Tedizolid: A new oxazolidinone antimicrobial

SUMMARYStreptococcus pneumoniaeinflicts a huge disease burden as the leading cause of community-acquired pneumonia and meningitis. Soon after mainstream antibiotic usage, multiresistant pneumococcal clones emerged and disseminated worldwide. Resistant clones are generated through adaptation to antibiotic pressures imposed while naturally residing within the human upper respiratory tract. Here, a huge array of related commensal streptococcal strains transfers core genomic and accessory resistance determinants to the highly transformable pneumococcus. β-Lactam resistance is the hallmark of pneumococcal adaptability, requiring multiple independent recombination events that are traceable to nonpneumococcal origins and stably perpetuated in multiresistant clonal complexes. Pneumococcal strains with elevated MICs of β-lactams are most often resistant to additional antibiotics. Basic underlying mechanisms of most pneumococcal resistances have been identified, although new insights that increase our understanding are continually provided. Although all pneumococcal infections can be successfully treated with antibiotics, the available choices are limited for some strains. Invasive pneumococcal disease data compiled during 1998 to 2013 through the population-based Active Bacterial Core surveillance program (U.S. population base of 30,600,000) demonstrate that targeting prevalent capsular serotypes with conjugate vaccines (7-valent and 13-valent vaccines implemented in 2000 and 2010, respectively) is extremely effective in reducing resistant infections. Nonetheless, resistant non-vaccine-serotype clones continue to emerge and expand.

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“…Tedizolid has demonstrated potent in vitro activity against penicillin-resistant S. pneumoniae, including linezolid-resistant strains (252).…”

Section: Oxazolidinone Resistancementioning

confidence: 99%

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

et al. 2016

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“…The recent emergence of MRSA, coagulase-negative staphylococci, and VRE with reduced susceptibilities to linezolid has been widely reported (5,6). Tedizolid (formerly torezolid) is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens, including MRSA, VRE, Streptococcus pneumoniae, beta-hemolytic streptococci, viridans group streptococci, and some linezolid-resistant strains (7)(8)(9)(10). Tedizolid has been shown to be effective in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) as well as hospital-acquired and ventilator-associated bacterial pneumonia and was approved by the U.S. Food and Drug Administration (FDA) in 2013 for the treatment of ABSSSIs caused by susceptible isolates of S. aureus (including MRSA and methicillin-susceptible S. aureus [MSSA], Streptococcus pyogenes, Streptococcus agalactiae, members of the Streptococcus anginosus group (including S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (7,(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

In Vitro Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia

Chen

Huang

Liao

et al. 2015

Antimicrob Agents Chemother

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Tedizolid is a novel, expanded-spectrum oxazolidinone with potent activity against a wide range of Gram-positive pathogens. A total of 425 isolates of Gram-positive bacteria were obtained consecutively from patients with acute bacterial skin and skin structure infections (ABSSSIs) or pneumonia. These isolates included methicillin-susceptible Staphylococcus aureus (MSSA) (n ‫؍‬ 100), methicillin-resistant Staphylococcus aureus (MRSA) (n ‫؍‬ 100), Streptococcus pyogenes (n ‫؍‬ 50), Streptococcus agalactiae (n ‫؍‬ 50), Streptococcus anginosus group (n ‫؍‬ 75), Enterococcus faecalis (n ‫؍‬ 50), and vancomycin-resistant enterococci (VRE) (Enterococcus faecium) (n ‫؍‬ 50). The MICs of tedizolid and linezolid were determined by the agar dilution method. Tedizolid exhibited better in vitro activities than linezolid against MSSA (MIC 90 s, 0.5 versus 2 g/ml), MRSA (MIC 90 s, 0.5 versus 2 g/ml), S. pyogenes (MIC 90 s, 0.5 versus 2 g/ml), S. agalactiae (MIC 90 s, 0.5 versus 2 g/ml), Streptococcus anginosus group (MIC 90 s, 0.5 versus 2 g/ml), E. faecalis (MIC 90 s, 0.5 versus 2 g/ml), and VRE (MIC 90 s, 0.5 versus 2 g/ml). The tedizolid MICs against E. faecalis (n ‫؍‬ 3) and VRE (n ‫؍‬ 2) intermediate to linezolid (MICs, 4 g/ml) were 1 g/ml and 0.5 g/ml, respectively. The tedizolid MIC 90 s against S. anginosus, S. constellatus, and S. intermedius were 0.5, 1, and 0.5 g/ml, respectively, and the rates of susceptibility based on the U.S. FDA MIC interpretive breakpoints to the isolates were 16%, 28%, and 72%, respectively. Tedizolid exhibited 2-to 4-fold better in vitro activities than linezolid against a variety of Gram-positive cocci associated with ABSSSIs and pneumonia. The lower susceptibilities of tedizolid against isolates of S. anginosus and S. constellatus than against those of S. intermedius in Taiwan were noted.

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“…Chemistry Tedizolid (formerly torezolid, TR-700; 2-oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-, (5R)) is a new, second-generation oxazolidinone developed after LZD [32]. The inactive prodrug of tedizolid is tedizolid phosphate (TR-701), which has significant solubility in water and excellent oral bioavailability [33].…”

Section: Body Of Reviewmentioning

confidence: 99%

“…The inactive prodrug of tedizolid is tedizolid phosphate (TR-701), which has significant solubility in water and excellent oral bioavailability [33]. Compared with LZD, the acetamide group in tedizolid is replaced by a hydroxymethyl group at the C-5 site of the A ring; furthermore, a new D-ring (methyltetrazolyl group) is placed to form tedizolid after optimization of the C-ring, which together provide higher binding affinity to the peptidyl transferase center (FIGURE 1) [24,[31][32][33]. These special modifications in the structure allow the antibacterial activity of tedizolid to be greater than that of LZD, the rate of selection of first-step mutants is lower, and it remains active in vitro against certain strains with the cfr gene [24,32].…”

Section: Body Of Reviewmentioning

confidence: 99%

“…Compared with LZD, the acetamide group in tedizolid is replaced by a hydroxymethyl group at the C-5 site of the A ring; furthermore, a new D-ring (methyltetrazolyl group) is placed to form tedizolid after optimization of the C-ring, which together provide higher binding affinity to the peptidyl transferase center (FIGURE 1) [24,[31][32][33]. These special modifications in the structure allow the antibacterial activity of tedizolid to be greater than that of LZD, the rate of selection of first-step mutants is lower, and it remains active in vitro against certain strains with the cfr gene [24,32]. Tedizolid has a similar mechanism of action to other oxazolidinones in that it binds to 23S ribosomal RNA of the 50S subunit, influences formation of the 70S initiation complex, and inhibits synthesis of bacterial proteins [31][32][33].…”

Section: Body Of Reviewmentioning

confidence: 99%

See 1 more Smart Citation

Tedizolid for treatment of acute bacterial skin and skin structure infections

Lu²

2015

Expert Review of Anti-infective Therapy

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Tedizolid is a newly approved drug of the oxazolidinone class. It has high in vitro activity against Gram-positive bacteria, including multidrug-resistant strains. Peak plasma concentration of tedizolid is obtained within 3 h of oral dosing (PO), with high bioavailability. Tedizolid is mostly metabolized via the liver, and is excreted in feces in the form of a sulfate conjugate. Tedizolid 200 mg taken once daily demonstrated non-inferior efficacy and a good safety profile in patients with acute bacterial skin and skin structure infections. Results of two pivotal Phase III clinical trials showed that 6 days of 200 mg tedizolid PO or sequential intravenous (IV)/PO once-daily treatment was non-inferior to 10 days of 600 mg linezolid PO or sequential IV/PO twice-daily treatment at 48-72 h (primary end point) and at the test-of-cure in patients with acute bacterial skin and skin structure infections. The Phase II and Phase III trials also demonstrated that tedizolid was well tolerated.

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Tedizolid: A new oxazolidinone antimicrobial

Abstract: Tedizolid is an investigational oxazolidinone antibiotic for the treatment of multidrug-resistant gram-positive pathogens such as MRSA, Streptococcus pneumoniae, and VRE, including some linezolid-resistant strains.

Cited by 65 publications

References 50 publications

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

Biological and Epidemiological Features of Antibiotic-Resistant Streptococcus pneumoniae in Pre- and Post-Conjugate Vaccine Eras: a United States Perspective

In Vitro Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia

Tedizolid for treatment of acute bacterial skin and skin structure infections

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