Journal of Antimicrobial Chemotherapy (2001) 47, 77-81
© 2001 The British Society for Antimicrobial Chemotherapy
Brief report |
In vitro activity of linezolid against multiply resistant Gram-positive clinical isolates
Servicio de Microbiología, Hospital General Universitario ‘Gregorio Marañón’, Dr Esquerdo 46, 28007 Madrid, Spain
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Abstract |
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The in vitro activity of the oxazolidinone linezolid was compared with the activities of vancomycin and teicoplanin against 450 Gram-positive clinical isolates, including a variety of multiply resistant strains. Linezolid inhibited all microorganisms tested at
4 mg/L, including methicillin- and teicoplanin-resistant staphylococci, glycopeptide-resistant enterococci, penicillin- and multiply resistant pneumococci and viridans streptococci, and erythromycin-resistant ß-haemolytic streptococci. The MIC90 of linezolid for all isolates was 2 mg/L. |
Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The increasing prevalence of Gram-positive cocci that are resistant to antimicrobials has complicated the treatment of infections due to these microorganisms. The spread of methicillin-resistant staphylococci, and penicillin- and macrolide-resistant pneumococci, the emergence of glycopeptide-resistant enterococci and staphylococci, and the increasing emergence of erythromycin-resistant strains of Streptococcus pyogenes underline the need for therapeutic alternatives.1–3 Linezolid is the first of a new group of agents, the oxazolidinones, which are synthetic antibacterial compounds unrelated to other known antimicrobial agents.4 The oxazolidinones have a unique mechanism of action, and do not exhibit cross resistance with existing agents.5 Previous studies have demonstrated that linezolid is active against Gram-positive bacteria, including methicillin-resistant staphylococci and glycopeptide-resistant enterococci.6–9 In this study, we examined the in vitro activity of linezolid against recently obtained clinical isolates of staphylococci, enterococci, ß-haemolytic streptococci, pneumococci and viridans streptococci, including a variety of multiply resistant strains.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Bacterial strains
We tested a total of 450 non-duplicate clinical isolates obtained recently (1998–99) in our microbiology laboratory from blood, sterile fluids, respiratory samples, wounds, abscesses and urine, derived from both in- and outpatients. The isolates included 81 (50 methicillin-resistant) Staphylococcus aureus strains, 74 (46 methicillin-resistant and 15 methicillin- and teicoplanin-resistant) coagulase-negative staphylococci, 42 (17 vancomycin-resistant) Enterococcus faecalis strains, 65 (38 vancomycin-resistant) Enterococcus faecium strains, 91 (27 penicillin-intermediate, MIC 0.12–1 mg/L; and 45 penicillin-resistant, MIC 
2 mg/L) Streptococcus pneumoniae strains, 45 (17 penicillin-intermediate, MIC 0.25–2 mg/L; and 11 penicillin-resistant, MIC 4 mg/L) viridans streptococci strains, 34 (29 erythromycin-resistant) S. pyogenes strains and 18 (five erythromycin-resistant) Streptococcus agalactiae strains.
Determination of MICs
Linezolid was provided by Pharmacia & Upjohn, Inc. (Kalamazoo, MI, USA), vancomycin by Lilly Research Laboratories (Indianapolis, IN, USA) and teicoplanin by Hoechst-Marion-Roussel, Inc. (Cincinnati, OH, USA). Linezolid was tested at two-fold increasing concentrations ranging from 0.01 to 16 mg/L, and vancomycin and teicoplanin at concentrations ranging from 0.01 to 1024 mg/L. Susceptibility studies were performed by the broth microdilution method with cation-adjusted Mueller–Hinton broth (Oxoid, Unipath Ltd, Basingstoke, UK) supplemented with 5% lysed horse blood when necessary. The recommendations of the National Committee for Clinical Laboratory Standards (NCCLS) were followed to determine the MIC endpoints.10 Susceptibility to penicillin, ampicillin, oxacillin, cefotaxime and erythromycin was determined with commercial panels (Sensititre; AccuMed International Ltd, West Sussex, England) following the recommendations given by the manufacturers. Vancomycin and teicoplanin MICs 16 mg/L defined resistance. A projected breakpoint of 4 mg/L was used to define percentages of susceptibility for linezolid. S. aureus ATCC 29213, E. faecalis ATCC 29212 and S. pneumoniae ATCC 49619 were used as control strains. Isolates were stored at –70°C, with three subcultures being made before the organisms were tested. Following inoculation (final inoculum concentration, c. 5 x 105 cfu/mL), MIC trays were incubated at 37°C in ambient air for 24 h before examination.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Linezolid inhibited all isolates tested (450) at concentrations of between 0.12 and 4 mg/L (Table
). The MIC of linezolid at which 90% of the isolates were inhibited (MIC90) was 2 mg/L. The MIC90s of linezolid, vancomycin and teicoplanin for methicillin-resistant S. aureus were the same (2 mg/L). Linezolid was also very active against methicillin-resistant coagulase-negative staphylococci, including teicoplanin-resistant strains (MIC90, 2 mg/L). Linezolid was equally active against vancomycin-susceptible and -resistant enterococci: all enterococci (including 47 VanA and eight VanB) were inhibited at 2 mg/L. This compound had similar high activity against penicillin-susceptible and -resistant S. pneumoniae and erythromycin-resistant S. pneumoniae, although vancomycin was two- to four-fold more active than linezolid. With viridans streptococci the figures were similar, linezolid was equally highly active against penicillin-susceptible and -resistant and erythromycin-resistant streptococci, and the MICs of linezolid were comparable to those of vancomycin. This new compound was very active against S. pyogenes and S. agalactiae, including erythromycin-resistant strains (Table).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Linezolid is a new oxazolidinone that inhibits bacterial protein synthesis by selectively binding to the 50S ribosomal subunit.5 This study shows that the activity of linezolid against a variety of multiply resistant Gram-positive clinical isolates is excellent. In our study, linezolid showed good activity against methicillin-resistant S. aureus and coagulase-negative staphylococci. Previous studies have reported similar MIC results for staphylococci, with MIC90s of 4 mg/L and, as in our study, no differences in activities against methicillin-resistant and -susceptible strains.7,9 The emergence of glycopeptide-insensitive staphylococci represents a therapeutic challenge. In our study, all teicoplanin-resistant coagulase-negative staphylococci were inhibited by 2 mg/L of linezolid. The activity of linezolid against enterococci was independent of vancomycin susceptibility, and all vancomycin-resistant isolates were inhibited at concentrations of between 1 and 2 mg/L of linezolid. These results are consistent with those reported by other groups.6,8 Other Gram-positive cocci were also tested in order to assess the general efficacy of the compound, and to better define the utility of linezolid in the treatment of infections due these organisms in humans. The in vitro activity of linezolid against S. pneumoniae appeared to be independent of penicillin and cefotaxime resistance, and in any case the MICs of linezolid were >2 mg/L. Linezolid also exhibited excellent activity against erythromycin-resistant S. pneumoniae. This suggests a potential therapeutic option for the treatment of infections due to multiply resistant pneumococci. Other studies have shown MIC results similar to ours.4,8,9 This is, to our knowledge, the first study in which the activity of linezolid has been evaluated against multiply resistant viridans streptococci, and this compound seemed to be active against all isolates independent of penicillin, cefotaxime and erythromycin resistance. The increasing emergence of macrolide-resistant S. pyogenes is a cause of concern,1 and for patients allergic to ß-lactams, therapeutic alternatives are required. Linezolid could be an alternative in these situations since this compound was very active against erythromycin-resistant isolates of S. pyogenes and S. agalactiae.
Linezolid is a potent new antimicrobial uniformly active against methicillin- and teicoplanin-resistant staphylococci, glycopeptide-resistant enterococci, penicillin- and erythromycin-resistant pneumococci and viridans streptococci, and erythromycin-resistant S. pyogenes and S. agalactiae. The excellent in vitro activity against multiply resistant Gram-positive isolates and the absence of cross-resistance with other antimicrobials make linezolid a promising new drug.
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Acknowledgments |
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This study was presented in part at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 26–29 September 1999. This is a fully independent study that has not received financial support.
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Notes |
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* Corresponding author. Tel: +34-91-586-8459; Fax: +34-91-504-4906; E-mail: fgarrote{at}efd.net
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References |
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1 . Baquero, F., García-Rodríguez, J. A., de Lomas, J. G. & Aguilar, L. (1999). Antimicrobial resistance of 914 beta-hemolytic streptococci isolated from pharyngeal swabs in Spain: results of a 1-year (1996–1997) multicenter surveillance study. The Spanish Surveillance Group for Respiratory Pathogens. Antimicrobial Agents and Chemotherapy 43, 178–80.
2 . Moellering, R. C. (1992). Emergence of Enterococcus as a significant pathogen. Clinical Infectious Diseases 14, 1173–8.[Web of Science][Medline]
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Received 10 April 2000; returned 24 July 2000; revised 25 August 2000; accepted 2 October 2000
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