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Antimicrobial Agents and Chemotherapy, March 2006, p. 841-851, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.841-851.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Maritza Barcia-Macay, Cristina Seral,{dagger} Marie-Paule Mingeot-Leclercq, Paul M. Tulkens, and Françoise Van Bambeke*

Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, B-1200 Brussels, Belgium

Received 17 August 2005/ Returned for modification 30 October 2005/ Accepted 8 December 2005

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 [ß-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 [Cmax; 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 Cmaxs (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.

* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 7370 Avenue E. Mounier 73, B-1200 Brussels, Belgium. Phone: 32-2-764.73.78. Fax: 32-2-764.73.73. E-mail: vanbambeke{at}facm.ucl.ac.be.

{dagger} Present address: Department of Clinical Microbiology, University Hospital "Lozano Blesa," Zaragoza, Spain.

Antimicrobial Agents and Chemotherapy, March 2006, p. 841-851, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.841-851.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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