Clostridioides difficile Infection in Hospitalised COVID-19 Patients: Antibiotic Exposure, Cardiovascular...

Background/Objectives: Clostridioides difficile infection (CDI) is an increasingly recognised nosocomial complication in patients hospitalised with coronavirus disease 2019 (COVID-19), driven by broad-spectrum antibiotic exposure, corticosteroid use, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related intestinal dysbiosis. The contribution of underlying cardiovascular comorbidities, particularly heart failure, to CDI susceptibility in hospitalised COVID-19 patients remains insufficiently characterised. We aimed to evaluate the prevalence, risk factors, and clinical impact of CDI in hospitalised COVID-19 patients at a tertiary Romanian infectious diseases centre, with a specific focus on cardiovascular disease and modifiable antimicrobial-prescribing factors. Methods: This single-centre retrospective observational cohort study enrolled 395 consecutive adult patients hospitalised with SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction (RT-PCR) at the "Victor Babeș" Clinical Hospital for Infectious Diseases and Pneumophthisiology, Timișoara, Romania, between 1 March 2020 and 31 December 2024. Patients were stratified into a CDI group (n = 24) and a non-CDI group (n = 371) on the basis of hospital-onset CDI. Demographic, clinical, laboratory, therapeutic, and outcome variables were extracted from electronic medical records. Continuous variables were compared using Student's independent-samples t-test, categorical variables using Fisher's exact test; odds ratios (ORs) with exact 95% confidence intervals (CIs) were computed for all binary comparisons, and a parsimonious multivariable logistic regression was used to adjust the antibiotic-exposure effect for age. Temporal relationships between CDI onset and sepsis documentation were also analysed. A two-sided p-value < 0.05 was considered statistically significant. Results: CDI was identified in 24 patients (prevalence 6.1%). The CDI and non-CDI groups were comparable in age (71.1 ± 10.2 vs. 71.7 ± 11.4 years; p = 0.817), sex distribution (50.0% vs. 45.8% female; p = 0.833), and vaccination status (p = 0.383). Heart failure prevalence did not differ between groups (29.2% vs. 26.7%; OR 1.13, 95% CI 0.46-2.81; p = 0.813). Any antibiotic therapy was strongly associated with CDI (95.8% vs. 70.6%; OR 9.57, 95% CI 1.28-71.74; p = 0.004), as was longer duration of antibiotic therapy (8.1 ± 2.2 vs. 5.2 ± 3.7 days; p < 0.001). In the multivariable model, each additional day of antibiotic therapy was independently associated with a 13.6% increase in the odds of CDI (adjusted OR 1.14 per day, 95% CI 1.03-1.26; p = 0.013) after adjustment for age. Piperacillin/tazobactam accounted for 65.2% (15/23) of the recorded pre-CDI broad-spectrum antibiotic regimens among antibiotic-exposed CDI patients. Documented sepsis was substantially more frequent in CDI patients (95.8% vs. 15.4%; p < 0.001) and length of hospitalisation was prolonged (15.6 ± 8.2 vs. 12.0 ± 8.1 days; p = 0.038). In-hospital mortality did not differ significantly (4.2% vs. 7.5%; p = 1.000). Conclusions: Hospital-onset CDI complicated 6.1% of hospitalised COVID-19 admissions and was independently associated with the cumulative duration of antibiotic therapy. Heart failure was not significantly associated with CDI in this cohort; however, given the limited number of CDI events, this should be interpreted as absence of evidence rather than evidence of absence. CDI was also associated with prolonged hospitalisation and high co-occurrence of documented sepsis, although causality cannot be inferred from the retrospective design. These findings support strengthened antibiotic stewardship and targeted CDI surveillance in COVID-19 inpatient wards.