1. Antimicrob Agents Chemother. 2011 Feb;55(2):649-58. Epub 2010 Dec 6.

Contrasting Effects of Acidic pH on the Extracellular and Intracellular
Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and
Delafloxacin against Staphylococcus aureus.

Lemaire S, Tulkens PM, Van Bambeke F.

Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute,
Université Catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200
Brussels, Belgium. francoise.vanbambeke@uclouvain.be.

In contrast to currently marketed fluoroquinolones, which are zwitterionic,
delafloxacin is an investigational fluoroquinolone with an anionic character that
is highly active against Gram-positive bacteria. We have examined the effect of
acidic pH on its accumulation in Staphylococcus aureus and in human THP-1 cells, 
in parallel with its activity against extracellular and intracellular S. aureus. 
Moxifloxacin was used as a comparator. Delafloxacin showed MICs 3 to 5 log(2)
dilutions lower than those of moxifloxacin for a collection of 35 strains with
relevant resistance mechanisms and also proved to be 10-fold more potent against 
intracellular S. aureus ATCC 25923. In medium at pH 5.5, this difference was
further enhanced, with the MIC decreasing by 5 log(2) dilutions. In infected
cells incubated in acidic medium, the relative potency was 10-fold higher than
that at neutral pH and the maximal relative efficacy reached a bactericidal
effect at 24 h. These results can be explained by a 10-fold increase in
delafloxacin accumulation in both bacteria and cells at acidic pH, making
delafloxacin one of the most efficient drugs tested in this model. Opposite
effects were seen for moxifloxacin with respect to both activity and
accumulation. As reported for zwitterionic fluoroquinolones, delafloxacin was
found associated with the soluble fraction in homogenates of eukaryotic cells.
Taken together, these properties may confer to delafloxacin an advantage for the 
eradication of S. aureus in acidic environments, including intracellular

PMID: 21135179 [PubMed - in process]