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Platelet profile in patients with acute bacterial skin and skin structure infections receiving tedizolid or linezolid: findings from the Phase 3 ESTABLISH clinical trials.

ABSTRACT: Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). The intent of this study was to characterize the platelet profiles of patients receiving tedizolid relative to linezolid over the course of treatment using pooled data from these two trials. The occurrences of clinically defined and statistical analysis plan-specified reduced platelet counts were assessed at the study days 7 to 9 visit, the study days 11 to 13 visit, and the posttherapy evaluation (PTE) visit. At the study days 7 to 9 visit, incidences of reduced platelet counts were low and largely similar between the groups. The only notable difference was a lower incidence of thrombocytopenia (platelet counts, <150,000 cells/mm(3)) among patients who received tedizolid (3.2%) relative to those who received linezolid (5.6%). At the study days 11 to 13 visit, patients who received tedizolid had lower incidences of platelet counts of <150,000 cells/mm(3) (-5.9%), <112,500 cells/mm(3) (-2.4%), and <100,000 cells/mm(3) (-1.9%) than patients in the linezolid group. Similar differences were noted at the PTE visit. Findings across the two phase 3 ABSSSI trials suggest that 6 days of 200 mg tedizolid daily confers a low potential for reduced platelet counts among patients with ABSSSIs. (The ESTABLISH-1 and ESTABLISH-2 trials have been registered at ClinicalTrials.gov under registration numbers NCT01170221 and NCT01421511, respectively.).

SUBMITTER: Lodise TP

PROVIDER: S-EPMC4249542 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Platelet profile in patients with acute bacterial skin and skin structure infections receiving tedizolid or linezolid: findings from the Phase 3 ESTABLISH clinical trials.

Lodise Thomas P TP Fang Edward E Minassian Sonia L SL Prokocimer Philippe G PG

Antimicrobial agents and chemotherapy 20140922 12

Tedizolid, the active moiety of tedizolid phosphate, is a recently approved oxazolidinone antibacterial with activity against a wide range of Gram-positive pathogens, including resistant strains such as methicillin-resistant Staphylococcus aureus. To date, 6 days of 200 mg tedizolid once daily has been shown to be noninferior to 10 days of 600 mg linezolid twice daily in two randomized, double-blind phase 3 trials (ESTABLISH-1 and ESTABLISH-2) for the treatment of patients with acute bacterial s ...[more]

PMID: 25246392

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Project description: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.).

Project description:BackgroundAcute bacterial skin and skin structure infections (ABSSSI) are a frequent cause of hospital admissions in the United States. Safe and effective outpatient treatments may lower ABSSSI-associated health care costs by reducing unnecessary hospital admissions. Using data from 2 phase 3 trials (ESTABLISH-1, NCT01170221; ESTABLISH-2, NCT01421511), this post-hoc analysis explored the efficacy and safety of tedizolid in an outpatient setting.MethodsSubgroup analysis was performed on US outpatients (defined as patients who were not in hospital at the time of treatment initiation) with ABSSSI caused by presumed or proven gram-positive pathogens. Patients were randomly assigned to receive tedizolid phosphate 200 mg once daily for 6 days (n = 403) or linezolid 600 mg twice daily for 10 days (n = 410). The primary end point was early clinical response (48-72 hours after the start of treatment). Secondary end points included investigator-assessed clinical response at end of therapy (EOT) and post-therapy evaluation (PTE; 7-14 days after therapy). Additional assessments included the patient-reported level of pain using a visual analog scale (VAS) and the per-pathogen favorable microbiological response rate at the PTE visit. Compliance with treatment and safety outcomes was also recorded.ResultsEarly clinical response was similar between treatment groups (tedizolid, 82.4%; linezolid, 79.0%), as was investigator-assessed clinical response at EOT (tedizolid, 87.1%; linezolid, 86.1%) and PTE (tedizolid, 83.1%; linezolid, 83.7%). Mean changes from baseline to days 10 to 13 in VAS scores were identical between treatment groups (tedizolid, -51.9 mm; linezolid, -51.9 mm). Microbiological eradication rates were generally similar in both treatment groups for all key pathogens. Patients in both groups had favorable response at PTE. More tedizolid-treated patients (89.3%) than linezolid-treated patients (77.3%) were compliant with treatment. The most frequently reported drug-related treatment-emergent adverse events were nausea (tedizolid, 10.7%; linezolid, 13.8%), diarrhea (tedizolid, 4.5%; linezolid, 5.9%), and headache (tedizolid, 5.5%; linezolid, 4.4%). Treatment discontinuation rates were low for both treatment groups (tedizolid, 0.7%; linezolid, 1.0%).ConclusionShort-course therapy with tedizolid can successfully treat patients with ABSSSI caused by presumed or proven gram-positive pathogens in an outpatient setting.

Dataset Information

Platelet profile in patients with acute bacterial skin and skin structure infections receiving tedizolid or linezolid: findings from the Phase 3 ESTABLISH clinical trials.

Publications

Platelet profile in patients with acute bacterial skin and skin structure infections receiving tedizolid or linezolid: findings from the Phase 3 ESTABLISH clinical trials.

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