Pancreaticoduodenectomy After Preoperative Biliary Drainage: A Single-Center Cohort Study of Piperacillin/Tazobactam Plus Fluconazole Prophylaxis and Infectious Outcomes

Background Pancreaticoduodenectomy (PD) is associated with high postoperative morbidity, particularly infectious complications. In patients undergoing preoperative biliary drainage (PBD), bile contamination is common and may lead to a mismatch between standard cephalosporin-based prophylaxis and biliary pathogens. Methods We conducted a retrospective single-center cohort study including 65 patients undergoing PD between December 2021 and May 2025. Of these, 42/65 (64.6%) underwent PBD. Patients received perioperative antibiotic prophylaxis with cefazolin or piperacillin/tazobactam plus fluconazole, according to institutional protocols. Intraoperative bile cultures were obtained in 44/65 patients, yielding 39 positive cultures with multiple isolates. Infectious complications and major morbidity (Clavien-Dindo > IIIA) were assessed. Multivariable logistic regression was performed to identify predictors of infectious complications, with subgroup analysis in drained patients. Results Positive bile cultures were observed in 38/42 (90.5%) drained patients compared with 1/23 (4.3%) non-drained patients (p<0.001). A total of 39 positive bile cultures yielded multiple isolates, including Enterococcus spp. in 24/39 (61.5%) cultures and Candida spp. in 10/39 (25.6%) cultures. Cefazolin did not provide coverage for at least one isolate in 30/39 (76.9%) cultures, compared with 13/39 (33.3%) for piperacillin/tazobactam plus fluconazole. In multivariable analysis restricted to drained patients, piperacillin/tazobactam plus fluconazole was independently associated with fewer infectious complications (odds ratio (OR): 0.13; 95% confidence interval (CI): 0.02-0.92; p=0.041). Conclusions In patients undergoing PD after PBD, bile contamination is frequent and characterized by enteric organisms and a relevant fungal component. Under these conditions, cefazolin prophylaxis shows a high rate of expected non-coverage, whereas piperacillin/tazobactam plus fluconazole provides broader microbiological coverage and is associated with reduced infectious complications. These findings support a tailored prophylactic strategy based on biliary colonization in PBD patients.