Dual-route levofloxacin delivery following revision surgery: a synergistic intravenous/intra-articular strategy for enhanced bactericidal effect against prosthetic pseudomonas aeruginosa infections.

Abstract

Purpose: Pseudomonas aeruginosa (PA)-associated periprosthetic joint infection (PJI) is notoriously difficult to treat due to biofilm formation and poor antibiotic penetration into joint tissues. This study investigates the efficacy of combined intravenous (IV) and intra-articular (IA) levofloxacin administration in targeting PA biofilms in PJI.

Methods: A retrospective cohort of nine knee PJI patients received daily IV (500 mg) and IA (100 mg) levofloxacin post-revision surgery. Patients were followed for ≥2 years for their long-term clinical outcomes, with synovial and serum levofloxacin concentrations analyzed to assess minimum biofilm eradication concentration (MBEC) attainment. Physiologically based pharmacokinetic (PBPK) modeling simulated levofloxacin distribution in plasma, synovial fluid, and synovium. In vitro studies quantified biofilm biomass and metabolic activity reduction, while scanning electron microscopy (SEM) evaluated biofilm disruption on 3D-printed knee implants.

Results: Over two years, no patients required reoperation, experienced mortality, or needed ongoing antibiotic suppression. Daily living activities and Knee Society Scores improved, with no major adverse events. On postoperative day 7, synovial levofloxacin concentrations reached 110.20 ± 39.20 mg/L, exceeding the MBEC for 80% of PA isolates. Serum levofloxacin concentrations were measured at 1.76 ± 0.37 mg/L, showing only a marginal increase compared to the levels specified in FDA-approved labeling. In vitro, levofloxacin reduced biofilm biomass to 28.65 ± 5.12% and metabolic activity to 39.66 ± 4.28% of baseline. SEM confirmed reduced bacterial cell counts and disrupted biofilm structure on 3D printed implants. PBPK modeling demonstrated elevated levofloxacin concentrations in synovial fluid and synovium, with minimal systemic exposure.

Conclusions: Combined IV and IA levofloxacin effectively targets PA biofilms in PJI without significant safety concerns, offering a promising therapeutic strategy for PA-induced PJI.