Antibiotic Resistance Monitoring & Reference Laboratory, Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT, UK
Sir,
Susceptibility testing with linezolid ought to be straightforward, since its MIC distributions are narrow, spanning only three or four doubling dilutions. Nevertheless, interpretative problems arise because several agencies have proposed breakpoints of 2 mg/L (Table 1), whereas some workers find MICs of 4 mg/L for many staphylococci and enterococci, including even control strains.1,2 The potential for confusion is exacerbated, especially in surveys (where MICs are most likely to be determined), if a breakpoint of 2 mg/L is advocated but no method of susceptibility testing is specified (Table 1
). The present study examines the effects of different testing methods on the linezolid MICs found for Gram-positive cocci, assessing whether particular conditions or media might bias the MICs, and lead to high rates of artefactual resistance.
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Several recorded MIC ranges reached 4 mg/L and a modal MIC of 4 mg/L was recorded for S. aureus as tested by the NCCLS broth method. In previous studies using the BSAC method we have commonly found MICs of 4 mg/L for enterococci. A situation whereby MICs may exceed a 2 mg/L breakpoint (Table 1) contingent on the precise methodology or upon the single-dilution run-to-run variation conventionally accepted in susceptibility testing evidently is unsatisfactory both for the treatment of patients and the surveillance of resistance. Breakpoints of 4 mg/L, as now adopted by the BSAC and EUCAST, seem more appropriate, although caution may be warranted if an MIC of 4 mg/L is recorded by a laboratory that mostly finds MICs of 1 mg/L for the same species. A breakpoint of 4 mg/L is also supported by pharmacodynamic data, which indicate that a 600 mg dose of linezolid achieves a serum drug concentration >4 mg/L throughout the 12 h inter-dose interval. Finally, it should added that linezolid MICs for resistant E. faecium selected in therapy5 are reported to be 3264 mg/L, well above any of the breakpoints detailed in Table 1
.
Acknowledgements
We are grateful to Pharmacia Corp., Milton Keynes, for financial support.
Notes
* Corresponding author. Tel: +44-20-8200-4400; Fax: +44-20-8358-3292; E-mail: DLivermore{at}phls.nhs.uk
References
1
.
Johnson, A. P., Warner, M. & Livermore, D. M. (2000). Activity of linezolid, a novel oxazolidonone, against multi-resistant gram-positive bacteria. Journal of Antimicrobial Chemotherapy 45, 22530.
2 . Zurenko, G. E., Yagi, B. H., Schaadt, R. D., Allison, J. W., Kilburn, J. O., Glickman, S. E. et al. (2000). In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrobial Agents and Chemotherapy 40, 83945.[Abstract]
3 . British Society for Antimicrobial Chemotherapy Working Party. (1991). A guide to sensitivity testing. Journal of Antimicrobial Chemotherapy 27, Suppl. D, 150.[ISI][Medline]
4 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA.
5 . Gonzales, R. D., Schreckenberger, P. C., Graham, M. B., Kelkar, S., DenBesten, K. & Quinn, J. P. (2001). Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 357, 1179.[ISI][Medline]