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Background: Superinfection is a new isolate pathogen after 48 h of antibiotic treatment or within one week of treatment discontinuation. In many studies carbapenem and piperacillin-tazobactam were associated with high risk of superinfection., Aim: To evaluate the rate of superinfections during carbapenem and piperacillin/tazobactam treatment. Also, to identify risk factors for superinfections., Methods: A Retrospective observational study was conducted in King Abdulaziz Medical City. Approval from the institutional Review Board was obtained. The study included all adult patient treated with carbapenem or piperacillin/tazobactam for more than 72 h. Univariate and multivariate analysis was conducted to compare piperacillin/tazobactam versus carbapenems and to identify the associated risk factor to develop superinfection., Finding: 507 patients were included in this study. The mean age of the patients was 61 years ± 19.33. Of these, 278 received carbapenems and 229 received piperacillin/tazobactam. In univariate analysis superinfections were significantly higher with carbapenems compared with piperacillin-tazobactam (28.77% versus 20.96%; P value = 0.044). After adjustment of cofounders in multivariate analysis, presence of tracheostomy, endotracheal ventilation, foley catheter and duration of antibiotic were associated with higher risk to developed superinfection adjusted odd ratio (aOR) 3.23 (95% CI,1.39-7.52) P < 0.01, aOR 2.556 (95% CI,1.30-5.02) P < 0.01, aOR 2.20 (95% CI,1.35-3.61) P < 0.001, aOR 1.051(95% CI,1.02-1.08) P < 0.001 respectively, but not carbapenems use aOR 1.052 (95% CI,0.657-1.685)., Conclusions: The use of carbapenems were not associated with higher risk to developed superinfection. The most important risk factors associated with superinfection were presence of tracheostomy, endotracheal mechanical ventilation, Foley catheter and the duration of antibiotics., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)