Is Clostridium difficile infection a risk factor for subsequent bloodstream infection?

BACKGROUND: Clostridium difficile infection (CDI) is a common nosocomial diarrheal illness increasingly associated with mortality in United States. The underlying factors and mechanisms behind the recent increases in morbidity from CDI have not been fully elucidated. Murine models suggest a mucosal barrier breakdown leads to bacterial translocation and subsequent bloodstream infection (BSI). This study tests the hypothesis that CDI is associated with subsequent BSI in humans. METHODS: We conducted a retrospective cohort study on 1132 inpatients hospitalized >72 h with available stool test results for toxigenic C. difficile. The primary outcome was BSI following CDI. Secondary outcomes included 30-day mortality, colectomy, readmission, and ICU admission. Unadjusted and adjusted logistic regression models were developed. RESULTS: CDI occurred in 570 of 1132 patients (50.4%). BSI occurred in 86 (7.6%) patients. Enterococcus (14%) and Klebsiella (14%) species were the most common organisms. Patients with BSI had higher comorbidity scores and were more likely to be male, on immunosuppression, critically ill, and have a central venous catheter in place. Of the patients with BSI, 36 (42%) had CDI. CDI was not associated with subsequent BSI (OR 0.69; 95% CI 0.44-1.08; P = 0.103) in unadjusted analysis. In multivariable modeling, CDI appeared protective against subsequent BSI (OR 0.57; 95% CI 0.34-0.96; P = 0.036). Interaction modeling suggests a complicated relationship among CDI, BSI, antibiotic exposure, and central venous catheter use. CONCLUSIONS: In this cohort of inpatients that underwent testing for CDI, CDI was not a risk factor for developing subsequent BSI.

Elevated fecal calprotectin associates with adverse outcomes from Clostridium difficile infection in older adults.

BACKGROUND: Clostridium difficile infection (CDI) causes a mild to moderate colitis in most patients, but some, especially older adults, develop severe, adverse outcomes. Biomarkers predicting outcomes are needed to optimize treatments. This study tested whether fecal calprotectin associated with a composite primary outcome of complicated CDI (intensive care unit admission, colectomy, or death due to CDI within 30 days of diagnosis) and/or 8-week recurrence. METHODS: Stool was collected in Cary-Blair media at the time of diagnosis from inpatients of age >60 years that tested positive for C. difficile (enzyme immunoassay [EIA] for toxin A/B or polymerase chain reaction for the tcdB gene). Fecal calprotectin was measured and normalized to solid stool weight. Analysis was performed using logistic regression. Variables were selected for the final model using likelihood ratio tests. RESULTS: Fifty patients were included with a mean age 72.8 (± 7.5), and 13 (26%) developed the primary outcome. Clinical variables such as age, gender, and comorbid disease did not associate with complicated CDI/recurrence, nor did traditional biomarkers such as serum albumin or white blood cell count. A high normalized fecal calprotectin (>2000 µg/g) associated with the primary outcome in the final model after adjustment for gender and detectable fecal toxin(s) by EIA (OR 24.9, 95% CI 2.4-257.9, p = 0.007) with a specificity of 91.9%. CONCLUSION: This study provides evidence that fecal calprotectin level associates with complications from CDI in older adults. Further studies are required to validate these findings in larger cohorts and incorporate them into clinical prediction algorithms.

Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.

BACKGROUND: Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. METHODS: Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. RESULTS: In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). CONCLUSIONS: Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

The systemic inflammatory response to Clostridium difficile infection.

BACKGROUND: The systemic inflammatory response to Clostridium difficile infection (CDI) is incompletely defined, particularly for patients with severe disease. METHODS: Analysis of 315 blood samples from 78 inpatients with CDI (cases), 100 inpatients with diarrhea without CDI (inpatient controls), and 137 asymptomatic outpatient controls without CDI was performed. Serum or plasma was obtained from subjects at the time of CDI testing or shortly thereafter. Severe cases had intensive care unit admission, colectomy, or death due to CDI within 30 days after diagnosis. Thirty different circulating inflammatory mediators were quantified using an antibody-linked bead array. Principal component analysis (PCA), multivariate analysis of variance (MANOVA), and logistic regression were used for analysis. RESULTS: Based on MANOVA, cases had a significantly different inflammatory profile from outpatient controls but not from inpatient controls. In logistic regression, only chemokine (C-C motif) ligand 5 (CCL5) levels were associated with cases vs. inpatient controls. Several mediators were associated with cases vs. outpatient controls, especially hepatocyte growth factor, CCL5, and epithelial growth factor (inversely associated). Eight cases were severe and associated with elevations in IL-8, IL-6, and eotaxin. CONCLUSIONS: A broad systemic inflammatory response occurs during CDI and severe cases appear to differ from non-severe infections.