tedizolid-phosphate and Soft-Tissue-Infections

Tedizolid is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Although tedizolid shares many similar properties with linezolid, another oxazolidinone used to treat ABSSSI, the two antibiotics have several key differences. Areas covered: This review provides a detailed summary of the overall pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of tedizolid for the treatment of ABSSSI. Expert opinion: Compared to other antibiotics used for ABSSSI, tedizolid has several advantages. Tedizolid has a long half-life, allowing for once daily dosing. Tedizolid also has broad spectrum of activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, Coagulase-negative Staphylococci, and Enterococci - including isolates demonstrating resistance to linezolid. It is available in both oral and intravenous formulations, and, has outstanding oral bioavailability, allowing for oral-step down therapy. There is also some evidence that, tedizolid has fewer significant interactions with serotonin reuptake inhibitors or monoamine oxidase inhibitors than linezolid. Finally, thrombocytopenia may occur less often with tedizolid than linezolid. However, these benefits must be weighed against the financial cost of tedizolid and the availability of alternative antibiotic choices.

Topics: Animals; Anti-Bacterial Agents; Biological Availability; Drug Interactions; Half-Life; Humans; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Soft Tissue Infections

To review the chemistry, pharmacology, microbiology, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug interactions, dosing, and administration of tedizolid phosphate (TDZ).. A search of PubMed using the terms "tedizolid," "torezolid," "TR-701," "TR-700," "DA-7157," and "DA-7218" was performed. The manufacturer's Web site was also reviewed to further identify relevant information.. All English-language articles from 2006 to November 2014 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not uncovered in the searches.. TDZ is the second oxazolidinone antibiotic with a spectrum of activity targeted against gram-positive organisms including methicillin-resistant Staphylococcus aureus . It is administered via intravenous infusion or orally without regard to food. The primary route of elimination is fecal excretion. Advanced age, hepatic dysfunction, or renal impairment does not alter its disposition. Phase III clinical trials have demonstrated that TDZ 200 mg daily for 6 days is noninferior to linezolid 600 mg twice daily for 10 days in the treatment of adults with skin and soft tissue infections caused or suspected to be caused by gram-positive organisms. TDZ has a side effect profile similar to that of linezolid and a lower potential for drug interactions.. TDZ has been shown to be safe and effective for the treatment of adults with skin and soft tissue infections. Further research is needed to refine its role, particularly for the treatment of patients requiring a longer duration of therapy and in those receiving concomitant serotonergic agents.

Topics: Adult; Anti-Bacterial Agents; Drug Interactions; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Soft Tissue Infections

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

The objective of this open-label, randomised (i.e. 2:1 ratio), Phase 3 study was to compare the efficacy and safety of tedizolid phosphate 200 mg, once-daily treatment with that of linezolid 600 mg, twice-daily treatment for 7-14 days in Japanese adult patients (N = 125) with skin and soft tissue infections (SSTIs) and/or for 7-21 days for those with SSTI-related bacteraemia, caused by confirmed or highly suspected methicillin-resistant Staphylococcus aureus (MRSA). Primary outcome was clinical cure rate at test-of-cure (TOC, in SSTI: 7-14 days, in bacteraemia: 4-6 weeks after end-of-therapy [EOT]) time point in the microbiologically evaluable MRSA (ME-MRSA) population (N = 39). Secondary endpoints were clinical and microbiological response rates at EOT. Safety parameters were evaluated in the safety analysis population up to follow up. Data analysis was descriptive in nature. Baseline characteristics of patients were similar between treatment groups. At TOC in the ME-MRSA population, clinical cure rate was similar in tedizolid phosphate (92.6%) and linezolid (88.9%) groups. At EOT, clinical cure (tedizolid phosphate: 93.1%, linezolid: 90.0%) and microbiological success (tedizolid phosphate: 93.1%, linezolid: 100.0%) rates were similar in the ME-MRSA population. Both treatments were well tolerated; overall treatment-emergent adverse events (TEAEs) in tedizolid phosphate (79.5%) and linezolid (75.6%) treatment groups were similar. Drug-related TEAEs were numerically lower with tedizolid phosphate versus linezolid (30.1%; 39.0%, respectively), as well as gastrointestinal (21.7%; 26.8%) and myelosuppression-related (2.4%; 22.0%) TEAEs. One death occurred in the linezolid group. Tedizolid phosphate may be an appropriate antibiotic for the treatment of SSTIs in Japanese adult patients. International clinical trial registration number: NCT01967225. Japanese clinical trial registration number: JapicCTI-132308.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Female; Humans; Japan; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Prospective Studies; Skin Diseases, Bacterial; Soft Tissue Infections; Treatment Outcome

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.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Organophosphates; Oxazoles; Oxazolidinones; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Skin Infections; Staphylococcus aureus; Treatment Outcome; Young Adult

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