tedizolid-phosphate and Pneumonia--Bacterial

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP.. In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population.. Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, -1.8%; 95% confidence interval [CI]: -8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, -7.6%; 97.5% CI: -15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively.. Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated.. NCT02019420.

Topics: Anti-Bacterial Agents; Double-Blind Method; Hospitals; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Pneumonia, Bacterial; Skin Diseases, Bacterial; Ventilators, Mechanical

To evaluate the in vitro antimicrobial activities of tedizolid, linezolid and other comparators against clinically significant Gram-positive cocci isolates from hospital-acquired pneumonia (HAP), skin and soft tissue infection (SSTI) and bloodstream infection (BSI), 2140 nonduplicate isolates (23.7 % isolated from HAP, 46.8 % from SSTI and 29.5 % from BSI) were consecutively collected in 26 hospitals in 17 cities across China during 2014. These pathogens included 632 methicillin-resistant Staphylococcus aureus, 867 methicillin-sensitive Staphylococcusaureus, 299 coagulase-negative Staphylococcus (CoNS), 104 Enterococcus faecalis, 99 Enterococcusfaecium, 13 Streptococcus pneumoniae, 23 α-haemolytic Streptococcus and 103 β-haemolytic Streptococcus. MICs of routine clinical antibiotics were determined by broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines 2015. Tedizolid, linezolid, vancomycin, daptomycin, teicoplanin and tigecycline showed high in vitro activity against Gram-positive pathogens (≥98.0 % susceptible), and tedizolid exhibited four- to eight fold greater activity than linezolid against the pathogens tested, with MIC90s of methicillin-resistant Staphylococcus aureus, α-haemolytic Streptococcus and β-haemolytic Streptococcus (0.25 vs 2 µg ml-1); methicillin-sensitive Staphylococcu saureus, E. faecalis and E. faecium (0.5 vs 2 µg ml-1); methicillin-resistant CoNS and methicillin-sensitive CoNS (0.25 vs 1 µg ml-1); and Streptococcuspneumoniae (0.125 vs 0.5 µg ml-1). Tedizolid MIC90s associated with different infections did not show significant differences, and the drug exhibited excellent activity against surveyed Gram-positive pathogens associated with HAP, SSTI and BSI, including linezolid-nonsusceptible strains. These data suggest that tedizolid could be an alternative to linezolid for the treatment of infections caused by Gram-positive organisms.

Topics: Anti-Bacterial Agents; China; Cross Infection; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Pneumonia, Bacterial; Sepsis; Skin Diseases, Bacterial; Soft Tissue Infections

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