Tedizolid measures up to linezolid for bacterial pneumonia mortality, but not clinical cure

In the treatment of patients with gram-positive hospital-acquired (HABP) or ventilator-associated bacterial pneumonia (VABP), tedizolid works as well as linezolid in terms of 28-day all-cause mortality but not investigator-assessed clinical response, according to the results of a phase III trial.

“HABP/VABP is a complex disease process, and it is possible that neither [endpoint] alone adequately captures the clinical benefit of antibacterial therapies in this patient population,” the authors said.

Tedizolid phosphate is an oxazolidinone prodrug approved for the treatment of acute bacterial skin and skin structure infections. It has demonstrated broad activity against gram-positive pathogens, including methicillin-, vancomycin-, and certain linezolid-resistant strains of Staphylococcus aureus, which is among the commonly isolated pathogens in HABP/VABP. [Antimicrob Agents Chemother 2009;53:3236-3239; Antimicrob Agents Chemother 2012;56:4608-4613; J Chemother 2019;31:188-194]

In the noninferiority, double-blind, double-dummy trial, 726 patients (median age 61 years, 69.3 percent male) with ventilated HABP/VABP were randomized to receive intravenous (IV) tedizolid phosphate 200 mg once daily for 7 days (n=366) or IV linezolid 600 mg every 12 hours for 10 days (n=360). Those with concurrent gram-positive bacteraemia were treated for 14 days. Baseline characteristics, including the incidence of methicillin-resistant S. aureus (31.3 percent overall), were well balanced.

Tedizolid showed noninferiority to linezolid for day-28 all-cause mortality (28.1 percent vs 26.4 percent, respectively; difference, –1.8 percent, 95 percent confidence interval [CI], –8.2 to 4.7). [Clin Infect Dis 2021;doi:10.1093/cid/ciab032]

“Mortality rates were consistently similar between treatment groups over time and were comparable to previously reported rates in gram-positive HABP/VABP clinical trials,” the authors noted. [Clin Infect Dis 2011; 52:31-40; Clin Ther 2003;25:980-992; Clin Infect Dis 2012;54:621-629]

However, investigator-assessed clinical cure at test of cure (TOC) with tedizolid did not meet the noninferiority criterion (56.3 percent vs 63.9 percent; difference, –7.6 percent, 97.5 percent CI, –15.7 to 0.5). None of the factors examined in the subgroup or posthoc analyses accounted for this difference in clinical response.

Both drugs were well tolerated, with treatment-emergent adverse events occurring in 8.1 percent of patients on tedizolid and 11.9 percent of those on linezolid.

“The difference in clinical outcome is unlikely to be due to insufficient dosing, as previous studies have demonstrated that tedizolid has excellent pulmonary penetration, with epithelial lining fluid (ELF) concentrations higher than free plasma concentrations for the entire dosing interval and an approximately 40:1 ELF-to-plasma penetration ratio,” the authors pointed out. [Antimicrob Agents Chemother 2012;56:2627-2634]

“In addition, the high rates of pharmacokinetic/pharmacodynamic target attainment at TOC and day 28 (97 percent) also suggest that insufficient dosing was not an issue in this population,” they said.

The study was limited by the large proportion of gram-positive pathogens identified in mixed microbial infections (51.1 percent and 48.5 percent of patients in the tedizolid and linezolid groups, respectively) and lack of data on gram-negative pathogen susceptibilities.

“Together, these limitations make it difficult to determine whether efficacy (or lack of efficacy) was primarily attributable to the gram-positive therapy, gram-negative therapy, or both,” the authors acknowledged.