title: 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.
abstract: 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.
authors.affiliation: National Center for Antimicrobials and Infection Control, Statens Serum Institut, 5 Artillerivej, Building 47/Room 201, DK-2300 Copenhagen S, Denmark. asa@ssi.dk
authors.forename: Anne
authors.initials: A
authors.lastname: Sandberg
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lemaire
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.forename: Diarmaid
authors.initials: D
authors.lastname: Hughes
authors.forename: Christof
authors.initials: C
authors.lastname: von Eiff
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004009:Dicloxacillin / Q000494:pharmacology* / Q000627:therapeutic use*; D000089662:Doublecortin Protein; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D006801:Humans; D000069349:Linezolid; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D023303:Oxazolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D010538:Peritonitis / Q000188:drug therapy*; D010641:Phenotype; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D023303:Oxazolidinones; D004009:Dicloxacillin; D000069349:Linezolid