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JAC Advance Access originally published online on February 1, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):629-635; doi:10.1093/jac/dkm542
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© The Author 2008. 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

Selection of linezolid-resistant Enterococcus faecium in an in vitro dynamic model: protective effect of doxycycline

Stephen H. Zinner1, Deborah Gilbert2, Irene Yu. Lubenko3, Kenneth Greer2 and Alexander A. Firsov3,*

1 Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA 2 Roger Williams Medical Center, Providence, RI, USA 3 Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia

Received 11 October 2007; returned 17 December 2007; revised 16 November 2007; accepted 18 December 2007

* Corresponding author. Tel: +7-495-708-3341; Fax: +7-495-245-0295; E-mail: firsov{at}dol.ru

Objectives: To relate the enrichment of linezolid-resistant Enterococcus faecium with linezolid pharmacokinetics, the pharmacodynamics of linezolid and its ability to prevent the selection of resistant mutants were studied in an in vitro model that simulates antibiotic concentrations in and out of the mutant selection window (MSW), i.e. the concentration range from the MIC to the mutant prevention concentration (MPC).

Methods: A clinical isolate of E. faecium (MIC 1.8 mg/L and MPC 7 mg/L) at a starting inoculum of 8 log cfu/mL was exposed to twice-daily linezolid, alone and in combination with once-daily doxycycline (MIC 0.2 mg/L and MPC 3.4 mg/L), for 3 consecutive days in a hollow-fibre two-compartment model.

Results: The ratios of 24 h area under the curve (AUC24) to MIC of linezolid were estimated at 70, 100 and 230 h and those of doxycycline were estimated at 230 and 720 h. At the two lower AUC24/MIC ratios of linezolid given alone, E. faecium resistant to 2 x MIC–16 x MIC and 2 x MIC–8 x MIC of linezolid, respectively, were selectively enriched with a concomitant slight loss in susceptibility. Neither growth on linezolid-containing media nor changes in susceptibility occurred at the high AUC24/MIC ratio. A similar protective effect was observed with the minimal AUC24/MIC ratio of linezolid (70 h) combined with doxycycline at an AUC24/MIC of 230 h.

Conclusions: This study suggests that selection of linezolid-resistant enterococci can be predicted from the MSW concept and can be prevented by linezolid given in combination with doxycycline, each at suboptimal AUC24/MIC ratios.

Keywords: pharmacodynamics , resistant E. faecium , oxazolidinones , enterococci


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