Tedizolid

Introduction:

Tedizolid phosphate is an oxazolidinone approved for the treatment of acute bacterial infections of the skin and skin structure (ABSSSI) and active against methicillin-resistant Staphylococcus aureus.

Objectives:

The objective of this article was to review the evidence for the efficacy and safety of tedizolid phosphate for the treatment of ABSSSI.

Review of evidence:

Approval of tedizolid phosphate for the treatment of ABSSSI was based on the results of two phases III randomized controlled trials, ESTABLISH-1 (NCT01170221) and ESTABLISH-2 (NCT01421511), comparing a 6-day tedizolid once a day versus 10-linezolid twice a day. In ESTABLISH-1, non-inferiority was met with early clinical response rates of 79.5% and 79.4% in the tedizolid and linezolid groups, respectively (difference 0.1%, 95% CI –6, 1% to 6.2%, with a non-inferiority margin of 10%).

In ESTABLISH-2, non-inferiority was met with early clinical response rates of 85% and 83% in the tedizolid and linezolid groups, respectively (difference 2.6%, 95% CI –3.0% at 8.2%). Pooled data from ESTABLISH-1 and ESTABLISH-2 indicated a lower frequency of thrombocytopenia in patients treated with tedizolid than in patients treated with linezolid.

Bottom Line:

Tedizolid offers the option of an intravenous to oral switch, allows once-daily administration, and has a lower risk of myelotoxicity when using a 6-day cycle for the treatment of ABSSSI. The higher economic cost associated with this antibiotic could be offset by the shorter duration of treatment and the possibility of oral administration in routine clinical practice, although sponsored or unsponsored post-marketing observational experience remains essential to ultimately confirm the effectiveness and tolerability of the drug. tedizolid outside of clinical trials.

Keywords:

ABSSSI, MRSA, oxazolidinone, Staphylococcus, efficacy, safety

Scope, aims, and objectives

Acute bacterial infections of the skin and skin structure (ABSSSI) are defined as bacterial infections of the skin with an area of ​​lesion of at least 75 cm2.1 Their clinical presentation is heterogeneous, from Mild infections to life-threatening invasive diseases.1,2 ABSSSI affects both outpatients and inpatients, and a significant increase in outpatient visits and hospital admissions for ABSSSI has been observed in the last two decades3,4. This reflects increases in the incidence and severity of ABSSSI, depending at least in part on the aging of the population and the related expansion of comorbid conditions, which predispose to the development or worsening of ABSSSI.

The severity of ABSSSI also depends on the causative agent, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the most feared pathogens, not only due to its known association with the development of an invasive infection but also due to the production of Panton-Valentine leukocidin from community-acquired strains of MRSA.5,6 In particular, the prevalence of MRSA among ABSSSI isolates of S. aureus may exceed 25% in some endemic countries.7 Consequently, anti-MRSA agents are often an essential component of the therapeutic approach to ABSSSI.

Methods

A Medline / PubMed search was performed using various combinations of keywords and MeSH terms: “tedizolid”, “TR-701”, “DA-7218”, “DA-7158” and “bacterial skin infection”. The relevant full texts, as well as abstracts and posters presented at the most recent international congresses, were then evaluated and discussed, and finally summarized in a narrative presentation of the topic based on the highest level of the available evidence, divided into sections: mechanism of action, formulation and dosage of the drug, in vitro antimicrobial activity, pharmacokinetics and pharmacodynamics, efficacy in clinical studies, safety in clinical studies, potential place in tedizolid phosphate therapy for the treatment of ABSSSI and conclusion.

Mechanism of action

Tedizolid exerts its bacteriostatic activity by inhibiting the synthesis of bacterial proteins through the binding of 23S ribosomal RNA of the 50S subunit.10 The chemical structure of tedizolid is similar to that of linezolid. Both are synthetic molecules that contain an oxazolidinone ring (A ring) and a C5 side chain, which enhances their activity against some Gram-positive bacteria and mycobacteria11.

The main chemical difference between the two compounds lies in the fact that tedizolid has a hydroxymethyl group in the side chain that is responsible for its activity against some bacterial strains with the CFR gene. Furthermore, tedizolid has a para-oriented ring structure (D -ring), which increases the number of binding sites with the center of the peptidyl transferase, thus increasing its potency relative to linezolid.

Drug formulation and dosage

Tedizolid has a dual formulation both orally and intravenously, which are almost equivalent. Due to a prolonged half-life of more than 10 hours, tedizolid only needs to be administered once a day, and the recommended dose of tedizolid for adults for its approved indication is 200 mg (regardless of the route of administration) for 6 days. Dose adjustments are not required in patients with hepatic and/or renal insufficiency or in those undergoing hemodialysis11.

In vitro antimicrobial activity

Tedizolid exerts potent in vitro activity against a broad spectrum of Gram-positive bacteria, including MRSA, methicillin-resistant S. epidermidis, and vancomycin-resistant enterococci13,14 In a recently published study by Karlowsky et al, tedizolid showed four times more potency in vitro against S. aureus (methicillin-sensitive and methicillin-resistant strains) than linezolid.15 Similarly, tedizolid and linezolid minimum inhibitory concentrations (MICs) of ABSSSI MRSA isolates were 0.125 to 0.5 mg and 0.25 to 4 mg / L, respectively.16 In another study involving 150 MRSA isolates, MICs of tedizolid were two to five times lower than those of linezolid.17 Similar results were seen against enterococci, 18 as also witnessed by another study in which the in vitro activity of tedizolid was greater than that of linezolid against 302 MRSA isolates and 220 vancomycin-resistant enterococci19.

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