Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach

Clostridium difficile (C. difficile) is a gram positive, spore-forming bacterium with sequelae ranging from mild diarrhea to life-threatening pseudomembranous colitis and even death [1, 2]. Persons at increased risk for C. difficile infection (CDI) have advanced age, recent antibiotic exposure, proton pump inhibitor use, long length of stay in healthcare settings, serious underlying illness, or immunocompromised conditions [3, 4]. Around 20 % to 30 % of patients will go on to have a recurrent episode of CDI [5]. In addition to the aforementioned risk factors, prior recurrences and healthcare acquired infection further increase the probability for subsequent recurrences [6, 7]. CDI most commonly recurs within a week after treatment cessation but can recur up to 6 to 8 weeks later.

A changing epidemiology of CDI in the United States (US) and other industrialized countries has been observed since the early 2000s resulting in a substantial increase in the incidence and severity of CDI, especially in patients over 65 years of age [6‐9]. Hospitalizations with CDI as a principal diagnosis more than doubled in the US from 33/100,000 population to 115/100,000 between 1993 and 2008 [10]. However, since 2009 a levelling-off or decline of CDI incidence has been observed in the hospital setting [11], which may be attributable to increased awareness, leading to improved environmental controls, hygiene or implementation of more comprehensive prevention strategies. A recent study reported an incidence of 48 and 93 per 100,000 population for community-associated and health care-associated infections, respectively in the US in 2011 [12]. These high incidence rates of disease may be due in part to the emergence of a highly virulent strain of C. difficile, known as restriction enzyme analysis type BI, North American Pulsed Field type 1 (NAP1), or polymerase chain reaction ribotype 027. The BI/NAP1/027 strain has spread widely after first outbreaks in the eastern US, Canada, and the United Kingdom [13]. While CDI is well-recognized as an infection that is hospital-acquired, recent studies have increasingly highlighted the importance of CDI in other settings such as the community or long-term, outpatient care settings [1, 12, 14].

Estimates of epidemiological and economic burden of CDI have relied on independent studies that vary considerably in their designs, populations, and methodologies or have reported this burden secondary to other objectives, making comparison and interpretation difficult [10, 12, 15‐24]. One published source of CDI incidence in the US reports 336,600 hospitalizations in 2009 but does not include community-acquired cases or provide estimates in higher risk groups [10]. Recurrence rates have been variously reported between 3 % and 65 % (with most estimates falling between 20 % and 30 %), depending on period of observation, and risk factors such as episode, age, strain, or other factors [3, 4, 10, 19, 21, 25, 26]. Mortality estimates are similarly highly heterogeneous with estimates ranging from 3 % to 36 % [4, 6, 8, 10, 19, 22, 26‐33]. The uncertainty in such estimates makes it difficult to understand the true CDI burden in the U.S. There is limited information on CDI burden occurring in the community, although more data are emerging in this area, as is the evidence of burden in specific high-risk patients, like the immunocompromised or organ transplant recipients. Economic burden estimates available from multiple sources vary widely, capturing different healthcare cost components in the management of CDI or cost perspective [34‐36]. There are limited estimates of economic burden that include indirect costs such as productivity losses.

Our objective was to obtain detailed estimates of the epidemiological and comprehensive economic burden of CDI in the US in 2014 using consistent methodology across different risk groups, healthcare settings and community.

We developed a decision-analytic model in order to better understand the current and projected CDI burden in the US. Our model allowed calculation of the number of initial and recurrent CDI cases, and mortality rates by age and risk groups and by setting of care. Previously published studies have lacked comparability and this level of granularity, thereby limiting clear interpretation of true burden [10, 12, 15‐24, 41]. Crude national estimates of incidence or mortality have not considered the strain of C. difficile or provided burden in specific patient populations with serious comorbid conditions.

Our results agree with available estimates from US CDI national surveillance [12]. Our model estimates that in 2014, the absolute annual number of incident CDI cases, when combining all healthcare settings and community-based cases, was over 439,000 cases vs. the Centers for Disease Control and Infection (CDC) figure of 453,000 cases in 2011 [12]. Our model estimates that 25.5 % of these cases originate within an LTC setting, compared to 26 % estimated by CDC. Furthermore, our model estimated that 34.2 % of CDI cases occurred in the community which compares with their figure of 32 % of patients who were defined as community onset and who did not have a hospital stay in the previous 12 weeks. Estimates of first recurrences were reasonably similar: our model estimated 96,807 in 2014 compared to the CDC figure of 83,000 in 2011. However, estimates of deaths differed. Our model estimates that 44,572 deaths occurred in 2014 which is close to the upper limit of CDC estimates of 29,300 (95 % CI, 16,500 – 42,100). One reason explaining this difference is that our model estimated up to 6 recurrences and hence more CDI-attributable deaths were possible in our model, while CDC figures estimated first recurrences only. It is interesting to note that CDI-attributable death estimates from both our model-based estimates and those of CDC exceed figures reported by the National Vital Statistics Reports (NVSS) of 7,994 in 2011. One reason that may explain the discrepancy with NVSS may be that the recorded cause of death in CDI patients with multiple comorbidities were attributed to other causes [42].

Previous estimates of the annual economic cost for CDI in the US ranged from $436 million to $4.8 billion (2008 US dollars) [34‐36]. However, it has been suggested that these are low estimates because they do not take into account factors such as outpatient costs, indirect costs, and decreases in productivity [36]. Our estimates, which factored these items, were accordingly higher, indicating a total cost of $5.4 billion annually. In our study, the main driver of costs was hospitalization, accounting for between half to three-quarters of total costs, depending on care setting. Up to one-third of total costs were associated with recurrent CDI for patients whose initial episode was associated with a healthcare facility, but this was much lower when the initial episode was community acquired. Indirect costs were found to be small relative to total economic burden, due to low labor participation in the majority of CDI patients who are over 65 years.

The results of the model described for this study are useful for better identification of the settings and risk- and age- groups in which CDI burden lies. Moreover, these data permit a greater understanding of the burden of recurrent episodes which has not been reported previously. Given the clinical challenges associated with the of treatment of recurrent CDI and the improved recognition of CDI in high risk groups, these data provide insights into the potential value of emerging new treatment options that could benefit patients with CDI.