Acid suppression therapy does not predispose to Clostridium difficile infection: the case of the potential bias.

Lena Novack,Slava Kogan,Ciarán P Kelly,Daniel A Leffler,Victor Novack,Larisa Gimpelevich,Abraham Borer,Michael Howell,Markus M Heimesaat

doi:10.1371/journal.pone.0110790

Abstract

ObjectiveAn 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.MethodsWe 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.ResultsPatients 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).ConclusionsThese 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.

Highlights

The morbidity and mortality rates caused by Clostridium difficile have increased lately, reflecting increased antibiotic use, the aging population and the emergence of high-level resistant strains [1,2] Outbreaks of Clostridium difficile infection (CDI) have been registered in hospitals worldwide [1,3], with reports of increased severity of disease, more frequent community acquired disease and rising CDI-associated healthcare costs [4,5]
Overview During the study period (2005–2010) the Soroka University Medical Center (SUMC) laboratory tested 2,343 stool samples for CDI, 337 were positive (Figure 1) and 212 out of 337 were found eligible for the study
As matching by age was performed with a caliper of 5 years, there was a small discrepancy in age between the study groups; controls with a negative test result were one year older and controls without a test were 2 years older compared to their cases

Summary

Introduction

The morbidity and mortality rates caused by Clostridium difficile have increased lately, reflecting increased antibiotic use, the aging population and the emergence of high-level resistant strains [1,2] Outbreaks of CDI have been registered in hospitals worldwide [1,3], with reports of increased severity of disease, more frequent community acquired disease and rising CDI-associated healthcare costs [4,5]. Antibiotic treatment has been shown to be the main risk factor for development of CDI. [6,7] Additional, well-established, risk factors include advancing age (e.g. older than 65), hospital admission, severe underlying disease, [8] prolonged hospitalization [9] and invasive gastrointestinal procedures. Gastric acid suppression treatment has been shown repetitively to be associated with an increased risk of hospital and community-acquired CDI. The association between acid suppression therapy and CDI has not been universal and was not found in some studies. The association between acid suppression therapy and CDI has not been universal and was not found in some studies. [12,20]

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Results

Discussion

Conclusion