1. Int J Antimicrob Agents. 2011 Jul;38(1):52-9. Epub 2011 May 18.

Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid
pH, towards extracellular and intracellular Staphylococcus aureus, Listeria
monocytogenes and Legionella pneumophila.

Lemaire S, Van Bambeke F, Tulkens PM.

Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200
Brussels, Belgium.

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

PMID: 21596526  [PubMed - in process]