title: Acid suppression therapy does not predispose to Clostridium difficile infection: the case of the potential bias.
abstract: OBJECTIVE
  An adverse effect of acid-suppression medications on the occurrence of Clostridium difficile infection (CDI) has been a common finding of many, but not all studies. We hypothesized that association between acid-suppression medications and CDI is due to the residual confounding in comparison between patients with infection to those without, predominantly from non-tested and less sick subjects. We aimed to evaluate the effect of acid suppression therapy on incidence of CDI by comparing patients with CDI to two control groups: not tested patients and patients suspected of having CDI, but with a negative test.
  
  
  METHODS
  We conducted a case-control study of adult patients hospitalized in internal medicine department of tertiary teaching hospital between 2005-2010 for at least three days. Controls from each of two groups (negative for CDI and non-tested) were individually matched (1:1) to cases by primary diagnosis, Charlson comorbidity index, year of hospitalization and gender. Primary outcomes were diagnoses of International Classification of Diseases (ICD-9)-coded CDI occurring 72 hours or more after admission.
  
  
  RESULTS
  Patients with CDI were similar to controls with a negative test, while controls without CDI testing had lower clinical severity. In multivariable analysis, treatment by acid suppression medications was associated with CDI compared to those who were not tested (OR = 1.88, p-value = 0.032). Conversely, use of acid suppression medications in those who tested negative for the infection was not associated with CDI risk as compared to the cases (OR = 0.66; p = 0.059).
  
  
  CONCLUSIONS
  These findings suggest that the reported epidemiologic associations between use of acid suppression medications and CDI risk may be spurious. The control group choice has an important impact on the results. Clinical differences between the patients with CDI and those not tested and not suspected of having the infection may explain the different conclusions regarding the acid suppression effect on CDI risk.
authors.affiliation: Department of Epidemiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Novack
authors.affiliation: Clinical Research Center, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Slava
authors.initials: S
authors.lastname: Kogan
authors.affiliation: Department of Epidemiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Larisa
authors.initials: L
authors.lastname: Gimpelevich
authors.affiliation: The University of Chicago Medicine, Chicago, Illinois, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.affiliation: Infectious Diseases Unit, Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Borer
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ciarán P
authors.initials: CP
authors.lastname: Kelly
authors.affiliation: The Celiac Center at BIDMC, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Leffler
authors.affiliation: Clinical Research Center, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Victor
authors.initials: V
authors.lastname: Novack
mesh_terms: D000328:Adult; D000368:Aged; D015982:Bias; D016360:Clostridioides difficile / Q000502:physiology*; D003015:Clostridium Infections / Q000139:chemically induced* / Q000382:microbiology*; D003710:Demography; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D006760:Hospitalization; D006801:Humans; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D054328:Proton Pump Inhibitors / Q000009:adverse effects*
chemical_list: D054328:Proton Pump Inhibitors