Journal of Antimicrobial Chemotherapy (2000) 45, 225-230
© 2000 The British Society for Antimicrobial Chemotherapy
Brief reports |
Activity of linezolid against multi-resistant Gram-positive bacteria from diverse hospitals in the United Kingdom
Antibiotic Resistance Monitoring and Reference Laboratory, Central Public Health Laboratory, Colindale, London NW9 5HT, UK
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
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The in vitro activity of linezolid, an oxazolidinone, was assessed against 374 Gram-positive cocci, with an emphasis on testing multi-resistant, epidemiologically unrelated isolates. MICs of linezolid for staphylococci, pneumococci and streptococci had a narrow range, from 0.5 to 2 mg/L, whereas MICs for enterococci were uniformly 4 mg/L. For all the species tested, the MICs of linezolid were unrelated to those of other antimicrobials. Linezolid appears to be a potentially useful drug for infections caused by Gram-positive cocci.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Antimicrobial resistance in Gram-positive bacteria is giving increasing cause for concern. Resistant organisms commonly encountered include methicillin-resistant Staphylococcus aureus (MRSA), ß-lactam- and macrolide-resistant pneumococci and glycopeptide-resistant enterococci.1 MRSA with intermediate glycopeptide resistance have been reported.2
Against this background, there is a clear need for new antimicrobial agents. One such drug is linezolid, an oxazolidinone,3 which is in Phase III clinical trials. The present study was undertaken to test the activity of linezolid against multi-resistant Gram-positive bacteria from UK hospitals, with an emphasis on testing diverse strains. To this end, isolates were chosen to include a variety of staphylococcal phage-types and streptococcal and pneumococcal serotypes from a wide geographical spread of hospitals.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Bacteria
The 374 isolates tested were selected by screening the database of organisms submitted to the Antibiotic Resistance Monitoring and Reference Laboratory for those with multiple resistance. Isolates of S. aureus, Streptococcus pneumoniae and streptococci of Lancefield groups A, B, C and G were further chosen to include a diversity of phage-types or serotypes while the isolates of all species were chosen to include a wide range of referring hospitals (Table I
). Duplicate isolates from the same patient were excluded.
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Sensitivity tests
MICs were determined on IsoSensitest agar (Oxoid, Basingstoke, UK) supplemented with either 5% lysed horse blood (TCS Microbiology, Buckingham, UK) for pneumococci, streptococci and enterococci or 2% lysed blood for staphylococci. The inocula comprised 104–105 cfu/spot, and incubation was for 18 h at 37°C in air, except when testing staphylococci with methicillin, when incubation was at 30°C for 48 h. Isolates were categorized as susceptible or resistant based on BSAC criteria.4
Statistical analysis
Statistical analysis was performed using the 
2 test.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Staphylococcus aureus
The 64 isolates of MRSA were from 51 hospitals and exhibited 33 different phage reaction patterns (Table I
). Nevertheless, 13 of the phage patterns were possible variants of that seen with EMRSA-16, while 19 isolates reacted with phage 75, which is characteristic of EMRSA-15. Among the MRSA isolates, 88% were resistant to erythromycin and 26% to gentamicin. Eighty-four per cent of the methicillin-sensitive S. aureus (MSSA), which were also from a wide range of hospitals and had a diversity of phage patterns (Table I), were resistant to penicillin, 32% to erythromycin and 10% to gentamicin. None of the staphylococci were resistant to glycopeptides or quinupristin/ dalfopristin and only two (both MRSA) were rifampicin resistant. Linezolid was equally active against MRSA and MSSA, with MICs of 1–2 mg/L for both groups (Table II).
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Enterococci
Enterococci were not typed (owing to a lack of discriminatory serotyping or phage-typing schemes), but were from a wide range of hospitals (Table I). Among the isolates of Enterococcus faecalis, 76% were resistant to vancomycin and 52% to teicoplanin; 48% had high level gentamicin resistance and 55% had high-level streptomycin resistance (MICs 
2048 mg/L). All were resistant to dalfopristin/ quinupristin. Among the Enterococcus faecium isolates, 85% were resistant to vancomycin, and 66% to teicoplanin; 54% and 59% had high-level resistance to gentamicin and streptomycin, respectively. With two exceptions, the isolates of E. faecium were susceptible to dalfopristin/ quinupristin, 4 mg/L. Resistance rates to rifampicin exceeded 60% for both species and those to erythromycin exceeded 90%. Three isolates of E. faecium were resistant to all the established agents tested except quinupristin/ dalfopristin and three E. faecalis isolates were resistant to all except ampicillin.
The seven isolates of Enterococcus gallinarum had low-level resistance to vancomycin (MICs 8–16 mg/L) but retained sensitivity to teicoplanin (VanC phenotype). One isolate was resistant to ampicillin (MIC 16 mg/L) and two had high-level resistance to streptomycin (Table II).
Linezolid showed extremely consistent anti-enterococcal activity, with MICs of 4 mg/L for all isolates, regardless of species and other resistances (Table II). Growth on plates containing linezolid at 1 mg/L was heavy, whereas growth with 2 mg/L of linezolid was sparse, indicating some inhibitory activity.
Streptococcus pneumoniae
The 17 penicillin-sensitive (pen-S) isolates comprised 13 serotypes, whereas the 36 penicillin-intermediate (pen-I) and 41 penicillin-resistant (pen-R) isolates comprised 13 and 11 serotypes, respectively (Table I). The pen-I isolates included three or more representatives of serotypes 6, 15, 19, 23 and the pen-R isolates included three or more representatives of serotypes 6, 9, 14, 19, 23.
Pen-I and pen-R isolates were more often resistant to cefotaxime, ciprofloxacin, erythromycin and tetracycline than were pen-S isolates (Table II). For example, 58% of the pen-R isolates were cross-resistant to cefotaxime, and rates of resistance to erythromycin were 6, 27 and 61% for pen-S, pen-I and pen-R isolates, respectively.
Linezolid was equally active against all the pneumococci irrespective of their penicillin resistance, with MICs in the range 0.5–2 mg/L (Table II). The proportion of isolates with MICs of linezolid of 2 mg/L was higher among pen-R than pen-S isolates (20% cf. 6%), but this excess was not statistically significant (P > 0.25).
Streptococci of Lancefield groups A, B, C and G
All isolates were sensitive to penicillin, glycopeptides and quinupristin/dalfopristin whereas resistance to erythromycin and tetracycline were widespread (Table II). Linezolid was uniformly active, with MIC50 and MIC90 values both of 2 mg/L (Table II).
Streptococcus oralis and Streptococcus sanguis
Linezolid was active against all the representatives of both species, with MICs in the range 0.5–2 mg/L. Moreover, it was equally active against isolates with resistance to penicillin, erythromycin or tetracycline as against isolates that were sensitive to these agents (Table II).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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In this study, linezolid was tested against multi-resistant Gram-positive bacteria from geographically diverse hospitals, thus minimizing the multiple inclusion of local epidemic strains. To further increase the likelihood of testing diverse strains, the staphylococci and streptococci were selected to include a range of phage-types and serotypes, respectively. There were nevertheless difficulties in this approach, as some strains, for example EMRSA 15 and 16, are so widespread in the UK5 that their over-representation was probably unavoidable. Similarly, much penicillin resistance in pneumococci is currently concentrated in a small number of serotypes.6
Linezolid was active against all the bacteria tested, with MICs in the narrow range 0.5–4 mg/L. Others have noted similarly narrow ranges, albeit with some variation in the actual values. Wise et al.7 found similar linezolid MICs to ourselves for pneumococci, streptococci and staphylococci, but lower MICs (mostly 1 mg/L) for enterococci. Conversely, Eliopoulos et al.8 generally found the MICs of linezolid to be 2–4 mg/L for enterococci. We cannot completely explain this variation, but note that in our study, enterococcal growth on the medium with 2 mg/L linezolid (i.e. the highest sub-inhibitory concentration) was very slight, though still discernible. When testing enterococci on the same medium with Etests, we typically find linezolid MICs of 2–4 mg/L, slightly below the present results but still above those found by Wise et al.7 Allowing for this variation and the pharmacokinetics of the drug, which give an average minimum serum concentration of 7.6 mg/L following oral administration of 400 mg every 8 h,9 we would support the tentative breakpoint of 4 mg/L proposed by Jones et al.10 in preference to the 2 mg/L value proposed by Wise et al.7
These results confirmed that there is no cross-resistance between linezolid and other agents that act by inhibiting protein synthesis, nor with cell-wall active agents. The activity of linezolid against diverse multi-resistant clinical isolates suggests that it has the potential to become a major therapeutic option for infections caused by Gram-positive organisms.
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Acknowledgments |
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This work was supported by a grant from Pharmacia & Upjohn Limited.
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Notes |
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* Corresponding author. Tel: +44-181-200-4400, ext. 4237; Fax: +44-181-200-7449; E-mail: ajohnson{at}phls.nhs.uk
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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1 . Johnson, A. P. (1998). Antibiotic resistance among clinically important Gram-positive bacteria in the UK. Journal of Hospital Infection 40, 17–26.[Web of Science][Medline]
2 . Hiramatsu, K. (1998). Vancomycin resistance in staphylococci. Drug Resistance Updates 1, 135–50.
3 . Ford, C. W., Hamel, J. C., Stapert, D., Moerman, J. K., Hutchinson, D. K., Barbachyn, M. R. et al. (1997). Oxazolidinones: new antibacterial agents. Trends in Microbiology 5, 196–200.[Web of Science][Medline]
4
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Working Party on Antibiotic Sensitivity Testing of the British Society for Antimicrobial Chemotherapy (1991). A guide to sensitivity testing. Journal of Antimicrobial Chemotherapy 27, Suppl. D, 1–50.
5 . British Society for Antimicrobial Chemotherapy, Hospital Infection Society and the Infection Control Nurses Association Working Party. (1998). Revised guidelines for the control of methicillinresistant Staphylococcus aureus infection in hospitals. Journal of Hospital Infection 39, 253–90.[Web of Science][Medline]
6 . George, R. C., Johnson, A. P., Speller, D. C., Efstratiou, A., Broughton, K. & Patel, B. C. (1997). Serogroups/types and antibiotic resistance of referred isolates of Streptococcus pneumoniae, 1993–1995. Communicable Disease Report CDR Review 7, R159–64.
7
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Wise, R., Andrews, J. M., Boswell, F. J. & Ashby, J. P. (1998). The in-vitro activity of linezolid (U-100766) and tentative breakpoints. Journal of Antimicrobial Chemotherapy 42, 721–8.
8 . Eliopoulos, G. M., Wennersten, C. B., Gold, H. S. & Moellering, R. C., Jr. (1998). In vitro activities of new oxazolidinone antimicrobial agents against enterococci. Antimicrobial Agents and Chemotherapy 40, 1745–7.[Abstract]
9 . Stalker, D. (1998). Linezolid pharmacokinetics. In Abstracts of Symposium on Oxazolidinones: the Second European Congress of Chemotherapy, Hamburg, Germany 1998.
10 . Jones, R. N., Johnson, D. M. & Erwin, M. E. (1996). In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones. Antimicrobial Agents and Chemotherapy 40, 720–6.[Abstract]
Received 26 May 1999; returned 9 September 1999; accepted 23 September 1999
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