1: Antimicrob Agents Chemother. 2009 Apr;53(4):1434-42. Epub 2009 Feb 2.

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.

Nguyen HA, Denis O, Vergison A, Theunis A, Tulkens PM, Struelens MJ, Van Bambeke 

Louvain Drug Research Institute, Unité de Pharmacologie Cellulaire et
Moléculaire, Université Catholique de Louvain, Brussels, Belgium.

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.

PMCID: PMC2663071 [Available on 2009/10/01]
PMID: 19188393 [PubMed - in process]

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