Original Investigation 

Infectious Diseases

Antibiotic Use and the Risk of Hospital-Onset Clostridioides Difficile Infection

Mayan Gilboa, Gili Regev-Yochay, Eyal Meltzer, et al

JAMA Netw Open Published Online: August 8, 2025

2025;8;(8):e2525252. doi:10.1001/jamanetworkopen.2025.25252

Key Points

Question  What is the hazard of Clostridioides difficile infection (CDI) between asymptomatic carriers compared with noncarriers of C difficile, and is this hazard associated with antibiotic exposure?

Findings  In this cohort study of 33 756 hospitalizations among 23 001 patients, asymptomatic carriers had a higher hazard of CDI. Antibiotic exposure, particularly to amoxicillin and clavulanate and piperacillin and tazobactam, was associated with an increased hazard of CDI, especially among noncarriers, with no additional hazard among carriers.

Meaning  These findings suggest that while antibiotic stewardship may be associated with a reduced hazard of CDI in asymptomatic carriers given their already elevated hazard, additional strategies may be warranted.

Abstract

Importance  Clostridioides difficile is a leading cause of health care–associated infections. Understanding the association among C difficile carriage, antibiotic use, and infection hazard is essential for infection prevention.

Objective  To evaluate the hazard of C difficile infection (CDI) among asymptomatic carriers vs noncarriers of C difficile and whether it is associated with antibiotic exposure.

Design, Setting, and Participants  This retrospective cohort study conducted between June 18, 2017, and June 21, 2023, analyzed hospitalizations from Sheba Medical Center in Ramat Gan, Israel, which routinely screens for C difficile in high-risk patients admitted to internal medicine. Adult patients (aged >18 years) without active CDI at admission were included.

Exposure  Antibiotic exposure during hospitalization, including specific classes.

Main Outcomes and Measures  The primary outcome was the development of CDI, as confirmed by laboratory testing for C difficile. Antibiotic exposure was assessed as a time-varying variable.

Results  The study included 33 756 hospitalizations among 23 001 patients (median [IQR] age, 78 [68-87] years; 52.8% men). C difficile infection occurred in 67 of 1624 hospitalizations (4.1%) with positive screening results and in 47 of 32 132 hospitalizations (0.1%) with negative screening results. A positive C difficile screening result at admission was associated with a high hazard of infection (hazard ratio [HR], 27.5; 95% CI, 18.7-40.3). Antibiotic exposure was associated with an increased hazard for CDI (HR, 1.98; 95% CI, 1.24-3.16). Piperacillin and tazobactam showed the most pronounced hazard for CDI (HR, 2.18; 95% CI, 1.41-3.36). Among asymptomatic carriers, antibiotic exposure was not significantly associated with a further increase in CDI hazard (HR, 1.07; 95% CI, 0.73-1.58).

Conclusions and Relevance  In this cohort study, carriers of C difficile had a substantially higher baseline hazard for hospital-onset CDI. Antibiotic exposure was associated with an increased hazard among noncarriers but was not significantly associated with additional hazard among carriers. These findings suggest that while antibiotic stewardship may reduce CDI risk in noncarriers, additional strategies may be needed for carriers given their elevated baseline risk.