Abstract
The emerging antibiotic resistance of Gram-positive pathogens represents a significant challenge to the management of human infections. The novel oxazolidinone tedizolid demonstrates antimicrobial activity across a broad range of Gram-positive pathogens and greater potency than linezolid against wild-type and drug-resistant pathogens, including linezolid-resistant Staphylococcus aureus strains possessing mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins L3 or L4. Strains harboring such mutations are also selected for much less frequently with tedizolid than with linezolid. In addition, tedizolid has a significant potency advantage over linezolid-resistant strains carrying the horizontally transferable cfr gene. Methylation of A2503 of 23S rRNA by the Cfr methyltransferase confers resistance to linezolid (and a variety of other 50S ribosomal subunit-targeted antibiotics) but not to tedizolid because of structural differences in A-ring C5 substituents between the 2 drugs. The greater potency and improved resistance profile of tedizolid provides the microbiologic basis for considering this molecule as an alternative to linezolid for the treatment of serious infections caused by Gram-positive pathogens.
Highlights
Comparative studies confirm that tedizolid offers more potent antimicrobial activity against a broad range of Gram-positive pathogens, including wild-type and linezolid-resistant strains, with a lower frequency of mutations leading to drug resistance
Medical writing support was provided by Bill Jacobs, PhD (Strategic HealthCOM, Somerville, NJ), funded by Cubist Pharmaceuticals
Comparative studies confirm that tedizolid offers more potent antimicrobial activity against a broad range of Gram-positive pathogens, including wild-type and linezolid-resistant strains (especially those possessing the cfr multidrug-resistance gene), with a lower frequency of mutations leading to drug resistance
Summary
Tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218) is the inactive prodrug of the biologically active moiety tedizolid (TR-700, formerly torezolid, DA-7157), which has been shown to have potent antimicrobial activity against a wide range of Gram-positive aerobic and anaerobic bacteria— notably MSSA, MRSA, methicillin-susceptible and -resistant coagulase-negative staphylococci (CoNS), vancomycin-resistant enterococci (VRE), S. pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae [5]. A monophosphate ester was found to be highly watersoluble (>50 mg/mL), stable across a pH range of 3–7, and rapidly hydrolyzed by phosphatase activity, to retain better than 90% oral bioavailability [7], and to have pharmacokinetic properties consistent with once-daily intravenous and oral dosing [5]. Results from the first of 2 phase 3 trials (ESTABLISH 1) confirming similar clinical outcomes with 6 days of 200 mg once-a-day oral tedizolid to 10 days of twice-daily oral 600 mg linezolid have been published [8]. Initial results from the second phase 3 study comparing outcomes with intravenous formulations of tedizolid and linezolid have recently been released [9]. The PTC binding site for tedizolid is similar to the binding site for linezolid [4] (Figure 1), the D-ring of tedizolid may engage additional sites on the ribosome and is likely responsible for the greater potency vs linezolid [6, 7, 11]
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