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STUDY DESIGN Systematic review OBJECTIVE.: The present review of clinical and preclinical in vivo studies focused on the local antibiotic administration for surgical site infection (SSI) in spinal fusion procedures and identifying new approaches or research direction able to release antibiotics in the infected environment. SUMMARY OF BACKGROUND DATA SSI is a severe complication of spinal fusion procedures that represents a challenging issue for orthopedic surgeons. SSIs can range from 0.7 to 2.3% without instrumentation up to 6.7% with the use of instrumentation with significant implications in health care costs and patient management. METHOD A systematic search was carried out by two independent researchers according to the PRISMA statement in three databases (www.pubmed.com, www.scopus.com and www.webofknowledge.com) in order to identify preclinical in vivo and clinical reports in the last ten years. Additionally, to evaluate ongoing clinical trials, three of the major clinical registry websites were also checked (www.clinicaltrials.gov, www.who.int/ictrp, https://www.clinicaltrialsregister.eu). RESULTS After screening, a total of 43 papers were considered eligible for the review: 36 clinical studies and 7 preclinical studies. In addition, six clinical trials were selected from the clinical registry websites. CONCLUSION The results reported that the topical vancomycin application seem to represent a strategy to reduce SSI incidence in spine surgery. However, the use of local vancomycin as a preventive approach for SSIs in spine surgery is mostly based on retrospective studies with low levels of evidence and moderate/severe Risk of Bias that do not allow to draw a clear conclusion. This review also underlines that several key points concerning the local use of antibiotics in spinal fusion still remains to be defined in order to allow this field to make a leap forward that would lead to the identification of specific approaches to counteract the onset of SSIs. LEVEL OF EVIDENCE 4.