Background/Objectives: The optimal duration of postoperative antibiotic therapy for bone and orthopaedic implant infections remains undefined. The SALATIO Trials are prospective randomised trials investigating whether shorter antibiotic courses are non-inferior to standard durations across different infection strata. This report presents the second interim analysis. Methods: Two unblinded non-inferiority RCTs were conducted (intention-to-treat population). Primary outcomes were remission, clinical failure, and microbiologically identical recurrence. In SALATIO 1 (material arm), participants with infected implants, retained or replaced during initial surgery, were randomised to short-course (six weeks) or long-course (twelve weeks) targeted systemic antibiotic therapy following debridement. In SALATIO 2 (non-material arm), participants undergoing implant removal or two-stage exchange were randomised to either a short-course (three weeks) or a long-course (six weeks) of antibiotic therapy. Results: We analysed 175 infections with a minimum follow-up period of one-year from October 2022 until July 2025: 69 (39%) in the material arm (38 short-course [55%], 31 long-course [45%]) and 106 (61%) in the non-material arm (44 short-course [42%], 62 long-course [58%]). No significant differences in clinical failure (19% overall) or microbiological recurrence (7%) were observed between treatment arms in either stratum. Multivariate analysis identified diabetes mellitus and number of debridements—but not antibiotic duration—as independent risk factors for clinical failure. Patients receiving short-course therapy experienced significantly fewer adverse events (median 0 versus 1; p=0.01). Formal non-inferiority has not yet been achieved due to limited statistical power. Conclusion: This interim analysis suggests no disadvantage of shorter antibiotic regimens in surgically treated orthopaedic infections, whilst reducing adverse events. Patient comorbidities and surgical factors appear to be more relevant to treatment outcomes than antibiotic duration. The SALATIO Trials are ongoing and may support improved antibiotic stewardship without compromising outcomes. Trials Registration: NCT05499481.

Background/Objectives: The optimal duration of postoperative antibiotic therapy for bone and orthopaedic implant infections remains undefined. The SALATIO Trials are prospective randomised trials investigating whether shorter antibiotic courses are non-inferior to standard durations across different infection strata. This report presents the second interim analysis. Methods: Two unblinded non-inferiority RCTs were conducted (intention-to-treat population). Primary outcomes were remission, clinical failure, and microbiologically identical recurrence. In SALATIO 1 (material arm), participants with infected implants, retained or replaced during initial surgery, were randomised to short-course (six weeks) or long-course (twelve weeks) targeted systemic antibiotic therapy following debridement. In SALATIO 2 (non-material arm), participants undergoing implant removal or two-stage exchange were randomised to either a short-course (three weeks) or a long-course (six weeks) of antibiotic therapy. Results: We analysed 175 infections with a minimum follow-up period of one-year from October 2022 until July 2025: 69 (39%) in the material arm (38 short-course [55%], 31 long-course [45%]) and 106 (61%) in the non-material arm (44 short-course [42%], 62 long-course [58%]). No significant differences in clinical failure (19% overall) or microbiological recurrence (7%) were observed between treatment arms in either stratum. Multivariate analysis identified diabetes mellitus and number of debridements—but not antibiotic duration—as independent risk factors for clinical failure. Patients receiving short-course therapy experienced significantly fewer adverse events (median 0 versus 1; p = 0.01). Formal non-inferiority has not yet been achieved due to limited statistical power; the current analysis includes 175 of the 280 episodes (62.5%) required for the final analysis. Conclusions: This interim analysis suggests no disadvantage of shorter antibiotic regimens in surgically treated orthopaedic infections, whilst reducing adverse events. Patient comorbidities and surgical factors appear to be more relevant to treatment outcomes than antibiotic duration. The SALATIO Trials are ongoing and may support improved antibiotic stewardship without compromising outcomes. Trials Registration: NCT05499481.