Efficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure Infection

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria in the United States, Europe, and other countries. In this multicenter, double-blind, phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the United States were randomized to receive 200 mg of tedizolid, intravenously (i.v.)/orally (p.o.), once daily for 6 days or 600 mg of linezolid, i.v./p.o.

Infections associated with, or in close proximity to, a prosthetic device 3.
Severe sepsis or septic shock 4.
Known bacteremia at time of screening 5.
Acute bacterial skin and skin structure infection (ABSSSI) due to or associated with any of the following:  Suspected or documented Gram-negative pathogens in patients with cellulitis/erysipelas or major cutaneous abscess that require an antibiotic with specific Gram-negative coverage. Patients with wound infections where Gram-negative adjunctive therapy is warranted may be enrolled if they meet the other eligibility criteria  Diabetic foot infections, gangrene, or perianal abscess  Concomitant infection at another site not including a secondary ABSSSI lesion (e.g. septic arthritis, endocarditis, osteomyelitis)  Infected burns  Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular disease (arterial or venous)  Any evolving necrotizing process (i.e. necrotizing fasciitis)  Infected human or animal bites. However, arthropod (e.g. insects, spiders, 'bugs') bites are allowed only if subject actually witnessed the arthropod bite through the skin in the area of the ABSSSI; these are not considered animal bites in this study  Infections at vascular catheter sites or involving thrombophlebitis  Incision surgical site infection with any of the following characteristics: o Follows clean-contaminated surgery (urgent  Use of antibiotics as follows:  Systemic antibiotic with activity against Gram-positive cocci for the treatment of any infection within 24 hours before the first infusion of study drug  Patients who failed prior therapy for the primary infection site are also excluded from enrollment  Topical antibiotic on the primary lesion within 24 hours before the first infusion of study drug except for antibiotic/antiseptic-coated dressing applied to the clean post-surgical wound 7.
Administration of linezolid within 30 days before the first infusion of the study drug 8.
Recent history of opportunistic infections where the underlying cause of these infections is still active (e.g. leukemia, transplant, acquired immunodeficiency syndrome [AIDS]) 9.
Receiving chronic systemic immunosuppressive therapy such as prednisone doses ≥20 mg per day for ≥3 of the last 12 months or therapies that in the Investigator's judgement could predispose to opportunistic infections 10. Chronic (daily for the previous 30 days) use of antipyretic medication (e.g. acetaminophen, paracetamol, non-steroidal anti-inflammatory drugs). Low-dose aspirin (≤200 mg per day) for cardiovascular prophylaxis is allowed 11. Receiving treatment for active tuberculosis 12. Last known CD4 count <200 cells/mm 3 in patients with AIDS 13. Current or anticipated neutropenia with absolute neutrophil count <1000 cells/mm 3 14. Severe renal disease defined as creatinine clearance <30 mL/min estimated by the Cockcroft-Gault formula or requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous dialysis, or other forms of renal filtration 15. Alanine aminotransferase or aspartate aminotransferase ≥5 upper limit of normal or moderate-to-severe hepatic disease with Child-Pugh score ≥7 defined by the following:  Presence of ascites upon examination  Evidence of encephalopathy upon examination  Total bilirubin ≥2 mg/dL  Serum albumin ≤3.5 g/dL  Prothrombin time ≥4 seconds longer than control, or international normalized ratio ≥1.7 16. Significant or life-threatening condition or organ or system condition or disease (e.g. endocarditis, meningitis, unstable CNS conditions, acidosis or history of Lv X, Alder J, Li L, O'Riordan W, Rybak MJ, Ye H, Zhang R, Zhang Z, Zhu X, Wilcox MH. Efficacy and safety of tedizolid phosphate versus linezolid in a randomized Phase 3 trial in patients with acute bacterial skin and skin structure infection 3 lactic acidosis) that would confound or interfere with the assessment of the ABSSSI 17. Electrocardiogram finding of corrected QT interval >500 msec using either Bazett's correction method (QTcB) or Fridericia's correction method (QTcF) 18. In patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or thyrotoxicosis, the use of the following medications within 2 days before the first infusion of study drug or planned use through the end of therapy (EOT) visit:  Systemic use of directly and indirectly acting sympathomimetic agents (e.g. pseudoephedrine, phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), or dopaminergic agents (e.g. dopamine, dobutamine). Use of a small amount of a vasoconstrictor (e.g. lidocaine containing epinephrine) during a minor surgical procedure under local anesthesia (e.g. incision and drainage) is allowed 19. Use of the following medications within 14 days before the first infusion of study drug or planned use through the EOT visit:  Monoamine oxidase A and B inhibitors (e.g. phenelzine, isocarboxazid)  Serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin 5hydroxytryptamine receptor agonists (triptans), meperidine, or buspirone 20. High tyramine diet 21. Treatment with any investigational medicinal product within 30 days before the first infusion of study drug and previous assignment to treatment during this study 22. Investigational device present, or removed <30 days before the first infusion of study drug or presence of device-related infection 23. Previous inclusion in the tedizolid phosphate development programme 24. Hypersensitivity to oxazolidinones or any component in the formulation 25. If aztreonam adjunctive therapy is required in patients with wound infections, history of hypersensitivity to ceftazidime or any component of the aztreonam formulation 26. For patients with wound infections, history of hypersensitivity to metronidazole or any component of the formulation, if metronidazole adjunctive therapy is required 27. Patients who the Investigator considers unlikely to adhere to the protocol, comply with study drug administration, or complete the clinical study 28. Close affiliation with the investigational site (e.g. a close relative of the Investigator, dependent person [e.g. employee or student of the investigational site]) Lv X, Alder J, Li L, O'Riordan W, Rybak MJ, Ye H, Zhang R, Zhang Z, Zhu X, Wilcox MH. Efficacy and safety of tedizolid phosphate versus linezolid in a randomized Phase 3 trial in patients with acute bacterial skin and skin structure infection 4

Detailed definitions of all secondary endpoints
Investigator's assessment of clinical response at 48-72-hour visit:  Improving: improvement in the overall clinical status of the ABSSSI that was compatible with continuation of study drug therapy  Stable: signs and symptoms were stable, no apparent change in the overall clinical status of the ABSSSI that was compatible with continuation of study drug therapy  Failure: patient did not meet the requirements of 'Improving' or 'Stable' clinical response

Investigator's assessment of clinical response at Day 7 visit:
 Improving: improvement in the overall clinical status of the ABSSSI that was compatible with continuation of study drug therapy; a decrease in primary ABSSSI lesion size was assessed (area, length and width) compared with baseline; investigator assessment of tenderness was mild or absent; and no purulent drainage from a wound infection, or the purulent drainage was assessed with a lesser intensity compared with baseline/screening  Failure: patient did not meet the requirements of 'Improving' clinical response

Programmatic objective clinical response at EOT (Day 11) visit:
 Sustained clinical success was defined if a patient was afebrile (<37.7°C oral, investigator reported) or fever ≥37.7°C was attributable to a cause other than the primary ABSSSI; a decrease in primary ABSSSI lesion size was assessed (area, length and width) compared with baseline; the investigator assessment of tenderness was mild or absent; and no purulent drainage from a wound infection or the purulent drainage was assessed with a lesser intensity compared with baseline/screening. o Additionally, the patient did not receive any systemic concomitant antibiotic treatment with activity against the baseline pathogen (with the exception of aztreonam and/or metronidazole for patients with wound infection); did not have a treatment-emergent adverse event leading to discontinuation of study drug requiring additional antibiotic therapy to treat their ABSSSI; did not receive any additional antibiotic to treat the primary ABSSSI; no unplanned major surgical intervention was performed to the primary ABSSSI; did not develop osteomyelitis after baseline; for a patient with a wound infection or an abscess, no incision plus drainage was performed after Day 1 unless it was planned at randomization; for a patient with cellulitis/erysipelas, no incision plus drainage was performed after the 48-72-hour visit.
Lv X, Alder J, Li L, O'Riordan W, Rybak MJ, Ye H, Zhang R, Zhang Z, Zhu X, Wilcox MH. Efficacy and safety of tedizolid phosphate versus linezolid in a randomized Phase 3 trial in patients with acute bacterial skin and skin structure infection 5  Clinical failure was defined if a patient was febrile (≥37.7°C oral, investigator reported) and fever was attributable to the primary ABSSSI; no decrease in primary ABSSSI lesion size compared with baseline was assessed; investigator assessment of tenderness was moderate or severe, or persistent purulent drainage from a wound infection at equivalent or greater intensity compared with baseline/screening. o Moreover, the patient received systemic concomitant antibiotic treatment with activity against the baseline pathogen (with the exception of aztreonam and/or metronidazole for patients with wound infection); or had a treatment-emergent adverse event leading to discontinuation of study drug requiring additional antibiotic therapy to treat their ABSSSI; or received any additional antibiotic to treat the primary ABSSSI; or an unplanned major surgical intervention was performed to the primary ABSSSI; or developed osteomyelitis after baseline; or for a patient with a wound infection or an abscess, incision plus drainage was performed after Day 1; or for a patient with cellulitis/erysipelas, an incision plus drainage was performed after the 48-72-hour visit; or death occurred within 28 days of the first infusion of study drug.  Indeterminate response was defined if the patient had osteomyelitis at baseline; or was lost to follow-up or withdrew consent prior to EOT; or a Gram-negative pathogen was confirmed at baseline that required a different antibiotic therapy for patients with cellulitis or abscess or a different antibiotic therapy other than aztreonam and/or metronidazole for patients with wound infection.

Investigator's assessment of clinical response at EOT and post-therapy evaluation (PTE) visits:
     ABSSSI: acute bacterial skin and skin structure infection a Signs and symptoms worsened but treatment was continued by investigator b Signs and symptoms did not improve as assessed by investigator Table S4. Improvements in regional/local signs in modified intent-to-treat population in post-hoc analyses