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By Tiffany Wong, PharmD
Clinical Pharmacist in Internal Medicine, Stanford University
Dr. Wong reports no financial relationships in this field of study.
GENERIC NAME: Tedizolid phosphate
TRADE NAME: Sivextro
FDA APPROVAL DATE: June 20th, 2014
SIMILAR DRUGS ON FORMULARY: Linezolid (Zyvox) — oxazolidinone antibiotic
FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible gram-positive organisms including Staphylococcus aureus (MRSA and MSSA), Streptococcus agalactiae, Streptococcus anginosus group, Streptococcus pyogenes, and Enterococcus faecalis.
Tedizolid phosphate is a prodrug that is converted to tedizolid. Tedizolid is an oxazolidinone antibiotic that binds the 50S subunit of the bacterial ribosome leading to inhibition of protein synthesis.
AUC/minimum inhibitory concentration (MIC) correlates with tedizolid activity in animal infection models.
In-vitro and clinical studies have shown tedizolid to be active against the following aerobic, gram-positive bacteria:
Staphylococcus aureus (including MRSA and MSSA isolates)
Streptococcus anginosus group (including S. anginosus, S. intermedius, and S. constellatus)
In vitro time-kill studies show tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.
Only in-vitro data have shown at least 90% of the following bacteria to exhibit a minimum inhibitory concentration (MIC) ≤ 0.5 mcg/mL for tedizolid. The safety and efficacy of tedizolid in treating infections due to these microorganisms have not been established in clinical trials.
Staphylococcus epidermidis (including methicillin-susceptible and methicillin-resistant isolates)
Oxazolidinone resistance occurs via mutations in the chromosomal genes encoding 23S rRNA of ribosomal proteins (L3 and L4) which confers cross-resistance to tedizolid. In-vitro studies showed that reduced tedizolid susceptibilities from spontaneous mutations occur at an infrequent rate (10-10) and the presence of the chloramphenicol-florfenicol resistance (cfr) gene did not result in tedizolid resistance.
No in-vitro studies showed synergy nor antagonism with the following antibiotics when combined with tedizolid:
CLINICAL TRIALS/EVIDENCE SUMMARY2-5
Phase 2 Trials
In a double-blind Phase 2 clinical trial, 188 patients were randomized to 200, 300, or 400 mg once daily tedizolid phosphate treatment for 5 to 7 days. Eligible infection types included abscess, surgical or post traumatic wound, and deep extensive cellulitis with clinical signs and symptoms of serious infections. The primary outcome was clinical response rate at the test-of-cure visit (7 to 14 days after completing treatment). Clinical cure rate was 87.8% in the modified intention to treat population, 95.7% in the clinically evaluable population, and 96.2% in the microbiological evaluable population.
Of 196 isolates, the most common pathogen was S. aureus (76% MRSA and 24% MSSA). The MICs for S. aureus were 0.12-0.5 μg/mL. Overall microbiological eradication rates at the test-of-cure visit were 97.7%, 97.9%, and 95.7% for all pathogens, MRSA, and MSSA, respectively.
Phase 3 Trials
In accordance with the FDA guidance on the development of systemic drugs to treat ABSSSIs, the ESTABLISH-1 and ESTABLISH-2 trials were conducted demonstrating non-inferiority to currently approved antibiotics, linezolid, as well as the efficacy of intravenous to oral tedizolid.
Adverse reactions were evaluated in Phase 2 and Phase 3 clinical trials comparing tedizolid to a comparator antibiotic (linezolid). The most common adverse reactions are nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%).
Selected adverse reactions occurring in <2% of patients receiving tedizolid
Cardiovascular: palpitations, tachycardia
Eye Disorders: asthenopia, vision blurred, visual impairment, vitreous floaters
General: infusion-related reactions
Immune System Disorders: drug hypersensitivity
Infections: Clostridium difficile-associated diarrhea (CDAD), oral candidiasis, vulvovaginal mycotic infection
Investigations: hepatic transaminases increased, white blood cell count decreased
Nervous System Disorders: hypoesthesia, paresthesia, seventh nerve paralysis
Psychiatric Disorders: insomnia
Skin and Subcutaneous Tissue Disorders: pruritus, urticarial, dermatitis
Vascular Disorders: flushing, hypertension
Neutropenia — The safety and efficacy of tedizolid has not been established in patients with neutropenia (neutrophil counts < 1000 cells/mm3). Animal studies showed the antibacterial activity of tedizolid was reduced in the absence of granulocytes.
Clostridium difficile-associated diarrhea (CDAD) Cases of CDAD have been reported with tedizolid ranging from mild diarrhea to fatal colitis.
Drug-resistant bacteria — Prescribing tedizolid in absence of proven or suspected bacterial infection or prophylactic indication increases the risk of drug-resistant bacteria.
PREGNANCY CATEGORY C
Tedizolid has not been studied in pregnant women. Tedizolid phosphate has been shown to produce fetal developmental toxicities in mice, rats, and rabbits.
Excretion in to human breast milk is unknown. Tedizolid is excreted in to breast milk of rats.
POTENTIAL FOR MEDICATION ERRORS
This drug is not a high-alert drug and is not a high-alert drug category according to ISMP.
This drug has low risk for error based on potential for look-alike/sound/alike drug names.
SAFETY STRATEGIES AND COMPETENCY1
No safety strategies are needed for this drug.
No technology-based user alerts are needed for this drug.
No competencies are needed for this drug.
No drug interactions involving CYP enzymes or membrane transporters were found.
In-vitro, tedizolid is a reversible inhibitor of monoamine oxidase (MAO). MAO inhibitor interactions could not be evaluated because patients taking MAO inhibitors were excluded from the Phase 2 and 3 clinical trials. Tedizolid was not found to enhance pressor responses in pseudoephedrine and tyramine challenge studies. Patients taking serotonergic agents (i.e. serotonin reuptake inhibitors, tricyclic antidepressants, etc.) were excluded from Phase 3 clinical trials. No difference in serotonergic effects of tedizolid versus placebo was found in animal studies.
DOSAGE AND ADMINISTRATION1
No dose adjustment necessary when changing from intravenous to oral administration. No dose adjustments necessary in patients with renal impairment, hemodialysis, or hepatic impairment.
PYXIS OVERRIDE STATUS
This drug does not need override privileges in Pyxis.
Tedizolid is a new oxazolidinone antibiotic that has activity against Staphylococcus aureus (MRSA and MSSA), Streptococcus agalactiae, Streptococcus anginosus group, Streptococcus pyogenes, and Enterococcus faecalis. Phase 3 clinical trials have shown tedizolid to be non-inferior to linezolid for treatment of acute bacterial skin and skin structure infections. Tedizolid is well tolerated with possibly less hematological adverse reactions than linezolid, although its safety in patients with decreased white blood cells has not been established. Dosing is once daily with no dose adjustments for IV to oral administration as well as renal or hepatic impairment.