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Antibiotic resistance due to extended-spectrum beta-lactamases is an increasing world-wide problem. In a previous study we identified antacid use (mainly proton pump inhibitors) as a possible novel risk factors for carriage of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) in the community in the region of Amsterdam. Because of the widespread use of proton pump inhibitors, we propose to confirm and quantify the risk associated with antacid use in two large case-control studies embedded in ongoing studies: the PIENTER study and ISIS-AR. In these two studies we will address different and complementary aspects, based on the different data that will be collected in PIENTER and that are available in ISIS-AR.


PIENTER is a national survey, held every 10 years to assess how well the population of the Netherlands is protected against infectious diseases covered by the national vaccination program. It involves questionnaires on general health, medication use, travel, and the collection of blood, saliva and fecal samples. For the present additional study, that will be embedded in the PIENTER survey, fecal samples will be analyzed for the presence of ESBL-E and carbapenemase-producing Enterobacteriaceae (CPE). Persons with ESBL-E and/or CPE positive samples (= cases) will be compared to persons with negative fecal cultures (= controls). Data extracted from the questionnaires will be analyzed by univariate and multivariate logistic regression.


ISIS-AR is an ongoing surveillance program of the National Institute for Public Health and the Environment (RIVM) in collaboration with the Dutch Society of Medical Microbiology and Dutch clinical microbiology laboratories and collects routine antibiotic susceptibility data from clinical microbiology laboratories. Patients of general practitioners with ESBL-E and/or CPE in urine specimens (= cases) will be compared to patients with urine specimens with sensitive Enterobacteriaceae (= controls). They will receive a questionnaire with detailed questions on antacid use and on relevant risk factors such as travel and antibiotic use. Data of this case-control study will also be analyzed by univariate and multivariate logistic regression.


The two case-control studies will be of sufficient size to analyze whether antacid use not only is an important risk factor for ESBL-E acquisition and infection by itself, but also whether it increases the risk of other risk factors, like travel or antibiotic use. If use of antacids is confirmed as a risk, this will corroborate the idea that ESBL-E are mainly acquired through ingestion and pass more easily through a less acid-producing stomach. This will have major public health consequences, since proton pump inhibitors (PPI) are used by more than two million people in the Netherlands.

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