Disk diffusion test interpretive criteria and quality control recommendations for testing linezolid (U-100766) and eperezolid (U-100592) with commercially prepared reagents

Abstract

Two new oxazolidinones were tested to determine interpretive susceptibility testing criteria for MIC and disk diffusion methods. Commercial lots of linezolid (formerly U-100766) and eperezolid (formerly U-100592) disks containing 30 microg of drug were tested against 728 isolates of bacteria with defined mechanisms of resistance. Results from linezolid were highlighted because of its choice for clinical development. By using preliminary pharmacokinetic data, a tentative susceptibility breakpoint of < or = 4 microg/ml was selected. Corresponding breakpoint zone diameters for linezolid were > or = 21 mm (< or = 4 microg/ml) for susceptibility and < or = 17 mm (> or = 16 microg/ml) for resistance. Regression statistics demonstrated a high correlation coefficient (r > or = 0.98), and absolute categorical agreement between methods was obtained, when staphylococci and enterococci were tested with the cited criteria. When Streptococcus spp. (including S. pneumoniae) were tested, only the susceptibility breakpoint was suggested. Quality control (QC) guidelines for linezolid disk diffusion tests were established by a multilaboratory trial as follows: 27 to 31 mm for Staphylococcus aureus ATCC 25923 and 28 to 34 mm for S. pneumoniae ATCC 49619. More than 95% of all QC results were within these proposed ranges. Although not advanced to clinical trials, eperezolid demonstrated potency comparable to that of linezolid and had identical interpretive testing criteria. These preliminary interpretive criteria and QC limits (accepted by the National Committee for Clinical Laboratory Standards) should be applied to linezolid tests during the clinical-trial phases of oxazolidinone drug development in order to ensure test accuracy and reproducibility.