• Infectious Disease Clinical Trials
• Bacterial Infections

In a Phase 3 study comparing tedizolid, a second generation oxazolidinone, to linezolid in patients with acute bacterial skin and skin structure infections (ABSSSI), tedizolid phosphate was noninferior and demonstrated high microbiological efficacy compared with linezolid. Carisa De Anda, PharmD, Trius Therapeutics, San Diego, California, USA, presented a poster [De Anda et al. ICAAC 2012 L1–1665] on the outcomes using the the new Food and Drug Administration (FDA) method for assessing clinical response, programmatic assessment, and the traditional post-treatment investigator assessment.

This was a randomized (1:1), double-blind, multicenter study of oral tedizolid phosphate (TDZ) 200 mg QD administered for 6 days versus oral linezolid 600 mg BID for 10 days in adult patients (mean age 43.4 years) with ABSSSI consisting of cellulitis/erysipelas (41%), infected wounds (29%), and major cutaneous abscesses (30%). Men and women aged ≥18 years with ABSSSI that started at least 7 days before screening were included. To be eligible, patients also had to have at least 1 of the following syndromes: cellulitis with erythema surface area of at least 75 cm² and at least 1 local sign and symptom (induration, warmth, pain/tenderness, or swelling), major cutaneous abscess with erythema surface area of at least 75 cm² and extending at least 5 cm from margin of pus collection and at least 1 local sign and symptom (fluctuance, incision and drainage required, warmth, pain/tenderness), or wound infection including surgical site infection and trauma with erythema surface area of at least 75 cm² extending at least 5 cm from margin and purulent drainage. All syndromes required at least 1 regional or systemic sign of infection (lymph node tenderness and increase in volume, fever ≥ 38°C, WBC ≥10,000 or <4000 or >10% immature neutrophils) and suspected or documented Gram-positive infection.

A total of 667 patients from North American, Europe, and South America were enrolled in the study. Demographics as well as surface area of lesion (188.3 cm² in the tedizolid phosphate group vs 190.0 cm² in the linezolid group) were comparable between the treatment groups.

Tedizolid phosphate once a day for 6 days was noninferior to linezolid administered twice a day for 10 days for both programmatic outcome (79.5% vs 79.4%; 95% CI, −6.1 to 6.2), defined as cessation of spread and no fever at the 48 to 72 hour visit after the first dose of study drug, and investigator's assessment performed at the 7 to 14 day post-therapy evaluation. In the intention-to-treat population, clinical success (defined by the investigator's assessment) was 85.5% in the tedizolid group and 86.0% in the linezolid group. There was >80% concordance between the programmatic outcome at the 48 to 72 hour visit and the investigator's assessment of clinical response at the post-therapy evaluation point.

The Biomarker Consortium of the Foundation for the National Institute of Health [Talbot GH et al. Clin Infect Dis 2012] recommended to the FDA that clinical success be defined as ≥20% decrease in lesion size from baseline at the 48 to 72 hour visit without fever included in the endpoint. The results were consistent with the primary outcome with a responder rate of 78% in the tedizolid arm and 76.1 % in the linezolid arm.

The most common baseline infection site pathogen was Gram-positive (63% of patients in both groups). In the tedizolid treatment group, methicillin-resistant Staphylococcus aureus (MRSA; 42.1%) and methicillin-sensitive S. aureus (MSSA; 39.7%) were the most common isolated pathogens. In the linezolid treatment group, similar percentages were reported for MRSA (43.1%) and MSSA (41.6%). The per-patient microbiological response at the post-therapy evaluation is shown in Table 1.

• © 2012 MD Conference Express®