Design Overview
We conducted a retrospective, nested, case-control study using the Wellmark Data Repository (Data Repository), which is housed at the University of Iowa College of Public Health, to identify persons with CDI from January 1, 2004 to December 31, 2007. The Data Repository is a limited, longitudinal data set consisting of de-identified healthcare claims for members and their covered family members who are fully-insured through policies underwritten by Wellmark, the largest provider of health insurance in Iowa and South Dakota. This study was approved by the University of Iowa Institutional Review Board.
We examined insurance claims for inpatient, outpatient, home health, extended care/skilled nursing, and outpatient pharmacy healthcare services provided to members with health and prescription drug coverage. These data included insurance coverage, demographic information, diagnosis codes, procedure codes, dates of service and, outpatient pharmacy data including fill dates and drug-days supplied.
Identification of Case and Control Patients
We identified cases as persons with a primary or secondary diagnosis of ICD-9 code 008.45 for 'Infection due to Clostridium difficile' listed on an inpatient or outpatient insurance claim. Case subjects were required to have a minimum of 12 months of continuous health and pharmacy insurance coverage before their diagnosis and not have a history of healthcare claims from a long-term care facility during the 6 months before their diagnoses. Only the first C. difficile diagnosis was included. The diagnosis date was defined as the date on which the ICD-9 code for CDI first appeared on a claim.
A case of CA-CDI either had: (1) a diagnosis of CDI in the outpatient setting with no history of hospital discharge in the 12 weeks before diagnosis, or (2) a primary diagnosis upon hospital admission and no history of hospital discharge in the 12 weeks before diagnosis. A case of HA-CDI had either: (1) a secondary diagnosis during hospitalization; (2) a primary diagnosis upon admission to a hospital with a history of hospital discharge in the 4 weeks before diagnosis; or, (3) a diagnosis of CDI in the outpatient setting with a history of hospital discharge in the 4 weeks before diagnosis. All other cases were defined as indeterminate (i.e., did not meet the definitions of CA-CDI or HA-CDI).
For each CA-CDI case subject, ten control subjects were randomly selected. Members were eligible to serve as controls if they met inclusion criteria for cases (i.e., minimum of 12 months of continuous health and pharmacy insurance coverage and no history of healthcare claims from a long-term care facility in the prior 6 months), but had not been diagnosed with CDI on or before the date of diagnosis for a corresponding case [17]. A member could be a control subject and subsequently a case subject if CDI was diagnosed later. The index date for each control was the diagnosis date for the matched case. No further matching criteria were imposed.
Assessment of Exposures to Antimicrobial Agents and Gastric Acid Suppressants among CA-CDI Cases and Controls
We examined outpatient prescription use of antimicrobials among CA-CDI cases and controls in the 180 days before the diagnosis or index date. Prescription medications were identified through National Drug Codes (NDCs) on outpatient prescription drug claims. We examined exposure to specific antimicrobial classes or agents (aminoglycosides, beta-lactam/beta-lactamase inhibitors, cephalosporins, clindamycin, fluoroquinolones, macrolides, penicillins, sulfonamides, tetracyclines, and intravenous vancomycin), the total number of different antimicrobial agents received, and the timing of antimicrobial use in relation to the diagnosis or index dates. We categorized the timing of the subjects' most recent antimicrobial exposures as use during the following mutually exclusive intervals before the diagnosis or index dates (calculated from the last prescription's fill date and the days of antimicrobial supplied): 1 to 30 days, 31 to 60 days, 61 to 90 days, 91 to 120 days, 121 to 150 days, and 151 to 180 days. We did not examine use of topical or ophthalmic antimicrobials. In addition, we did not include use of metronidazole or oral vancomycin as possible risk factors, because they are used to treat CDI.
We also examined use of prescription gastric acid suppressants--proton pump inhibitors and histamine-2 receptor antagonists. Proton pump inhibitors included lansoprazole, omeprazole, pantoprazole, and rabeprazole. Histamine-2 receptor antagonists included cimetidine, and ranitidine. We categorized use of these medications as "never-used" or "ever-used" in the 180 days before the diagnosis or index dates.
Assessment of Comorbidity and Healthcare Utilization among CA-CDI Cases and Controls
We used the Charlson Comorbidity Index to measure underlying comorbidity among CA-CDI cases and their controls [18, 19]. Charlson comorbid conditions were considered "present" if the corresponding ICD-9 code was listed as a primary or secondary diagnosis on one inpatient claim or on two outpatient claims occurring 30 or more days apart in the year before the diagnosis or index dates [20]. We identified hospitalizations in the year before the diagnosis or index dates. We also determined whether or not patients had inflammatory bowel disease (i.e., Crohn's disease [ICD-9 codes: 555.0-555.9) and ulcerative colitis [ICD-9 codes: 556-556.9]).
Identification of Adverse Outcomes among CA-CDI Cases
Potential adverse outcomes following CA-CDI included colectomies, subsequent hospitalizations for CDI, and relapse of infection. We determined whether persons with CA-CDI had colectomies (ICD-9 procedure codes: partial/subtotal [45.79], cecal [45.72], left colon [45.75], multiple segmental [45.71], right colon [45.73], sigmoid [45.76], subtotal [45.8], and transverse colon [45.74]) during the 180 days following diagnosis [21]. We defined hospitalization related to CDI as an admission with a primary diagnosis of CDI occurring on the date of diagnosis of CA-CDI or during the following 8 weeks [22]. We considered claims for metronidazole or oral vancomycin prescriptions submitted after claims for the initial therapy and within 180 days of the diagnosis date to be markers for CDI recurrence or relapse.
Statistical Analyses
The incidence rates for CA-CDI and HA-CDI were the number of incident cases per 100,000 person-years of observation time. The denominator data were calculated based on duration of insurance coverage for each person in the Data Repository population for each year.
We calculated summary statistics for demographic characteristics, healthcare utilization, comorbid conditions, and medication among CA-CDI cases and controls. We used conditional logistic regression to estimate odds ratios (ORs) for the associations between CA-CDI and any antimicrobial use, use of individual antimicrobials, timing of antimicrobial use, number of antimicrobial agents prescribed, and use of gastric acid suppressants, while adjusting for covariates including comorbidity, inflammatory bowel disease (IBD), hospitalizations, age (in categories), and gender. In separate models, we estimated the ORs for the associations between CA-CDI and use of each antimicrobial class and also CA-CDI and the number of different antimicrobials. Because aminoglycosides and intravenous vancomycin were used infrequently, we excluded them from models for individual agents. When we assessed timing of antimicrobial use, we considered 'no antimicrobial use in the prior 180 days' to be the reference group. We used SAS version 9.2 (SAS Institute Inc., Cary, NC) for all analyses.