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JAC Advance Access originally published online on August 27, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):990-992; doi:10.1093/jac/dkp309
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Decreased linezolid uptake in an in vitro-selected linezolid-resistant Staphylococcus epidermidis mutant

J. M. Sierra1,*, M. Ortega1, C. Tarragó1, C. Albet1, J. Vila2, J. Terencio1 and A. Guglietta1

1 Pharmaceutical Research and Development Center, Ferrer International S.A., Barcelona, Spain 2 Department of Microbiology, CDB, Hospital Clínic de Barcelona, Spain

Received 30 April 2009; returned 15 June 2009; revised 3 August 2009; accepted 3 August 2009

* Corresponding author. Present address: Infectious Diseases Dptm., Hospital Clínic of Barcelona, Villarroel 170, Ed Helios, 08036 Barcelona, Spain. Tel: +34-93-227-5708; E-mail: jmsierra{at}clinic.ub.es

Objectives: The aim of this study was to characterize the mechanism of resistance to linezolid in an in vitro-selected linezolid-resistant Staphylococcus epidermidis mutant.

Methods: A linezolid-resistant strain of S. epidermidis was selected by serial passages with increasing concentrations of linezolid. The MICs of linezolid, ciprofloxacin, tetracycline, rifampicin, vancomycin, gentamicin, tobramycin, chloramphenicol and oxacillin were determined. The 23S rRNA gene was amplified and sequenced, to search for mutations conferring linezolid resistance. The MIC of linezolid was also determined in the presence of reserpine. Finally, the accumulation of linezolid was measured and quantified by HPLC/UV.

Results: The obtained resistant strain had an MIC of linezolid of 64 mg/L and was stable after several passages on blood agar. The MIC measured in the presence of 25 mg/L reserpine, an efflux pump inhibitor, was not altered (MIC of 64 mg/L). The sequence of the 23S rRNA gene showed that the mutation G2576T (Escherichia coli numbering) was not present and no other mutation was found. An analysis of the accumulation of linezolid was performed, comparing the uptake of the resistant strain with that of the susceptible one. This showed that the resistant strain had significantly lower levels of linezolid accumulation than its susceptible parental strain.

Conclusions: The mechanism of resistance to linezolid, in this resistant strain, may be related to a decrease in the antimicrobial uptake. This new mechanism of resistance was also related to a little loss of fitness.

Keywords: accumulation , antimicrobial resistance , staphylococci , oxazolidinones


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