The oxazolidinones as a new family of antimicrobial agent
2001; Elsevier BV; Volume: 7; Linguagem: Inglês
10.1046/j.1469-0691.2001.00060.x
ISSN1469-0691
AutoresAnna Marchese, Gian Carlo Schito,
Tópico(s)Antibiotic Use and Resistance
ResumoThe oxazolidinones are a new chemical class of synthetic antimicrobials characterized by a unique mechanism of protein synthesis inhibition. Linezolid is the first compound of this class and has recently received approval for the treatment of community- and hospital-acquired pneumonia and skin and skin structure infections. In vitro tests demonstrate that linezolid possesses a significant activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate strains (VISA) and penicillin-resistant pneumococci (PRPN). Combined with other drugs linezolid interacts favourably against many important pathogens and it is able to affect some bacterial virulence factors as well as produce a postantibiotic effect.Results from experimental models of infection reveal linezolid to be highly active in vivo against infections due to Gram-positive pathogens.Linezolid may be administered either intravenously or orally with oral bioavailability of approximately 100% and limited adverse effects. The clinical efficacy of linezolid has been investigated in several phase II and III trials. Linezolid has been proved to be useful in severe infections sustained by multiresistant Gram-positive micro-organisms. Synthesis of the second-generation oxazolidinones with improved potency against Gram-positive and negative bacteria is currently under way. The oxazolidinones are a new chemical class of synthetic antimicrobials characterized by a unique mechanism of protein synthesis inhibition. Linezolid is the first compound of this class and has recently received approval for the treatment of community- and hospital-acquired pneumonia and skin and skin structure infections. In vitro tests demonstrate that linezolid possesses a significant activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate strains (VISA) and penicillin-resistant pneumococci (PRPN). Combined with other drugs linezolid interacts favourably against many important pathogens and it is able to affect some bacterial virulence factors as well as produce a postantibiotic effect. Results from experimental models of infection reveal linezolid to be highly active in vivo against infections due to Gram-positive pathogens. Linezolid may be administered either intravenously or orally with oral bioavailability of approximately 100% and limited adverse effects. The clinical efficacy of linezolid has been investigated in several phase II and III trials. Linezolid has been proved to be useful in severe infections sustained by multiresistant Gram-positive micro-organisms. Synthesis of the second-generation oxazolidinones with improved potency against Gram-positive and negative bacteria is currently under way. The oxazolidinones are a new synthetic class of antimicrobials, structurally unrelated to any agent presently available to the clinician. Discovered by E.I. du Pont de Nemours and colleagues in 1987, oxazolidinones are heterocyclic molecules with nitrogen and oxygen in a five-membered ring and bridged with a carbonyl group [1Slee AM Wuonola MA McRipley RJ et al.Oxazolidinones, a new class of synthetic antibacterial agents: in vitro activities of DuP 105 and DuP 721.Antimicrob Agents Chemother. 1987; 31: 1791-1797Crossref PubMed Scopus (192) Google Scholar]. The two positional forms are the 4- and 5-isomers. The 5-substituted oxazolidinones are especially endowed with antibacterial activity. Linezolid (PNU-100766), the first compound of this class approved by the US FDA in 2000, is a 3-(fluorophenil)-2-oxazolidinone that has a morpholin-1yl group substitution (Figure 1) [2Ford C Hamel J Stapert D et al.Oxazolidinones: a new class of antimicrobials.Infect Med. 1999; 16: 435-445Google Scholar]. The oxazolidinone appear to have significant activity against Gram-positive bacterial pathogens such as S. aureus, S. epidermidis, Streptococcus pneumoniae, Enterococcus faecalis and E. faecium. Importantly, these molecules also have activity against several pathogens that are resistant to one or more antibiotics, namely methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate strains (VISA) and penicillin-resistant pneumococci (PRPN) [3Clemett D Markham A Linezolid.Drugs. 2000; 59: 815-827Crossref PubMed Scopus (271) Google Scholar]. According to its spectrum of activity linezolid received approval for the treatment of community- and hospital-acquired pneumonia, skin and skin structure infections (uncomplicated and complicated), including cases caused by drug-resistant Gram-positive pathogens (MRSA, VRE) [4Mirasol F Oxazolidinones emerge as a new class of antibiotics.http://www.findarticles.comGoogle Scholar]. Studies on the mechanism of action of oxazolidinones concluded that they function by inhibiting a very early step in bacterial protein synthesis [5Lin AH Murray RW Vidmar TJ et al.The oxazolidinone eperezolid binds to the 50S ribosomial subunit and competes with binding of chloramphenicol and lincomycin.Antimicrob Agents Chemother. 1997; 41: 2127-2131Crossref PubMed Google Scholar,6Shinabarger DL Marotti KR Murray RW et al.Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions.Antimicrob Agents Chemother. 1997; 41: 2132-2136Crossref PubMed Google Scholar]. Oxazolidinone binding to the 50S subunit distorts the site for formyl-methionyl RNA (tRNAfMet), inhibiting ternary initiation complex formation and thus preventing initiation of translation. The linezolid binding site has been found to be located in the ribosomal peptidyl transferase centre (domain V of 23S rRNA) [7Shinabarger D Mechanisms of resistance to oxazolidinones [abstract 1134].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar,8Kloss P Xiong LQ Shinabarger DL Mankin AS Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the rybosomal peptidyl transferase center.J Mol Biol. 1999; 294: 93-101Crossref PubMed Scopus (185) Google Scholar]. Following uncoupling of the transcription-translation reaction, linezolid demonstrates a modest effect on elongation and termination of translation. This unique mechanism of action of oxazolidinones avoids cross-resistance with other inhibitors of protein synthesis (such as chloramphenicol, macrolides, lincosamides, streptogramins, aminoglycosides and tetracyclines) [9Fines M Leclercq R Activity of linezolid against G+ cocci possessing genes conferring resistance to protein synthesis inhibitors.J Antimicrob Chemother. 2000; 45: 797-802Crossref PubMed Scopus (71) Google Scholar]. Laboratory testing to select for resistant mutants has met with only limited success [10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar,11Kaatz GW Seo SM In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis.Antimicrob Agents Chemother. 1996; 40: 799-801PubMed Google Scholar]. Spontaneous mutation frequencies ranged from <8×10−11 to <1×10−9 for several strains of methicillin-susceptible and -resistant S. aureus and S. epidermidis[10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar,11Kaatz GW Seo SM In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis.Antimicrob Agents Chemother. 1996; 40: 799-801PubMed Google Scholar]. After exposure to linezolid at 2×, 4×, 8× minimal inhibitory concentrations (MICs) no mutants were found in the strains tested [10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar,11Kaatz GW Seo SM In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis.Antimicrob Agents Chemother. 1996; 40: 799-801PubMed Google Scholar]. Step pressure selection did not produce rapid development of resistance in staphylococci and enterococci [10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar]. In vivo development of resistance to linezolid has been described for E. faecium in two patients after 4 or 6 weeks of treatment. Linezolid MICs increased from 2 mg/L to 16–32 mg/L and in addition the strains were resistant to almost every agent tested [12Zurenko GE Todd WM Hafkin B et al.Development of linezolid-resistant Enterococcus faecium in two compassionate use program patients treated with linezolid [abstract 848].in: Program and Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA. American Society for Microbiology, Washington, DC1999Google Scholar]. In Gram-negative micro-organisms other studies have demonstrated that linezolid penetrates the E. coli outer membrane but this is rapidly excreted from the cell by efflux pumps. The susceptibility of Gram-positive organisms to the oxazolidinones can be attributed to a lack of transmembrane pumps with an oxazolidinone specificity [13Buysse JM Demyan WF Dunyak DS et al.Mutation of the Acr AB antibiotic efflux pump in Escherichia coli confers susceptibility to oxazolidinone antibiotics [abstract 848].in: Program and Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New OrleanS. American Society for Microbiology, Washington, DC1996Google Scholar]. Two tentative breakpoints for linezolid have been proposed. Supported by preliminary pharmacokinetic data [14Stalker DJ Wajszczuk CP Batts DH Linezolid safety, tolerance, and pharmacokinetics following oral dosing twice daily for 14.5 days [abstract A115].in: Program and Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC1997Google Scholar,15Stalker DJ Wajszczuk CP Batts DH Linezolid safety, tolerance, and pharmacokinetics after intravenous dosing twice daily for 7.5 days [abstract A116].in: Program and Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC1997Google Scholar] some authors have suggested the following values: MICs 4 mg/L for susceptibility and 16 mg/L for resistance [16Biedenbach DJ Jones RN Disk diffusion test interpretative criteria and quality control recommendations for testing linezolid (U100766) and eperezolid (U-100592) with commercially prepared reagents.J Clin Microbiol. 1997; 35: 3198-3202PubMed Google Scholar]. More recently Wise et al proposed a breakpoint of 2 mg/L after analysis of distribution of susceptibilities [17Wise R Andrews JM Boswell FJ Ashby JP The in-vitro activity of linezolid (U-100766) and tentative breakpoints.J Antimicrob Chemother. 1998; 42: 721-728Crossref PubMed Scopus (75) Google Scholar], but the first breakpoint seems more likely to be accepted. Oxazolidinones display bacteriostatic activity against many important pathogens including MRSA, coagulase-negative staphylococci and VRE. Bactericidal activity was demonstrated against S. pneumoniae, B. fragilis and C. perfringens[10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar,18Jorgensen JH McElmeel ML Trippy CW In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase negative Staphylococcus species.Antimicrob Agents Chemother. 1997; 41: 465-467PubMed Google Scholar, 19Kaatz GW Seo SM In vitro activity of oxazolidinone compounds U100592 and U100766 versus. Staphylococcus aureus and Staphylococcus epidermidiS.Antimicrob Agents Chemother. 1996; 40: 799-801PubMed Google Scholar, 20Bostic GD Perri MB Thal LA et al.Comparative in vitro and bactericidal activity of oxazolidinone antibiotics against multidrug-resistant enterococci.Diagn Microbiol Infect Dis. 1998; 30: 109-112Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. Human serum did not affect linezolid efficacy [21Schaadt RD Batts DH Daley-Yates PT et al.Serum inhibitory titers and serum bactericidal titers for human subjects receiving multiple doses of the antibacterial oxazolidinones eperezolid and linezolid.Diagn Microbiol Infect Dis. 1997; 28: 201-204Abstract Full Text PDF PubMed Scopus (23) Google Scholar], while incubation in CO2 was found to depress the activity of linezolid only against pneumococci [22Hamilton-Miller JMT Shah S Susceptibility testing of linezolid by two standard methids.Eur J Clin Microbiol Infect Dis. 1999; 18: 225-227Crossref PubMed Scopus (6) Google Scholar]. Linezolid possesses good activity against staphylococci, comparable with that of vancomycin. All isolates of S. aureus tested had MIC values 4 mg/L [10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar,18Jorgensen JH McElmeel ML Trippy CW In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase negative Staphylococcus species.Antimicrob Agents Chemother. 1997; 41: 465-467PubMed Google Scholar,23Henwood CJ Livermore DM Johnson AP et al.Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid.J Antimicrob Chemother. 2000; 46: 931-940Crossref PubMed Scopus (129) Google Scholar, 24Borek AP Peterson LR Noskin GA Activity of linezolid against medically important Gram-positive bacteria from 1997 to 1999 [abstract 2299].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 25Bowker KE Wootton M Holt HA Macgowan AP In vitro activity of linezolid against Gram-positive infection in continuous ambulatory peritoneal dialysis patients [abstract 2300].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 26Noskin GA Siddiqui F Stosor V Hacek D Peterson LR In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycin-resistant enterococci.Antimicrob Agents Chemother. 1999; 43: 2059-2062PubMed Google Scholar, 27Mezzatesta ML Stefani S Tempera G et al.Comparative activity of linezolid against Staphylococci and Enterococci isolated in Italy [abstract 2302].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 28Betriu C Redondo M Boloix A Gomez M Culebras E Picazo JJ Comparative in vitro activities of linezolid and other new agents against methicillin-resitant Staphylococcus aureus and teicoplanin-intermediate coagulase-negative Staphylococci [abstract 2994].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 29Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google Scholar, 30Eliopoulos GM Wennersten CB Gold HS In vitro activities of new oxazolidinone antimicrobial agents against enterococci.Antimicrob Agents Chemother. 1996; 40: 1745-1747PubMed Google Scholar, 31Betriu C Redondo M Palau ML et al.Comparative in vitro activities of linezolid, quinupristin-dalfopristin, moxifloxacin, and trovafloxacin against erythromycin-susceptible and –resistant streptococci.Antimicrob Agents Chemother. 2000; 44: 1838-1841Crossref PubMed Scopus (54) Google Scholar, 32Spangler SK Jacobs MR Appelbaum PC Activities of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents against 203 penicillin-susceptible and -resistant pneumococci.Antimicrob Agents Chemother. 1996; 40: 481-484PubMed Google Scholar, 33Rybak MJ Cappelletty DM Moldowan T Aeschlimann JR Kaatz GW Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium.Antimicrob Agents Chemother. 1998; 42: 721-724Crossref PubMed Scopus (78) Google Scholar, 34Cercenado E Garcia-Garronte F Bouza E In vitro activity of linerzolid against multiply resistant Gram-positive clinical isolates.J Antimicrob Chemother. 2001; 47: 77-81Crossref PubMed Scopus (68) Google Scholar]. The same holds true for S. epidermidis and S. haemolyticus (MIC range from 1 to 2 mg/L) [10Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar,25Bowker KE Wootton M Holt HA Macgowan AP In vitro activity of linezolid against Gram-positive infection in continuous ambulatory peritoneal dialysis patients [abstract 2300].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar,28Betriu C Redondo M Boloix A Gomez M Culebras E Picazo JJ Comparative in vitro activities of linezolid and other new agents against methicillin-resitant Staphylococcus aureus and teicoplanin-intermediate coagulase-negative Staphylococci [abstract 2994].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar,32Spangler SK Jacobs MR Appelbaum PC Activities of RPR 106972 (a new oral streptogramin), cefditoren (a new oral cephalosporin), two new oxazolidinones (U-100592 and U-100766), and other oral and parenteral agents against 203 penicillin-susceptible and -resistant pneumococci.Antimicrob Agents Chemother. 1996; 40: 481-484PubMed Google Scholar] (Table 1). MICs of linezolid were not affected by resistance to β-lactams or fluoroquinolones in staphylococci [35Von Eiff C Peters G Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinpristin/dalfopristin and linezolid against staphylococci.J Antimicrob Chemother. 1999; 43: 569-573Crossref PubMed Scopus (59) Google Scholar]. In fact, MIC90 ranges for MRSA and methicillin-resistant coagulase-negative staphylococci were superimposable (Table 1). Against VISA and glycopetide-resistant coagulase-negative staphylococci linezolid maintains complete activity [36Tenover FC Lancaster MV Hill BC et al.Characterization of staphylococci with reduced susceptibilities to vancomycin and other glycopeptides.J Clin Microbiol. 1998; 36: 1020-1027PubMed Google Scholar, 37Marchese A Balistreri G Tonoli E Debbia EA Schito GC Heterogeneous vancomycin resistance in methicillin-resistant S. aureus strains isolated in a large Italian Hospital.J Clin Microbiol. 2000; 38: 866-869PubMed Google Scholar, 38Rybak MJ Hersberger E Moldovan T Grucz RG In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against staphylococci and enterococci, including vancomycin-intermediate and- resistant strains.Antimicrob Agents Chemother. 2000; 44: 1062-1066Crossref PubMed Scopus (313) Google Scholar].Table 1MIC90 ranges of linezolid against Gram-positive aerobic cocciMicro-organismMIC90 range (mg/L)ReferenceS. aureus1–418Jorgensen JH McElmeel ML Trippy CW In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase negative Staphylococcus species.Antimicrob Agents Chemother. 1997; 41: 465-467PubMed Google Scholar, 23Henwood CJ Livermore DM Johnson AP et al.Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid.J Antimicrob Chemother. 2000; 46: 931-940Crossref PubMed Scopus (129) Google Scholar, 24Borek AP Peterson LR Noskin GA Activity of linezolid against medically important Gram-positive bacteria from 1997 to 1999 [abstract 2299].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 25Bowker KE Wootton M Holt HA Macgowan AP In vitro activity of linezolid against Gram-positive infection in continuous ambulatory peritoneal dialysis patients [abstract 2300].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google ScholarS. aureus MS2–410Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar, 23Henwood CJ Livermore DM Johnson AP et al.Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid.J Antimicrob Chemother. 2000; 46: 931-940Crossref PubMed Scopus (129) Google Scholar, 26Noskin GA Siddiqui F Stosor V Hacek D Peterson LR In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycin-resistant enterococci.Antimicrob Agents Chemother. 1999; 43: 2059-2062PubMed Google Scholar, 27Mezzatesta ML Stefani S Tempera G et al.Comparative activity of linezolid against Staphylococci and Enterococci isolated in Italy [abstract 2302].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 29Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google Scholar, 33Rybak MJ Cappelletty DM Moldowan T Aeschlimann JR Kaatz GW Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium.Antimicrob Agents Chemother. 1998; 42: 721-724Crossref PubMed Scopus (78) Google Scholar, 34Cercenado E Garcia-Garronte F Bouza E In vitro activity of linerzolid against multiply resistant Gram-positive clinical isolates.J Antimicrob Chemother. 2001; 47: 77-81Crossref PubMed Scopus (68) Google ScholarS. aureus MR2–410Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar, 23Henwood CJ Livermore DM Johnson AP et al.Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid.J Antimicrob Chemother. 2000; 46: 931-940Crossref PubMed Scopus (129) Google Scholar, 24Borek AP Peterson LR Noskin GA Activity of linezolid against medically important Gram-positive bacteria from 1997 to 1999 [abstract 2299].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 26Noskin GA Siddiqui F Stosor V Hacek D Peterson LR In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycin-resistant enterococci.Antimicrob Agents Chemother. 1999; 43: 2059-2062PubMed Google Scholar, 27Mezzatesta ML Stefani S Tempera G et al.Comparative activity of linezolid against Staphylococci and Enterococci isolated in Italy [abstract 2302].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 29Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google Scholar, 33Rybak MJ Cappelletty DM Moldowan T Aeschlimann JR Kaatz GW Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium.Antimicrob Agents Chemother. 1998; 42: 721-724Crossref PubMed Scopus (78) Google Scholar, 34Cercenado E Garcia-Garronte F Bouza E In vitro activity of linerzolid against multiply resistant Gram-positive clinical isolates.J Antimicrob Chemother. 2001; 47: 77-81Crossref PubMed Scopus (68) Google ScholarS. epidermidis MS2–410Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar, 26Noskin GA Siddiqui F Stosor V Hacek D Peterson LR In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycin-resistant enterococci.Antimicrob Agents Chemother. 1999; 43: 2059-2062PubMed Google Scholar, 27Mezzatesta ML Stefani S Tempera G et al.Comparative activity of linezolid against Staphylococci and Enterococci isolated in Italy [abstract 2302].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 29Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google Scholar, 33Rybak MJ Cappelletty DM Moldowan T Aeschlimann JR Kaatz GW Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium.Antimicrob Agents Chemother. 1998; 42: 721-724Crossref PubMed Scopus (78) Google ScholarS. epidermidis MR2–410Zurenko GE Yagi BH Schaadt RD et al.In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents.Antimicrob Agents Chemother. 1996; 40: 839-845PubMed Google Scholar, 26Noskin GA Siddiqui F Stosor V Hacek D Peterson LR In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycin-resistant enterococci.Antimicrob Agents Chemother. 1999; 43: 2059-2062PubMed Google Scholar, 27Mezzatesta ML Stefani S Tempera G et al.Comparative activity of linezolid against Staphylococci and Enterococci isolated in Italy [abstract 2302].in: Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON. American Society for Microbiology, Washington, DC2000Google Scholar, 29Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google Scholar, 33Rybak MJ Cappelletty DM Moldowan T Aeschlimann JR Kaatz GW Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium.Antimicrob Agents Chemother. 1998; 42: 721-724Crossref PubMed Scopus (78) Google ScholarS. haemolyticus MS129Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google ScholarS. haemolyticus MR129Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google ScholarCoagulase-negative staphylococci1–229Jones RN Johnson DM Erwin ME In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.Antimicrob Agents Chemother. 1996; 40: 720-726PubMed Google Scholar, 18Jorgensen JH McElmeel ML Trippy CW In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase negative Staphylococcus species.Antimicrob Agents Chemother. 1997; 41: 465-467PubMed Google Scholar, 23Henwood CJ Livermore DM Johnson AP et al.Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid.J Antimicrob Chemother. 2000; 46: 931-940Crossref PubMed Scopus (129) Google Scholar, 25Bowker KE Wootton M Holt HA Macgowan AP In vitro
Referência(s)