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

Richard G Wunderink, Antoine Roquilly, Martin Croce, Daniel Rodriguez Gonzalez, Satoshi Fujimi, Joan R Butterton, Natasha Broyde, Myra W Popejoy, Jason Y Kim, Carisa De Anda, Richard G Wunderink, Antoine Roquilly, Martin Croce, Daniel Rodriguez Gonzalez, Satoshi Fujimi, Joan R Butterton, Natasha Broyde, Myra W Popejoy, Jason Y Kim, Carisa De Anda

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.

Keywords: Staphylococcal infections; gram-positive cocci; healthcare-associated bacterial pneumonia; ventilator-associated bacterial pneumonia.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Patient disposition. Abbreviations: CE, clinically evaluable; ITT, intention-to-treat; LZD, linezolid; mITT, microbiological intention-to-treat; TOC, test of cure; TZD, tedizolid. aPatients may have been excluded for multiple reasons. bFour patients were randomized to receive tedizolid phosphate but were administered linezolid in error. These patients were included in the tedizolid ITT population for efficacy analyses but were included in the linezolid safety population. One patient was randomized to receive linezolid but was administered tedizolid phosphate in error. This patient was included in the linezolid ITT population for efficacy analyses but was included in the tedizolid safety population. cReasons for exclusion from these populations are provided in the Supplementary Appendix (Supplementary Table 7).

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