Treatment of helicobacter pylori infection : Experimental and clinical studies

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine at Huddinge University Hospital

Sammanfattning: Treatment of Helicobacter Pylori Infection Experimental and Clinical Studies Mikael Sörberg, Division of Infectious Diseases, Karolinska Institutet Danderyd Hospital, S-182 88 Danderyd, Sweden The general aims of the present study were to investigate the reason for failed H. pylori eradication, and to improve the recommendations for treating H. pylori infection. Our in vitro studies are based on microscopy, viable count and bioluminescence assay of bacterial adenosine triphosphate (ATP). In a study of morphological conversion of H. pylori, the coccoid form had a 1000-fold lower ATP level per cell than the bacillary form. Addition of fresh broth increased the intracellular ATP level 10-fold in the transition phase from bacillary to coccoid form. This indicates that the coccoid form has potential metabolic activity and may revert to a bacillary form in connection with the transition phase, possibly explaining treatment failure. In pharrnacodynamic studies of H. pylori exposed to amoxicillin, clarithromycin, metronidazole, omeprazole and lansoprazole, the parameters determined were change in morphology, change in cell density, postantibiotic effect (PAE) and control related effective regrowth time (CERT). PAE is the delayed regrowth after brief exposure to antibiotics or acid pump inhibitors. CERT measures the combined effect of initial killing and PAE, and was defined as the time required for the bacteria to resume logarithmic growth and return to the pre exposure inoculum in the test culture minus the corresponding time for the control culture. Amoxicillin caused a long PAE when assayed by bioluminescence, but no PAE or negative PAE when assayed by viable count. Similarly long CERT was seen with both methods. The pharmacodynamic effects of amoxicillin were concentration dependent up to a maximun response. Clarithromycin and metronidazole caused long PAE and CERT using both methods, which were concentration dependent, with no maximum response. Omeprazole and lansoprazole induced no PAE or CERT. The long CERT for all three antibiotics suggests that high doses and long dosing intervals are preferable. Possible selection of resistant subpopulations of H. pylori was studied with population analyses during exposure to amoxicillin, clarithromycin or metronidazole. Amoxicillin caused a small increase in resistant subpopulations, indicating a need for surveillance to detect decreasing susceptibility. No such increase was demonstrated during clarithromycin exposure. Metronidazole selected resistant subpopulations, which caused a high level resistance in H. pylori indicating need to study whether combination therapy can prevent this development. Patients with peptic ulcer disease and H. pylori infection were treated with a two-week regime of omeprazole, amoxicillin and metronidazole. The same drug combination was given again after two months to the patients still infected. H. pylori was eradicated in 84% after the first treatment and in 100% after the second treatment, suggesting that retreatment with the same combination is still effective. Repeated blood samples from patients who were successfully cured by the first treatment were analysed by enzyme immunoassay (EIA) and by immunoblot. All patients but one had significant decrease of IgG (EIA) after 6-12 months. The decrease for IgA (EIA) and the H. pylori specific proteins in the immunoblot was slower than for IgG (EIA). This shows that IgG (EIA) was the best serological parameter for monitoring eradicabon of H. pylori. Key words; Helicobacter pylori, coccoid form, treatment, pharmacodynamics, resistance, serology Stockholm 1997 ISBN 91-628-2584-4

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