Comparative activity of linezolid and other new agents against methicillin-resistant Staphylococcus aureus and teicoplanin-intermediate coagulase-negative staphylococci
Carmen Betriu,*,
Montserrat Redondo,
Ana Boloix,
María Gómez,
Esther Culebras and
Juan J. Picazo
Department of Clinical Microbiology, Hospital Clínico San Carlos, Plaza Cristo Rey s/n, 28040 Madrid, Spain
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Abstract
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The activity of linezolid was determined against 225 recently isolated methicillin-resistant Staphylococcus aureus (MRSA) and 20 methicillin-resistant coagulase-negative staphylococci (CoNS) with decreased levels of susceptibility to teicoplanin. Linezolid activity was compared with other new agents (quinupristindalfopristin, trovafloxacin, moxifloxacin, levofloxacin and telithromycin) and six other antimicrobials (erythromycin, clindamycin, gentamicin, vancomycin, teicoplanin and rifampicin). The in vitro activity of linezolid was similar to that of vancomycin. Linezolid inhibited all MRSA strains at between 0.1 and 2 mg/L and all CoNS strains tested at between 0.2 and 0.5 mg/L. These results suggest that linezolid would be useful for the treatment of infections involving these organisms.
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Introduction
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Over the last two decades, the increasing incidence of methicillin-resistant staphylococci has caused significant clinical concern worldwide. Methicillin resistance in Staphylococcus aureus, as well as in coagulase-negative staphylococci (CoNS) is also associated with resistance to several commonly used antimicrobial agents such as the macrolides, lincosamides, quinolones, trimethoprimsulfamethoxazole and aminoglycosides. Glycopeptides have traditionally been considered as the drug of choice in the treatment of infections caused by these organisms. Since the first reports of teicoplanin resistance in methicillin-resistant CoNS in the USA and the UK, the emergence of glycopeptide-resistant CoNS in patients treated for long periods with vancomycin or teicoplanin has been increasingly documented.1 Strains of S. aureus with reduced susceptibility to glycopeptides have been reported from several parts of the world.2 Infections with these strains emerged in patients infected with methicillin-resistant S. aureus (MRSA) who had been receiving long-term vancomycin therapy. In Japan, the transmission within hospitals of MRSA strains with heterogeneous resistance to vancomycin has been reported.3 With the increasing incidence of multidrug-resistant staphylococci and the emergence of resistance to glycopeptides in CoNS, as well as in MRSA, therapeutic options have become increasingly limited. Thus, there is a clear need for novel agents as alternatives in the treatment of infections caused by these organisms.
Linezolid belongs to a new synthetic class of antimicrobials, the oxazolidinones. They are active against a wide variety of Gram-positive organisms, including methicillin-resistant staphylococci, penicillin-resistant pneumococci and vancomycin-resistant enterococci.47 Linezolid binds to the 50S ribosomal subunit and inhibits bacterial protein synthesis by interfering with the formation of the initiation complex in bacterial translation systems. Because this agent possesses a novel structure and unique mechanism of action, it does not display cross-resistance with other classes of antimicrobial agents.
We determined the activity of linezolid against 245 recently isolated methicillin-resistant staphylococci. This activity was compared with that of other new agents including the streptogramin quinupristindalfopristin, the ketolide telithromycin, and the fluoroquinolones moxifloxacin, trovafloxacin and levofloxacin. We also tested the susceptibilities of isolates to erythromycin, clindamycin, gentamicin, vancomycin, teicoplanin and rifampicin.
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Materials and methods
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A total of 245 clinical strains of methicillin-resistant staphylococci collected from January 1999 to March 2000 at Hospital Clínico San Carlos, Madrid, Spain were tested. These included 225 MRSA and 20 methicillin-resistant CoNS (15 Staphylococcus epidermidis and five Staphylococcus haemolyticus) strains with decreased levels of susceptibility to teicoplanin (MICs 16 mg/L). Organisms were identified by standard methods.8 CoNS strains were further identified using the ID 32 STAPH system (bioMérieux, Marcy l'Étoile, France). Only one isolate per patient was studied to avoid duplication. Sources of the isolates included skin and soft tissue (65.3%), blood (17.2%), respiratory tract (6.1%), catheter (5.7%), body fluid (2.5%) and others (1.2%).
Laboratory powders were supplied as follows: oxacillin, SmithKline Beecham S.A. (Madrid, Spain); linezolid and clindamycin, Pharmacia & Upjohn Co., Barcelona, Spain; quinupristindalfopristin, levofloxacin, telithromycin and teicoplanin, Aventis Pharma S.A., Madrid, Spain; moxifloxacin, Bayer, Barcelona, Spain; trovafloxacin, Pfizer Inc., New York, NY, USA; erythromycin, Abbott Laboratories S.A., Madrid, Spain; gentamicin, Schering-Plough S.A., Madrid, Spain; vancomycin, Lilly S.A., Madrid, Spain; rifampicin, SigmaAldrich Química S.A., Madrid, Spain.
MICs were determined on MuellerHinton agar using the agar dilution method described by the NCCLS.9 Isolates were confirmed to be oxacillin resistant by supplementing the agar with 2% NaCl. An inoculum of 104 cfu/spot was used. Agar plates were inoculated with a Steers replicator and incubated aerobically for 1824 h at 35°C. S. aureus ATCC 29213 was used as a control strain.
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Results and discussion
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The activities of linezolid and the other agents tested are shown in the Table
. Vancomycin and teicoplanin showed comparable activities against MRSA strains, with MICs at which 90% of the isolates were inhibited (MIC90s) of 1 and 2 mg/L, respectively. Among the MRSA isolates tested, the in vitro activity of linezolid was similar to that of the glycopeptides, with overall MIC50s and MIC90s both of 1 mg/L. No cross-resistance to any other antibiotic tested was seen. This drug inhibited all MRSA strains between 0.1 and 2 mg/L and all CoNS isolates tested between 0.2 and 0.5 mg/L. Overall, trovafloxacin was the most active of the new fluoroquinolones tested. Against MRSA isolates, trovafloxacin was one- to two-fold more active than moxifloxacin and three- to four-fold more active than levofloxacin. However, as previously described,4,7 isolates with elevated MICs of the new fluoroquinolones were detected. We found 29 (11.8%) isolates with MICs of 1632 mg/L for levofloxacin. Jones et al.4 studied 189 strains of MRSA resistant to ciprofloxacin and reported a MIC90 of 16 mg/L and a range of 164 mg/L for levofloxacin. More than half the MRSA strains were resistant to gentamicin and only two (0.8%) were resistant to rifampicin. All but one of the CoNS isolates tested were gentamicin resistant. The majority (81%) of strains were highly resistant to both erythromycin and clindamycin, with MICs of
256 mg/L (MLSB constitutive resistance phenotype). Telithromycin was inactive against these strains, while the erythromycin-susceptible isolates were inhibited by clindamycin and telithromycin at concentrations in the range of
0.06 0.2 mg/L. Quinupristindalfopristin showed high activity against all staphylococci isolates tested. For all strains, quinupristindalfopristin yielded a MIC50 of 0.2 mg/L and a MIC90 of 0.5 mg/L. These data are similar to those reported by other investigators.4,5,7
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Table. In vitro activity of linezolid compared with that of other antibiotics against methicillin-resistant staphylococci
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The excellent in vitro activity of linezolid found in this study agrees with the findings of previous studies,4,5,7 although our MICs are slightly lower than those reported by Noskin et al.6 Linezolid has an acceptable safety profile for both intravenous and oral administration and has proven to be effective in the treatment of infections due to methicillin-resistant staphylococcal species in critically ill patients.10 All of these data, together with the results of this study, suggest that linezolid could be useful for the treatment of infections due to MRSA as well as to teicoplanin-intermediate CoNS isolates. Of the other new agents tested, quinupristindalfopristin, trovafloxacin and moxifloxacin also appear to be good therapeutic options in infections involving these organisms.
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Acknowledgements
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This work was supported by grant 99/0434 from the Fondo de Investigación Sanitaria, Madrid, Spain. This study was presented at the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 1720 September, 2000.
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Notes
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* Corresponding author. Tel: +34-91-3303486; Fax: +34-91-3303478; E-mail: cbetriu{at}efd.net 
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References
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Received 24 April 2001;
returned 27 July 2001; revised 23 August 2001;
accepted 3 September 2001