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

c 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.)

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

“…This outcome was observed independently of the differences in exposure times (31,32). Pooled data from these clinical trials suggested a potentially clinically relevant difference in terms of adverse platelet outcomes between linezolid and tedizolid, but the authors concluded that longer-term studies were necessary to ascertain this possibility (59).…”

Thrombocytopenia with Tedizolid and Linezolid

“…In the tedizolid post-approval period, the risk of thrombocytopenia was over 30 times higher with both tedizolid and linezolid as compared with adverse event reports from other medications. In the period prior to tedizolid approval, the risk of thrombocytopenia was 12 times higher with linezolid (5,14).…”

“…A "substantially low platelet count" has been defined as <75% of the lower limit of normal or baseline, where the lower limit of normal (LLN) is 150,000 cells/mm 3 , resulting in a platelet count of 112,500 cells/mm 3 (3,5,15). However, a lower threshold of less than 100,000 cells/mm 3 is considered clinically relevant and has been used to operationally define thrombocytopenia (5,14).…”

Multidrug‐resistant Enterobacteriaceae, Pseudomonas aeruginosa, and vancomycin‐resistant Enterococcus: Three major threats to hematopoietic stem cell transplant recipients

“…Tigecycline has major limitations as outlined in Table , and sparse clinical data support the use of these alternative agents for VRE bacteremia. Tedizolid is a new oxazolidinone that appears to be less myelosuppressive than linezolid, and thus is an attractive candidate for use in HSCT recipients. However, animal models have demonstrated that the efficacy of tedizolid is markedly reduced in the setting of neutropenia, thus making it a less attractive alternative for VRE infections in neutropenic patients.…”