Background: This study aimed to evaluate the effectiveness of piperacillin-tazobactam as antibiotic prophylaxis in patients affected by a peri-ampullary tumor submitted to pancreatic surgery. Methods: A prospective, non-randomized, non-blinded, interventional study was conducted from January 2015 to March 2018. Patients were screened pre-operatively for Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL-PE). During the baseline period (January 2015-October 2016), surgical prophylaxis was performed with ampicillin-sulbactam. In the intervention phase (November 2016-March 2018), patients received piperacillin-tazobactam. Statistical analysis was performed by univariable and multivariable analysis with logistic regression models. Results: Overall, 383 patients were included in the baseline period and 296 in the intervention period. The surveillance strategy identified 47 ESBL-PE carriers (14%) in the baseline phase and 29 (10%) in the intervention phase. In the baseline period, the patients had a higher rate of hospital-acquired infection (43% versus 33%; p = 0.004), superficial surgical site infection (SSI) (11% versus 2%; p < 0.001), and pneumonia (16% versus 9%; p = 0.006). After the logistic regression, the baseline group had an odds ratio to develop superficial SSI and pneumonia of 7.7 (95% confidence interval [CI] 3-20) and 1.8 (95% CI 1-3.3), respectively. The ESBL colonization increased the mortality rate significantly (8% versus 3%; p = 0.017). Conclusions: Adopting antibiotic prophylaxis based on piperacillin-tazobactam is associated with a reduction in post-operative SSI, particularly superficial-SSIs. Further randomized studies would be warranted to evaluate this antibiotic combination more extensively in preventive strategies.

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