<i>In vitro</i> antibiofilm and intracellular activity of delafloxacin against <i>Staphylococcus aureus</i> and <i>Staphylococcus epidermidis</i> in bone and joint infections

Staphylococcal bone and joint infections (BJIs) represent significant challenges for treatment. Fluoroquinolone-based combination therapies, especially involving levofloxacin, are pivotal antimicrobials in their management. However, resistance to levofloxacin is prevalent in methicillin-resistant strains. Delafloxacin, a novel broad-spectrum fluoroquinolone, may offer a therapeutic alternative. This study aimed to investigate the <i>in vitro</i> antibiofilm and intracellular activities of delafloxacin in a bone context. The antibiofilm activity of delafloxacin was assessed using two pairs of levofloxacin-susceptible/resistant <i>Staphylococcus aureus</i> strains (6850-S/6850-R; Clin-S/Clin-R), as well as 10 clinical strains from BJI (<i>S. aureus</i>, <i>n</i> = 5; <i>Staphylococcus epidermidis</i>, <i>n</i> = 5). The 90% minimal biofilm eradication concentration (MBEC90) of delafloxacin was compared with that of rifampicin, vancomycin, and levofloxacin after a 24-h treatment of biofilm-embedded staphylococci. Additionally, the intracellular activity of delafloxacin and comparators was evaluated using the 6850-S/6850-R and Clin-S/Clin-R strains in an intraosteoblastic (MG-63) infection model. Delafloxacin showed significant activity against levofloxacin-susceptible staphylococci in planktonic (minimum inhibitory concentration [MIC]: [0.008-0.016] mg/L) and biofilm states (MBEC90: [0.008-0.064] mg/L), and inside osteoblasts (bacterial eradication at bone concentration: -75.0% for 6850-S and -34.8% for Clin-S), but a strain-dependent activity against levofloxacin-resistant staphylococci (MIC [0.032-8] mg/L), both in biofilm (MBEC90: [0.064->4] mg/L) and in the intracellular compartment (bacterial eradication at bone concentration: -63.6% for 6850-R and null for Clin-R). This study confirms the promising potential of delafloxacin to treat staphylococcal BJIs, but further investigations, including animal models and clinical trials, are needed to better understand its efficacy, particularly its variable effect against levofloxacin-resistant strains.IMPORTANCEStaphylococcal bone and joint infections (BJIs) represent significant challenges for treatment. Fluoroquinolones, especially levofloxacin, play a key role in their management; however, resistance to levofloxacin is common among methicillin-resistant strains. Delafloxacin, a novel broad-spectrum fluoroquinolone, may represent a therapeutic alternative, but very limited data are available regarding its clinical utility in BJIs. In this context, our study aimed to investigate the <i>in vitro</i> antibiofilm and intracellular activities of delafloxacin in a bone context, using both levofloxacin-susceptible and levofloxacin-resistant staphylococcal strains (<i>Staphylococcus aureus</i> and <i>Staphylococcus epidermidis</i>). Our results demonstrate a significant activity of delafloxacin against levofloxacin-susceptible staphylococci both in biofilm and within osteoblasts. However, its efficacy against levofloxacin-resistant strains was variable and appeared to be strain-dependent, both in biofilm and intracellular conditions. This study confirms the promising potential of delafloxacin to treat staphylococcal BJIs, but further investigations, including animal models and clinical trials, are needed to better understand its efficacy.