title: Selection of linezolid-resistant Enterococcus faecium in an in vitro dynamic model: protective effect of doxycycline.
abstract: OBJECTIVE
  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.
authors.affiliation: Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.forename: Deborah
authors.initials: D
authors.lastname: Gilbert
authors.forename: Irene Yu
authors.initials: IY
authors.lastname: Lubenko
authors.forename: Kenneth
authors.initials: K
authors.lastname: Greer
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000502:physiology; D016984:Enterococcus faecium / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D000069349:Linezolid; D008826:Microbial Sensitivity Tests / Q000379:methods; D008954:Models, Biological; D023303:Oxazolidinones / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D023303:Oxazolidinones; D000069349:Linezolid; D004318:Doxycycline