A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

Abstract

Background Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. Methods In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. Results Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, –1.8%; 95% confidence interval [CI]: –8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, –7.6%; 97.5% CI: –15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. Conclusions Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. Clinical Trials Registration NCT02019420.

New Insights in the Pathophysiology of Hospital- and Ventilator-Acquired Pneumonia: A Complex Interplay between Dysbiosis and Critical-Illness–Related Immunosuppression

“…In this setting, the sterilization of lung airways with antimicrobial therapies cannot restore lung homeostasis, which can explain why the rates of treatment failure still reach 30% in the most recent studies evaluating treatment of HAP. 3 4 92…”

Pharmacokinetics and Pharmacodynamics of Tedizolid

“…In addition to clinical studies in skin and skin-structure infections, in the first phase III clinical study in patients with hospital-acquired and ventilator-associated pneumonia, TDZ (200 mg/day for 6 days) was non-inferior to LNZ (600 mg twice daily for 10 days) in the primary outcome (28 days all-cause mortality). However, the non-inferiority of TDZ to LNZ was not established while comparing the secondary outcome (investigator-assessed clinical response at test of cure) [ 96 ]. There are no clear reasons for this discrepancy but the complexity of the disease and the subjectivity of defining “clinical cure” by clinicians can lead to this lack of consistency in the clinical outcomes.…”

Antibiotic Approvals in the Last Decade: Are We Keeping Up With Resistance?

“…17 -36 Table 2 highlights the primary end point results of pivotal clinical trials that were conducted to assess their efficacy in the management of various disease states. 37 -86 Table 3 summarizes their contraindications, warnings and precaut...…”

“…73,74 Recently, in a phase 3 trial, tedizolid was shown to be noninferior to linezolid in the treatment of HABP/VABP for all-cause mortality at day 28; however, tedizolid failed to meet noninferiority for investigator-assessed clinical response at test of cure. 75 Tedizolid is an alternative option for the treatment of ABSSSIs but is not commonly used in clinical practice because of the availability of generic linezolid and other inexpensive options. Tedizolid has been used off-label with a varying degree of success in the treatment of prosthetic joint infections, osteomyelitis, central nervous system infections, mycobacterial infections, and pneumonia.…”