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Antimicrobial Agents and Chemotherapy, July 2003, p. 2283-2292, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2283-2292.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Quantitative Analysis of Gentamicin, Azithromycin, Telithromycin, Ciprofloxacin, Moxifloxacin, and Oritavancin (LY333328) Activities against Intracellular Staphylococcus aureus in Mouse J774 Macrophages

Cristina Seral, Françoise Van Bambeke, and Paul M. Tulkens*

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

Received 19 August 2002/ Returned for modification 20 February 2003/ Accepted 17 April 2003

Using J774 macrophages, the intracellular activities of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) against Staphylococcus aureus (strain ATCC 25923) have been quantitatively assessed in a 24-h model. S. aureus was positively localized in phagolysosomes by confocal and electron microscopy, and extracellular growth was prevented with 0.5 mg of gentamicin/liter (1x MIC) in controls. When tested at extracellular concentrations equivalent to their maximum concentrations in human serum, all antibiotics except azithromycin caused a significant reduction of the postphagocytosis inoculum within 24 h, albeit to markedly different extents (telithromycin [2 mg/liter], 0.60 log; ciprofloxacin [4.3 mg/liter], 0.81 log; gentamicin [18 mg/liter], 1.21 log; moxifloxacin [4 mg/liter], 1.51 log; oritavancin [25 mg/liter], 3.49 log). Intracellular activities were not systematically related to drug accumulation (apparent cellular-to-extracellular concentration ratios in infected cells: ciprofloxacin, 3.2; gentamicin, 6.8; telithromycin, 8.7; moxifloxacin, 13.4; azithromycin, 50; oritavancin, 348). Intracellular activity was not directly correlated to extracellular activity as measured in broth. Conditions of pH 5 (i.e., mimicking that of phagolysosomes) markedly reduced the activity of gentamicin, azithromycin, and telithromycin (≥32x) and fairly extensively reduced that of ciprofloxacin and moxifloxacin (≥4x) but did not affect oritavancin activity. We conclude that the cellular accumulation of antibiotics is not the only parameter to take into account for intracellular activity but that local environmental conditions (such as pH) and other factors can also prove critical.

* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200 Brussels, Belgium. Phone: 32 2 7647371. Fax: 32 2 7647373. E-mail: tulkens{at}facm.ucl.ac.be.

Antimicrobial Agents and Chemotherapy, July 2003, p. 2283-2292, Vol. 47, No. 7
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.7.2283-2292.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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