25-Year US Analysis Links Most Fatal C difficile Cases to White Patients, Women, and Urban Care Settings

A 25-year national analysis presented at IDWeek 2025 found that deaths associated with Clostridioides difficile infection (CDI) in the United States were disproportionately concentrated among White patients, women, and people living in large metropolitan areas, and that most of these deaths occurred in healthcare settings.

Using Centers for Disease Control and Prevention (CDC) WONDER mortality data from 1999 to 2023, investigators identified 216,311 US deaths attributed to C difficile. White individuals accounted for 83.9% of CDI-related deaths, compared with 8.1% among African American/Black individuals and 5.5% among Hispanic individuals. Women accounted for nearly three-fifths (58.2%) of these deaths. According to the authors, these patterns challenge the usual expectation that severe outcomes from healthcare-associated infections fall disproportionately on racial and ethnic minority groups and patients with less access to care.

In a conversation with Contagion, Muhammad Sohaib Asghar, MBBS, MD, resident physician at AdventHealth Sebring and presenting author, discussed methods, drivers, and implications of the findings.

Contagion: How did you define a CDI-related death (underlying vs multiple-cause coding), and what steps did you take to minimize misclassification in CDC WONDER?

Asghar: We used CDC WONDER death-certificate data and ran analyses using both the underlying cause of death field and the multiple-cause fields (ie, any mention of C difficile on the certificate). The underlying-cause approach captures deaths directly attributed to CDI, while the multiple-cause approach is more sensitive for deaths in which CDI contributed but was not selected as the underlying cause. To minimize misclassification we:

(1) Included both approaches in sensitivity analyses and present both sets of rates where they diverged

(2) Used consistent ICD-10 codes for C difficile across years

(3) Restricted some analyses to ages and settings where coding is most reliable (for example, inpatient deaths)

(4) Examined temporal coding artifacts by comparing trends in the underlying-cause series to the multiple-cause series

These steps reduce but do not eliminate misclassification; death certificates systematically under-report contributors in some settings, so we interpret absolute counts cautiously and emphasize trends and relative differences. To bring things to perspective, 216,311 deaths were reported as multiple cause of death file analysis, and 59.75% of these deaths were directly attributed to C.Dif as underlying cause of death (n=129,237).

Contagion: What clinical or system factors might explain higher CDI mortality among White individuals, women, and residents of large metro areas, and how confident are you that this isn’t a denominator or coding artifact?

Asghar: Possible explanations are multifactorial. Clinical/system factors that can raise observed mortality in these subgroups include:

(A) Real differences in exposure to health-care settings and antibiotics (eg, higher hospitalization or antibiotic use patterns in some groups)

(B) Differences in age and comorbidity distributions (older or more comorbid populations have higher case-fatality)

(C) Access and patterns of care that alter where deaths occur (more deaths recorded in hospitals/long-term care in metro areas)

(D) Differential testing and coding practices across hospitals and jurisdictions that may increase detection/reporting in some populations

We tested for denominator/coding artifacts by age-adjusting rates, by comparing underlying vs multiple-cause results, and by inspecting geographic and facility-level (rural-urban) patterns; these checks reduced but did not eliminate the disparities, which suggests at least some of the pattern is real rather than purely a coding artifact. That said, residual confounding (eg, unmeasured comorbidities, differing testing thresholds) could account for part of the differences, so we remain cautious about causal claims. Since, this is an epidemiological relying solely on data provided by death certificates and diagnosis codes without any clinical data available, there will always be a chance of misrepresentation of the data.

Contagion: With most deaths in inpatient and long-term care, which infection-prevention and antimicrobial-stewardship practices most reliably reduce mortality today, and where are the largest implementation gaps?

Asghar: Practices with the strongest evidence for reducing CDI burden (and therefore deaths) are:

(1) Robust antimicrobial stewardship to limit unnecessary broad-spectrum antibiotics

(2) Strict contact-precautions and environmental cleaning (including sporicidal agents)

(3) Rapid diagnostic testing coupled with early isolation and appropriate therapy

(4) Use of first-line CDI therapies that reduce recurrences (IDSA now prefers fidaxomicin or oral vancomycin for initial episodes, as recurrence prevention lowers downstream mortality risk)

Large implementation gaps remain in many hospitals and long-term care facilities: inconsistent stewardship program resources, variable access to fidaxomicin (cost/coverage issues), lapses in environmental cleaning in high-turnover wards, and limited infection-prevention staffing in long-term care. Addressing these gaps—especially stewardship and access to therapies that prevent recurrence—will have the most immediate impact on mortality. With the recent emergence of readily accessible FDA-approved fecal microbiota transplant modes of administration, healthcare facilities should also rely more on preventing the recurrence of the disease, which significantly impacts the mortality.

Contagion: Mortality peaked in 2006–2015 and has since declined. How much reflects guideline changes, diagnostics, strain dynamics, or therapeutics, and what should clinicians prioritize now to sustain the decline?

Asghar: The decline is plausibly multifactorial. Key contributors likely include

(A) Improved infection-control awareness and programs after recurrent epidemics

(B) Maturation and spread of stewardship programs that reduced high-risk antibiotic exposures

(C) Shifts in diagnostic algorithms (some changes reduced overdiagnosis from sensitive PCR testing when used without clinical criteria)

(D) Therapeutic advances (wider use of vancomycin and, increasingly, fidaxomicin and adjuncts that reduce recurrence)

Strain dynamics (changes in the prevalence of hypervirulent strains) also likely played a role in the mid-2000s peak and later declines. It’s difficult to assign precise percentages to each driver from death-certificate data alone; however, the convergence of stewardship, guideline updates, better therapeutics, and uniform preventive efforts is the most plausible explanation. To sustain the decline, clinicians should prioritize strong antimicrobial stewardship (reduce unnecessary exposures), adherence to infection-prevention bundles (isolation, cleaning), prompt clinically directed testing (avoid testing asymptomatic patients), and use of treatments that minimize recurrence where appropriate (recognizing access/cost constraints). Continued surveillance for strain changes and equitable access to effective therapies are essential. The healthcare awareness should take place at the level of community with well-informed primary care providers about the recent advancements. The readily accessible modes of FDA-approved fecal microbiota transplant are a game-changer for long-term prevention of recurrence and hence will direct impact the mortality from the disease.

The analysis also characterized where and in whom CDI deaths occur. More than 8 in 10 CDI-related deaths (83.8%) occurred in and around large urban areas, compared with 16.2% in nonmetropolitan areas. Regionally, 33% of recorded deaths occurred in the south, followed by 24.4% in the midwest, 22.2% in the northeast, and 20.3% in the west; Rhode Island had the highest crude CDI mortality rate at 6.55 per 100,000. Most CDI deaths occurred in the same settings where patients were already receiving medical care: 71.2% of deaths occurred in hospital inpatients, and another 21.2% occurred in nursing homes, long-term acute care facilities, outpatient or emergency departments, or hospice. The authors said this pattern reinforces CDI as a healthcare-associated threat, particularly for older adults and medically complex patients with prolonged or repeated healthcare exposure.

Mortality trends over time showed a pronounced rise beginning in the mid-2000s, with CDI-related deaths climbing sharply starting in 2006 and staying elevated through 2015. The national CDI mortality rate increased from .5 per 100,000 people in 1999 to 3.6 per 100,000 in 2006 and remained at that level for nearly a decade. Investigators linked that increase to the spread of hypervirulent C difficile strains and increasing resistance to standard therapies, and noted that the rise was “especially profound” in White patients.

Since 2015, CDI mortality has declined across all census regions. The investigators attributed this downward trend to stronger infection prevention and control, broader antimicrobial stewardship programs to limit unnecessary antibiotic exposure, and advances in therapy such as fidaxomicin and fecal microbiota–based options. Fidaxomicin became the recommended first-line therapy for CDI in 2021 in Infectious Diseases Society of America guidance, reflecting a shift toward agents associated with lower recurrence risk. Asghar said these data “underscore the importance of sustained preventive strategies to further reduce the burden of this infection.

Reference

IDSA. New Analysis Reveals Racial and Other Demographic Differences in C. diff Deaths Over 25 Years. October 19, 2025. Accessed October 27, 2025. https://www.idsociety.org/news--publications-new/articles/2025/new-analysis-reveals-racial-and-other-demographic-differences-in-c.-diff-deaths-over-25-years