Background—Eradication ofHelicobacter pylori cures and prevents the relapse of duodenal ulceration and also results in histological resolution of chronic active gastritis. Aim—To compare four treatment regimens lasting seven days of a proton pump inhibitor and two antibiotics in the eradication of H pylori.Patients—Men or women with H pylori positive duodenal ulceration or gastritis, or both.Methods—A single blind, prospectively randomised, parallel group, comparative, multicentre study. After a positive CLO test, patients underwent histology, H pylori culture, and a 13C urea breath test to confirm H pyloristatus. Treatment with one of four regimens: LAC, LAM, LCM, or OAM, where L is 30 mg of lansoprazole twice daily, A is 1 g of amoxycillin twice daily, M is 400 mg of metronidazole twice daily, C is 250 mg of clarithromycin twice daily, and O is 20 mg of omeprazole twice daily, was assigned randomly. A follow up breath test was done at least 28 days after completing treatment.Results—H pylori eradication (intention to treat) was 104/121 (86.0%) with LAC, 87/131 (66.4%) with LAM, 103/118 (87.3%) with LCM, and 94/126 (74.6%) with OAM. There was a significant difference (p < 0.001) in the proportion of patients in whom eradication was successful between LAC and LCM when compared with LAM, but no significant difference (p = 0.15) between LAM and OAM. Metronidazole resistance before treatment was identified as a significant prognostic factor with regard to eradication of H pylori. The regimens which contained metronidazole were significantly less effective than those without metronidazole in the presence of pretreatment resistant H pylori. There was no difference among the treatment groups with regard to the incidence and severity of adverse events reported. Conclusions—All four treatment regimens were safe and effective in eradicating H pylori in the patient population studied. LAC was the most efficacious treatment in patients with pretreatment metronidazole resistant H pylori, and was significantly better than LAM and OAM in this group of patients.

Background.Vast numbers of therapeutic studies of various drug regimens used for the cure of H. pylori infection have been published. However, many of these studies have been uncontrolled, included small numbers of patients, were published only as abstracts, differed widely in dosage sizes, schedules and durations and were of insufficient statistical power to make meaningful statements concerning their efficacy. Furthermore, there are no clear or universally accepted guidelines for the treatment of H. pylori infection. Thus, there remains profound confusion among practitioners on whom and how to treat.Objective.To critically review the currently available management strategies for H. pylori infection.Methods.Review of the literature.Results.Treatment of H. pylori requires the use of multiple drug regimens (triple therapy) which can be expensive and is often associated with side effects. Bad choice of treatments, poor patient counseling and compliance will lead to the emergence of resistant H. pylori strains. Resistance to H. pylori to metronidazole is already widespread and resistance to other antimicrobial agents is increasing. The resource/financial implications are not negligible.Conclusions.The introduction of kits that will enable the identification of pathogenic strains of H. pylori in the office setting may decrease the number of patients being given H. pylori eradication therapy, but much more evidence is needed to establish the practical value of such tests. In the meantime, as many clinicians adhere to the idea that the only good H. pylori is a dead H. pylori, the best practical policy option is education concerning the correct diagnostic methodology, correct choice of patients and the correct choice of treatment regimens. The discovery of Helicobacter pylori (H. pylori) has revolutionized our concepts of etiology, pathophysiology and treatment of many foregut diseases. Gastritis, gastric ulcer (GU), duodenal ulcer (DU), gastric cancer, MALT gastric lymphoma and other conditions are now regarded as being dependent on the colonization of the stomach by H. pylori. Many aspects of pathophysiology, such as the abnormalities of gastric acid secretion in duodenal ulcer disease, now for the first time fall into a logical and comprehensible pattern.

EDITOR,-The study by Harris et al (Gut 1996; 38: 663-7) demonstrating that gastric acid secretion in the basal state, as well as gastrin releasing peptide and pentagastrin stimulated states, decreases after H pylon eradication in duodenal ulcer patients is interesting and adds further weight to the hypothesis that Hpylon is responsible for driving the acid secretory abnormalities in duodenal ulcer disease. The significant fall in pentagastrin stimulated output, seen in their eight patients, is particularly interesting in the light of the inability ofmost previous studies to show such an effect. However from the data and methods presented, an alternative explanation for this result might be possible. That is that H pylon eradication reduces gastrin stimulated acid output if patients have previously been primed with an infusion of gastrin releasing peptide (GRP), rather than a specific change in parietal cell mass. There may be several explanations for such an effect related to H pylon pathophysiology. Functional and absolute deficiency of somatostatin has been clearly documented in Hpylori infection.' '2 In addition to being a potent gastrin secretagogue GRP increases release of both antral and fundic somatostatin3 and in animal experiments increases somatostatin gene expression.4 This ability to stimulate both inhibitory and stimulatory pathways may explain why GRP stimulated acid secretion is the most impressive of the changes in Hpylon infection. Somatostatin has a variety of inhibitory actions against parietal cells and ECL cells and it has clearly been shown that somatostatin can inhibit gene transcription and transcription factor function.5 It is unclear for how long such inhibitory influences would act after stimulation of somatostatin release by any agent and whether they have returned to normal after the wash out period. In addition to local mechanisms leading to somatostatin release, GRP also stimulates the release of a variety of small intestinal hormones including the enteroglucagons, cholecystokinin and gastric inhibitory polypeptide, which all probably inhibit gastric acid secretion by the intermediary of gastric somatostatin release. The half lives of oxyntomodulin and glucagon-like peptide-l (up to 17 minutes) appear to be significantly longer than that of gastrin-17 (five minutes) and it is possible that significant functional acid inhibitory concentrations of these peptides were still circulating after the wash out period. Because of the relative somatostatin deficiency, the potent acid inhibitory effects of these peptides would be diminished in Hpylon positive patients and then restored with eradication. Thus somatostatin deficiency could explain the changes in pentagastrin stimulated acid output after the priming with GRP. An alternative explanation may reside in the biological activities of pro-gastrin processing products. Classically the carboxy terminus non-amidated gastrins have been regarded as biologically inactive, but it is now clear that non-amidated gycine extended gastrin-1 7 (G-Gly) has actions on the parietal cell and as

Although there are numerous publications reporting eradication results, the general picture is confused by the bewildering multiplicity of treatment schedules employed by the various workers. The over-riding need now is for large scale trials, and more especially for direct comparisons of different treatment regimens in the same populations of patients. Such data are entirely absent from the literature at present. Standardization of definitions and of methodology pertaining to diagnosis of eradication, recording of side effects, measurement of compliance and determination of recurrence or of reinfection, is badly needed. As the definition of eradication remains arbitrary, it is important to include genome fingerprinting techniques in the long-term follow-up for recurrence, so that the question of reinfection versus recrudescence can be examined (Bell et al, 1993b; Xia et al, 1994). Because of the wide differences in the agents used in H. pylori eradication therapies, proper double-blinding of treatment trials remains a difficult problem. This can be dealt with to some extent by ensuring that the interpretation of tests for H. pylori eradication is performed by personnel unaware of the clinical details. Review of the existing data on eradication of H. pylori indicates that clinically useful results can be achieved in some 70 to 95% of patients, on an intention to treat basis. Compliance, side effects and resistance to metronidazole remain the limiting factors. Efficacy, freedom from side effects, simplicity and low cost will determine the success of any regimen in the future. At present, it is not possible to make firm recommendations in favour of one regimen over another, but it seems reasonable to forecast that dual therapies consisting of a PPI and an antibiotic will receive much attention. Preparations consisting of an H2RA associated with a bismuth compound, which are used together with an antibiotic are an interesting approach. Compliance should be as good as with a normal dual therapy and the eradication results look promising (Wyeth et al, 1994; Webb et al, 1994). The advantages of dual therapies that include a PPI lie in their simplicity, in not relying on imidazole for their anti-H. pylori effect but on the profound inhibition of acid output produced by the PPI. Thus PPI based dual therapy can probably evoke better compliance than the more complicated regimens. The use of PPIs has other advantages in addition to decreasing the MIC90 of the antibiotic combined with it. This is because administration of a powerful inhibitor of gastric acid secretion, such as a PPI, will aid the rapid healing of an ulcer crater and will rapidly relieve the symptoms of peptic ulceration. Gastrin releasing peptide-stimulated acid secretion is raised in duodenal ulcer patients to approximately sixfold over control levels according to El-Omar et al (1993b), and although it returns to normal following the eradication of H. pylori, this process takes time to become effective (El-Omar et al, 1993a). Suppression of acid output provides an immediate therapeutic shield, while the decrease in inflammation and acid output secondary to H. pylori eradication can be established. The most widespread resistance to antibiotics exhibited by H. pylori is with respect to imidazoles. The prevalence of metronidazole resistance is widespread in the emergent countries (Glupczynski et al, 1990), but it is also appreciable in the West, especially in women, who may have been given metronidazole in the treatment of pelvic infections (Rautelin et al, 1992; Banatvala et al, 1994). Moreover, H. pylori becomes resistant to metronidazole very easily and often as a result of treatment which includes an imidazole compound (Malfertheiner, 1993; Banatavala et al, 1994). On the other hand, H. pylori resistance to macrolides is not widespread and does not develop easily during their administration. It is difficult to forecast which antibiotic will be the most widely used agent

Introduction In 1983 Warren and Marshall' successfully cultured Helicobacter pylori from the stomachs of patients with chronic gastritis. Their discovery has revolutionised our understanding of the pathogenesis and treatment of peptic ulcer disease. Yet despite the passage of 13 years and over 700 publications on eradication therapy, consensus on the optimum treatment for H pylori infection remains elusive. Antibacterial treatment of H pylori is difficult because of the habitat occupied by the organism below the layer of mucus adherent to the gastric mucosa. It is also difficult because of resistance to antimicrobial agents, especially to nitroimidazoles and increasingly to macrolides, which develops rapidly during treatment, or preexists in the community.2 These factors have led to the concurrent use of several drugs, as exemplified by triple

BACKGROUND: Factors that determine gastric metaplasia in the duodenal bulb are ill defined. It is more common and extensive in the presence of high acid output and possibly in the presence of Helicobacter pylori. However, no quantitative relation between acid output and the extent of gastric metaplasia has been demonstrated and its relation to H pylori is uncertain. AIM: To determine the relation between H pylori infection and acid output and the presence and extent of gastric metaplasia in the duodenal bulb. subjects: H pylori positive and negative patients with duodenal ulcer and healthy controls were studied. METHODS: Quadrantic duodenal bulb biopsy specimens were taken and the presence and extent of gastric metaplasia determined using a computer enhanced image intensifier. Basal and stimulated acid outputs were measured. RESULTS: gastric metaplasia was significantly (p < 0.05 more common and significantly (p < 0.05) greater in extent in patients with duodenal ulcer than in controls. Neither the prevalence or extent of gastric metaplasia was affected by H pylori status. There were significant (p < 0.01) direct correlations between acid output and extent of gastric metaplasia. CONCLUSIONS: Prevalence and extent of gastric metaplasia are not related to H pylori in controls, or in patients with duodenal ulcer. Rather, high acid response to gastrin may be more important.

BACKGROUND--Patients with duodenal ulcer (DU) have high basal (BAO) and peak (PAO) acid outputs. The effect of Helicobacter pylori eradication on these variables is unclear. AIM--To discover if gastric acid hypersecretion in patients with DU is caused by H pylori. PATIENTS AND METHODS--BAO, gastrin releasing peptide (GRP), and pentagastrin stimulated PAO in 10 H pylori negative controls, and in 10 H pylori positive patients with DU was measured before and six months after H pylori eradication. H pylori status was determined by histology, culture, and by the 13C-urea breath test. After collecting a 30 minute basal aspirate, GRP 40 pmol/kg/h was infused for 45 minutes, and after a 30 minute washout, pentagastrin 6 micrograms/kg was injected intramuscularly. RESULTS--Basal and stimulated acid output (PAOGRP and PAOPg) were significantly higher in H pylori positive DU than in H pylori negative controls. Six months after H pylori eradication, basal and stimulated acid outputs were all significantly lower than before H pylori eradication. CONCLUSIONS--This study has shown that BAO, PAOGRP, and PAOPg are higher in H pylori positive DU than in H pylori negative controls. All decreased significantly six months after H pylori eradication, to fall within the range of controls. These results are compatible with a hypothesis that acid hypersecretion in duodenal ulcer disease is caused by H pylori infection.

The objective of this study was to conduct a survey of the opinions and practices of gastroenterologists in the United Kingdom concerning the impact of Helicobacter pylori infection on the management of upper gastrointestinal diseases. A postal questionnaire was sent to all medically qualified members of the British Society of Gastroenterology working in the UK. Replies were received from 670 of 1037 eligible BSG members (65%). Of these, 73% thought that H pylori was a cause of duodenal ulcer and 84% thought that eradication of H pylori decreased ulcer recurrence in comparison with acid suppression. While 80% used anti-H pylori therapy for a chronic relapsing duodenal ulcer, only 25% used such therapy for an ulcer at first presentation and 17% never used anti-H pylori therapy for patients with duodenal ulcer. Although 75% of respondents did not agree that H pylori was a cause of non-ulcer dyspepsia, 69% used anti-H pylori therapy to treat a patient with this condition. At the time of the survey, 69% of those who used anti-H pylori therapy adopted some variant of standard triple therapy. Only 7% routinely tested for bacterial sensitivity to antibiotics and only 22% assessed their patients for eradication after treatment. There was a lack of consensus about whether H pylori was a cause of gastric ulcer or gastric cancer with only 47% and 17% respectively believing in these associations. In conclusion, at the time of the survey, the use of anti-H pylori therapy had been accepted by a majority of specialist UK gastroenterologists in the management of upper gastrointestinal disease. There was, however, a substantial degree of uncertainty and divergence about which patients should be treated.

Omeprazole is a powerful inhibitor of gastric acid and may suppress Helicobacter pylori by effecting the pKa of H pylori urease, by altering the pattern of infection, or by promoting overgrowth of other bacteria. At routine endoscopy H pylori was detected by histology and culture before and after four weeks' treatment with omeprazole, 40 mg each morning. A 13C-urea breath test was also done at t = 0, 2, 4, and 6 weeks. Thirty nine patients with duodenal ulcer (n = 25) or reflux oesophagitis (n = 14) were studied, of whom 29 of 39 had H pylori infection. During omeprazole treatment, 13C-urea breath test values fell significantly--mean (SEM) values before treatment and at four weeks were 23.0 (2.1) and 15.5 (2.7) per mil respectively, p < 0.001. Before treatment H pylori was seen in 28 of 29 antral, 29 of 29 corpus, and 28 of 29 fundic biopsy specimens. After four weeks of omeprazole treatment, the histological density of H pylori in the antrum and corpus was reduced (p < 0.001), while that in the fundus was increased. The migration of H pylori from the antrum to the fundus was associated with a corresponding decrease in the activity of antral gastritis. H pylori was not seen in antral biopsy specimens from 12 of 29 patients whose median excess delta 13CO2 excretion fell from 23.0 to 9.9 per mil. In the body mucosa, 26 of 29 specimens were still positive for H pylori and there was no significant change in the gastritis type. Two weeks after finishing treatment, the mean (SEM) excess delta 13CO2 excretion returned to levels before treatment. Omeprazole decreases antral H pylori colonisation but increases that in the fundus. The changes in the intragastric distribution of the organism are associated with concomitant changes in the activity of gastritis and are matched by a progressive fall in the excretion of delta 13CO2.