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Efficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure Infection.

ABSTRACT: Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria in the United States, Europe, and other countries. In this multicenter, double-blind, phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the United States were randomized to receive 200?mg of tedizolid, intravenously (i.v.)/orally (p.o.), once daily for 6?days or 600?mg of linezolid, i.v./p.o. twice daily for 10?days. The primary endpoint was early clinical response rate at 48 to 72?h. Secondary endpoints included programmatic and investigator-assessed outcomes at end-of-therapy (EOT) and posttherapy evaluation (PTE) visits. Safety was also evaluated. In the intent-to-treat (ITT) population, 75.3% of tedizolid-treated patients and 79.9% of linezolid-treated patients were early responders (treatment difference, -4.6%; 95% confidence interval [CI], -11.2, 2.2). After exclusion of patients who never received the study drug (tedizolid, n?=?8; linezolid, n?=?1; modified ITT), comparable early response rates were observed (tedizolid, 77.4%; linezolid, 80.1%; treatment difference, -2.7%; 95% CI, -9.4, 3.9). Secondary endpoints showed high and similar clinical success rates in the ITT and clinically evaluable (CE) populations at EOT and PTE visits (e.g., CE-PTE for tedizolid, 90.4%; for linezolid, 93.5%). Both drugs were well tolerated, and no death occurred. Eight patients experienced phlebitis with tedizolid while none did with linezolid; hence, drug-related treatment-emergent adverse events were reported in a slightly higher proportion in the tedizolid (20.9%) arm than in the linezolid arm (15.8%). The study demonstrated that tedizolid in a primarily Asian population was an efficacious and well-tolerated treatment option for ABSSSI patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02066402.).

SUBMITTER: Lv X

PROVIDER: S-EPMC6591607 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Efficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure Infection.

Lv Xiaoju X Alder Jeff J Li Li L O'Riordan William W Rybak Michael J MJ Ye Hui H Zhang Ruiping R Zhang Zhongqi Z Zhu Xu X Wilcox Mark H MH

Antimicrobial agents and chemotherapy 20190624 7

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria in the United States, Europe, and other countries. In this multicenter, double-blind, phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the United States were randomized to receive 200 mg of tedizolid, intravenously (i.v.)/orally (p.o.), once daily for 6 days or 600 mg of linezolid, i.v./p.o. twice daily for 10 days. The pr ...[more]

PMID: 30988146

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Project description:Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P=0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P=0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P=0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.).

Project description:IntroductionAcute bacterial skin and skin structure infections (ABSSSI) represent one of the most common reasons for emergency department visits, and are frequent complications of intravenous drug use in persons who inject drugs (PWID). This study examined the efficacy and safety of omadacycline, versus linezolid, in PWID and persons who do not inject drugs, in the Phase 3 Omadacycline in Acute Skin and Skin Structure Infection (OASIS-1, OASIS-2) studies.MethodsEligible participants were aged ≥ 18 years with qualifying skin infections: wound infection, cellulitis, erysipelas, or major abscess. The primary efficacy endpoint was early clinical response (ECR) in the modified intent-to-treat (mITT) population, defined as survival with ≥ 20% reduction in lesion size at 48-72 h after the first dose of omadacycline or linezolid. Key secondary endpoints included investigator-assessed clinical response at the post-treatment evaluation (PTE) in the mITT and clinical per-protocol populations, and clinical response at PTE in the micro-mITT population. Safety was assessed based on adverse events (AEs) and standard clinical laboratory tests. Efficacy endpoints of clinical response at ECR and PTE were analyzed for the mITT and clinically evaluable (CE) PTE populations.ResultsIn total, 1380 patients (822 PWID, 558 non-PWID) were included in this secondary analysis. Wound infections were reported more frequently in the PWID subgroup (72.8%) at baseline; cellulitis or erysipelas (43.9%) and major abscess (37.4%) were the most frequently reported baseline infections in the non-PWID subgroup. Clinical success rates at ECR and PTE in the mITT population, and at PTE in the CE population, were high for patients receiving omadacycline or linezolid. Severe or serious treatment-emergent AEs (TEAEs), and TEAEs leading to discontinuation, were infrequent.ConclusionThis subgroup analysis showed that omadacycline was effective and well tolerated, regardless of PWID status.

Project description:BackgroundAcute bacterial skin and skin structure infections (ABSSSI) are a frequent cause of hospital admissions in the United States. Safe and effective outpatient treatments may lower ABSSSI-associated health care costs by reducing unnecessary hospital admissions. Using data from 2 phase 3 trials (ESTABLISH-1, NCT01170221; ESTABLISH-2, NCT01421511), this post-hoc analysis explored the efficacy and safety of tedizolid in an outpatient setting.MethodsSubgroup analysis was performed on US outpatients (defined as patients who were not in hospital at the time of treatment initiation) with ABSSSI caused by presumed or proven gram-positive pathogens. Patients were randomly assigned to receive tedizolid phosphate 200 mg once daily for 6 days (n = 403) or linezolid 600 mg twice daily for 10 days (n = 410). The primary end point was early clinical response (48-72 hours after the start of treatment). Secondary end points included investigator-assessed clinical response at end of therapy (EOT) and post-therapy evaluation (PTE; 7-14 days after therapy). Additional assessments included the patient-reported level of pain using a visual analog scale (VAS) and the per-pathogen favorable microbiological response rate at the PTE visit. Compliance with treatment and safety outcomes was also recorded.ResultsEarly clinical response was similar between treatment groups (tedizolid, 82.4%; linezolid, 79.0%), as was investigator-assessed clinical response at EOT (tedizolid, 87.1%; linezolid, 86.1%) and PTE (tedizolid, 83.1%; linezolid, 83.7%). Mean changes from baseline to days 10 to 13 in VAS scores were identical between treatment groups (tedizolid, -51.9 mm; linezolid, -51.9 mm). Microbiological eradication rates were generally similar in both treatment groups for all key pathogens. Patients in both groups had favorable response at PTE. More tedizolid-treated patients (89.3%) than linezolid-treated patients (77.3%) were compliant with treatment. The most frequently reported drug-related treatment-emergent adverse events were nausea (tedizolid, 10.7%; linezolid, 13.8%), diarrhea (tedizolid, 4.5%; linezolid, 5.9%), and headache (tedizolid, 5.5%; linezolid, 4.4%). Treatment discontinuation rates were low for both treatment groups (tedizolid, 0.7%; linezolid, 1.0%).ConclusionShort-course therapy with tedizolid can successfully treat patients with ABSSSI caused by presumed or proven gram-positive pathogens in an outpatient setting.

Dataset Information

Efficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure Infection.

Publications

Efficacy and Safety of Tedizolid Phosphate versus Linezolid in a Randomized Phase 3 Trial in Patients with Acute Bacterial Skin and Skin Structure Infection.

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