We estimated that C. difficile caused approximately 453,000 incident infections and was associated with approximately 29,000 deaths in the United States in 2011 on the basis of data from active population- and laboratory-based surveillance across diverse geographic locations in the United States. Persons 65 years of age or older, whites, and females had higher incidences than their comparators. This national estimate of C. difficile infection is higher than previous U.S. estimates (240,000 to 333,000) that relied on passive surveillance, data from health care facilities in a single state, administrative data, or data from managed-care populations in a specific region.23-25 However, comparisons with previous estimates are limited by differences in definitions of C. difficile infection and in analytical methods, especially the emergence of NAAT testing.

Only an estimated 24% of cases occurred in hospital settings, leading to an estimate of approximately 107,600 hospital-onset infections nationally. This number is higher than the 80,400 cases of hospital-onset infections that were recently reported from a point-prevalence survey conducted from May 2011 through September 2011 in the 10 EIP sites with the use of similar definitions.9 A possible explanation for this difference is the uptake of molecular testing for C. difficile diagnosis by hospital laboratories during 2011.5,19

According to our estimates, nearly 345,400 cases occurred outside of hospitals, indicating that the prevention of C. difficile infection should go beyond hospital settings. Although 46.2% of those cases were community-associated and by definition had no documented inpatient health care exposure, in a recent study that used the same surveillance program and sites but included earlier years of data, 82% of patients with community-associated C. difficile infection reported during telephone interviews that they had visited outpatient health care settings, such as a doctor's or dentist's office, in the 12 weeks before the collection of a C. difficile–positive stool sample.11 Therefore, most patients with C. difficile infection had either inpatient or outpatient health care exposures before disease onset. Finally, our adjusted national rate of community-associated infection of 51.9 per 100,000 population is higher than the rate of 20 to 40 per 100,000 population that was reported from population-based studies outside the United States that were conducted before the introduction of NAAT.26,27 However, it is possible that some of the cases detected by NAAT represent colonization rather than true infection, given that NAAT detects the presence of the organism but not necessarily if it is disease-causing and has high sensitivity.28,29 The rate of asymptomatic colonization in nonhospitalized adults is estimated to be 2%, with a higher rate, up to 26%, in those with health care exposures.30-32

Recurrence rates for health care–associated C. difficile infection have been reported to vary from 5% to 50%, with an average of 20%.33-35 In our study, at least one recurrence of C. difficile infection occurred in approximately 21% of cases of health care–associated infection and 14% of cases of community-associated infection on the basis of repeated stool testing between 14 and 56 days after the initial C. difficile episode, leading to an estimated burden of 83,000 first recurrent infections. These numbers are worrisome, given challenges in treating recurrent infections and the ongoing risk of transmission when symptoms recur.32,36,37

C. difficile is known to cause severe disease and death.2,3 The estimated total number of deaths within 30 days after the diagnosis of C. difficile infection nationally was 29,300, and the majority of these deaths were among patients with health care–associated infection. This number equated to an observed 30-day crude case fatality rate of 9.3% for patients with health care–associated infection, a rate that is similar to that reported in studies of hospitalized patients with C. difficile infection.38-40 Since the mortality that is attributable to C. difficile infection is estimated to be approximately 50% of the crude mortality,38 the total number of deaths in our study that would be attributable to C. difficile infection is about 15,000. The three most common strains we observed in both community-associated and health care–associated infection (NAP1, NAP4, and NAP11) are similar to the strains that have been reported in other countries.41,42 The NAP7 strain has been isolated from food and food animals and represented around 4% of the isolates in our collection; this finding is consistent with the prevalence observed in England (4%), but lower than the 8% prevalence reported from a hospital survey involving 34 European countries.43-46

Our analyses have several limitations. First, the case definition relied solely on positive results on C. difficile toxin or molecular assay because diarrhea is usually poorly documented in charts and existing guidelines for laboratory practice recommend C. difficile testing only on unformed stools.47,48 It has been documented that laboratories are adopting stricter policies to reject formed stools when transitioning to NAAT.19 Second, the type of C. difficile diagnostic test that is used has implications for measured disease incidence. Several studies have shown that laboratories transitioning to NAAT are expected to observe an increase in C. difficile incidence, which may partially represent overdiagnosis of C. difficile infection owing to a highly sensitive assay that does not distinguish between colonization and disease.5,6,19,28,29 Our estimates of incidence and disease burden were based on a rate of NAAT use of 52%, which was observed across the EIP sites. Although this rate may not be representative of the rate of NAAT use in the United States, a sensitivity analysis showed how the burden estimate varies on the basis of NAAT use (Fig. S1 in the Supplementary Appendix). Third, since we collected data on rates of recurrence and death in a random sample of cases, these rates may not be representative. In addition, our study underestimates both recurrence and mortality, given that we assessed only first recurrences and deaths that were documented in the medical record. It is likely that a subset of patients had multiple recurrences or died after discharge from the hospital or nursing home. Additional limitations are discussed in the Supplementary Appendix.

Despite these limitations, our national estimates are based on a large, longitudinal, U.S. population–based surveillance for C. difficile infection and on active laboratory case finding by trained personnel. Our results also support the growing evidence that C. difficile is no longer restricted to acute care settings. Thus, in the absence of a vaccine, future efforts to prevent C. difficile will cross health care settings and focus more on appropriate antibiotic use, which has been shown to be successful in decreasing rates of C. difficile infection in England, where a multifaceted program including antimicrobial stewardship was implemented.49 The prevention of C. difficile infection is a U.S. priority, with 2020 national reduction targets being established and all hospitals participating in the Hospital Inpatient Quality Reporting Program of the Centers for Medicare and Medicaid Services, which has reported data regarding C. difficile infection to the National Healthcare Safety Network since 2013.50,51

In conclusion, on the basis of active population- and laboratory-based surveillance across 10 U.S. geographic areas, we estimated that C. difficile caused almost half a million infections in the United States in 2011. An estimated 83,000 of the patients with such infections had at least one recurrence, and approximately 29,000 died within 30 days after the initial diagnosis. Continued surveillance for C. difficile infection will be needed to monitor progress toward prevention.