Approximately 3% of hospitalized patients with community-acquired bacterial pneumonia (CABP) develop healthcare-associated Clostridioides difficile infection (HCA-CDI). The validated Davis risk score (DRS) indicates that patients with a DRS ≥ 6 are at an increased risk of 30-day HCA-CDI. In the phase 3 OPTIC CABP study, 14% of CABP patients with DRS ≥ 6 who received moxifloxacin developed CDI vs. 0% for omadacycline. This study assessed the potential economic impact of substituting current guideline-concordant CABP inpatient treatments with omadacycline in hospitalized CABP patients with a DRS ≥ 6 across US hospitals. A deterministic healthcare-decision analytic model was developed. The model population was hospitalized adult CABP patients with a DRS ≥ 6 across US hospitals (100,000 patients). In the guideline-concordant arm, 14% of CABP patients with DRS ≥ 6 were assumed to develop an HCA-CDI, each costing USD 20,100. In the omadacycline arm, 5 days of therapy was calculated for the entire model population. The use of omadacycline in place of guideline-concordant CABP inpatient treatments for CABP patients with DRS ≥ 6 was estimated to result in cost savings of USD 55.4 million annually across US hospitals. The findings of this simulated model suggest that prioritizing the use of omadacycline over current CABP treatments in hospitalized CABP with a DRS ≥ 6 may potentially reduce attributable HCA-CDI costs. The findings are not unique to omadacycline and could be applied to any antibiotic that confers a lower risk of HCA-CDI relative to current CABP inpatient treatments.