A pair of studies presented at Infectious Disease Week (IDWeek) 2025 Annual Meeting in Atlanta described the biggest risk factors for colonized patients progressing to infection in a single health system as well as the demographics of those who died from Clostridioides difficile infections in the US over the past quarter of a century.

Sustained exposure to high-risk antibiotics strongly predicted the likelihood that patients with C difficile colonization will progress to an infection. Following infection, White patients were at a greater risk for death from C difficile infections than Black or Hispanic patients.

The research presented overall “re-emphasized the fragility and lack of resiliency of microbiome integrity in patients known to be colonized with C difficile who are subjected to another health stress, especially systemic antibiotic use,” said Sean M. Anderson, MD, clinical fellow in infectious diseases at Johns Hopkins Medicine, Baltimore, who was not involved in either study but attended the session where they were presented.

“Leveraging knowledge of C difficile colonization status into clinical decision-making is a significant gray area in practice currently, even for experts in the field, given the lack of reproducible studies investigating regimens and outcomes of C difficile prophylaxis,” Anderson told Medscape Medical News. “The accumulation of scientific evidence such as presented here is critical for developing guidelines to improve patient care in this highly common, highly morbid infection.”

C difficile “remains a significant public health concern in the United States” that contributes to a “significant amount of mortality and morbidity, especially among the hospitalized patients and the elderly age groups,” Sohaib Asghar, MBBS, lead author of the CDC WONDER study and an internal medicine resident at AdventHealth Internal Medicine in Sebring, Florida, said in a press briefing ahead of the meeting.

“The findings of this study underscore the importance of sustained preventive strategies to further reduce the burden of this infection,” Asghar said. “What he found most striking from the findings was that those with the most access to healthcare were most prone to the disease.”

His analysis of 25 years of data from the CDC found that White patients made up 83.9% of deaths related to C difficile compared with 8.1% Black patients, 5.5% Hispanic patients, and 2.2% others. Other risk factors included being women, being hospitalized, and living in the US South.

“Traditionally we think that infections, especially healthcare-associated infections or wild infections like HIV and hepatitis, have social determinants, so we expect people who are getting infected or dying from these infections are usually from low socioeconomics or those people who have lesser access to healthcare utilization,” Asghar said during the briefing.

“However, in C diff, it’s actually the opposite,” Asghar said. “It’s the White population. They have more resources, they have more access to healthcare utilization, and they are more prone to being exposed to antibiotics or other risk factors” such as being in a nursing home.

Analysis of National CDC Data

Asghar and his colleagues used data from the CDC’s WONDER database to analyze all 216,311 deaths of people in the US of any age who had C difficile colitis as a primary diagnosis between 1999 and 2023. They found that more women (58.2%) than men (41.9%) died from C difficile, with deaths in metropolitan areas accounting for 83.8%, while 16.2% occurred in nonmetro areas.

The geographic region at the highest risk for death was the South, which bore 33.1% of deaths compared with 22.2% in the Northeast, 24.4% in the Midwest, and 20.3% in the West. However, after adjustment for age, mortality trends were highest in the Northeast region. States with the highest crude mortality rates, ranging, respectively, from 4.1 to 6.6 per 100,000 people, included Missouri, West Virginia, Vermont, Ohio, Maine, and Rhode Island, while states with the lowest mortality rates, ranging, respectively, from 0.77 to 1.6 per 100,000 people, were Hawaii, Alaska, Utah, Louisiana, Mississippi, and Georgia.

People in healthcare settings were most susceptible to C difficile deaths. The majority of deaths (71.2%) occurred in inpatients. Another 1.65% occurred in other medical facilities, while 15% occurred in nursing homes or long-term care, and 4.6% occurred in hospice facilities. Only 5.5% of deaths occurred in the patient’s home.

Mortality trends remained stable over time in nursing homes and long-term care facilities, but they increased for inpatients. Emerging antibiotic-resistant pathogens likely drove the upsurge in C difficile deaths seen between 2006 and 2015, Asghar said. Starting with a mortality rate of 0.5 per 100,000 people in 1999, it rose to 3.6 per 100,000 people in 2006 and remained there until 2016, when it began declining.

Among the factors that have helped contribute to that decline are the use of fidaxomicin and more effort spent on preventing recurrences by starting patients on stool microbiota transplants after their first recurrence, Asghar said.

“It’s very effective. It’s reducing their readmissions, it’s reducing the overall healthcare burden, and it’s also reducing the mortality, especially in the elderly group and especially those who are prone to develop fulminant C diff infection,” he said.

But he pointed to another major reason for the overall decrease in deaths.

“The gradual decline in the mortality rate is mostly attributed to improved infection and control practices and antimicrobial stewardship programs,” Asghar said. “The irrational use of antibiotics has been one of the most associated risk factors associated with C diff infection.”

High-Risk Antibiotic Use Still a Threat

The other study presented at the meeting underscored the continuing role of antibiotics in the progression of C difficile colonization to infection. Patients with C difficile colonization had nearly triple the odds of progressing to an infection if they were exposed for an extended period to high-risk antibiotics that include clindamycin, fluoroquinolones, and third- and fourth-generation cephalosporins, Sophia Chang, fourth-year medical student at Duke University School of Medicine, Durham, North Carolina, told attendees.

Chang and her colleagues conducted a retrospective case-control study of 2212 adults with C difficile colonization who underwent at least two two-step stool tests in the Duke University Health System between March 2020 and December 2023.

The researchers identified 71 cases of patients who progressed to infection — a positive nucleic acid amplification test (NAAT) and a positive result for the toxin enzyme immunoassay — and matched them to 133 controls who were NAAT+ and toxin-negative.

The patients were matched on the basis of date of index testing within a year, and the researchers compared patients’ demographic and clinical characteristics during the 90 days before index testing and a period of no more than 90 days between their index and repeat tests, considered the exposure period. The median exposure period was 28 days.

For both the preexposure and exposure periods, the researchers identified patients’ receipt of antibiotics as high risk (clindamycin, fluoroquinolones, and third- and fourth-generation cephalosporins), low risk (all other antibiotic classes), or none. Then they stratified the patients into patterns of cumulative antibiotic exposure (none-none, none-low, low-high, etc.).

One of the strongest predictors of progression to infection was receiving high-risk antibiotics in both the preexposure and exposure periods. Patients with this antibiotic exposure pattern had 2.7 greater odds of infection after adjusting for other characteristics (adjusted odds ratio [aOR], 2.7; P = .03).

“It was quite striking to note that over 80% of the case group who developed EIA+ [enzyme immunoassay] C diff infection received systemic antimicrobials during the study window, including over 60% who received a ‘high-risk’ antibiotic despite prior detection of C diff colonization,” Anderson said about the findings. “Oftentimes, the use of these agents is unavoidable and minimally substitutable in many contexts, but it emphasizes the importance of taking into account knowledge of prior C diff colonization into clinical decision-making.”

Other major risk factors included admission for a cardiovascular diagnosis during the exposure period (aOR, 6.5; P = .003), peptic ulcer disease (aOR, 5; P = .02), and a Charlson Comorbidity Index score ≥ 10 (aOR, 6.1; P = .01) compared with those with a CCI score of 0-2. The finding about peptic ulcer disease as a risk factor was new, Anderson told Medscape Medical News.

The study was limited by its small sample size, retrospective single-center design, and lack of data on illness severity or C difficile culture.

Nevertheless, the findings “reinforce the need for vigilant antimicrobial stewardship across the continuum of care, especially in high-risk populations,” Chang said. “The period following colonization represents a particularly critical window during which avoiding high-risk antibiotics may offer the greatest opportunity for targeted stewardship interventions.”

Anderson noted another limitation of the study that “a blanket classification of ‘NAAT+/EIA-’ patients as ‘colonized’ rather than active disease is difficult to justify given that the EIA test has been shown to only be approximately 60%-70% sensitive for detecting active C diff disease.” He acknowledged, however, that “this testing pattern is the best and most reproducible proxy we have for comparing presumed colonized patients with presumed active infection patients, especially for retrospective, her [electronic health record]-based studies.”

Asghar reported receiving support from the HIV Medicine Association and reported having no industry disclosures. Chang reported having no disclosures, and her research was funded by the Duke University School of Medicine Eugene A. Stead Student Research Scholarship. Anderson reported being a sub-investigator in Vedanta’s phase 3 clinical trial for VE303, a novel microbiome replacement therapy for recurrent C difficile infection, but for no financial compensation.

Tara Haelle is a science/health journalist based in Dallas.