1: J Antimicrob Chemother. 2005 Apr;55(4):511-7. Epub 2005 Feb 24. 

Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin
and garenoxacin) against extracellular and intracellular infection by Listeria
monocytogenes and Staphylococcus aureus in J774 macrophages.

Seral C, Barcia-Macay M, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F.

Unite de pharmacologie cellulaire et moleculaire, Universite catholique de
Louvain, Brussels, Belgium.

OBJECTIVES: Quinolones accumulate in eukaryotic cells and show activity against
a large array of intracellular organisms, but systematic studies aimed at
examining their pharmacodynamic profile against intracellular bacteria are
scarce. The present work aims at comparing intracellular-to-extracellular
activities in this context. METHODS: We assessed the activities of
ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin against the
extracellular (broth) and intracellular (infected J774 macrophages) forms of
Listeria monocytogenes (cytosolic infection) and Staphylococcus aureus
(phagolysosomal infection) using a range of clinically meaningful extracellular
concentrations (0.06-4 mg/L). RESULTS: All four quinolones displayed
concentration-dependent bactericidal activity against extracellular and
intracellular L. monocytogenes and S. aureus for extracellular concentrations in
the range 1-4-fold their MIC. Compared at equipotent extracellular
concentrations, intracellular activities against L. monocytogenes were roughly
equal to those that were extracellular, but were 50-100 times lower against S.
aureus. Because quinolones accumulate in cells (ciprofloxacin, approximately 3
times; levofloxacin, approximately 5 times; garenoxacin, approximately 10 times,
moxifloxacin, approximately 13 times), these data show that, intracellularly,
quinolones are 5-10 times less potent against L. monocytogenes (P=0.065
[ANCOVA]), and at least 100 times less potent (P < 0.0001) against S. aureus.
Because of their lower MICs and higher accumulation levels, garenoxacin and
moxifloxacin were, however, more active than ciprofloxacin and levofloxacin when
compared at similar extracellular concentrations. CONCLUSIONS: Quinolone
activity is reduced intracellulary. This suggests that either only a fraction of
cell-associated quinolones exert an antibacterial effect, or that intracellular
activity is defeated by the local environment, or that intracellular bacteria
only poorly respond to the action of quinolones.

PMID: 15731197 [PubMed - in process]