tedizolid-phosphate and Acute-Disease

We evaluated safety and tolerability of tedizolid phosphate at the 200-mg once-daily dose approved for 6-day treatment of skin and skin-structure infections.. Clinical adverse event (AE) and laboratory data were pooled across completed clinical studies (13 phase 1, two phase 2, and two phase 3), for all participants who received ≥1 dose of tedizolid 200 mg, linezolid 600 mg (phase 3 only), or placebo (phase 1 only).. 1280 participants received tedizolid (phase 1: n = 355; phase 2/3: n = 925). In total, 13% received >6 doses of tedizolid (range: 7-21); in phase 2/3, 94% of participants received ≥5 doses (range: 5-10). Drug-related AEs occurred in 27% of participants (most commonly gastrointestinal reactions in 13% of participants and headache in 4%). Most AEs were mild-moderate in severity; <1% of participants discontinued treatment due to AEs. Tedizolid and linezolid had similar frequency, severity, and types of drug-related AEs. Tolerability in clinically important subpopulations (obese, n = 346; elderly, n = 99; renal impairment, n = 40; hepatic disease/impairment, n = 294) appeared comparable to the overall population.. Tedizolid, given orally or intravenously at 200 mg, has a favorable safety profile. Clinical trial and postmarketing experience with treatment ≥7 days is limited.

Topics: Acute Disease; Administration, Intravenous; Administration, Oral; Anti-Bacterial Agents; Clinical Trials as Topic; Humans; Linezolid; Organophosphates; Oxazoles; Severity of Illness Index; Skin Diseases, Bacterial

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.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Resistance, Multiple, Bacterial; Humans; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Treatment Outcome

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.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Resistance, Bacterial; Humans; Organophosphates; Oxazoles; Skin Diseases, Bacterial

Tedizolid phosphate (TR-701), a prodrug of tedizolid (TR-700), is a next-generation oxazolidinone that has shown favorable results in the treatment of acute bacterial skin and skin-structure infections in its first Phase III clinical trial. Tedizolid has high bioavailability, penetration, and tissue distribution when administered orally or intravenously. The activity of tedizolid was greater than linezolid against strains of Staphylococcus spp., Streptococcus spp., and Enterococcus spp. in vitro studies, including strains resistant to linezolid and those not susceptible to vancomycin or daptomycin. Its pharmacokinetic characteristics allow for a once-daily administration that leads to a more predictable efficacy and safety profile than those of linezolid. No hematological adverse effects have been reported associated with tedizolid when used at the therapeutic dose of 200 mg in Phase I, II, or III clinical trials of up to 3 weeks of tedizolid administration. Given that the clinical and microbiological efficacy are similar for the 200, 300, and 400 mg doses, the lowest effective dose of 200 mg once daily for 6 days was selected for Phase III studies in acute bacterial skin and skin-structure infections, providing a safe dosing regimen with low potential for development of myelosuppression. Unlike linezolid, tedizolid does not inhibit monoamine oxidase in vivo, therefore interactions with adrenergic, dopaminergic, and serotonergic drugs are not to be expected. In conclusion, tedizolid is a novel antibiotic with potent activity against Gram-positive microorganisms responsible for skin and soft tissue infections, including strains resistant to vancomycin, linezolid, and daptomycin, thus answers a growing therapeutic need.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Biological Availability; Drug Resistance, Bacterial; Gram-Positive Bacteria; Humans; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Soft Tissue Infections; Tissue Distribution

Acute bacterial skin and skin structure infections (ABSSSIs), including cellulitis or erysipelas, major cutaneous abscesses, and wound infections, can be life-threatening and may require surgery and hospitalization. Increasingly, ABSSSIs are associated with drug-resistant pathogens, and many antimicrobial agents have adverse effects restricting their use. Tedizolid phosphate is a novel oxazolidinone in development for the treatment of ABSSSIs.. To establish the noninferiority of tedizolid phosphate vs linezolid in treating ABSSSIs and compare the safety of the 2 agents.. The Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs 10-day Oral Linezolid Therapy (ESTABLISH-1) was a phase 3, randomized, double-blind, noninferiority trial that was conducted from August 2010 through September 2011 at 81 study centers in North America, Latin America, and Europe. The intent-to-treat analysis set consisted of data from 667 adults aged 18 years or older with ABSSSIs treated with tedizolid phosphate (n = 332) or linezolid (n = 335).. A 200 mg once daily dose of oral tedizolid phosphate for 6 days or 600 mg of oral linezolid every 12 hours for 10 days.. The primary efficacy outcome was early clinical response at the 48- to 72-hour assessment (no increase in lesion surface area from baseline and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours). A 10% noninferiority margin was predefined.. In the intent-to-treat analysis set, the early clinical treatment response rates were 79.5% (95% CI, 74.8% to 83.7%) of 332 patients in the tedizolid phosphate group and 79.4% (95% CI, 74.7% to 83.6%) of 335 patients in the linezolid group (a treatment difference of 0.1% [95% CI, -6.1% to 6.2%]). The sustained clinical treatment response rates at the end of treatment (day 11) were 69.3% (95% CI, 64.0% to 74.2%) in the tedizolid phosphate group and 71.9% (95% CI, 66.8% to 76.7%) in the linezolid group (a treatment difference of -2.6% [95% CI, -9.6% to 4.2%]). Results of investigator-assessed clinical treatment success rates at a posttherapy evaluation visit (1-2 weeks after the end-of-treatment visit) were 85.5% (95% CI, 81.3% to 89.1%) in the tedizolid phosphate group and 86.0% (95% CI, 81.8% to 89.5%) in the linezolid group (a treatment difference of -0.5% [95% CI, -5.8% to 4.9%), and were similar for 178 patients with methicillin-resistant Staphylococcus aureus isolated from the primary lesion.. Tedizolid phosphate was a statistically noninferior treatment to linezolid in early clinical response at 48 to 72 hours after initiating therapy for an ABSSSI. Tedizolid phosphate may be a reasonable alternative to linezolid for treating ABSSSI.. clinicaltrials.gov Identifier: NCT01170221.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Treatment Outcome; Young Adult

Topics: Acute Disease; Anti-Bacterial Agents; Glycopeptides; Humans; Lipoglycopeptides; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Teicoplanin

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 (MIC90s, 0.5 versus 2 μg/ml), MRSA (MIC90s, 0.5 versus 2 μg/ml), S. pyogenes (MIC90s, 0.5 versus 2 μg/ml), S. agalactiae (MIC90s, 0.5 versus 2 μg/ml), Streptococcus anginosus group (MIC90s, 0.5 versus 2 μg/ml), E. faecalis (MIC90s, 0.5 versus 2 μg/ml), and VRE (MIC90s, 0.5 versus 2 μg/ml). The tedizolid MICs against E. faecalis (n = 3) and VRE (n = 2) intermediate to linezolid (MICs, 4 μg/ml) were 1 μg/ml and 0.5 μg/ml, respectively. The tedizolid MIC90s against S. anginosus, S. constellatus, and S. intermedius were 0.5, 1, and 0.5 μg/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.

Topics: Acute Disease; Anti-Bacterial Agents; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Pneumonia, Bacterial; Staphylococcal Skin Infections; Streptococcal Infections; Streptococcus agalactiae; Streptococcus anginosus; Streptococcus pyogenes; Taiwan; Vancomycin-Resistant Enterococci