Phase 2, randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections.

Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, Suite 105, San Diego, CA 92121, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 02/2011; 55(2):583-92. DOI: 10.1128/AAC.00076-10
Source: PubMed

ABSTRACT Torezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistant Staphylococcus aureus (MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections. S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients with S. aureus isolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials.

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    ABSTRACT: Treatment of multidrug-resistant Gram-positive infections continues to challenge clinicians as the emergence of new resistance mechanisms outpaces introduction of novel antimicrobial agents. Tedizolid phosphate is a next-generation oxazolidinone with activity against both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. Tedizolid has consistently shown potency advantages over linezolid against Gram-positive microorganisms including those with reduced susceptibility to linezolid. Of particular significance, minimum inhibitory concentrations of tedizolid appear to be largely unaffected by the chloramphenicol-florfenicol resistance (cfr) gene, which has been implicated in a number of published linezolid-resistant organism outbreaks. Tedizolid phosphate also has been found to have a favorable pharmacokinetic profile allowing for once-daily dosing in both oral and intravenous forms. Potency and pharmacokinetic advantages have allowed for lower total daily doses of tedizolid, compared to linezolid, being needed for clinical efficacy in the treatment of acute bacterial skin and skin structure infections (ABSSSI). The decreased total drug exposure produced may in part be responsible for a decrease in the observed adverse effects including thrombocytopenia. Tedizolid phosphate is currently indicated for the treatment of ABSSSI and under investigation for the treatment of nosocomial pneumonia. Although much of the role of tedizolid remains to be defined by expanding clinical experience, tedizolid is likely a welcomed addition to the mere handful of agents available for the treatment of multidrug-resistant Gram-positive infections.
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    ABSTRACT: Tedizolid, a novel oxazolidinone antibacterial, was administered to Long Evans rats by oral gavage once daily for up to 9 months at doses near the maximum tolerated dose (MTD) to evaluate for potential neurotoxicity. Mean plasma exposures of tedizolid at the low, mid, and high dose levels (7.5, 15, and 30 mg/kg/day for males; 2.5, 5, and 10 mg/kg/day for females) were similar between males and females and were 1.9-, 4.0-, and 8.2-fold greater than exposures in patients at the therapeutic dose (200 mg once daily). Evaluated end points included survival, clinical observations, body weight, and food consumption. At 1, 3, 6, and 9 months, ophthalmic examinations, functional observational batteries, and locomotor activity measures were conducted; brain weights/size were recorded; and perfusion-fixed tissues were collected from 12 rats/sex/group/time point. A detailed morphologic assessment was conducted on brain, eyes, optic nerve/tract, spinal cord, peripheral nerves (includes sciatic, sural, tibial, peroneal, trigeminal), and skeletal muscle. At the end of 9 months, less body weight gain was seen in high-dose males (-6.7%) and females (-5.8%) compared with controls. There were no tedizolid-related adverse neurobehavioral effects or tedizolid-related histopathologic changes in the central/peripheral nervous systems, including the optic nerve. Results of this study indicate that tedizolid was not neurotoxic when administered long-term to pigmented rats at doses near the MTD, which were up to 8-fold higher than the human therapeutic exposure.
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    ABSTRACT: Acute bacterial skin and skin structure infections (ABSSSI) are associated with remarkable morbidity, and often require hospitalization. The cause of most ABSSSI is aerobic Gram-positive cocci, including Staphylococcus aureus, and β-hemolytic streptococci. Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety is tedizolid. It has shown potent in vitro activity against Gram-positive pathogens, encompassing methicillin-resistant S. aureus (MRSA) and strains resistant to vancomycin or linezolid. Animal studies suggested bactericidal activity in vivo. Pharmacokinetic studies demonstrated a good penetration into skin and soft tissues, and suitability for once-daily administration, either orally or intravenously at the same dosage. Pivotal phase III studies showed that tedizolid phosphate at 200 mg once daily for 6 days is noninferior to linezolid 600 mg twice daily for 10 days in ABSSSI patients, whereas gastrointestinal disorders were less frequent with tedizolid phosphate than linezolid. Tedizolid phosphate has been approved by the U.S. FDA, as Sivextro® to treat adult patients with ABSSSI. Copyright 2014 Prous Science, S.A.U. or its licensors. All rights reserved.
    Drugs of today (Barcelona, Spain: 1998) 11/2014; 50(11):729-737. DOI:10.1358/dot.2014.50.11.2233783 · 1.00 Impact Factor

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