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Incidence and Costs of Clostridium difficile Infections in Canada

CDI has a substantial epidemiologic, and economic, burden; and the largest proportion of costs arise from prolonged hospitalization. Interventions reducing the severity of infection and/or relapses requiring rehospitalization are likely to have the largest absolute effect on direct medical cost.

Evidence is accumulating that the epidemiology of Clostridium difficile infection is worsening, with marked increases in both incidence and case-fatality in Canada [1], the United States [2,3], Europe [4], and other countries [5]. Although the reasons are multifactorial, 1 cause is the emergence of a new, "hypervirulent" strain designated restriction endonuclease analysis type BI, North American pulsed-field gel electrophoresis type 1 (NAP1), or polymerase chain reaction (PCR) ribotype 027 (ie, BI/NAP1/027) [6]. Although it was first identified in Quebec [7], transmission of this strain is now of global concern [8]. In addition, although it is not known whether recurrence rates have changed, reduced susceptibility and increased rates of C difficile infection are being observed in the community [9].
The existing literature on the burden of illness of C difficile infection is sparse, with incidence estimates derived primarily from teaching hospitals [1]. As such, there are no published Canada-wide estimates of the prevalence or the economic burden attributable to C difficile infection. The objective of this study was to estimate the annual number of persons infected with C difficile in Canada in 2012 and the direct medical and lost productivity costs.

METHODS
Using prevalence-based burden of illness model, we estimated the annual mean number of persons infected with C difficile in Canada and the direct medical costs and lost productivity costs [10]. Numbers of infected persons were tabulated by treatment location (acute care hospital, community-dwelling, and long-term care) and, for those in acute care, stratified by first versus recurrent infection, disease severity, and age group [11].
Given its episodic nature, the mean number of infections per province between 2010 and 2012 was estimated. These data are from a laboratory that uses PCR methods for diagnosis of C difficile. Resource use and costs of typical management patterns were estimated for each treatment location and other stratification variables. A societal perspective was adopted by including lost productivity costs. The model was developed in Microsoft Excel 2010, and the statistical analyses were conducted in Stata 12.

Data Sources
Sources of data used included the following: (1) the number of bed-days attributed to persons infected with C difficile in Canadian acute care hospitals, from the Canadian Institute for Health Information (CIHI); (2) the estimated proportion of recurrent acute care infections, from the Providence Health Care ([PHC] Vancouver, British Columbia) Infection Prevention and Control C difficile infection surveillance program dataset; and (3) the estimated proportions of infections occurring among hospital-and community-based individuals and distributions of severity, obtained from the literature [12,13].
Resources expended for diagnosing persons in Canada infected with C difficile came from published literature, clinician interviews, and data from PHC Infection Prevention and Control and other Canadian surveillance programs (Table 1). Costs were obtained from PHC Infection Prevention and Control and PHC Finance. Clinical experts included hospital (n = 3) and community (n = 1) physicians and infection control experts (n = 2), medical directors of long-term care facilities (n = 3), and acute care nurses who care for patients infected with C difficile (n = 2). Lost productivity was quantified using labor statistics [14]. Use of the PHC Infection Prevention and Control data was approved by the ethical review boards of PHC and the University of British Columbia.

Number of Infected Persons With Clostridium difficile in Canada
The annual aggregated number of initial and recurrent infections in Manitoba was obtained from published sources [12,15]. Other than Manitoba, there is no published information on the numbers of C difficile in Canadian provinces or territories so these estimates were derived indirectly ( Figure 1 ). In step 1, the province-specific mean annual estimated rates of persons newly infected in hospital were multiplied by the total number of patient days per province from CIHI [12,[16][17][18][19][20]. In step 2, the numbers of person newly infected while living in the community or in long-term care were estimated by using the ratio of hospital-to community-based source of infections observed in Manitoba: 64.2 to 35.8 [12]. In step 3, the province-specific numbers of infections were determined by adding in the estimated proportion of C difficile infections that were recurrent (0.271). Because of different definitions of time periods reported by different agencies, recurrent infections included both relapses (variously defined as within 4, 6, or 8 weeks of initial infection) and reinfections.

Stratification
The costs of treating C difficile depend on the severity of illness, location of treatment, and patient age. Severity was classified according to the Society for Healthcare Epidemiology of America-Infectious Diseases Society of America (SHEA-IDSA) guidelines definitions of mild-to-moderate, severe, and fulminant infection [11]. Estimates of the distribution of infections by severity were taken from the literature [21] and from the PHC Infection Prevention and Control program, which showed that 2.1% of hospital infections result in fulminant disease.
As a result of a lack of population-based Canadian data, the proportion of infections managed in hospital (53%) was based on data from the Rochester Epidemiology Project [22]. In the base case, the number of infections (n = 1605) managed in long-term care was imputed based on a recent US populationbased study [22].

Management and Resource Use
The frequency of tests among community-managed C difficile infections was estimated from the literature [23,24], and the severity-specific mean number of physician visits was elicited from clinical experts. Pharmacologic treatment was assumed to follow the SHEA-IDSA guidelines for hospitalized patients [11]. The costs of managing severe or recurrent C difficile infections in the community were based on 2011 data [25, Personal Communication with community pharmacist in Ontario, February 13, 2012].

Costs
Direct costs attributable included the following: laboratory tests, hospitalizations for other causes that were extended due to infection, rehospitalization due to infection, medication, surgical procedures, and physician visits (Appendix Table 1) [26,27]. Incremental costs of in-hospital resource use were estimated from the PHC Infection Prevention and Control dataset using a generalized linear regression model.
Estimates for lost productivity while in hospital were derived by multiplying the number of days in hospital attributable to C difficile infection by age-specific probabilities of being employed, of working full time, and by the 2012 mean daily wage rate [14].
Unit costs were inflated to 2012 Canadian dollars ($CAD) where necessary using the healthcare component of the Canadian consumer price index. Costs of infection control practices and of direct nonmedical resources were excluded.

Sensitivity Analyses
Key parameters were varied in sensitivity analyses. The proportion of infections managed in hospital was varied in sensitivity analyses, assuming the frequency of hospital treatment for C difficile infections was as high as 70% of all infections (based on clinical experts). In another sensitivity analysis, it was assumed that 7108 infections would be managed in long-term care based on recent population-based data from Canada and the United States (suggesting that 25% of cases originate from the long-term care, and that 10% of these require hospitalization) [12,22].
In the absence of robust data, a plausible range of number of infections was determined as ±10% of the base case. This number was derived as follows: Manitoba Health reported 831 hospital or community, initial or recurrent, C difficile infections over 2010-2012. Using the algorithm used here based on Canadian Nocosomial Infection Surveillance Program data, we calculated that 752 infections occurred in Manitoba over the same period, indicating that the algorithm underestimated the actual number of infections by 9%. To estimate a plausible range of direct costs, the PHC Infection Prevention and Control dataset was bootstrapped 1000 times; the generalized linear model was fit at each iteration, and the estimated cost was recorded. Costs were log transformed, and a log likelihood with Gamma link model was fit to the data. A confidence interval was then calculated from the 2.5th and 97.5th percentiles of the bootstrapped estimates [28]. A detailed description of the cost analyses is available upon request.  (Table 2) infections with C difficile was highest in Quebec, followed by Ontario, British Columbia, and Alberta. Of those in hospital, approximately 73% were new infections and 27% were recurrent, 61% were mild to moderate, and 54% occurred in those aged 75 years and older. Quebec had the highest total number of infections, followed by Ontario, British Columbia, and Alberta ( Figure 2).
Resource use and unit cost estimates are provided in Appendix Table 2. The largest component was the incremental hospitalization costs of C difficile infection, with an estimated mean of $11 930 for the initial episode and $15 330 for a recurrent episode. The largest portion of this difference was due to the longer mean number of hospital days attributable to C difficile for recurrent infections.
The economic burden was estimated to surpass CAD $280 million dollars ( plausible range, $254 to $309 million dollars), almost 90% of which was incurred in hospital (Table 3). Treating 5400 recurrent infections in the hospital was estimated to account for over $80 million. Four percent ($12 million) of the burden was incurred as direct medical costs in the community, and 4% ($10 million) was due to lost productivity.
The key inputs to which the model results were the most sensitive included the following (Table 4): (1) the length of stay in hospital attributable to C difficile, which resulted in a decrease in total costs of 40% when the mean number of days was reduced from 13.6 to 6.0; and (2) the ratio of hospital-based to community-based management, which resulted in an increase in total costs of 65% when the ratio changed from 53:47 to 70:30.

DISCUSSION
Management of hospital-acquired infections in Canada has been broadly characterized as "crisis-motivated" or "reactive", with an influx of resources when an outbreak becomes severe, such as the hypervirulent strain of C difficile in Quebec [31]. As such, most Canadian infection control programs do not meet expert recommendations with regards to investments in infection controls programs [32].
Applying reasonable assumptions to the limited existing Canadian data, there were an estimated 38 000 infections of C difficile infection in 2012 that, under conservative assumptions, cost CAD $280 million dollars to Canadian society. Extended hospital stays and rehospitalizations accounted for the lion's share-92%-of the total. The 37 932 number of cases we estimated in Canada in 2012 was approximately 8% of the 453 000 estimated in the United States in 2011 [33], and the Canadian cost estimate of $280 million was approximately 9% of the $3.2 billion dollars per year in the United States [34], with both estimates nearly proportionate to the population sizes. For context, the estimated $272 million in direct medical costs represents 0.1% of the CAD $207 billion spent on healthcare in Canada in 2012.
The annual burden of illness is likely increasing due to the aging demographics of the population, leading to increased numbers of patients at risk, and the indiscriminate use of both antibiotics and proton pump inhibitors. From an economic perspective, hospital managers are often allocated inadequate funding for infection control because of a failure in budgetary mechanisms [35], the decentralization of budgets and responsibility, or uncertainty over the benefits of infection control [36]. Inadequate staffing, lower standards of hygiene in healthcare facilities, privatization of cleaning services, and overcrowding in hospitals have also been suggested as reasons why the number of C difficile infections in Canada have increased [32]. This burden will also potentially be affected by changing diagnostic practices with the expansion of new and more sensitive assays [37]. Given the high costs of hospitalization, preventing recurrence of C difficile is likely to lead to the largest reduction in direct medical costs by avoiding readmissions to hospital. Interventions that have been shown to reduce recurrence include the following: infection control measures; [36] reduced use of proton pump inhibitors which has been inferred based on 1.4-to 2.7fold increase in risks of C difficile infections after observed use of these medications; [38] antimicrobial stewardship including removing concomitant systemic antibiotics and escalating antibiotic therapy when appropriate; [39] or the use of newly marketed antibiotics [13,40]. While the technical and allocative efficiency of such programs and therapies is not yet adequately characterized in Canada, those that have the highest reduction in recurrence are likely to offer the highest value for money.  This study has important limitations. First, by comparing against data reported from Manitoba with the algorithm developed here, we noted a 9% underestimate in the number of C difficile infections. If this was the case in all provinces, the results reported here would underestimate the actual burden. Second, the estimated incremental hospital costs may have been confounded by the fact that hospitalized patients with C difficile infection had more comorbid medical conditions and longer lengths of stay than uninfected hospitalized patients. This was addressed by developing additional statistical models to adjust for health status unrelated to C difficile infection using the PHC Infection Prevention and Control dataset (available upon request). Third, we assumed that treatment followed the SHEA-IDSA guidelines [11], recognizing that this likely underrepresented the variability in treatment patterns between facilities in Canada. Fourth, the impact of excluding emerging therapies such as fecal transplant was low because use of new therapies is still rare in Canada. Fifth, costs that were excluded because of lack of data included: (1) Infection prevention and control procedures and services in hospitals (specifically, staffing levels of nurses, doctors, and epidemiologists in the infection prevention and control team, the proportion of those persons' time spent on infection surveillance and control, and the actual implementation and monitoring of prevention and control strategies) were excluded. Although potentially substantial, it would be challenging to validly allocate a proportion of these costs to C difficile because these procedures and services focus on all hospital-acquired infections; (2) No adequate data exist on lost productivity or on other direct medical and non-medical costs (such as caregiver burden). Lost productivity costs are challenging to quantify in a population such as this, which tends to have high levels of comorbidity and advanced age, and few people are able to return to paid work once they leave hospital, which would mean that using mean age-specific employment rates would inflate estimates of economic impact. On the other hand, there are serious equity implications of valuing lost time only among employed persons. Additional data collected via a patient or caregiver survey would be of value to quantify the magnitude of this burden. Finally, there were other potential, less influential sources of misclassification such as the use of clinical experts other than Public Health Agency of Canada Working Groups, interprovincial differences in costs, and others. We are confident that the results using different values of resource utilization or costs from these sources would be contained within the results sensitivity analyses presented.

CONCLUSIONS
This study highlights gaps in understanding the epidemiology and burden of C difficile, including the frequency and management in the community, robust estimates of incremental length of stay attributable to the infection, and costs of infection prevention and control programs and services in hospitals. Future studies can incorporate the information presented here to estimate the value of information of new research [41]. Understanding the relationship between recurrence and total costs, as well as the interplay among in-hospital, nursing home, and community-based costs, is critical for evaluating efforts designed to minimize the burden of C difficile infection.