite diagnostic test for H. pylori infection was gastroscopy with biopsies (55%), followed by standard and office-based serology (24% and 18%, respectively), and 13C urea breath test (5%). H. pylori-eradication was prescribed in patients with peptic ulcer, reflux oesophagitis and functional dyspepsia by 64%, 43% and 66% of GPs, respectively. Only 7% of GPs adopted a test-and-treat approach. Proton pump inhibitor-based triple therapies were used by almost all physicians. In peptic ulcer disease, most of GPs re-tested patients in order to confirm H. pylori eradication (50% by gastroscopy with biopsies and 30% by serology only 2 months after therapy). Uncertainty seems to persist among Italian GPs concerning the indications for H. pylori treatment, the use of diagnostic tests, and patient follow-up. In contrast, no doubts exist regarding the first choice eradication regimens. This survey suggests that further efforts should be made to spread scientific knowledge and guidelines on H. pylori diagnosis and management in primary care in Italy.

A systematic review of Helicobacter pylori eradication therapy--the impact of antimicrobial resistance on eradication rates.

We systematically reviewed all available data in the literature to determine the overall eradication rates of currently advised Helicobacter pylori eradication regimens and to resolve conflicting evidence on the impact of antimicrobial resistance on the eradication rates. A comprehensive search of all published trials on H. pylori eradication therapy was carried out via an electronic database search, hand-searching and checking reference lists of pharmaceutical companies and other reviews. Full papers and abstracts in the English language which study currently advised eradication regimes were included. 770 study-arms were analysed. Mean eradication rates for bismuth based triple, proton pump inhibitor triple, quadruple and ranitidine bismuth citrate combination therapies vary from 65 to 92%. In case of nitroimidazole resistance, a drop in efficacy of up to 50% was found for bismuth-based triple and proton pump inhibitor-based triple therapies. For quadruple therapy, a significant difference in efficacy was found in the equal-effects analysis; however, this could not be confirmed in the random-effects analysis. In case of clarithromycin resistance, a mean drop in efficacy of 56% was found for one- and two-week clarithromycin containing proton pump inhibitor-triple therapies and of 58% for two-week ranitidine bismuth citrate combined with clarithromycin therapies. For ranitidine bismuth citrate combined with clarithromycin and nitroimidazole, no difference in efficacy was found in case of nitroimidazole or clarithromycin resistance, but data are still scarce. The cure rate with most regimens dropped significantly, in case of nitroimidazole-resistant strains, compared to nitroimidazole-susceptible strains. In case of clarithromycin resistance, the efficacy of most regimens is also decreased; however, data are still scarce. These data should allow physicians to make a better choice of an appropriate therapy for their patients.

The Maastricht recommendations and their impact on general practice.

At a meeting organized in Maastricht by the European Helicobacter Pylori Study Group, European consensus guidelines for the treatment of Helicobacter pylori were established by determining what relevant information from research could be translated into clinical practice. Many of the patients infected with H. pylori can be diagnosed and treated in the primary care setting. Dyspeptic patients under 45 years of age, with no alarm symptoms or risk of gastric or oesophageal malignancy, can be tested non-invasively and treated in the primary care setting. For diagnosis, a validated non-invasive method is recommended, such as the 13C-urea breath test or laboratory-based serology if properly validated in the region in which it is used. The meeting strongly recommended that all patients with peptic ulcer are treated with eradication therapy. Patients over the age of 45 years and those with alarm symptoms should be referred with no hesitation to the specialist After full consideration of the treatments used to date, it was strongly recommended that treatment should be with proton-pump inhibitor-based triple therapy, consisting of a proton-pump inhibitor and two of the following: clarithromycin, a nitroimidazole (metronidazole or tinidazole) and amoxycillin. The evidence supporting the use of these therapies has been substantiated in large clinical trials that were recently completed.

Bismuth triple therapy

Bismuth triple therapy (bismuth compound, metronidazole and tetracycline) is the oldest effective regimen to cure Helicobacter pylori infection. When tetracycline is replaced by amoxycillin the cure rate decreases. In 1990, it was the first-line regimen. However, the great number of pills in the rather complicated regimen, together with a relative high rate of side-effects, have stimulated the search for other regimens. In developed countries, it has now mainly been surpassed by the simpler, but much more expensive proton-pump inhibitor-based triple therapies. In many developing countries however, bismuth-based therapy is the only effective therapy patients can afford. Worldwide, this drug combination is therefore probably one of the most widely used regimens. The efficacy of bismuth triple therapy can be improved by adding acid suppressants (quadruple therapy), increasing treatment duration or increasing the total daily dose of metronidazole. The choice of the bismuth compound and the total daily dose of tetracycline seem less important. Treatment can be shorter (7 days) in areas with a low rate of metronidazole resistance or when acid inhibition is added. Bismuth is usually given four times daily; tetracycline is usually given 500 mg q.i.d. in a 7- or 10-day treatment, but this can probably be reduced to 250 mg q.i.d. in a 14-day regimen. A higher total daily dose of metronidazole increases the cure rate but also gives more side-effects. A daily dose of 1000-1200 mg metronidazole in three or four divided doses for one week suffices in areas with a low rate of metronidazole resistance. In areas with a higher rate of resistance one can either increase the treatment duration to 10-14 days or increase the daily dose of metronidazole to 1500-1600 mg and leave the treatment duration at 7 days.

The importance of clarithromycin dose in the management of Helicobacter pylori infection: a meta‐analysis of triple therapies with a proton pump inhibitor, clarithromycin and amoxycillin or metronidazole

It is not clear which dose of clarithromycin (500 mg b.d. or 250 mg b.d.) is more effective for Helicobacter pylori eradication in proton pump inhibitor-based triple therapies. We undertook a meta-analysis of the effect of 7-day triple therapies consisting of a proton pump inhibitor (P), and clarithromycin (C) and amoxycillin (A) or metronidazole (M). A meta-analysis of all clinical trials performed in an adult population and published in English up to March 1998 was undertaken. Studies with doses of clarithromycin 500 mg b.d. or 250 mg b.d. only were included. A total of 82 studies (31 papers and 51 abstracts) involving 110 treatment arms and 6123 patients were analysed that met the predetermined inclusion and exclusion criteria. In the PAC combination, the pooled eradication rate in patients treated with clarithromycin 500 mg b.d. was 89.5% (95% CI: 86.9-92. 0%) by per protocol analysis and 86.6% (95% CI: 81.0-89.3%) by intention-to-treat analysis. These rates are significantly higher than those achieved with clarithromycin 250 mg b.d. (83.3% by per protocol and 78.2% by intention-to-treat analysis, both P < 0.0001). This difference was confirmed in head-to-head comparative studies. In the PMC regimen, clarithromycin 500 mg b.d. eradicated 90.8% (95% CI: 87.0-94.5%) of the infections compared to 88.5% (95% CI: 85.5-91. 5%) in patients treated with clarithromycin 250 mg b.d. by per protocol analysis (P = 0.082). The corresponding rates by intention-to-treat analysis for clarithromycin 500 mg b.d. and 250 mg b.d. was 88.3% and 86.7%, respectively (P = 0.259). Seven-day triple therapies with a proton pump inhibitor, clarithromycin and amoxycillin or metronidazole are highly effective treatments for the eradication of H. pylori. Clarithromycin 500 mg b. d. should be used in these combinations to achieve the best first treatment results, which can minimize the subsequent development of bacterial resistance to clarithromycin and metronidazole.

The effect of antibiotic resistance on the outcome of three 1-week triple therapies against Helicobacter pylori.

Resistance of Helicobacter pylori to antibiotics may be a major reason for treatment failure. To evaluate the effect of primary H. pylori resistance to antibiotics on the cure rates of three anti-H. pylori 1-week triple therapies. One hundred and sixteen consecutive patients diagnosed H. pylori-positive by gastric histology, rapid urease test and culture were enrolled. Activity of tested antibiotics was determined by means of the E-test. Patients were treated for 7 days with: (i) pantoprazole 40 mg o.d. plus amoxycillin 1 g b.d. and metronidazole 250 mg q.d.s. (PAM); (ii) pantoprazole 40 mg o.d. plus clarithromycin 250 mg b.d. and metronidazole 250 mg q.d.s. (PCM); or (iii) pantoprazole 40 mg o.d. plus amoxycillin 1 g b.d. and clarithromycin 250 mg b.d. (PAC). Two months after completion of therapy, endoscopy and gastric biopsies were repeated. Primary resistance rates to metronidazole, clarithromycin and amoxycillin were 17.2, 6.9 and 0%, respectively. Overall H. pylori cure rates expressed as intention-to-treat and per protocol analyses were, respectively, 79% and 86% with PAM, 82% and 89% with PCM, and 85% and 85% with PAC. Significantly lower cure rates were observed in metronidazole-resistant patients treated with PAM (56% vs. 96%, P = 0.01) or PCM (50% vs. 97%, P = 0.01). A trend towards lower H. pylori cure rates was observed in clarithromycin-resistant patients treated with PCM (67% vs. 91%, P = 0.74) or PAC (50% vs. 87%, P = 0.68). Primary resistance to metronidazole influences the H. pylori cure rate of anti-H. pylori proton pump inhibitor-based triple therapies which include this antibiotic. A similar trend exists for primary clarithromycin resistance.

Review: eradication of Helicobacter pylori. Problems and recommendations.

The successful isolation of Helicobacter pylori from stomachs of patients with gastritis and peptic ulcer has revolutionized our concepts of the pathogenesis of gastritis, peptic ulcer, gastric cancer and gastric B cell lymphoma. Eradication of H. pylori heals gastritis and H. pylori-related peptic ulcer. After a successful cure of H. pylori infection, virtually no recurrence of duodenal ulcer is seen. However, treatment to cure the infection has proved difficult. Numerous clinical trials have been attempted, but as yet no ideal regimen has been identified. Monotherapies have many drawbacks and should be avoided. Dual therapies combining a proton pump inhibitor (PPI) and an antimicrobial agent provide higher eradication rates than those involving two antimicrobial agents. Bismuth-based triple therapies are more effective than dual therapies in eradicating H. pylori infections. However, poor compliance and frequent adverse effects have made these combinations less favourable in clinical practice. Proton pump inhibitor-based triple therapies have shown more consistent and higher eradication rates with a short duration of treatment, good patient compliance, fewer side effects, prompt symptom relief and fast ulcer healing. Results from PPI-based quadruple therapies are promising; however, large multicentre clinical trials are needed to confirm the effect and the complex regimen again may compromise compliance outside of the clinical trial setting. Eradication of H. pylori infection is cost-effective in the long-term management of peptic ulcer disease compared with maintenance therapy with antisecretory drugs.