Once-daily oral omadacycline was noninferior to twice-daily oral linezolid in adults with acute bacterial skin and skin structure infections (ABSSSI), according to phase 3 study results published in the Lancet Infectious Diseases.
In this double-blind double-dummy noninferiority trial (OASIS-2; ClinicalTrials.gov identifier: NCT02877927) conducted at 33 sites in the United States, adults aged >18 years were randomly assigned 1:1 to receive either oral omadacycline (2 once-daily 450-mg doses over 48 hours, then 300 mg once daily) or linezolid (600 mg twice daily) in an outpatient setting for 7 to 14 days. Randomization was stratified by type of infection (wound infection, cellulitis, erysipelas, or major abscess). Qualifying infections needed to be at least 75 cm2 in affected skin area.
There were 2 primary end points: to comply with (1) recommendations and guidelines of the United States Food and Drug Administration (FDA) and (2) of the European Medicines Agency (EMA). A noninferiority margin of 10% was used for both primary outcomes.
The FDA primary end point was early clinical response in the modified intention-to-treat (mITT) population, which included all randomly assigned patients without solely Gram-negative ABSSSI pathogens at baseline, since linezolid is not active against Gram-negative bacteria. An early clinical response was defined as survival with at least a 20% reduction in lesion size 48 to 72 hours after the first dose of study drug without rescue antibacterial therapy.
The EMA primary end point was the investigator assessment of clinical response at post-treatment evaluation (derived from the end of treatment visit and post-treatment evaluation 7 to 14 days after the last dose of study drug) in the mITT and clinically evaluable populations. The clinically evaluable population included mITT patients who had a qualifying infection per study-entry criteria, received study drug, did not receive a confounding antibiotic, and had an assessment of outcome during the protocol-defined window.
Of the 735 patients in the ITT population, 15 had Gram-negative bacteria as the sole causative pathogen at baseline, leaving 720 patients in the mITT population (360 in each group). Most patients were white (91%), men (63%), and intravenous drug users (72%). In the mITT population, median lesion sizes were 322 cm2 in the omadacycline group and 294 cm2 in the linezolid group at baseline.
For the FDA primary end point, omadacycline was noninferior compared with linezolid (88% vs 83%; percentage-point difference, 5.0; 95% CI, −0.2 to 10.3).
Similarly, omadacycline showed noninferiority compared with linezolid for the EMA primary end point. Clinical success at investigator-assessed clinical response post-treatment evaluation was reported in 84% of patients in the omadacycline group and in 81% of patients in the linezolid group (percentage-point difference, 3.3; 95% CI, −2.2 to 9.0). In the clinically evaluable population, clinical success at investigator-assessed clinical response post-treatment evaluation was reported in 98% of patients (278 of 284) in the omadacycline group and 96% of patients (279 of 292) in the linezolid group (percentage-point difference, 2.3; 95% CI, −0.5 to 5.8).
In a subgroup analysis in the mITT population, the percentage of patients achieving early clinical response success was similar in patients who were intravenous drug users vs patients who not. In addition, researchers observed similar efficacy between treatment groups with subgroups based on infection type and lesion size, and in a population with a high percentage of identified bacterial pathogens, including methicillin-resistant Staphylococcus aureus.
Nausea and vomiting were more frequently associated with omadacycline than linezolid within the first 2 days of treatment, when the patients were receiving an increased dosage, but were not associated with maintenance oral treatment. Moderate nausea was associated with omadacycline discontinuation in 1 patient.
The study was underpowered to conclude noninferiority by infection type and in clinically important subgroups (eg, large lesion sizes). Moreover, patients with various comorbidities and commonly encountered skin infections such as chronic wound infections were excluded from the study. Further, as a result of the study-mandated therapy duration, this study was limited in its ability to inform the usefulness of omadacycline in short therapies.
Researchers noted that while additional real-world data would be beneficial, “administration of oral-only omadacycline could reduce the proportion of patients who are admitted to hospital solely for infusion therapy to treat ABSSSI, as well as reducing the related treatment costs.”
Disclosure: This clinical trial was supported by Paratek Pharmaceuticals. Data analyses and interpretation were done by the funder in conjunction with the authors. Please see the original reference for a full list of authors’ disclosures.
O’Riordan W, Cardenas C, Shin E, et al; OASIS-2 Investigators. Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial [published online August 29, 2019]. Lancet Infect Dis. doi:10.1016/S1473-3099(19)30275-0