1: Antimicrob Agents Chemother. 2006 Mar;50(3):841-51. 

Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics
against Staphylococcus aureus in a Model of THP-1 Macrophages.

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

Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de
Louvain, UCL 7370 Avenue E. Mounier 73, B-1200 Brussels, Belgium.

The pharmacodynamic properties governing the activities of antibiotics against
intracellular Staphylococcus aureus are still largely undetermined. Sixteen
antibiotics of seven different pharmacological classes (azithromycin and
telithromycin [macrolides]; gentamicin [an aminoglycoside]; linezolid [an
oxazolidinone]; penicillin V, nafcillin, ampicillin, and oxacillin
[beta-lactams]; teicoplanin, vancomycin, and oritavancin [glycopeptides];
rifampin [an ansamycin]; and ciprofloxacin, levofloxacin, garenoxacin, and
moxifloxacin [quinolones]) have been examined for their activities against S.
aureus (ATCC 25923) in human THP-1 macrophages (intracellular) versus that in
culture medium (extracellular) by using a 0- to 24-h exposure time and a wide
range of extracellular concentrations (including the range of the MIC to the
maximum concentration in serum [C(max); total drug] of humans). All molecules
except the macrolides caused a net reduction in bacterial counts that was time
and concentration/MIC ratio dependent (four molecules tested in detail
[gentamicin, oxacillin, moxifloxacin, and oritavancin] showed typical sigmoidal
dose-response curves at 24 h). Maximal intracellular activities remained
consistently lower than extracellular activities, irrespective of the level of
drug accumulation and of the pharmacological class. Relative potencies (50%
effective concentration or at a fixed extracellular concentration/MIC ratio)
were also decreased, but to different extents. At an extracellular concentration
corresponding to their C(max)s (total drug) in humans, only oxacillin,
levofloxacin, garenoxacin, moxifloxacin, and oritavancin had truly intracellular
bactericidal effects (2-log decrease or more, as defined by the Clinical and
Laboratory Standards Institute guidelines). The intracellular activities of
antibiotics against S. aureus (i) are critically dependent upon their
extracellular concentrations and the duration of cell exposure (within the 0- to
24-h time frame) to antibiotics and (ii) are always lower than those that can be
observed extracellularly. This model may help in rationalizing the choice of
antibiotic for the treatment of S. aureus intracellular infections.

PMID: 16495241 [PubMed - in process]