Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular , and

Sandrine Lemaire (1) , Françoise van Bambeke (1) , Paul M. Tulkens (1)

1 UCL - Université Catholique de Louvain = Catholic University of Louvain

Finafloxacin, an 8-cyano-substituted fluoroquinolone, expresses enhanced activity at acidic pH and is less susceptible to several fluoroquinolone resistance determinants. In this study, finafloxacin and ciprofloxacin were compared for (i) activity against ciprofloxacin-susceptible and -resistant as well as wild-type and Lde efflux-positive (Lde+) , (ii) accumulation in THP-1 macrophages and (iii) intracellular activity towards phagocytised , and (developing in acidic, neutral and mildly acidic environments, respectively), using a pharmacological approach assessing drug potencies and maximal relative efficacies (). Finafloxacin minimum inhibitory concentrations (MICs) were two-fold lower than those of ciprofloxacin against meticillin-susceptible ATCC 25923, were only modestly increased in an isogenic strain overexpressing NorA and were ≤0.25mg/L for community-acquired meticillin-resistant . No loss of activity was seen in Lde+ . An acidic pH decreased the MIC of finafloxacin and increased that of ciprofloxacin both for and , in parallel with corresponding changes in drug accumulation (tested with ATCC 25923 only). Finafloxacin accumulated less than ciprofloxacin in THP-1 cells, but the situation was reversed by exposure of cells to acid pH. In -infected cells, acid pH increased the potency of finafloxacin without change of , whilst decreasing the potency and the maximal relative efficacy of ciprofloxacin (less negative ). Finafloxacin was more potent and showed larger than ciprofloxacin against phagocytised , but was less potent against phagocytised . Finafloxacin appears to be an acid pH-favoured antibiotic that may find useful applications in infections where the local pH is low.

Mots clés: Fluoroquinolones; THP-1 macrophages; Acid pH; Intracellular

Domaines: Microbiologie et Parasitologie

Sandrine Lemaire, Françoise van Bambeke, Paul M. Tulkens. Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular , and. International Journal of Antimicrobial Agents, 2011, ⟨10.1016/j.ijantimicag.2011.03.002⟩. ⟨hal-00703149⟩