Proton pump inhibitors and gastroenteritis

Authors: RobertJan Hassing Annelies Verbon Herman de Visser Albert Hofman Bruno H Stricker

Publish Date: 2016/03/10

Volume: 31, Issue: 10, Pages: 1057-1063

PDF Link

Abstract

An association between proton pump inhibitor PPI therapy and bacterial gastroenteritis has been suggested as well as contradicted The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study The Rotterdam Study is a populationbased cohort study among 14926 subjects aged 45 years and older with up to 24 years of followup Analyses were performed with a generalized estimating equations method in participants who handedin a diagnostic stool sample Furthermore a nested case–control analysis was performed using the total cohort as a reference group A bacterial microorganism was isolated in 125 samples whereas 1174 samples were culture negative In the generalized estimating equations analysis we found that participants with a bacterial gastroenteritis were more likely than controls to be current users of PPIs adjusted OR 194 95  CI 115–325 Different sensitivity analyses did not change this result A considerably higher effect was observed adjusted OR 614 95  CI 381–991 using the total cohort as a reference in a nested case–control analysis Current PPI therapy is associated with an increased risk of bacterial gastroenteritis However by reducing the risk of selection and information bias in our study design we demonstrated that the effect is lower than previously assumedProton pump inhibitors PPIs are among the most frequently prescribed drugs worldwide but seem to be associated with an increased risk of bacterial gastroenteritis 1 2 3 4 5 6 7 8 9 As a result warnings are introduced for people using PPIs such as avoiding raw meat consumption and antibiotic treatment on demand for travels to the tropics to prevent food borne infections This cohort study was designed to asses if the magnitude of this risk warrants preventive recommendationsCommon indications for PPIs are dyspepsia peptic ulcer disease reflux esophagitis and Barrett’s oesophagus 10 PPIs reduce gastric acid production by up to 99  by irreversible blocking of H+/K+ ATPase of parietal cells in the stomach 11 They have a maximal effect within 4 days and the effect may persist up to 3 days after stopping use 12 Associations between PPIs and infectious adverse events such as pneumonia Clostridium difficileassociated diarrhoea and bacterial gastroenteritis have often been described 1 2 3 4 5 6 7 8 9 13 14 15 16 17 An increased risk of gastroenteritis might be explained by the strong reduction in gastric acid resulting in increased susceptibility to bacterial infections Exogenous bacteria are usually destroyed in the stomach when the pH is 30 For species such as Vibrio cholerae and Campylobacter jejuni it has been shown in vitro that they are very sensitive to pH 18 However Salmonella species have been found to respond to low pH by developing adaptive mechanisms that allow survival in acid environments 19 Furthermore PPIs change the gut flora which provides a homeostatic protection against ingested pathogens 20 21 PPIs also reduce the antibacterial activity of neutrophils which may facilitate Salmonella and Campylobacter infections 22 23 Several case–control studies have shown an increased risk of acquiring gastrointestinal infections caused by Campylobacter or Salmonella species in patients using PPIs 1 2 3 4 5 6 7 8 In these case–control studies a relatively high adjusted odds ratio aOR or relative risk was observed ranging from 29 to 117 In one nested case–control study in which participants with a gastroenteritis prior to first PPI prescription were excluded a considerably lower effect was observed aOR 16 9 It has even been stated that there is no evidence that PPIs are associated with gastrointestinal infections based on outcomes adjusted for pretreatment susceptibility to bacterial gastrointestinal infections and timedependent confounding factors 24 which observation suggests that previous case–control studies have suffered from selection or information bias Therefore we designed a nested case control study within The Rotterdam Cohort a prospective cohort study to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis To minimize the risk of information bias we used participants with negative stool samples as a control group To test the hypothesis that an incorrect control group will influence the study results we also analysed the association using the total cohort as a control groupThe study was performed in The Rotterdam Study a prospective populationbased cohort study in 14926 people aged ≥45 years from one district Ommoord in the city of Rotterdam the Netherlands 25 In short from 1990 through 1993 7983 participants were included cohort I In 2000 an additional 3011 participants who had become 55 years old or older or who had moved into the district were enrolled cohort II In 2006 another 3932 participants aged 45 years and older were included cohort III Followup examinations are conducted every 4–5 years Participants are continuously monitored through linkage of records from general practitionersThe Rotterdam Study was approved by the medical ethics committee according to the Wet Bevolkingsonderzoek ERGO Population Study Act Rotterdam Study executed by the Ministry of Health Welfare and Sports of the Netherlands All study participants provided written informed consentA case was defined as a communitydwelling nonhospitalized individual with a positive stool sample for Campylobacter Salmonella Yersinia or Shigella species A control was defined as an individual with a negative stool sample Stool sample results were obtained from Star Medisch Diagnostisch Centrum StarMDC a centre for medical diagnostics for outpatients in the city of Rotterdam The majority of all laboratory tests including microbiology tests of patients from general practitioners within the Ommoord district of Rotterdam are performed at StarMDC Of all participants of The Rotterdam Study of whom informed consent was obtained for requesting medical information positive and negative microbiology tests between 1999 and April 2013 were obtained Stool samples were selected and samples in which parasites were isolated were excluded Detection of bacterial enteric pathogens in stool samples at StarMDC is performed by Multiplex polymerase chain reaction PCR followed by culture and microscopy in case of a positive result Until December 2010 when PCR was introduced at StarMDC detection of bacterial enteric pathogens was performed by conventional culture and microscopy onlyParticipants were considered as current user of PPI if the calendar date of the stool sample fell within a prescription episode of a PPI Prescription episodes were calculated by dividing the total number of supplied pills by the recommended daily number Additional covariables assessed were age sex cohort calendar date year BMI household status past use of proton pump inhibitors current or past use of H2receptor antagonists current use of chronic medication antidiabetic medication antihypertensive medication or statins intestinal antiinflammatory agents corticosteroids immunosuppressant medication meat consumption red meat consumption chicken consumption egg consumption and alcohol consumption for all dietary variables yes/no and gram/daysBMI and household status was obtained from baseline characteristics of The Rotterdam Study Medication use was obtained through automated linkage with pharmacy filled prescription data available from January 1st 1991 until April 2013 Dietary data were available from 1 week food consumption questionnaires obtained at the first visit of cohort I and cohort III and at the third visit of cohort II Multiple imputation 10× of missing dietary data and BMI was performed using all covariables

Keywords: