Study Population

We performed a retrospective chart review of electronic medical records for all patients who had had a positive fecal result for C. difficile toxin from June 2005 through May 2006, a period of increased incidence of severe CDAD in this hospital. During June–April 2006, CDAD was diagnosed by cytotoxic assay for cytopathic effects in cell culture. During May 2006, our laboratory changed to a toxin A and B ELISA. Before assay replacement, samples were tested with both techniques and results were comparable (A. Onderdonk, pers. comm., 2008).

All inpatients >18 years of age who had had a positive fecal C. difficile toxin result were included in the study. Ambulatory and emergency department patients were not included.

Study Variables and Data Collection

Study variables included those identified as risk factors for development of CDAD, those associated with disease severity in previous studies, or those that logically predisposed patients to other severe disease outcomes. We collected patient demographic, historic, radiographic, and laboratory information.

Demographic variables included age, gender, hospital service (i.e., medical, surgical, obstetric, or gynecologic), date of positive C. difficile toxin sample, and length of hospitalization. We also collected number of antimicrobial drug classes used during hospitalization before positive C. difficile assay result, class and number of days used for each antimicrobial drug, and starting date and type of CDAD treatment initiated on or after the day the positive C. difficile toxin samples.

Historic data included use of corticosteroids, immunomodulating drugs, chemotherapy for hematologic and solid organ malignancies, proton pump inhibitors, and histamine-2 blockers. All medication data were limited to the 30 days before each patient’s first positive C. difficile toxin result. Physician-documented medical conditions included cardiovascular disease, diabetes mellitus, chronic kidney disease, past or current need for hemodialysis (not including intensive care unit [ICU] setting), pulmonary disease, hematologic malignancy, solid tumor malignancy, and immunocompromisation (i.e., solid organ or hematopoietic stem cell transplantation, immunoglobulin deficiencies, use of immunosuppressive agents, and severe autoimmune syndromes not associated with other malignancy).

Laboratory data were collected for a 7-day interval spanning 4 days before and 2 days after the day of submission of the first C. difficile–positive fecal specimen. This interval was chosen to account for variability in the promptness of C. difficile testing and initiation of treatment among healthcare providers. We recorded maximum leukocyte, serum glucose, creatinine, alanine aminotranferase levels, and minimum serum albumin concentrations.

Other variables were clinical or radiographic evidence of a small bowel obstruction or ileus in addition to abdominal and pelvic computed tomography (CT) scans with abnormal findings (colitis, pericolonic stranding, and abnormal rectal findings) documented anytime during hospitalization before laboratory diagnosis of CDAD. We also included skilled-nursing home or rehabilitation stays within 60 days before laboratory diagnosis of C. difficile infection, acute-care hospitalization within 30 days before diagnosis, date of death, date and number of admissions to ICU, number of surgical procedures, and enteral or total parenteral nutrition within 30 days before diagnosis of CDAD.

Definition of Severe CDAD

Patients were defined as having severe CDAD if they met at least 1 of the following criteria: 1) death within 30 days after onset of symptoms or positive assay in which C. difficile infection was a major contributor; 2) >1 ICU admissions in which C. difficile infection was a major contributor; 3) colectomy or other surgery directly attributed to C. difficile; or 4) intestinal perforation in the presence of C. difficile infection. To minimize subjectivity, cases were reviewed independently by 2 study personnel directly involved with data collection and extraction and were counted as severe only if both reviewers agreed. A third investigator, who was not involved with data collection, reviewed each case and acted as a tie-breaker.

Statistical Methods

The analysis was conducted in 3 stages. First, all-cause deaths and incidence of severe CDAD and death directly related to CDAD were explored in relation to age group. Second, univariate analyses were used to identify significant differences in variables for patients with severe and nonsevere disease. Chi-square testing with continuity correction was used to compare intergroup variation between nonparametric variables. Fisher exact tests were used if expected counts were <5. Mann-Whitney tests of ranked data were used to compare ordinal/parametric variables given the size discrepancy between the severe– and nonsevere–disease cohorts and to adjust for potential deviation from a normal distribution. Third, 2 logistic regression models were created. The first model was designed to evaluate independent associations between disease severity and antimicrobial drug use, demographics, and significant clinical variables identified from univariate analyses (prior nursing home/rehabilitation stays or acute-care hospitalizations, immunocompromisation, small bowel obstruction or ileus, and abnormal radiographic findings). The second model was designed to assess independent associations of laboratory variables with CDAD severity. Clinical variables likely to influence these laboratory values, such as hemodialysis, steroid use, and chemotherapy use, were included in this model. We used 2 models, rather than combining all variables into 1 model, because the small number of severe CDAD cases relative to total number of CDAD cases and large number of variables and covariates with potential collinearity in a combined model would decrease the power to detect statistical significance. Odds ratios (ORs) and 95% confidence intervals were calculated for each variable in the regression models (SPSS version 10; SPSS Inc., Chicago, IL, USA).

Study Population

For the study interval, we identified 336 patients and 373 hospitalizations. However, to minimize the underestimation of variance among our sample population, we analyzed data from only 1 admission per patient (initial hospitalization), for a total of 336 hospitalizations.

The all-cause crude mortality rate during initial admissions was 10.1%. Most (82%) CDAD patients were >50 years of age; crude mortality rate in this group was 12.0%. For patients <50 years of age, crude mortality rate (1.7%) was markedly lower; for patients >70 years of age, crude mortality rate was highest (15.4%) (Table 1).

The study definition for severe CDAD was met by 41 (12.2%) patients. Incidence of severe CDAD among all patients with CDAD was markedly higher in patients >70 years of age (p = 0.001). Of all patients, 21 (6.3%) died as a result of CDAD according to physician impression from chart review; none was <50 years of age (Table 2). Proportion of severe CDAD cases among patients with CDAD on these services did not differ significantly according to service (p = 0.18): 64% medical, 33% surgical, and 3% obstetric or gynecologic. Numbers of days from admission to laboratory diagnosis of CDAD patients with or without severe CDAD were similar (6.6 vs. 8.2; p = 0.13), as were lengths of hospitalization (18.3 vs. 18.2; p = 0.70).

Univariate Analysis

Table 3 lists variables (except antimicrobial drug use) and laboratory values included in univariate analysis. Mean age of patients was 64 years. Patients with severe CDAD were significantly older (mean age 71 years) than those without severe disease (mean age 63 years); p = 0.001, Mann-Whitney test of ranked data. Proportion of male and female patients with or without severe CDAD did not differ significantly.

Other variables that did not differ significantly between patients with or without severe CDAD were underlying medical illness, malignancy, use of nonantimicrobial medications (including steroids and chemotherapy), and enteral or parenteral feeding (Table 3). CDAD was significantly less severe in patients who were immunocompromised or receiving immunosuppressive medications than in those who were not immunocompromised (OR 0.22, p = 0.044).

Other variables associated with severe disease included small bowel obstruction or ileus (OR 3.33, p = 0.014), abdominal CT results suggestive of colorectal pathologic changes (OR 13.09, p<0.001), acute-care hospitalization within 30 days before CDAD laboratory diagnosis (OR 2.12, p = 0.036), and rehabilitation or skilled-nursing facility stay within the 60 days before CDAD diagnosis (OR 2.17, p = 0.043). Maximum leukocyte count was significantly higher for patients with severe CDAD, and significantly more patients with severe disease had a maximum leukocyte count >20,000 cells/μL, minimum albumin level <2.5 g/dL, maximum glucose level >150 mg/dL, and serum creatinine level >2 mg/dL (Table 3).

Some exposure to antimicrobial drugs during the 30 days before laboratory diagnosis of CDAD was noted for ≈85% of patients. Exposure to, or number of, antimicrobial drugs did not differ significantly among patients with or without severe CDAD. In the severe and nonsevere CDAD cohorts, 85.4% of patients had used any antimicrobial drugs (p = 1.0). In addition, no significant differences were found between exposure to any of the following groups of antimicrobial drugs for patients with severe or nonsevere CDAD: fluoroquinolones; penicillin derivatives with or without β-lactamase inhibitor; aminoglycosides; clindamycin; first-generation cephalosporins; second- through fourth-generation cephalosporins; carbapenems; trimethoprim/sulfamethoxazole; intravenous vancomycin; systemic antifungal drugs. Use of oral or intravenous metronidazole before laboratory diagnosis of CDAD (p = 0.860) did not differ significantly.

Antimicrobial drugs (including oral and rectal vancomycin and metronidazole) for CDAD were given to 291 (86.7%) patients during their hospitalization. A higher percentage of patients with severe CDAD than without CDAD were treated with oral vancomycin (OR 8.27, p<0.001), rectal vancomycin (OR 20.35, p<0.001), or intravenous metronidazole (OR 4.2, p<0.001) on or after the day of laboratory diagnosis of C. difficile infection. There was no significant difference in frequency of severe outcomes among patients treated with or without oral metronidazole (OR 1.02, p = 1.0). All patients with severe CDAD were treated with at least 1 antimicrobial drug with activity against C. difficile.

Regression Analyses

The following variables from the logistic regression model to identify covariates independently associated with severe CDAD were significant (p<0.05): age >70 years, ileus or small bowel obstruction, and abnormal abdominal CT image (Table 4). The following variables were not significantly associated with development of severe CDAD when adjusted for covariates: immunocompromisation status, prior acute-care hospitalization, and stay in a skilled-nursing facility. The independent association of laboratory values with severe CDAD was also investigated by using a single binary logistic regression model covariate adjusted with factors that would logically or historically influence each value. Maximum leukocyte count >20,000 cells/μL, maximum creatinine level >2 mg/dL, and minimum albumin level <2.5 g/dL were all independently associated with severe CDAD (p<0.05; Table 5).