tedizolid-phosphate and Staphylococcal-Skin-Infections

In 2013 the US Food and Drug Administration (FDA) issued recommendations and guidance on developing drugs for treatment of skin infection using a new definition of acute bacterial skin and skin-structure infection (ABSSSI). The new classification includes cellulitis, erysipelas, major skin abscesses and wound infection with a considerable extension of skin involvement, clearly referring to a severe subset of skin infections. The main goal of the FDA was to better identify specific infections where the advantages of a new antibiotic could be precisely estimated through quantifiable parameters, such as improvement of the lesion size and of systemic signs of infection. Before the spread and diffusion of methicillin-resistant Staphylococcus aureus (MRSA) in skin infections, antibiotic therapy was relatively straightforward. Using an empiric approach, a β-lactam was the preferred therapy and cultures from patients were rarely obtained. With the emergence of MRSA in the community setting, initial ABSSSI management has been changed and readdressed. Dalbavancin, oritavancin and tedizolid are new drugs, approved or in development for ABSSSI treatment, that also proved to be efficient against MRSA. Dalbavancin and oritavancin have a long half-life and can be dosed less frequently. This in turn makes it possible to treat patients with ABSSSI in an outpatient setting, avoiding hospitalization or potentially allowing earlier discharge, without compromising efficacy. In conclusion, characteristics of long-acting antibiotics could represent an opportunity for the management of ABSSSI and could profoundly modify the management of these infections by reducing or in some cases eliminating both costs and risks of hospitalization.

Topics: Ambulatory Care; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Glycopeptides; Humans; Lipoglycopeptides; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Teicoplanin; United States; United States Food and Drug Administration

Tedizolid phosphate is the second commercially available oxazolidinone antibiotic, although the first one in class that is dosed once daily. It is a prodrug that is rapidly converted to the active compound tedizolid. Tedizolid has activity against a wide range of gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. It is approved to treat acute bacterial skin and skin structure infections (ABSSSIs). In 2 randomized controlled phase 3 trials, 6 days of tedizolid (200 mg once daily) has been proven to be noninferior to 10 days of linezolid (600 mg twice daily). These 2 ABSSSI studies have positioned tedizolid among the growing armamentarium of newer, novel, anti-gram-positive agents. Tedizolid appears to differ from linezolid in the incidence of gastrointestinal and hematologic side effects and appears to lack drug interactions with selective serotonin reuptake inhibitors. Conditions other than ABSSSI are currently being evaluated in clinical studies.

Topics: Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Drug Interactions; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Skin Diseases, Bacterial; Staphylococcal Skin Infections

In the Staphylococcus aureus neutropenic murine thigh-infection model, the ratio of the free area under the 24-hour concentration-time curve to the minimum inhibitory concentration (fAUC/MIC) was found to be the pharmacodynamic index most closely linked to bacterial effect, with a ratio of approximately 50 producing a static effect. Further work was undertaken in neutropenic versus non-neutropenic animals. The presence of granulocytes increased the activity of tedizolid considerably, 25-fold on average, and maximal effect was achieved at an exposure equivalent to approximately 200 mg tedizolid phosphate per day in humans (dosing regimen used in phase 2 and 3 clinical trials). The fAUC/MIC was also found to be the pharmacodynamically linked variable in the S. aureus neutropenic murine pneumonia model; the fAUC/MIC ratio required for a static effect was approximately 20. Pharmacokinetic (PK) data demonstrate that tedizolid penetrates well into the epithelial lining fluid (ELF) of the lung. Data from the pneumonia infection model and ELF penetration PK study support exploring its use in pneumonia.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Disease Models, Animal; Humans; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Pneumonia, Staphylococcal; Staphylococcal Skin Infections; Staphylococcus aureus

The novel oxazolidinone tedizolid phosphate is in late-stage development for acute bacterial skin and skin structure infections (ABSSSIs). Preclinical and phase 1 trials have shown that 200-mg once-daily tedizolid phosphate dosing achieves the appropriate pharmacokinetic goals for optimal antimicrobial effect, and a randomized phase 2 dose-ranging trial confirmed that tedizolid phosphate may be an option for the treatment of ABSSSIs at the 200-mg dose, the lowest effective dose, over a mean of 6.4 days of therapy. In the first of two phase 3 trials, 6 days of 200-mg once-daily oral tedizolid phosphate (plus 4 days of placebo) was noninferior to 10 days of 600-mg twice-daily oral linezolid when evaluated at both the early (48- to 72-hour assessment) and test-of-cure (7-14 days after the last dose of active or placebo agent was given) time points. Initial results from the second phase 3 trial (intravenous to oral therapy design) confirm the study met all primary and secondary endpoints and continues to add insight into the clinical utility of tedizolid phosphate.

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Humans; Organophosphates; Oxazoles; Staphylococcal Skin Infections; Treatment Outcome

The novel oxazolidinone tedizolid phosphate is in late-stage clinical development. In an effort to improve efficacy and safety, the adverse event profile and safety aspects of tedizolid phosphate have been evaluated in several preclinical animal models and through ongoing clinical trials. Early dose-ranging studies demonstrated a favorable overall adverse event profile and low thrombocytopenia rates, which have been consistently confirmed in phase 2 and 3 clinical trials. Pharmacokinetic modeling suggests a lower potential for monoamine oxidase interaction, and animal and human subject testing has confirmed these predictions. Studies in special patient populations showed a consistent and predictable pharmacokinetic profile across age groups and comorbid conditions, without evidence of increased incidence of adverse effects over matched controls. The favorable safety profile makes tedizolid phosphate an important new option for the management of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus.

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Humans; Organophosphates; Oxazoles; Staphylococcal Skin Infections

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). In a pooled analysis of 1,333 ABSSSI patients from the ESTABLISH clinical trials, treatment with tedizolid or linezolid demonstrated similar early and posttherapy clinical responses in nonsevere and severe disease, irrespective of the parameters used to measure ABSSSI severity. Shorter 6-day treatment of ABSSSI, including those that were severe, with tedizolid phosphate demonstrated efficacy comparable to that of 10-day treatment with linezolid. (The ESTABLISH studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01170221 and NCT01421511.).

Topics: Adolescent; Adult; Anti-Bacterial Agents; Double-Blind Method; Humans; Linezolid; Organophosphates; Oxazoles; Skin; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Young Adult

Tedizolid (TR-700, formerly torezolid) is the active moiety of the prodrug tedizolid phosphate (TR-701), a next-generation oxazolidinone, with high potency against Gram-positive species, including methicillin-resistant Staphylococcus aureus (MRSA). A recently completed randomized, double-blind phase 2 trial evaluated 200, 300, or 400 mg of oral tedizolid phosphate once daily for 5 to 7 days in patients with complicated skin and skin structure infections. This report examines the in vitro activity of tedizolid and Zyvox (linezolid) against Gram-positive pathogens isolated at baseline and describes the microbiological and clinical efficacy of tedizolid. Of 196 isolates tested, 81.6% were S. aureus, and of these, 76% were MRSA. The MIC(50) and MIC(90) of tedizolid against both methicillin-susceptible S. aureus (MSSA) and MRSA were 0.25 μg/ml, compared with a MIC(50) of 1 μg/ml and MIC(90) of 2 μg/ml for linezolid. For coagulase-negative staphylococci (n = 7), viridans group streptococci (n = 15), and beta-hemolytic streptococci (n = 3), the MICs ranged from 0.03 to 0.25 μg/ml for tedizolid and from 0.12 to 1 μg/ml for linezolid. The microbiological eradication rates at the test-of-cure visit (7 to 14 days posttreatment) in the microbiologically evaluable population (n = 133) were similar in all treatment groups, with overall eradication rates of 97.7% for all pathogens, 97.9% for MRSA, and 95.7% for MSSA. The clinical cure rates for MRSA and MSSA infections were 96.9% and 95.7%, respectively, across all dose groups. This study confirms the potent in vitro activity of tedizolid against pathogenic Gram-positive cocci, including MRSA, and its 4-fold-greater potency in comparison with linezolid. All dosages of tedizolid phosphate showed excellent microbiological and clinical efficacy against MRSA and MSSA.

Topics: Acetamides; Adolescent; Adult; Aged; Anti-Bacterial Agents; Culture Media; Double-Blind Method; Drug Administration Schedule; Female; Humans; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Organophosphates; Oxazoles; Oxazolidinones; Skin; Staphylococcal Skin Infections; Staphylococcus; Tetrazoles

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

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Neutropenia; Organophosphates; Oxazoles; Staphylococcal Skin 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