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Background Guidelines for perioperative antibiotic prophylaxis in lung transplantation (LT) are limited; since Pseudomonas colonization has been linked to acute graft rejection and development of bronchiolitis obliterans syndrome, some centers utilize an anti-pseudomonal β-lactam as part of the surgical prophylaxis regimen. Internal data from our large academic medical center, a center that does not frequently transplant cystic fibrosis patients, identified low rates of Pseudomonascolonization and infection in LT patients. The surgical prophylaxis regimen was therefore narrowed from vancomycin/piperacillin–tazobactam (VPT) in 2013 to vancomycin/ceftriaxone (VCT). The purpose of this study was to examine the protocol change to on the incidence of Pseudomonas isolation in the post-operative period for lung transplant recipients. Methods This was a single-center, retrospective quasi-experimental before-after study of lung transplant recipients from July 2006 to February 2017 comparing patients who received VPT to VCT for surgical prophylaxis. Patients receiving other surgical prophylaxis regimens due to allergy or colonization history were excluded. Donor and recipient culture data from bronchoscopy samples were collected to determine the incidence of Pseudomonas in the 14-day post-transplant period. The secondary outcome was the incidence of post-transplant CDC-defined pneumonia. Statistical analysis was performed using SAS 9.4 (Cary, NC). Results One hundred patients were included in the pre-protocol group (VPT), and 65 in the post-protocol group (VCT). Pseudomonas was recovered in recipient BALs on post-op day 2–14 in 8 (8%) patients in the VPT group compared with 5 (7.7%) patients in the VCT group (P = 1.0). Mean time to Pseudomonas isolation was 8.4 days in the VPT group compared with 5.4 days in the VCT group. Incidence of pneumonia on post-op day 2–14 was 6% in the VPT group vs. 3% in the VCT group (P = 0.48). Surgical site infections were rare in the VCT group with an incidence of 1.5% (1/65). Conclusion Isolation of Pseudomonas was rare in both time periods and an increase was not detected when anti-pseudomonal coverage was removed from the surgical prophylaxis regimen. Safe deescalation of surgical prophylaxis regimens are an important antimicrobial stewardship initiative. Disclosures E. Heil, ALK-Abelló: Grant Investigator, Research grant.