Abstract

The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited. To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery. This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were excluded for ineligibility. A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen. The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1 year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality. Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups. This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications. ClinicalTrials.gov Identifier: NCT01479283.

Highlights

  • Question Can a 5-day regimen of postoperative, prophylactic, intravenous antibiotics reduce the rate of surgical site infections in patients with a lower extremity bone tumor undergoing complex endoprosthetic reconstruction compared with a 1-day regimen?. In this randomized clinical trial including 604 patients in the primary analysis, the 5-day regimen did not reduce the rate of surgical site infection compared with the 1-day regimen, it resulted in a higher rate of antibiotic-related complications, notably Clostridioides difficile–associated colitis

  • Meaning The results of this study suggest that prolonging use of postoperative antibiotics beyond 1 day does not reduce the rate of surgical site infection but increases the risk of clinically significant antibiotic-related complications

  • Study Patients Of the 604 patients included in the final analysis, 293 were randomized to a 5-day regimen and 311 to a 1-day regimen

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Summary

Methods

Trial Design and Oversight This intention-to-treat study was an investigator-initiated, international, blinded (patients, surgeons, outcomes assessors, and data analysts), parallel, superiority randomized clinical trial. The rationale, design, and methods of the trial have been previously published.[10] Written informed consent was required to participate in the study, and all data were deidentified. Supplement 1 (the Trial Protocol) and Supplement 2 provide information on eligibility criteria, interventions, blinding, follow-up, outcomes definitions, and statistical analysis. The Hamilton Integrated Research Ethics Board as well as the relevant local ethics committee at each participating site approved the trial protocol and its amendments before local study initiation. The following regulatory bodies approved the trial protocol and its amendments: Health Canada, the Brazilian National Health Surveillance Agency, the European Medicines Agency (including the competent authorities in Austria and Spain), the Indian Council of Medical Research, and the Republic of South Africa’s Department of Health. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline

Results
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