1. Antimicrob Agents Chemother. 2011 Apr;55(4):1443-52. Epub 2011 Jan 31.

Intra- and Extracellular Activities of Dicloxacillin and Linezolid against a
Clinical Staphylococcus aureus Strain with a Small-Colony-Variant Phenotype in an
In Vitro Model of THP-1 Macrophages and an In Vivo Mouse Peritonitis Model.

Sandberg A, Lemaire S, Van Bambeke F, Tulkens PM, Hughes D, von Eiff C,
Frimodt-Møller N.

National Center for Antimicrobials and Infection Control, Statens Serum Institut,
5 Artillerivej, Building 47/Room 201, DK-2300 Copenhagen S, Denmark. asa@ssi.dk.

The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been
associated with difficult-to-treat infections, reduced antimicrobial
susceptibility, and intracellular persistence. This study represents a detailed
intra- and extracellular investigation of a clinical wild-type (WT) S. aureus
strain and its counterpart with an SCV phenotype both in vitro and in vivo, using
the THP-1 cell line model and the mouse peritonitis model, respectively. Bacteria
of both phenotypes infected the mouse peritoneum intra- and extracellularly. The 
SCV phenotype was less virulent and showed distinct bacterial clearance, a
reduced multiplication capacity, and a reduced internalization ability. However, 
some of the SCV-infected mice were still culture positive up to 96 h
postinfection, and bacteria of this phenotype could spread to the mouse kidney
and furthermore revert to the more virulent WT phenotype in both the mouse
peritoneum and kidney. The SCV phenotype is therefore, despite reduced virulence,
an important player in S. aureus pathogenesis. In the THP-1 cell line model, both
dicloxacillin (DCX) and linezolid (LZD) reduced the intracellular inocula of
bacteria of both phenotypes by approximately 1 to 1.5 log(10) in vitro, while DCX
was considerably more effective against extracellular bacteria. In the mouse
peritonitis model, DCX and LZD were also able to control both intra- and
extracellular infections caused by either phenotype. Treatment with a single dose
of DCX and LZD was, however, insufficient to clear the SCVs in the kidneys, and
the risk of recurrent infection remained. This stresses the importance of an
optimal dosing of the antibiotic when SCVs are present.

PMID: 21282430 [PubMed - in process]