1: J Antimicrob Chemother 2003 May;51(5):1167-73
Influence of P-glycoprotein and MRP efflux pump inhibitors on the
intracellular
activity of azithromycin and ciprofloxacin in macrophages infected by
Listeria
monocytogenes or Staphylococcus aureus.
Seral C, Carryn S, Tulkens PM, Van Bambeke F.
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique
de
Louvain, UCL 73.70 Avenue E. Mounier 73, B-1200 Brussels, Belgium.
Antibiotic efflux pumps expressed in eukaryotic cells can decrease the
intracellular accumulation of the corresponding drugs and therefore
impair their
activity against intracellular bacteria. We have investigated whether
verapamil
(an inhibitor of P-glycoprotein) and gemfibrozil (an inhibitor of
multidrug
resistance proteins (MRP) and other organic anion transporters), can
modulate
the intracellular activity of azithromycin and ciprofloxacin against
Listeria
monocytogenes and Staphylococcus aureus in J774 macrophages. In
parallel, we
have measured the cell accumulation and subcellular distribution of
both drugs.
Antibiotics were used at equipotent extracellular concentrations (from
0.5 x to
10 x MIC) to allow for pharmacological comparisons. Azithromycin was
bacteriostatic against L. monocytogenes and slightly bactericidal
against S.
aureus. Verapamil did not improve the maximal activity of azithromycin
but
allowed it to reach a similar effect at extracellular concentrations
about
seven-fold lower in both models. Azithromycin was predominantly
localized in
cell granules (66%), the remainder being in the cytosol and in the
'nuclei/unbroken cells' fraction. Verapamil increased the cellular
accumulation
of azithromycin by almost 2.4-fold without modifying its subcellular
distribution. Ciprofloxacin displayed a strong concentration-dependent
bactericidal activity in both models. Gemfibrozil increased
ciprofloxacin
activity almost 2.5-fold against L. monocytogenes, but not against S.
aureus.
Ciprofloxacin was predominantly (65%) distributed in the cytosol.
Gemfibrozil
increased ciprofloxacin total accumulation by approximately 2.4-fold,
but the
excess was only found in the cytosol. Inhibition of efflux pumps may be
a useful
strategy to improve antibiotic efficacy against intracellular bacteria
when
increased accumulation can be obtained in the compartment where
bacteria
sojourn.
PMID: 12697643 [PubMed - in process]