In this study, we evaluated risk factors for gram-negative fracture-related infection in a mixed cohort of gram-positive and gram-negative fracture-related infections to guide perioperative antibiotic prophylaxis for surgical fixation of fractures. We performed a retrospective review of all patients with fracture who were treated at an urban academic level I trauma center between February 1, 2012, and June 30, 2017. Inclusion criteria were as follows: (1) open or closed fracture with internal fixation; (2) deep, acute to subacute (<6 weeks), culture-positive fracture-related infection; and (3) age 18 years or older. Infections were classified as gram positive, gram negative, or polymicrobial. Demographic, surgical, and postoperative characteristics were compared among groups. Of 3360 patients, 43 (1.3%) had a fracture-related infection (15 gram negative, 14 gram positive, and 14 polymicrobial). Risk factors for gram-negative infection included initial external fixation (=.038), the need for soft tissue coverage of an open fracture site (=.039), lower albumin level at the time of infection (=.005), and hospitalization for longer than 10 days (=.018). Perioperative gram-negative antibiotic prophylaxis for fracture fixation surgery should be considered for those who have been staged with external fixation, require soft tissue coverage, are at risk for malnutrition in the postoperative period, and have prolonged inpatient hospitalization. [. 2022;45(2):91-96.].

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