Peri-Operative Dosage and Therapeutic Concentrations of Cefazolin Administered for Surgical Site Infection Prophylaxis in Elective Surgery—A Systematic Review

<b>Background/Objectives</b>: Cefazolin is commonly administered for surgical antibiotic prophylaxis. This review aims to examine whether target unbound plasma and tissue cefazolin concentrations are reached following prophylactic administration across multiple surgical subtypes. The primary outcome was a lower limit of cefazolin concentration variability (mean-SD, lower quartile, or lower range) in unbound plasma and/or tissue > 2 mg·L^-1, the epidemiological cut-off (ECOFF) value for <i>Staphylococcus aureus</i> at skin incision and/or closure. <b>Methods</b>: Prisma 2020 guidelines were followed, and the protocol is registered in PROSPERO (CRD42021080289). A literature search using MEDLINE (PubMed), Embase, CENTRAL, CINAHL, and further databases was performed to identify studies in which prophylactic cefazolin was administered to adult surgical patients (≥18 years old) undergoing elective surgery, and unbound plasma and tissue concentrations were measured at skin incision and closure. Exclusion criteria included languages other than English, emergency surgery, cefazolin being administered for any reason other than surgical site prophylaxis, and whether patients received any cefazolin within the 48 h prior to the prophylactic dose. The search was repeated in August 2025 to ensure currency. A narrative assessment of the methodological quality was performed. The data were synthesised in a narrative and tabular form, and the certainty of the evidence was assessed using the GRADE approach. <b>Results</b>: A total of 37 studies with 1102 patients met the inclusion criteria. Twelve bariatric studies and 378 patients, 9 cardiac studies and 197 patients, 8 obstetric studies and 277 patients, 6 orthopaedic studies and 176 patients, 3 abdominal surgery studies and 62 patients, and 1 vascular study and 12 patients were included. Two studies met the inclusion criteria for both bariatric and abdominal surgery. The lower limit of variability of the unbound plasma concentration was consistently >2 mg·L^-1. The reported lower limits of variability in tissue concentrations of bariatric surgery were conflicting. Only one study in cardiac surgery assessed the current dosing regimens. The lower range of variability of tissue concentrations was consistently >2 mg·L^-1 in the orthopaedic, obstetric, abdominal, and vascular surgery subtypes. <b>Conclusions</b>: The current dosing approaches in the obstetric, orthopaedic, abdominal, and vascular surgery groups are reassuring for achieving effective concentrations, although the overall data are sparse. It is unclear if increased dosing is warranted in bariatric surgery patients, and further investigations in cardiac surgery with current dosing regimens are required.