Efficacy for SIVEXTRO

Efficacy in phase 3 clinical trials

SIVEXTRO was evaluated in 2 randomized controlled noninferiority phase 3 trials in patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI):

  • ESTABLISH 1 trial in adults: All-oral course of SIVEXTRO vs linezolid (n=667)
  • ESTABLISH 2 trial in patients ≥12: IV/oral switch of SIVEXTRO vs linezolid (n=666)

ESTABLISH 1 ABSSSI trial

SIVEXTRO delivered efficacy with a short, 6-day course of treatment

Phase 3 Clinical Trial: All Oral Therapy

(a) Intent-to-treat (ITT) population.

Noninferiority for the primary endpoint was concluded if the lower limit of the 95% confidence interval was greater than –10%. The treatment difference (95% confidence interval) was 0.1 (–6.1, 6.2) for the primary endpoint and –0.5 (–5.8, 4.9) for the secondary endpoint.1

ESTABLISH 2 ABSSSI trial

SIVEXTRO delivered efficacy with a short, 6-day course of treatment

Phase 3 Clinical Trial: IV/Oral Therapy

(a) Intent-to-treat (ITT) population.

Noninferiority for the primary endpoint was concluded if the lower limit of the 95% confidence interval was greater than -10%. The treatment difference (95% confidence interval) was 2.6 (-3.0, 8.2) for the primary endpoint and 0.3 (-4.8, 5.3) for the secondary endpoint.2

ABSSSI patients

Trials included ABSSSI patients with significant lesions,1,2 such as

  • Cellulitis/erysipelas
  • Major cutaneous abscess
  • Wound infection
Trials Included ABSSSI Patients With Abscess

Clinical Trials Tested Patients With ABSSSI Cellulitis

Trial Population Included ABSSSI Patients With Wound Infections

Patients evaluated had infection surrounded by erythema with a minimum total lesion surface area of at least 75 cm2, which were suspected or documented to be associated with a Gram-positive pathogen.1,2

Patients also exhibited at least 1 of the following regional or systemic signs of infection1:

  • Lymphadenopathy, fever, white blood cell count ≥ 10,000 cells/mm3, or <4,000 cells/mm3, or >10% immature neutrophils

The median infection area for patients treated with SIVEXTRO was 188 cm2 in ESTABLISH 1 and 231 cm2 in ESTABLISH 2.

Trial design

Both randomized, multicenter, multinational, double-blind, noninferiority ESTABLISH trials compared SIVEXTRO 200 mg once daily for 6 days to linezolid 600 mg every 12 hours for 10 days in adults. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for Gram-negative bacterial coverage, if needed. In the ESTABLISH 2 trial, patients taking SIVEXTRO received at least 1 day of IV treatment.

For the secondary endpoint of post-therapy evaluation, clinical success was defined as resolution or near resolution of disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), and no further antibiotic treatment required for the treatment of the primary ABSSSI lesion.

Pediatric patients

The safety and efficacy of SIVEXTRO in pediatric patients 12 to <18 years of age were investigated in a randomized, single blind, active-controlled trial of 120 patients with clinically documented ABSSSI (91 receiving tedizolid, 29 receiving comparator). Patients were randomized in a 3:1 ratio with stratification by geographic region to receive SIVEXTRO IV and/or oral therapy, dosed 200 mg once daily for 6 days, or comparator IV and/or oral therapy, dosed over 10 days. Comparator therapy was selected by the investigator from a list of 5 IV and 4 oral comparators per local standard of care. The most frequently used comparators were cefazolin (11 patients) and vancomycin (8 patients).

The primary objective was to evaluate the safety and tolerability of SIVEXTRO. The trial was not powered for comparative inferential efficacy analysis. Clinical response at the test of cure visit (Day 18-25) was assessed by a blinded investigator in the ITT population (all randomized patients). Clinical successes were required to have resolution or near resolution of all related signs and symptoms such that no further antibacterial therapy was needed. Early clinical response, defined as at least a 20% reduction in lesion size at 48-72 hours after start of treatment, was also assessed in the ITT population.

Clinical success at test of cure was 96.7% (88/91) in the tedizolid group and 93.1% (27/29) in the comparator group (difference 3.6%, 95% CI: -6.3, 13.5). Early clinical response at 48-72 hours was 92.3% (84/91) in the tedizolid group and 96.6% (28/29) in the comparator group (difference -4.2%, 95% CI: -12.9, 4.4).

References:

  1. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections. The ESTABLISH-1 randomized trial. JAMA. 2013;309(6):559-569.
  2. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2 ): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014;14(8):696-705.

Indication

SIVEXTRO is an oxazolidinone-class antibacterial indicated in adults and pediatric patients 12 years of age and older for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus), and Enterococcus faecalis.

 

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of SIVEXTRO and other antibacterial drugs, SIVEXTRO should be used only to treat ABSSSI that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Selected Safety Information

Patients with neutropenia: The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm³) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes. Alternative therapies should be considered when treating patients with neutropenia.

 

Clostridioides difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including SIVEXTRO. Evaluate all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.

 

Development of drug-resistant bacteria: Prescribing SIVEXTRO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

 

Adverse reactions: The most common adverse reactions (≥2%) in adults for SIVEXTRO are nausea (7%), headache (5%), diarrhea (4%), vomiting (3%), and dizziness (2%).

 

In adult patients receiving SIVEXTRO intravenously, infusion- or injection-related adverse reactions including but not limited to: phlebitis, injection- or infusion-site pain or swelling, injection-site reaction, erythema, or induration, and infusion-related reaction occurred (4%).

 

The most common adverse reactions (>2%) in pediatric patients 12 years of age and older are phlebitis (3%) and increased hepatic transaminases (3%).

 

Drug interactions with BCRP substrates: SIVEXTRO (when administered orally) can increase the plasma concentrations of orally administered Breast Cancer Resistance Protein (BCRP) substrates and the potential for adverse reactions. Monitor for adverse reactions related to the concomitant BCRP substrates if coadministration cannot be avoided.

 

Before prescribing SIVEXTRO, please read the accompanying Prescribing Information. The Patient Information also is available.

Indication

SIVEXTRO is an oxazolidinone-class antibacterial indicated in adults and pediatric patients 12 years of age and older for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus), and Enterococcus faecalis.

 

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of SIVEXTRO and other antibacterial drugs, SIVEXTRO should be used only to treat ABSSSI that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

SIVEXTRO is an oxazolidinone-class antibacterial indicated in

SIVEXTRO is an oxazolidinone-class antibacterial indicated in adults and pediatric patients 12 years of age and older for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms

Selected Safety Information

Patients with neutropenia: The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm³) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes. Alternative therapies should be considered when treating patients with neutropenia.

 

Clostridioides difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including SIVEXTRO. Evaluate all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.

 

Development of drug-resistant bacteria: Prescribing SIVEXTRO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

 

Adverse reactions: The most common adverse reactions (≥2%) in adults for SIVEXTRO are nausea (7%), headache (5%), diarrhea (4%), vomiting (3%), and dizziness (2%).

 

In adult patients receiving SIVEXTRO intravenously, infusion- or injection-related adverse reactions including but not limited to: phlebitis, injection- or infusion-site pain or swelling, injection-site reaction, erythema, or induration, and infusion-related reaction occurred (4%).

 

The most common adverse reactions (>2%) in pediatric patients 12 years of age and older are phlebitis (3%) and increased hepatic transaminases (3%).

 

Drug interactions with BCRP substrates: SIVEXTRO (when administered orally) can increase the plasma concentrations of orally administered Breast Cancer Resistance Protein (BCRP) substrates and the potential for adverse reactions. Monitor for adverse reactions related to the concomitant BCRP substrates if coadministration cannot be avoided.

 

Before prescribing SIVEXTRO, please read the accompanying Prescribing Information. The Patient Information also is available.

Patients with neutropenia: The safety and efficacy of SIVEXTRO

Patients with neutropenia: The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm³) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes