oxazolidinones new fam ab

The oxazolidinones as a new family of antimicrobial agent A. Marchese and G.C. Schito Institute of Microbiology, Genoa, Italy ABSTRACT 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. Keywords oxazolidanone, linezolid, in vitro activity, in vivo activity Clin Microbiol Infect 2001: 7 (Supplement 4): 66±74 CHEMICAL STRUCTURE 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 [1]. 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) [2]. SPECTRUM OF ACTIVITY 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 # 2001 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 7 (Suppl. 4), 66±74 Ahed Bhed Ched Dhed Ref marker Fig marker Table marker Ref end Ref start Corresponding author and reprint requests: A. Marchese, Institute of Microbiology, Largo R. Benzi 10, 16132, Genoa, Italy Tel: +39 010 3537655 Fax: +39 010 504837 E-mail: [email protected] O N F O N O H H N O CH 3 Figure 1 Chemical structure of linezolid. Paper 60 Disc

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