This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nguyen, H. A.
Right arrow Articles by Van Bambeke, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nguyen, H. A.
Right arrow Articles by Van Bambeke, F.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 2009, p. 1434-1442, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01145-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Intracellular Activity of Antibiotics in a Model of Human THP-1 Macrophages Infected by a Staphylococcus aureus Small-Colony Variant Strain Isolated from a Cystic Fibrosis Patient: Pharmacodynamic Evaluation and Comparison with Isogenic Normal-Phenotype and Revertant Strains{triangledown} ,{dagger}

Hoang Anh Nguyen,1 Olivier Denis,2 Anne Vergison,3 Anne Theunis,4 Paul M. Tulkens,1 Marc J. Struelens,2 and Françoise Van Bambeke1*

Université Catholique de Louvain, Louvain Drug Research Institute, Unité de Pharmacologie Cellulaire et Moléculaire,1 Hôpital Erasme, Department of Microbiology, Laboratoire de Référence MRSA-Staphylocoques,2 Hôpital des Enfants Reine Fabiola, Département de Maladies Infectieuses Pédiatriques,3 CHU Saint Pierre-Huderf-CHU Brugmann, Département Interhospitalier de Dermatologie, Université Libre de Bruxelles, Brussels, Belgium4

Received 26 August 2008/ Returned for modification 15 November 2008/ Accepted 17 January 2009

Small-colony variant (SCV) strains of Staphylococcus aureus show reduced antibiotic susceptibility and intracellular persistence, potentially explaining therapeutic failures. The activities of oxacillin, fusidic acid, clindamycin, gentamicin, rifampin, vancomycin, linezolid, quinupristin-dalfopristin, daptomycin, tigecycline, moxifloxacin, telavancin, and oritavancin have been examined in THP-1 macrophages infected by a stable thymidine-dependent SCV strain in comparison with normal-phenotype and revertant isogenic strains isolated from the same cystic fibrosis patient. The SCV strain grew slowly extracellularly and intracellularly (1- and 0.2-log CFU increase in 24 h, respectively). In confocal and electron microscopy, SCV and the normal-phenotype bacteria remain confined in acid vacuoles. All antibiotics tested, except tigecycline, caused a net reduction in bacterial counts that was both time and concentration dependent. At an extracellular concentration corresponding to the maximum concentration in human serum (total drug), oritavancin caused a 2-log CFU reduction at 24 h; rifampin, moxifloxacin, and quinupristin-dalfopristin caused a similar reduction at 72 h; and all other antibiotics had only a static effect at 24 h and a 1-log CFU reduction at 72 h. In concentration dependence experiments, response to oritavancin was bimodal (two successive plateaus of –0.4 and –3.1 log CFU); tigecycline, moxifloxacin, and rifampin showed maximal effects of –1.1 to –1.7 log CFU; and the other antibiotics produced results of –0.6 log CFU or less. Addition of thymidine restored intracellular growth of the SCV strain but did not modify the activity of antibiotics (except quinupristin-dalfopristin). All drugs (except tigecycline and oritavancin) showed higher intracellular activity against normal or revertant phenotypes than against SCV strains. The data may help rationalizing the design of further studies with intracellular SCV strains.

* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL73.70 avenue Mounier 73, 1200 Brussels, Belgium. Phone: 32 2 764 73 78. Fax: 32 2 764 73 73. E-mail: francoise.vanbambeke{at}uclouvain.be

{triangledown} Published ahead of print on 2 February 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1434-1442, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01145-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nguyen, H. A., Denis, O., Vergison, A., Tulkens, P. M., Struelens, M. J., Van Bambeke, F. (2009). Intracellular Activity of Antibiotics in a Model of Human THP-1 Macrophages Infected by a Staphylococcus aureus Small-Colony Variant Strain Isolated from a Cystic Fibrosis Patient: Study of Antibiotic Combinations. Antimicrob. Agents Chemother. 53: 1443-1449 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»