In this population-based study, we determined the period of risk of C. difficile infection that might be related to antibiotic exposure and found that about 50% of patients had no history of antibiotic exposure in the 45 days before admission because of C. difficile infection. We also demonstrated that a significant proportion of hospital admissions because of incident C. difficile infection occurred within 90 days after discharge from hospital, confirming the importance of the hospital experience in the epidemiology of this disease.
Using a large sample of patients identified from the community, we have again documented that antibiotic use is not a prerequisite to the development of C. difficile
A number of smaller studies have reported similar observations.3,19–22
Substantially lower rates of prior antibiotic exposure in community-acquired C. difficile
infection support the tenet that there may be significant confounding of the association between antibiotics and C. difficile
infection with hospital admission.7
Clindamycin, cephalosporins and gatifloxacin were the antibiotics associated with the highest risk in this study. Recent studies of nosocomial C. difficile
infection in the same province23,24
demonstrated no significant increase in risk associated with clindamycin. Clindamycin and cephalosporins are frequently associated with gastrointestinal side effects and have previously been labelled high-risk drugs associated with C. difficile-
These features are likely to increase ascertainment bias, since patients with gastrointestinal symptoms, particularly those who have received reputedly high-risk antibiotics, are more likely to be tested. The antibiotic associated with the highest risk for C. difficile-
associated diarrhea has not been consistent among studies, and almost all antibiotics have been associated with an increased risk of C. difficile
infection, irrespective of their spectrum of activity on either the normal flora or C. difficile
. The inconsistency among studies of results implicating particular antibiotics, as well as the nonspecificity of the drugs, support the hypothesis that some of the risk attributed to antibiotics may be confounded.
The strengths of our study include use of a community-based population of high-risk patients for whom there was complete data about medication exposure and hospital admission. We also used a clinically relevant case definition. By restricting the population to community-based patients, we controlled for factors associated with hospital admission. We controlled for confounding by severity of illness both by matching and by adjustment in the analysis. We studied a high-risk population and included incident cases only. Antibiotic exposure among patients who have had a previous episode of C. difficile infection may be modified by the first event, and physicians may be less likely to use antibiotics considered to present a high risk. Therefore, the exclusion of cases with recurrent disease decreased the risk of bias in the antibiotic estimates.
Our study has limitations. The study population was restricted to a specific population of elderly patients with at least 1 prior hospital admission in the previous 8 years. Because the case definition was restricted to patients with severe infection, the risk factors observed may differ from those for the general population and for patients with less severe disease.
The information obtained from administrative databases also has limitations. Two previous studies25,26
examining a diagnosis of C. difficile
infection based on codes from the International Classification of Diseases, 9th revision, showed that the definition had high specificity (over 99%) but lower sensitivity, which could result in case misclassification and might have affected some of the risk estimates that we obtained. We did not obtain any confirmatory laboratory data, as this information was not available in the database; however, it is unlikely that patients who had been admitted to hospital would be recorded as having C. difficile
infection in the absence of testing. The drug database might not have taken into consideration administration of antibiotics or other drugs from physician samples, but this was deemed unlikely to be significant. It is also possible that patients who were classified as having been exposed to antibiotics because a prescription was dispensed did not actually take the medication. Some of the patients defined as having community-acquired infection may have been residing in long-term care institutions, but such cases probably represented less than 5% of the elderly population27
and were unlikely to substantially affect the estimates.
Similarly, the assignment of comorbid diagnoses using administrative databases has limitations, and previous research with such databases has shown that many of the diagnoses of comorbidity have high specificity, with sensitivity varying greatly by condition.16,28
This might have led to misclassification in our study, and since these misclassifications were likely nondifferential, our estimates of relative risk were likely underestimated. We believe, however, that the extent of such information bias was minimal. Therefore, the associations that we found were likely real, especially given that they have been documented in previous research, including studies that we conducted using another validated research database.4,5
Community-acquired C. difficile infections were common and developed without prior exposure to antibiotics in the study population. Testing for C. difficile should be considered in community patients with diarrhea in whom a history of antibiotic exposure cannot be elicited.
@@ See related commentary by Kuijper and van Dissel, page 747