Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients
Jeffrey F Barletta
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David A Sclar
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Department of Pharmacy Practice, College of Pharmacy-Glendale, Midwestern University
,
19555 N 59th Avenue, Glendale, AZ 85308
,
USA
Methods: This retrospective, case-control study was conducted using the Multiparameter Intelligent Monitoring in Intensive Care II database, a large publically available database of more than 35,000 ICU patients. Adult patients with CDI were identified using the ICD-9 code for Clostridium difficile listed as a secondary diagnosis. To be included, patients had to be present in an ICU for 48 hours prior to Clostridium difficile acquisition. These patients were then matched to patients without CDI using the ICD-9 primary diagnosis, age (+/5 years) and SOFA score (+/1). Successfully matched patients were reviewed for PPI exposure and other potential confounding variables for CDI. PPI exposure was characterized as short (<2 days) or long (2 days). Multivariate modeling was performed to identify independent risk factors for CDI. Results: There were 408 patients evaluated and 81% received a PPI. The percentage of patients who had a long exposure to PPIs was 83% in the CDI group compared to 73% with controls (P = 0.012). Upon inclusion of the following variables into a multivariate analysis (long PPI exposure, histamine-2-receptor antagonist administration, antibiotic administration, immunosuppression and study duration), long PPI exposure (odds ratio (OR) (95% confidence interval (CI) = 2.03 (1.23 to 3.36), P = 0.006) and antibiotic use (OR (95% CI) = 2.52 (1.23 to 5.18), P = 0.012) were identified as independent predictors of CDI. Conclusions: Proton pump inhibitors are independent risk factors for the development of CDI in ICU patients. This risk is particularly exposed after two or more days of therapy.
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Introduction
Clostridium difficile infection (CDI) is the leading cause
of hospital-associated infectious diarrhea with
considerable impact on length of stay and costs [1]. The
prevalence of CDI in mechanically ventilated, intensive care
unit (ICU) patients is 6.6% with most cases (69%) being
diagnosed during the ICU admission [2]. The high
frequency of CDI in critically ill patients is particularly
concerning given the multiple risk factors that are present
and the increased risk for adverse outcomes in this
population.
Recently, proton pump inhibitors (PPIs) have been
widely implicated as a significant risk factor for
hospitalacquired CDI [3-9]. In one large database study of ICU
patients, the odds ratio (OR) for CDI was significantly
greater with PPI use compared to histamine-2-receptor
antagonists (H2RA) (OR (95% confidence interval (CI) =
1.29 (1.04 to 1.64)). Infection-related risks with PPIs are
believed to be greatest shortly after starting therapy
[3,10-12]. One study evaluating the relationship between
duration of PPI therapy and nosocomial CDI revealed a
significant increase in risk after only two days of PPI
use [3].
PPIs have become the most common modality for the
provision of stress ulcer prophylaxis (SUP) in critically
ill patients [13,14]. While PPI use for this indication is
generally short-term, even an abbreviated exposure could
lead to substantial increases in morbidity and overall
hospital costs. The objective of this study was to further
describe the relationship between PPI use and
hospitalacquired CDI in critically ill patients and evaluate duration
of inpatient PPI exposure as a risk factor for CDI.
Methods
This case-control study was conducted using the
Multiparameter Intelligent Monitoring in Intensive Care II
(MIMIC II) database, version 2.6 [15,16]. This database
is a large, publically available database that encompasses
more than 35,000 patients admitted to the Beth Israel
Deaconess Medical Center from 2001 to 2008. Beth
Israel Deaconess Medical Center is a 620-bed tertiary
academic medical center in Boston, MA, USA with 77
critical care beds [16]. The MIMIC II database provides
a high-resolution record of time-stamped clinical
variables, physiologic data, diagnoses and interventions that
have been de-identified in a Health Insurance Portability
and Accountability Act-compliant manner. The database
was queried in August, 2013. Institutional Review Board
approval was obtained (Midwestern University, AZ#754)
prior to study initiation. The need for informed consent
was waived.
Adult patients with CDI were first identified using the
International Classification of Diseases, Ninth Revision
(ICD-9) code for Clostridium difficile (008.45) listed as a
secondary diagnosis. To be included, patients had to
be present in an ICU for at least 48 hours prior to its
acquisition. These patients were then matched to patients
without CDI in a 1-to-1 ratio using the ICD-9 primary
diagnosis, Sequential Organ Failure Assessment (SOFA)
score (+/1) and age (+/5 years). Patients were
excluded if Clostridium difficile was listed as a primary
admitting diagnosis, if a successful match could not
be obtained or if the medication rec (...truncated)