Can Local Antibiotics Replace Long Course Systemic Therapy in Fracture-Related Infection?

Purpose Fracture-related infection (FRI) is traditionally managed with surgery and prolonged systemic antibiotics. Shortening the duration of systemic therapy could reduce adverse events and improve antimicrobial stewardship. We hypothesized that local therapy could allow safe reduction in the duration of systemic antibiotics in FRI. Methods A multi-national, non-inferiority randomized controlled trial was conducted in patients with 2018 Consensus Definition confirmed FRI. All had local antibiotics implanted, in a licenced carrier, at the time of definitive surgery. Patients were randomized to either a short (≤7 days) or long (≥4 weeks) course of systemic antibiotics. Patients having DAIR were excluded from recruitment, as were those with systemic infections (endocarditis, bacteraemia etc.) requiring prolonged antibiotics and those with cultures fully resistant to the implanted local antibiotic. The primary outcome was treatment failure at 12 months, assessed by a blinded endpoint committee. The non-inferiority margin was 10%. Results 287 patients were randomized (71% male; mean age 52.4yrs). 277 were eligible for analysis at one year (136 short arm; 141 long arm). 58.5% had unhealed FRIs at surgery (FRI Classification types F2-F4). Staph. aureus was the most common pathogen (39.4%) and 20.2% were polymicrobial. FRI was most frequent in the tibia (119; 43%), followed by femur (59; 21.3%), upper limb (43; 15.6%) and ankle (27; 9.7%). Surgery was performed in a single stage, always with skin closure. 22.7% of patients required flap reconstruction and 162 (59%) had either new internal fixation or external fixation applied during the index surgery. Treatment failure occurred in 28 patients (10.1%) with 13/136 in the short arm (9.6%) and 14/141 in the long arm (10.6%)(Odds ratio 1.13; 95%CI 0.515-2.47). The non-inferiority margin was met. Length of hospital stay and adverse events, including antibiotic-associated events, were also reduced in the short arm (OR −28.0; −36.4 to −19.6). Multivariate analysis showed that polymicrobial infection and FRI of the ankle were associated with increased risk of failure in both groups (Odds ratio 3.1; 1.35-7.13 and 2.24; 0.98-6.48 respectively). Conclusion In the presence of antibiotics delivered locally in a carrier material, ≤7 days of systemic therapy is non-inferior to the current standard of care (≥4 weeks), in the management of confirmed FRI. Further work is now required to optimize the choice of local antibiotic, in order to maximize the number of patients who may benefit from shorter systemic therapy. Local treatment could provide a major improvement in antibiotic stewardship in FRI management.