Eijkman-Winkler Center, UMCU, Room G04. 614, PO Box 85500, 3508 GA Utrecht, The Netherlands
Received 4 February 2002; returned 3 April 2002; revised 22 April 2002; accepted 8 May 2002
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Abstract |
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Introduction |
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Oxazolidinones are the first truly novel class of antimicrobial agents to be developed over the last 30 years. They have the potential to meet some of the needs described above (e.g. activity against MRSA and vancomycin-resistant enterococci). The antibacterial activities of the oxazolidinones were first identified by DuPont.1 However, the clinical development of these early derivatives was discontinued. In the 1990s the class was re-investigated and linezolid and an analogue, eperezolid, were studied in detail.2 Linezolid was developed further following promising microbiology results3 and clinical trials, which showed that it has a broad activity against Gram-positive organisms.4 AZD2563, a new oxazolidinone, is currently in clinical development.
The purpose of this study was to define the in vitro activity of AZD2563 against a range of European Gram-positive cocci.
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Materials and methods |
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A total of 1543 Gram-positive isolates were collected in 27 European centres from 16 countries between 1998 and 2000. Each hospital was requested to send consecutive isolates deemed to be clinically relevant. The majority of isolates came from pneumonia, bloodstream, lower respiratory tract, wound and soft tissue infections; only one isolate per patient was permitted. Each isolate was identified at the referring hospital, and sent to the Eijkman-Winkler Institute, University Medical Center Utrecht, using Amies charcoal medium transport swabs (Difco, Chicago, IL, USA). Each isolate was accompanied by relevant data, including genus and species name, and method of identification. Upon receipt, isolates were subcultured on to blood agar to ensure purity. Isolate identity was confirmed, if necessary, using a Vitek system (bioMérieux, Marcy lÉtoile, France) and/or standard microbiological procedures. Isolates were stored at 70°C until further use using Microbank (Pro-Lab Diagnostics, Neston, Wirral, UK).
MIC testing
MIC testing was carried out according to NCCLS methodology.5 Microtitre plates with frozen antibiotic solutions were supplied by Trek Diagnostic Systems (Westlake, OH, USA). Plates with different antibiotic compositions were used for enterococcal, staphylococcal and streptococcal isolates. Plates were read using a semi-automated system supplied by Trek Diagnostic Systems.
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Results |
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One hundred and twenty-two MRSA isolates were compared with 179 methicillin-susceptible S. aureus (MSSA) isolates. Of the 98 Staphylococcus epidermidis isolates, 56% were resistant to methicillin, whereas 90% of the 51 Staphylococcus haemolyticus isolates and 34% of the 56 other coagulase-negative staphylococci tested were methicillin resistant. Among staphylococci, AZD2563 performed equally well or better (for S. aureus) against methicillin-resistant isolates compared with methicillin-susceptible isolates. MICs of AZD2563 ranged from 0.5 to 1 mg/L for MRSA compared with 0.5 to 4 mg/L for MSSA, but only one isolate had an MIC of 4 mg/L. S. epidermidis isolates, whether methicillin resistant or susceptible, showed MIC ranges of AZD2563 between 0.25 and 1 mg/L. For S. haemolyticus isolates and other coagulase-negative staphylococci, the MIC ranges were 0.252 and 0.122 mg/L, respectively. Among all groups of staphylococcal isolates, the distribution for MICs of AZD2563 was shifted by one or two dilution steps to lower values compared with linezolid.
The MICs of AZD2563 against pneumococci ranged from 0.12 to 2 mg/L. The MIC50 and MIC90 for all pneumococci and penicillin- or erythromycin-resistent pneumococci were identical (0.5 and 1 mg/L, respectively). Again, the MIC distribution for AZD2563 among pneumococcal isolates was shifted by one dilution step as compared with linezolid.
AZD2563 was also active against other streptococcal isolates, with no isolate displaying an MIC > 2 mg/L. Again, among all groups of streptococci tested the distribution of AZD2563 MICs was shifted by one to two dilution steps to lower values as compared with linezolid.
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Discussion |
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In summary, AZD2563 is a potent new oxazolidinone in vitro, with no isolate tested showing an MIC > 4 mg/L, and 94.4% having an MIC 2 mg/L. Compared with linezolid, the distribution of MICs for all groups and species of Gram-positive bacteria tested, with the exception of E. faecium, was shifted by one or two dilution steps to lower values for AZD2563. AZD2563 is a promising new antibiotic that should be further investigated for the treatment of infection caused by Gram-positive pathogens, including those that may present therapeutic difficulties owing to their resistance to the currently licensed antibiotic classes.
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Acknowledgements |
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Footnotes |
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References |
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2 . Ford, C. W., Hamel, J. C., Wilson, D. M., Moerman, J. K., Stapert, D., Yancey, R. J., Jr et al. (1996). In vivo activities of U-100592 and U-100766, novel oxazolidinone antimicrobial agents, against experimental bacterial infections. Antimicrobial Agents and Chemotherapy 40, 150813.[Abstract]
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Johnson, A. P., Warner, M. & Livermore, D. M. (2000). Activity of linezolid against multi-resistant Gram-positive bacteria from diverse hospitals in the United Kingdom. Journal of Antimicrobial Chemotherapy 45, 22530.
4 . Perry, C. M. & Jarvis, B. (2001). Linezolid: a review of its use in the management of serious Gram-positive infections. Drugs 61, 52551.[ISI][Medline]
5 . National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: M7-A5. NCCLS, Villanova, PA.
6 . Jones, R. N., Anderegg, T. R., Biedenbach, D. J. & Pfaller, M. A. (2001). In vitro antimicrobial activity of AZD2563, a novel oxazolidinone, tested against Staphylococcus aureus and coagulase-negative staphylococci. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1029, p. 224. American Society for Microbiology, Washington, DC, USA.
7 . Peric, M., Clark, C. L., Lin, G., Jacobs, M. R. & Appelbaum, P. C. (2001). Anti-pneumococcal activity of AZD2563, a new oxazolidinone, compared with nine other agents. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1032, p. 224. American Society for Microbiology, Washington, DC, USA.
8 . Eliopoulos, G. M., Wennersten, C. B. & Moellering, R. C., Jr (2001). Comparative in vitro activity of the new oxazolidinone, AZD2563, against enterococci. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1034, p. 225. American Society for Microbiology, Washington, DC, USA.
9 . Johnson, A. P., Warner, M., Parsons, T. & Livermore, D. M. (2001). In vitro activity of a novel oxazolidinone, AZD2563, against Gram-positive cocci, including diverse multi-resistant isolates. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1026, p. 223. American Society for Microbiology, Washington, DC, USA.
10 . Turner, P. J., Wookey, A., Greenhalgh, J. M., Clarke, J. & Eastwood, M. (2001). Investigations into the antibacterial spectrum of AZD2563 against recent clinical isolates from North America and Europe. In Program and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-1024, p. 222. American Society for Microbiology, Washington, DC, USA.