OBJECTIVES: The prognosis of bone and joint infections (BJI) caused by Gram-negative bacilli (GNB) worsens significantly in the face of fluoroquinolone-resistance. In this setting, scarce pre-clinical and clinical reports suggest that intravenous beta-lactams plus colistin may improve outcome. Our aim was to assess the efficacy and safety of this treatment in a well-characterized prospective cohort. METHODS: Observational, prospective, non-comparative, multicenter (14 hospitals) study of adults with BJI caused by fluoroquinolone-resistant GNB treated with surgery and intravenous beta-lactams plus colistin for ≥ 21 days. The primary endpoint was the cure rate. RESULTS: Of the 44 cases included (median age 72 years [IQR 50-81], 22 [50%] women), 32 (73%) had an orthopedic device-related infection, including 17 (39%) prosthetic joints. Enterobacterales were responsible for 27 (61%) episodes, and Pseudomonas spp for 17 (39%), with an overall rate of MDR/XDR GNB infections of 27/44 (61%). Patients were treated with colistin plus intravenous beta-lactam for 28 days (IQR 22-37), followed by intravenous beta-lactam alone for 19 days (IQR 5-35). The cure rate (intention-to-treat analysis
median follow-up = 24 months, IQR 19-30) was 82% (95% CI 68%-90%) and particularly, 80% (95% CI 55%-93%) among patients managed with implant retention. Adverse events (AEs) leading to antimicrobial withdrawal occurred in 10 (23%) cases, all of which were reversible. Colistin AEs were associated with higher plasma drug concentrations (2.8 mg/L vs. 0.9 mg/L, p = 0.0001). CONCLUSIONS: Combination therapy with intravenous beta-lactams plus colistin is an effective regimen for BJI caused by fluoroquinolone-resistant GNB. AEs were reversible and potentially preventable by close therapeutic drug monitoring.