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JAC Advance Access originally published online on September 13, 2006
Journal of Antimicrobial Chemotherapy 2007 59(6):1261-1264; doi:10.1093/jac/dkl380
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© The Author 2006. 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

Special section: Efflux

Intracellular accumulation of linezolid in Escherichia coli, Citrobacter freundii and Enterobacter aerogenes: role of enhanced efflux pump activity and inactivation

Anja Schumacher1, Rainer Trittler2, Jürgen A. Bohnert1, Klaus Kümmerer3, Jean-Marie Pagès4 and Winfried V. Kern1,*

1 Center for Infectious Diseases and Travel Medicine, University Hospital Hugstetter Strasse 55, D-79106 Freiburg, Germany 2 Pharmacy Service, University Hospital Hugstetter Strasse 55, D-79106 Freiburg, Germany 3 Institute of Environmental Medicine and Hospital Epidemiology Breisacher Strasse 115B, D-79106 Freiburg, Germany 4 EA2197—Enveloppe Bactérienne, Perméabilité et Antibiotiques, IFR48, Faculté de Médecine, Université de la Méditerranée F-13385 Marseille Cédex 05, France

Received 12 July 2006; returned 8 August 2006; revised 15 August 2006; accepted 21 August 2006

*Correspondence address. Medizinische Universitätsklinik, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Tel: +49-761-270-1819; Fax: +49-761-270-1820; E-mail: kern{at}if-freiburg.de

Objectives: The oxazolidinone class of antibiotics such as linezolid have a narrow spectrum of activity that targets Gram-positive bacteria. We hypothesized that the poor activity of linezolid in Gram-negative bacteria is in part caused by relatively low intracellular concentration due to efflux.

Methods: Using whole cell accumulation assays we estimated the intracellular concentration of linezolid in Escherichia coli and other Enterobacteriaceae. We included test strains with enhanced RND-type multidrug efflux pump activity and with genetic inactivation of the pump or functional inhibition by carbonyl cyanide m-chlorophenylhydrazone as inhibitor of the proton motive force or 1-(1-naphthylmethyl)-piperazine (NMP), an efflux pump inhibitor.

Results: Consistent with susceptibility studies, enhanced pump activity caused decreased accumulation, and pump inactivation and inhibition caused increased accumulation, of linezolid. The accumulation levels in test strains of E. coli, Citrobacter freundii and Enterobacter aerogenes with functional pumps were lower than in control strains of Staphylococcus aureus and Enterococcus faecium, but were higher after pump inactivation and correlated with ethidium bromide and pyronin Y accumulation.

Conclusions: The intracellular concentration of linezolid is comparatively low owing to efficient efflux of the drug and could be increased substantially by inhibition of RND-type efflux pumps.

Keywords: oxazolidinones , multidrug resistance , efflux pumps , Enterobacteriaceae


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