SIVEXTRO (Page 5 of 7)

12.4 Microbiology

Mechanism of Action

The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis. Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other non-oxazolidinone class antibacterial drugs; therefore, cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely. The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.

Resistance

Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to tedizolid. In the limited number of Staphylococcus aureus strains tested, the presence of the chloramphenicol-florfenicol resistance (cfr) gene did not result in resistance to tedizolid in the absence of chromosomal mutations. Mutations in 23SrRNA (G2576T mutation) have been associated with tedizolid resistance in S. aureus isolates.

Spontaneous mutations conferring reduced susceptibility to tedizolid occur in vitro at a frequency rate of approximately 10-10.

Interaction with Other Antimicrobial Drugs

In vitro drug combination studies with tedizolid and aztreonam, ceftriaxone, ceftazidime, imipenem, rifampin, trimethoprim/sulfamethoxazole, minocycline, clindamycin, ciprofloxacin, daptomycin, vancomycin, gentamicin, amphotericin B, ketoconazole, and terbinafine demonstrate neither synergy nor antagonism.

Antimicrobial Activity

Tedizolid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in Indications and Usage (1).

Aerobic bacteria

Gram-positive bacteria
Staphylococcus aureus
(including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates)
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus
Group (including S. anginosus , S. intermedius , and S. constellatus)
Enterococcus faecalis

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for tedizolid against isolates of similar genus or organism group. However, the efficacy of SIVEXTRO in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria

Gram-positive bacteria

Staphylococcus epidermidis
(including methicillin-susceptible and methicillin-resistant isolates)
Staphylococcus haemolyticus
Staphylococcus lugdunensis
Enterococcus faecium

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Long-term carcinogenicity studies have not been conducted with tedizolid phosphate.

Mutagenesis

Tedizolid phosphate was negative for genotoxicity in all in vitro assays (bacterial reverse mutation (Ames), Chinese hamster lung (CHL) cell chromosomal aberration) and in all in vivo tests (mouse bone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolid phosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolid was positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity in other in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrow micronucleus assay.

Impairment of Fertility

In a fertility study, oral tedizolid phosphate administered in doses of 5, 15, and 50 mg/kg/day for 28 days before mating and during mating to male rats had no adverse effects on the fertility or reproductive performance, including spermatogenesis, at the maximum tested dose (50 mg/kg/day) with a plasma tedizolid AUC approximately 5-fold greater than the plasma AUC value in humans at the maximum recommended human dose (MRHD). Tedizolid phosphate administered in doses of 2.5, 5, and 15 mg/kg/day for 14 days before mating, during mating, and until Gestation Day (GD)7 to female rats also had no adverse effects on the fertility or reproductive performance at doses up to the maximum tested dose of 15 mg/kg/day (approximately 4-fold higher than exposures in humans at the MRHD based on plasma AUC comparison).

13.2 Animal Toxicology and/or Pharmacology

Repeated-oral and intravenous dosing of tedizolid phosphate in rats in 1-month and 3-month toxicology studies produced dose- and time-dependent bone marrow hypocellularity (myeloid, erythroid, and megakaryocyte), with associated reduction in circulating RBCs, WBCs, and platelets. These effects showed evidence of reversibility and occurred at plasma tedizolid exposure levels (AUC) ≥6-fold greater than the plasma exposure associated with the human therapeutic dose. In a 1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure associated with the therapeutic dose.

14 CLINICAL STUDIES

14.1 Acute Bacterial Skin and Skin Structure Infections

Adults

A total of 1333 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in two multicenter, multinational, double-blind, non-inferiority trials. Both trials compared SIVEXTRO 200 mg once daily for 6 days versus linezolid 600 mg every 12 hours for 10 days. In Trial 1, patients were treated with oral therapy, while in Trial 2, patients could receive oral therapy after a minimum of one day of intravenous therapy. 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. The intent-to-treat (ITT) patient population included all randomized patients.

In Trial 1, 332 patients with ABSSSI were randomized to SIVEXTRO and 335 patients were randomized to linezolid. The majority (91%) of patients treated with SIVEXTRO in Trial 1 were less than 65 years old with a median age of 43 years (range: 18 to 86 years). Patients treated with SIVEXTRO were predominantly male (61%) and White (84%); 13% had BMI ≥35 kg/m2 , 8% had diabetes mellitus, 35% were current or recent intravenous drug users, and 2% had moderate to severe renal impairment. The overall median surface area of infection was 188 cm2. The types of ABSSSI included were cellulitis/erysipelas (41%), wound infection (29%), and major cutaneous abscess (30%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (87% of patients), temperature 38°C or higher (16% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (42%), or 10% or more band forms on white blood cell differential (4%).

The primary endpoint in Trial 1 was early clinical response defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population.

In Trial 2, 332 patients with ABSSSI were randomized to SIVEXTRO and 334 patients were randomized to linezolid. The majority (87%) of patients treated with SIVEXTRO in Trial 2 were less than 65 years old with a median age of 46 years (range: 17 to 86 years). Patients treated with SIVEXTRO were predominantly male (68%) and White (86%); 16% had BMI ≥35 kg/m2 , 10% had diabetes mellitus, 20% were current or recent intravenous drug users, and 4% had moderate to severe renal impairment. The overall median surface area of infection was 231 cm2. The types of ABSSSI included were cellulitis/erysipelas (50%), wound infection (30%), and major cutaneous abscess (20%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (71% of patients), temperature 38°C or higher (31% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (53%), or 10% or more band forms on white blood cell differential (16%).

The primary endpoint in Trial 2 was early clinical response defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population (Table 6).

Table 6: Early Clinical Response in the ITT Adult Patient Population
SIVEXTRO(200 mg) Linezolid(1200 mg) Treatment Difference(2-sided 95% CI)
CI=confidence interval
*
Primary endpoint for Trial 1; sensitivity analysis for Trial 2
Primary endpoint for Trial 2; sensitivity analysis for Trial 1
No increase in lesion surface area from baseline and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours at 48-72 hours *
Trial 1, N 332 335
Responder, n (%) 264 (79.5) 266 (79.4) 0.1 (-6.1, 6.2)
Trial 2, N 332 334
Responder, n (%) 286 (86.1) 281 (84.1) 2.0 (-3.5, 7.3)
At least a 20% decrease from baseline in lesion area at 48-72 hours
Trial 1, N 332 335
Responder, n (%) 259 (78.0) 255 (76.1) 1.9 (-4.5, 8.3)
Trial 2, N 332 334
Responder, n (%) 283 (85.2) 276 (82.6) 2.6 (-3.0, 8.2)

An investigator assessment of clinical response was made at the post-therapy evaluation (PTE) (7 — 14 days after the end of therapy) in the ITT and CE (Clinically Evaluable) populations. Clinical success was defined as resolution or near resolution of most disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal WBC count), and no new signs, symptoms, or complications attributable to the ABSSSI requiring further treatment of the primary lesion (Table 7).

Table 7: Investigator-Assessed Clinical Response at Post-therapy Evaluation in ITT and CE Adult Patient Populations from Two Phase 3 ABSSSI Trials
SIVEXTRO(200 mg)n/N (%) Linezolid(1200 mg)n/N (%) Treatment Difference(2-sided 95% CI)
CI=confidence interval; ITT=intent-to-treat; CE=clinically evaluable
Trial 1
ITT 284/332 (85.5) 288/335 (86.0) -0.5 (-5.8, 4.9)
CE 264/279 (94.6) 267/280 (95.4) -0.8 (-4.6, 3.0)
Trial 2
ITT 292/332 (88.0) 293/334 (87.7) 0.3 (-4.8, 5.3)
CE 268/290 (92.4) 269/280 (96.1) -3.7 (-7.7, 0.2)

Clinical success by baseline pathogens from the primary infection site or blood cultures for the microbiological intent-to-treat (MITT) patient population for two integrated Phase 3 ABSSSI studies are presented in Table 8 and Table 9.

Table 8: Early Clinical Response by Baseline Pathogen from Two Phase 3 ABSSSI Adult Trials (MITT Population)
Pathogen No increase in lesion surface area from baseline and oral temperature of ≤37.6°C * At least a 20% decrease from baseline in lesion area
SIVEXTRO(200 mg)n/N (%) Linezolid(1200 mg)n/N (%) SIVEXTRO(200 mg)n/N (%) Linezolid(1200 mg)n/N (%)
Pooled analysis; n=number of patients in the specific category; N=Number of patients with the specific pathogen isolated from the ABSSSI
*
Primary endpoint of Trial 1
Primary endpoint of Trial 2
Staphylococcus aureus 276/329 (83.9) 278/342 (81.3) 280/329 (85.1) 276/342 (80.7)
Methicillin-resistant S. aureus 112/141 (79.4) 113/146 (77.4) 114/141 (80.9) 111/146 (76.0)
Methicillin-susceptible S. aureus 164/188 (87.2) 167/198 (84.3) 166/188 (88.3) 167/198 (84.3)
Streptococcus pyogenes 27/33 (81.8) 18/20 (90.0) 25/33 (75.8) 16/20 (80.0)
Streptococcus anginosus Group 22/30 (73.3) 26/28 (92.9) 22/30 (73.3) 25/28 (89.3)
Streptococcus agalactiae 6/9 (66.7) 8/10 (80.0) 6/9 (66.7) 7/10 (70.0)
Enterococcus faecalis 7/10 (70.0) 3/4 (75.0) 6/10 (60.0) 1/4 (25.0)

Baseline bacteremia in the tedizolid arm with relevant pathogens included two subjects with MRSA, four subjects with MSSA, two subjects with S. pyogenes , one subject with S. agalactiae , and one subject with S. constellatus. All of these subjects were Responders at the 48-72 hour evaluation. At the Post-therapy Evaluation (PTE), 8 of 10 subjects were considered clinical successes.

Table 9: Clinical Response at PTE by Baseline Pathogen from Two Phase 3 ABSSSI Adult Trials (MITT Population)
Pathogen Clinical Response at PTE
SIVEXTRO(200 mg)n/N (%) Linezolid(1200 mg)n/N (%)
Pooled analysis; n=number of patients in the specific category; N=Number of patients with the specific pathogen isolated from the ABSSSI
Staphylococcus aureus 291/329 (88.5) 303/342 (88.6)
Methicillin-resistant S. aureus 118/141 (83.7) 119/146 (81.5)
Methicillin-susceptible S. aureus 173/188 (92.0) 186/198 (93.9)
Streptococcus pyogenes 30/33 (90.9) 19/20 (95.0)
Streptococcus anginosus Group 21/30 (70.0) 25/28 (89.3)
Streptococcus agalactiae 8/9 (88.9) 8/10 (80.0)
Enterococcus faecalis 7/10 (70.0) 4/4 (100.0)

Baseline bacteremia in the tedizolid arm with relevant pathogens included two subjects with MRSA, four subjects with MSSA, two subjects with S. pyogenes , one subject with S. agalactiae , and one subject with S. constellatus. All of these subjects were Responders at the 48-72 hour evaluation. At the Post-therapy Evaluation (PTE) 8 of 10 subjects were considered clinical successes.

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).

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.