RCT shows tedizolid may be effective alternative to linezolid for gram-positive HABP, VABP
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In a randomized controlled trial, tedizolid was noninferior to linezolid for day 28 all-cause mortality in the treatment of gram-positive ventilated hospital-acquired bacterial pneumonia and ventilator-associated pneumonia.
“However,” researchers wrote, “the result for the key secondary end point in this study does not support the primary end point, as investigator-assessed clinical outcome did not meet the noninferiority criterion.”
“Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated pneumonia (VABP) are important health care-associated infections and are associated with high mortality rates,” Carisa S. De Anda, PharmD, executive director of clinical research at Merck Research Laboratories, told Healio. “HABP/VABP can be caused by Staphylococcus aureus, including MRSA. There are limited treatment options for treatment of MRSA HABP/VABP. “
De Anda and colleagues performed a randomized, noninferiority, double-blind, double-dummy, global phase 3 trial in which patients were randomly assigned in a 1:1 ratio to receive IV tedizolid phosphate 200 mg once daily for 7 days or IV linezolid 600 mg every 12 hours for 10 days. The primary efficacy end points were day 28 all-cause mortality (ACM) and investigator-assessed clinical response at test of cure (TOC) in the intention-to-treat population. In total, 726 patients were randomly assigned 366 to receive tedizolid and 360 to receive linezolid.
The study demonstrated that tedizolid was noninferior to linezolid for the day 28 ACM rates, which were 28.1% and 26.4%, respectively (95% CI, –8.2 to 4.7). The investigator-assessed clinical cure at TOC was 56.3% in the tedizolid group and 63.9% in the linezolid group; 97.5% CI, –15.7 to 0.5). The researchers said a post hoc analysis found no single factor that accounted for the difference in clinical response between the treatment groups.
“Based on assessment of mortality, tedizolid showed efficacy comparable to linezolid for the treatment of gram-positive HABP/VABP. Interestingly, this finding was not consistent with the clinical response endpoint,” De Anda said. “While multiple underlying patient characteristics were assessed for their contribution to this discordant result, no single factor or combination of factors [were] identified that could explain the result, nor did pharmacokinetic analyses point toward a pharmacodynamic explanation. These results underscore the difficulty of conducting studies in the HABP/VABP population.”
Perspective
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In this study of ventilated HABP/VABP, tedizolid shows promise as an alternative to linezolid because it was noninferior to linezolid for the primary study endpoint, day 28 ACM. However, a concerning finding was that tedizolid did not meet noninferiority to linezolid for the other primary endpoint ⎼⎼ investigator-assessed clinical response at TOC. Unfortunately, the investigators were unable to determine factors responsible for the difference seen in this outcome with subsequent analyses. Of note, approximately one-half (380/726) of the patients included in the study had data available on isolated respiratory pathogens, which comprised the microbiological intention-to-treat population (MITT). Of the MITT population, about 50% had mixed infections with both gram-positive and gram-negative organisms. Unfortunately, no assessment of the appropriateness of therapy for the treatment of gram-negative bacteria was reported, making clinical cure evaluations problematic. In the safety population, more patients treated with linezolid had a platelet count below the lower limit of normal compared with those who received tedizolid. However, the rate of drug-related treatment-emergent thrombocytopenia was very low and similar between the two groups. In summary, although this study suggests that tedizolid may be an effective alternative to linezolid (particularly when thrombocytopenia is major concern), more data comparing the efficacy of tedizolid and linezolid in patients with monomicrobial gram-positive pneumonia are needed.
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