Incidence of and risk factors for community-associated Clostridium difficile infection: A nested case-control study

Clostridium difficile is the most common cause of nosocomial infectious diarrhea in the United States. Several reports indicate that the incidence and the severity of C. difficile infections (CDI) are increasing [1–3], possibly related to the new virulent BI/NAP1 strain [4]. Investigators have identified numerous risk factors for hospital-acquired CDI (HA-CDI) (e.g., antimicrobial use, older age, underlying diseases) [5–9]. However, recent published reports have described CDI cases in people without traditional risk factors [10–12], including people without recent exposures to antimicrobials. These reports suggest that community-associated CDI (CA-CDI) cases are occurring in persons who are younger, have fewer comorbidities, and less exposure to healthcare than persons with HA-CDI [10–15].

Few large studies have been conducted to identify risk factors for CDI in the community-setting, and investigators have not determined if or to what extent the epidemiology of CA-CDI differs from that of HA-CDI. Furthermore, most studies of CA-CDI in the United States are based on brief periods of voluntary surveillance in limited geographic areas and in targeted populations [12, 15, 16]. The purpose of this study was to examine the epidemiology of CA-CDI in a broad population. Specifically, this study estimates the incidence of CA-CDI and HA-CDI within an employer-based, insured population covering two states, identifies patient-related risk factors for CA-CDI, and describes adverse health outcomes of CA-CDI.

CA-CDI cases were more likely than controls to receive antimicrobials in the previous 180 days (adjusted OR 6.09, 95% CI 4.59-8.08) (Table 2). After adjusting for all covariates including antimicrobial use; age 19 years and older (with ≤ 18 years as the reference group), IBD, and gastric acid suppressant use significantly increased the risk of CA-CDI. Eighteen percent of CA-CDI cases and 5% of controls received gastric acid suppressants in the 180 days before their diagnosis or index dates (adjusted OR 2.30, 95% CI 1.56-3.39) (Table 2), and 84% of persons with CA-CDI who received gastric acid suppressants also received one or more antimicrobial agents (data not shown).

We performed a sensitivity analysis to examine the relationship between risk factors and onset of CA-CDI after we redefined the diagnosis date as the date of the first: (1) CDI diagnosis code, (2) prescription for oral vancomycin or antimotility medication, or (3) diagnosis code for non-specific diarrheal disease. When we utilized this approach, 122 cases retained their original diagnosis dates based on ICD-9 codes, while 177 cases had revised diagnosis dates based on prescription medication use or diagnosis of diarrheal disease. The results of this analysis, which included cases with original and revised diagnosis dates and their controls, were essentially the same as those reported in Table 3.

No one with CA-CDI required a colectomy. Seventy-seven CA-CDI cases were admitted (79 admissions) with the primary diagnosis of ICD-9 code 008.45 entered on the diagnosis date or within 8 weeks, for a hospitalization rate of 25.3%. Of the 77 first-time admissions, sixty-three (81.8%) occurred on the date of diagnosis, 10 (12.7%) occurred 1 day after the CDI diagnosis, and 1 each occurred 4, 20, 24, and 30 days after diagnosis. The mean time between the diagnosis of CA-CDI and hospital admission was 1.14 days (Median: 0 days; Std. Dev: 4.87).

Of 304 CA-CDI cases, 21 (6.9%) received at least one additional prescription for metronidazole or oral vancomycin after their initial therapy; 12 cases received 1 additional prescription for metronidazole or oral vancomycin, 3 received 2 prescriptions, 4 received 3 prescriptions, and, 2 received 4 prescriptions. Of these cases, 76% were retreated within 30 days of their CDI diagnoses and 90% were retreated within 60 days.

Our results demonstrate that CA-CDI is occurring among populations not traditionally considered 'high-risk' (i.e., younger people, people without underlying illness, people not exposed to hospitals or antimicrobials). In fact, among our relatively young study population, the incidence rates of CA-CDI and HA-CDI were similar; 44% of all cases were community-associated.

Similar to other studies of CA-CDI, our study found that a substantial proportion of persons with CA-CDI did not have traditional risk factors for this infection: 27% did not receive any antimicrobials in the 180 days before their diagnoses and 17% did not have any of the traditional risk factors for CDI (i.e., no antimicrobial or gastric acid suppressant exposure, no underlying illness, and no history of hospitalization) [13, 14]. The risk factors we identified for CA-CDI were similar to risk factors for HA-CDI. For example, prior antimicrobial use was the most common risk factor, and the 'highest-risk' antimicrobials were similar to those commonly-associated with HA-CDI (i.e., clindamycin, fluoroquinolones). Also, we found that most antimicrobials were associated with some risk for CDI and each additional antimicrobial agent increased the risk for CA-CDI further. These results support calls from organizations including the Centers for Disease Control and Prevention and the Infectious Diseases Society of America for physicians to eliminate inappropriate antimicrobial use for both inpatients and outpatients.

Our study also found that persons exposed to antimicrobial agents are at risk for CA-CDI longer than suggested by prior studies [23, 24]. As expected, the highest risk for CA-CDI in our study population was within the first 30 days after the last antimicrobial exposure. But the risk remained relatively high until 60 days after exposure and did not return to baseline until 150-days after exposure.

Prior studies found that gastric acid suppressant medications increase the risk for CDI, although risk estimates for CA-CDI have varied [25–28]. In our population, use of gastric acid suppressants increased the risk for CA-CDI, even after controlling for use of antimicrobials and for gastrointestinal disease. However, most (84%) patients with CA-CDI who took gastric acid suppressants also took antimicrobials. Thus, although we did not find a statistical interaction between the effects of these medication classes, a portion of the risk attributed to gastric acid suppression may be related to concurrent antimicrobial use.

CA-CDI had economic implications in this population. Although persons in our study population did not require surgical interventions for CA-CDI, approximately one out of four cases was hospitalized, and hospitalized patients stayed an average of 4 days. Thus, our population of healthy persons with CA-CDI had about 308 hospital treatment days for these infections, which added substantially to the cost of care. Although the estimated relapse rate was relatively low, 21 (6.9%) people had relapses and received a total of 38 additional antimicrobial prescriptions for either oral vancomycin or metronidazole. Moreover, about half of the persons with CA-CDI had claims submitted for "non-specific diarrheal disease" in the month before their claims for CDI. Thus, about 150 persons experienced avoidable treatment delays and additional out-patient visits that increased the morbidity and costs associated with CDI.

Our study has several limitations. First, although the ICD-9 code for CDI has reasonable sensitivity and specificity for detecting CDI cases in inpatient settings [29, 30], it has not been validated as thoroughly in community settings. We could not validate the coding in our data set because we did not have access to the patients' medical records. Future studies are needed to validate ICD-9 code 008.45 in community settings. Moreover, we could not determine either the date symptoms first occurred or the date on which C. difficile testing occurred. Rather, as noted previously, we had to define the date of CDI diagnosis based on the date the ICD-9 code 008.45 first appeared on insurance claims. Second, this identification strategy is contingent upon patients being tested for CDI and diagnosed in a clinical setting, thus we may have underestimated the true burden of CA-CDI. Third, we most likely underestimated the use of gastric acid suppressants because patients may purchase these medications over-the-counter. However, we presume that misclassification would be nondifferential and could attenuate the association between these agents and CA-CDI. In addition, prescription drug claims were included in our data set only if they were submitted and paid. Thus, we may have underestimated antimicrobial use if patients did not submit claims for their antimicrobial prescriptions. Fourth, inflammatory bowel disease was a significant risk factor for CA-CDI, but this association was based on only 12 cases and 4 controls. Also, patients with IBD often have diarrhea. Thus, higher rates of CA-CDI among patients with IBD than among other patients could be due to surveillance bias. Finally, the persons in our population were fully-insured through either individual or employer-based plans. In addition, the database excluded Medicare and Medicare Supplement Insurance coverage, so the number of persons 65 years or older was limited to those who also purchased commercial insurance. Thus, our results may not be generalizable to older populations. For example, the incidence of HA-CDI and of complications (i.e., none of the cases underwent colectomies) in our study may be lower than in other studies because our population was relatively young. This may also account for the low CDI relapse rate among our population.

We studied a young, healthy insured population and found the incidence of CA-CDI to be equal to that of HA-CDI, suggesting that hospital-based CDI surveillance may substantially underestimate the incidence of this infection in community settings. In general, the risk factors for CDI in our study population were similar to those identified for hospitalized populations, yet over 25% of the patients had not been exposed to antimicrobial agents. On the other hand, the population-attributable-risk percent for antimicrobial use was nearly 58% [31], indicating that over half of the cases were related to antimicrobial use, and the risk associated with antimicrobial agents persisted over several months. Moreover, it seems that many cases of CA-CDI were not diagnosed upon symptom onset, indicating that physicians may not consider this diagnosis initially. A substantial proportion of the patients were hospitalized for treatment, indicating that these infections were serious, and they increased the cost of care.

Our study documented that the epidemiology of CDI is changing significantly and the population at risk for this infection is much larger than previously thought. Clinicians should be aware of these changes and obtain appropriate diagnostic testing on outpatients with diarrhea and antimicrobial exposure, including remote exposure (i.e., up to 150 days prior to disease onset). To curb spread of C. difficile in the community setting, we must decrease antimicrobial use among outpatients and we must conduct further research to determine the source of C. difficile in this setting.