Carisa De Anda

Tedizolid Phosphate vs Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections: The ESTABLISH-1 Randomized Trial

IMPORTANCE 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. OBJECTIVES To establish the noninferiority of tedizolid phosphate vs linezolid in treating ABSSSIs and compare the safety of the 2 agents. DESIGN, SETTING, AND PATIENTS 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). INTERVENTIONS 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. MAIN OUTCOME MEASURES 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. RESULTS 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. CONCLUSIONS AND RELEVANCE 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01170221.

Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial

BACKGROUND New antibiotics are needed to treat infections caused by drug-resistant bacteria. Tedizolid is a novel oxazolidinone antibacterial drug designed to provide enhanced activity against Gram-positive pathogens. We aimed to assess the efficacy and safety of intravenous to oral tedizolid for treatment of patients with acute bacterial skin and skin-structure infections. METHODS ESTABLISH-2 was a randomised, double-blind, phase 3, non-inferiority trial done between Sept 28, 2011, and Jan 10, 2013, at 58 centres in nine countries. Patients (aged ≥12 years) with acute bacterial skin and skin-structure infections (cellulitis or erysipelas, major cutaneous abscess, or wound infection) that had a minimum lesion area of 75 cm(2) and were suspected or documented to be associated with a Gram-positive pathogen, were randomly assigned (1:1), via an interactive voice-response system with block randomisation, to receive intravenous once-daily tedizolid (200 mg for 6 days) or twice-daily linezolid (600 mg for 10 days), with optional oral step-down. Randomisation was stratified by geographic region and type of acute bacterial skin and skin-structure infection. The primary endpoint was early clinical response (≥20% reduction in lesion area at 48-72 h compared with baseline), with a non-inferiority margin of -10%. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01421511. FINDINGS 666 patients were randomly assigned to receive tedizolid (n=332) or linezolid (n=334). 283 (85%) patients in the tedizolid group and 276 (83%) in the linezolid group achieved early clinical response (difference 2·6%, 95% CI -3·0 to 8·2), meeting the prespecified non-inferiority margin. Gastrointestinal adverse events were less frequent with tedizolid than linezolid, taking place in 52 (16%) of 331 patients and 67 (20%) of 327 patients in the safety population. Treatment-emergent adverse events leading to discontinuation of study drug were reported by one (<1%) patient in the tedizolid group and four (1%) patients in the linezolid group. INTERPRETATION Intravenous to oral once-daily tedizolid 200 mg for 6 days was non-inferior to twice-daily linezolid 600 mg for 10 days for treatment of patients with acute bacterial skin and skin-structure infections. Tedizolid could become a useful option for the treatment of acute bacterial skin and skin-structure infections in the hospital and outpatient settings. FUNDING Cubist Pharmaceuticals.

Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections

ABSTRACT Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P = 0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P = 0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P = 0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.)

Clinical Response of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections by Severity Measure Using a Pooled Analysis From Two Phase 3 Double-Blind Trials

ABSTRACT 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.)

262Effect of NSAID/Corticosteroid Use on the Efficacy of Tedizolid in Acute Bacterial Skin and Skin Structure Infections: Pooled Data From the Phase 3 ESTABLISH-1 and ESTABLISH-2 Studies

Background. Tedizolid (TZD) is a novel oxazolidinone with potent activity against a wide range of Gram-positive pathogens, including MRSA, and with a favorable safety profile. In two Phase 3 trials, ESTABLISH-1 and ESTABLISH-2, TZD (200 mg once daily for 6 days) demonstrated noninferiority to linezolid (LZD) (600 mg twice daily for 10 days) in patients with acute bacterial skin and skin structure infections (ABSSSI). Use of non-steroidal anti-inflammatory drugs (NSAID) and/or corticosteroids (CS) is common in patients with ABSSSI. Due to their anti-inflammatory properties, it is possible that concomitant use of these agents may reduce lesion size and confound the primary outcome of ≥20% reduction in lesion size at the 48–72 hour visit. This subgroup analysis of pooled data from ESTABLISH-1 and -2 examined the effect of concomitant NSAID/CS use on early clinical response in patients with ABSSSI receiving TZD or LZD. Methods. Patients with ABSSSI (lesion surface area ≥75 cm and ≥1 regional or systemic sign of infection) received TZD 200 mg qd for 6 days or LZD 600 mg bid for 10 days. The use of NSAIDS/CS was documented for each patient and the primary outcome for both therapies at the 48-72 h visit was measured with/without NSAID/ CS use. Results. A total of 1333 patients were randomly assigned to TZD or LZD. Patients were mostly male (63.1%); average age of 44 years. The most common ABSSSI was cellulitis (45.3% and 45.9% in TZD and LZD treatment groups, respectively), followed by major cutaneous abscess (25.3% and 24.8%), and wound infections (29.4% and 29.3%). Overall, 44 of 664 patients (6.6%) in the TZD treatment group and 63 of 669 patients (9.4%) in the LZD group received NSAID or oral CS during the first 72 hours of treatment. Among patients receiving NSAID/CS, early clinical response rates at the 48-72 h visit were similar between TZD and LZD groups (70.5% vs 69.8%), but lower overall than compared with patients not receiving NSAID/CS (82.4% with TZD vs 80.4% with LZD). Conclusion. Early clinical response rates were similar in patients treated with either TZD or LZD for ABSSSI in the ESTABLISH-1 and -2 trials, regardless of NSAID/ CS use. This finding suggests there is an absence of bias with anti-inflammatory use in assessing early clinical response rates in ABSSSI clinical trials. Disclosures. T. Sandison, Cubist: Employee, Salary C. De Anda, Cubist: Employee and Shareholder, Salary A. Das, Cubist: Consultant, Consulting fee; Cempra: Consultant, Consulting fee; Cerexa: Consultant, Consulting fee; Nabriva: Consultant, Consulting fee; Paratek: Consultant, Consulting fee; Trius: Consultant, Consulting fee; Achaogen: Consultant, Consulting fee; Durata: Consultant, Consulting fee P. Prokocimer, Cubist: Employee and Shareholder, Salary