National Trends (2007-2013) of Clostridium difficile Infection in Patients with Septic Shock: Impact on Outcome

Additional Analyses

Lastly, we performed an additional analysis to confirm our hypothesis that a CDI by itself is rarely a cause of SS, and that CDI as the principal diagnosis would constitute an extremely low number of patients with SS in an administrative dataset. In NIS 2013, there were 105,750 cases with CDI as the primary diagnosis. A total of 4470 (4.2%) had a secondary diagnosis of sepsis and only 930 (0.9%) cases had a secondary diagnosis of SS.

This is the first study to report on the prevalence and outcome of CDI complicating SS. By using a large nationally representative sample, we found CDI was very prevalent among individuals hospitalized with SS and, at a level in excess of that seen in other populations. Of interest, we did not observe an increase in mortality of SS when complicated by CDI. On the other hand, patients with SS complicated by CDI were more much likely to have a prolonged hospital LOS and a higher risk of 30-day hospital readmission.

The prevalence of CDI exploded between the mid-1990s and mid-2000s, including community, hospital, and intensive care unit (ICU)–related disease.^6,7,17-20 Patients with SS often have multiple risk factors associated with CDI and thus represent a high-risk population for developing CDI.⁷ Our findings are consistent with the suggestion that individuals with SS are at a higher risk of developing CDI. Compared to the rate of CDI in all hospitalized patients, our data suggest an almost 10-fold increase in CDI rate for patients with SS.⁶ Patients with SS and CDI may account for as much as 10% of total CDIs.^6,7 As has been reported for CDI in general, we observed that CDI complicating SS was more common in those > 65 years of age.^4,21 The prevalence of CDI we observed in patients with SS was also higher than has been reported in ICU patients in general (1%), and higher than reported for patients requiring mechanical ventilation (6.6%), including prolonged mechanical ventilation (5.3%); further supporting the conclusion that patients with SS are a particularly high-risk group for acquiring CDI, even compared with other ICU patients.^20,22,23 Similarly, the rate of CDI among SS was 8 times higher than that of recently reported hospital-onset CDI among patients with sepsis in general (incidence 1.08%).²⁴ We have no data regarding why patients with SS have a higher rate of CDI; however, the intensity and duration of antibiotic treatment of these patients may certainly play a role.²⁵ It has recently been reported that CDI in itself can be a precursor leading to intestinal dysbiosis that can increase the risk of subsequent sepsis. Similarly, patients with SS may have higher prevalence of dysbiosis that, in turn, might predispose them to CDI at a higher rate than other individuals.

Following the increase in CDIs in the mid-1990s and the mid-2000s, since 2007 the overall prevalence of CDIs has been stable, albeit at the higher rate. More recently, the Centers for Disease Control and Prevention (CDC) has reported a decrease in hospital onset CDI after 2011.²⁶

The finding that CDI in SS patients was not associated with an increase in mortality is consistent with other reports of CDI in ICU patients in general as well as higher-risk ICU populations such as patients requiring mechanical ventilation, including those on long-term mechanical ventilator support.^{17,18,20,22,23} Why the mortality of ICU patients with CDI is not increased is not completely clear. It has been suggested that this may be related to early recognition and treatment of CDI developing in the ICU.²² Along these lines, it has been previously observed that for patients with CDI on mechanical ventilation, patients who were transferred to the ICU from the ward had worse clinical outcomes compared to patients directly admitted to the ICU, likely due to delayed recognition and treatment in the former.²² Similarly, ICU patients in whom CDI was identified prior to ICU admission had more severe CDI, and mortality that was directly related to CDI was only observed in patients who had CDI identified pre-ICU transfer.¹⁸ The increase in mortality observed in patients with sepsis in general with CDI may reflect similar factors.²⁴ We observed a trend of decreasing mortality in SS patients with or without CDI during 2007 to 2013 consistent to what has been generally reported in SS.^13,14

The increase in LOS observed in SS patients with CDI is also consistent with what has been observed in other ICU populations, as well as in patients with sepsis in general.^17,22-24 Of note, in addition to the increase in median LOS, we found a significant increase in the number of patients with a prolonged LOS associated with having SS with CDI. It is important to note that development of CDI during hospitalization is affected by pre-CDI hospital LOS, so prolonged LOS may not be solely attributable to CDI. The interaction between LOS and CDI remains complex in which higher LOS might be associated with higher incidence of CDI occurrence, and once established, CDI might be associated with changes in LOS for the remaining hospitalization.

Hospitalized patients with CDI have an overall higher resource utilization than those without CDI.²⁷ A recent review has estimated the overall attributable cost of CDI to be $6.3 billion; the attributable cost per case of hospital acquired CDI being 1.5 times the cost of community-acquired CDI.⁵ We did not look at cost directly. However, in the high-CDI risk ICU population requiring prolonged mechanical ventilation, those with CDI had a substantial increase in total costs.²³ Given the substantial increase in LOS associated with CDI complicating SS, there would likely be a significant increase in hospital costs related to providing care for these patients. Further adding to the potential burden of CDI is our finding that CDI and SS was associated with an increase in 30-day hospital readmission rate. This is consistent with a recent report that ICU patients with CDI who are discharged from the hospital have a 25% 30-day hospital readmission rate.²⁸ However, we do not have data either as to the reason for hospital readmission or whether the initial CDI or CDI recurrence played a role. This suggests that, in addition to intervention directed toward preventing CDI, efforts should be directed towards identifying factors that can be modified in CDI patients prior to or after hospital discharge.

This study has several limitations. Using an administrative database (such as NIS) has an inherent limitation of coding errors and reporting bias can lead to misclassification of cohort definition (SS) and outcome (CDI). To minimize bias due to coding errors, we used previously validated ICD-9-CM codes and approach to identify individuals with SS and CDI.^13-15 Although the SS population was identified with ICD-9-CM codes using an administrative database, the in-hospital mortality for our septic population was similar to previously reported mortality of SS, suggesting the population selected was appropriate.¹³ SS due to CDI could not be identified; however, CDI by itself causing SS is rare, as described in recent literature.^29,30 An important potential bias that needs to be acknowledged is the immortal time bias. The occurrence of CDI in itself can be influenced by pre-CDI hospital LOS. Patients who were extremely sick could have died early in their hospital course before they could acquire CDI, which would influence the mortality difference between the group with CDI and group without CDI. Furthermore, we did not have information on either the treatment of CDI or SS or any measures of severity of illness, which could lead to residual confounding despite adjusting for multiple variables. In terms of readmission data, it was necessary to exclude nonresidents of a state for the 30-day readmission analysis, as readmissions could not be tracked across state boundaries by using the NRD. This might have resulted in an underrepresentation of the readmission burden. Lastly, it was not possible to identify mortality after hospital discharge as the NIS provides only in-hospital mortality.

In conclusion, CDI is more prevalent in SS than are other ICU populations or the hospital population in general, and CDI complicating SS is associated with significant increase in LOS and risk of 30-day hospital readmission. How much of the increase in resource utilization and cost are in fact attributable to CDI in this population remains to be studied. Our finding of high prevalence of CDI in the SS population further emphasizes the importance of maintaining and furthering approaches to reduce incidence of hospital acquired CDI. While reducing unnecessary antibiotics is important, a multipronged approach that includes education and infection control interventions has also been shown to reduce the incidence of CDI in the ICU.³¹ Given the economic burden of CDI, implementing these strategies to reduce CDI is warranted. Similarly, the risk of 30-day hospital readmission with CDI highlights the importance of identifying the factors that contribute to hospital readmission prior to initial hospital discharge. Programs to reduce CDI will not only improve outcomes directly attributable to CDI but also decrease the reservoir of CDI. Finally, to the extent that CDI can be reduced in the ICU, the utilization of ICU resources will be more effective.