Pharmacological therapy of Helicobacter pylori infection

Sammanfattning: The discovery of Helicobacter pylori (H. pylori) opened the doors to new insight and therapy for peptic ulcer disease. Earlier eradication treatment modalities based on bismuth compounds, with or without additional antimicrobials, were not well accepted mainly because of the, at least hypothetical, risks for neurological and/or renal side effects. The first proton pump inhibitor, omeprazole, had been proven as a very effective short-term anti-ulcer therapy, but after withdrawal of the drug, the recurrence rate was high. theoretically, acid suppression was believed to increase the H. pylori infestation as the environment became more neutral. On the other hand, acid suppression could increase the effect of acid labile antimicrobials. This was not investigated before the studies presented in this thesis were performed.A small pilot study (Paper I) in 24 patients showed that 7 out of 8 patients treated for fourteen days with omeprazole 40 mg o.m. + amoxicillin 750 mg b.i.d. were cleared of H. pylori, while it remained in 7/8 patients on omeprazole as monotherapy and in 2/7 patients on amoxicillin as monotherapy. However, the eradication rates 4 weeks after treatment were 5/8, 0/8 and 1/7 in the three groups, respectively. These results were confirmed in a large study (Paper II) comprising 248 consecutive patients with active duodenal ulcer disease. All had an initial treatment period for two weeks with omeprazole 40 mg o.m., followed by continued omeprazole in combination with amoxicillin 750 mg b.i.d. or amoxicillin placebo for a further two weeks. In the dual therapy group, 54% of patients were H. pylori eradicated compared to 4% in the omeprazole mono therapy group. Furthermore, the duodenal ulcer relapse rate was significantly lower in the combination group compared to the monotherapy group (p<0,001). Paper III represents a study that was preformed to assess whether improved results could be obtained by adding two antimicrobials to omeprazole. In total 787 patients were randomized to six treatment arms, where omeprazole was combined with two of the three antimicrobials amoxicillin, metronidazole and c!arithromycin in various doses and combinations. The results showed that one week's treatment was sufficient for a very high eradication rate. A combination of omeprazole 20 mg b.i.d. + amoxicillin 1000 mg b.i.d. + clarithromycin 500 mg b.i.d. was superior to a combination with a lower clarithromycin dose of 250 mg b.i.d. or amoxicillin in combination with metronidazole, but not significantly better than the other two arms containing metronidazole+ clarithromycin in a dose of 250 mg b.i.d. 500 mg b.i.d. Paper IV was designed to establish whether or not acid suppression is necessary during antimicrobial treatment. In total 539 patients were randomized. Eradication rates with omeprazole added to antimicrobials were much higher than in treatment groups not receiving omeprazole. In metronidazole resistant strains, only 76% were eradicated in comparison to 95% in susceptible strains. Amoxicillin resistance did not occur and clarithromycin resistance was found in only 3% of patients. Thus, papers I-IV proved the efficacy ofthe new treatment modality, which, however, represented high costs in the short-term perspective.The cost-effectiveness of various treatment strategies in regular use at that time was evaluated in paper V. The economic model showed that in comparison to continuous therapy with gastric acid suppressive drugs, the extra initial cost for eradication therapy was paid within one year and, in comparison to intermittent therapy, within three years.Conclusion: These studied have shown convincingly that eradication of H. pylori with a combination of gastric acid suppression and two antimicrobials (amoxicillin and clarithromycin) is the most effective treatment in PUD, giving a high eradication rate and consequently lower peptic ulcer recurrence. Thus, this treatment strategy is also very cost-effective for society.

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