Characterization of Neurologic and Ophthalmologic Safety of Oral Administration of Tedizolid for Up to 21 Days in Healthy Volunteers

Fang, Edward; Muñoz, Kelly A.; Prokocimer, Philippe

doi:10.1097/mjt.0000000000000534

Cited by 16 publications

(5 citation statements)

References 32 publications

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“…It is also in line with the suggestion that the selection of tedizolid as clinical candidate was based more on improved intrinsic activity (including against linezolidresistant strains) than safety considerations (24). In phase I studies (with escalating dose and treatment duration up to 21 days), tedizolid was, however, shown to cause less thrombocytopenia (65) and no clinical or subclinical neurologic or ophthalmologic changes (66). Moreover, tedizolid, administered for 9 months to rats at doses up to 8-fold larger than its approved human use did not cause significant neuropathies, which are known to develop with linezolid under these conditions (27).…”

Section: Discussionsupporting

confidence: 70%

Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes

Milošević

Payen

Sonveaux

et al. 2018

Antimicrob Agents Chemother

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Linezolid, the first clinically available oxazolidinone antibiotic, causes potentially severe toxicities (myelosuppression, lactic acidosis, and neuropathies) ascribed to impairment of mitochondrial protein synthesis and consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone, shows an enhanced activity compared to linezolid but is also a more potent inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid for (i) inhibition of the expression of subunit I of cytochrome -oxidase (CYTox I; Western blot analysis), (ii) cytochrome-oxidase activity (biochemical assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) alteration of mitochondrial ultrastructure (electron microscopy) using HL-60 promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of modal MIC against ) and therapeutically ( - ) pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h) inhibition of CYTox I expression, cytochrome-oxidase activity, and spare respiratory capacity, with conspicuous swelling of the mitochondrial matrix and loss of their cristae. Globally, tedizolid was a more potent inhibitor than linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully reversible upon drug withdrawal. Using an alternation of exposure to and withdrawal from drug mimicking their approved schedule of administration (twice daily and once daily [qD] for linezolid and tedizolid, respectively), only partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid reversal of toxic effects upon discontinuous administration may mitigate oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its reported lower preclinical and clinical toxicity.

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Section: Discussionsupporting

confidence: 70%

Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes

Milošević

Payen

Sonveaux

et al. 2018

Antimicrob Agents Chemother

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“…No cases of lactic acidosis or peripheral or optical neuropathy were described during tedizolid use in our study. In fact, in the study conducted by Fang et al in volunteers receiving different doses of tedizolid for up to 21 days, they found no evidence of neurologic or visual changes (30). Kim et al, in their study of patients receiving tedizolid during a median of 91 days, reported peripheral neuropathy in five patients (20%).…”

Section: Discussionmentioning

confidence: 94%

Safety and Tolerability of More than Six Days of Tedizolid Treatment

Mensa-Vendrell

Pitarch

Lletí

et al. 2020

Antimicrob Agents Chemother

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Tedizolid has demonstrated its efficacy and safety in clinical trials; however, data concerning its tolerability in long-term treatments are scarce. The aim of the study was to assess the indications and to describe the long-term safety profile of tedizolid. A multicentric retrospective study of patients who received tedizolid for more than 6 days was conducted. Adverse events (AEs) were identified from patients’ medical records and laboratory data. The World Health Organization causality categories were used to discern AEs that were probably associated with tedizolid. Eighty-one patients, treated with tedizolid 200 mg once daily for a median (interquartile range [IQR]) duration of 28 (14 to 59) days, were included; 36 (44.4%) had previously received linezolid. The most common reasons for selecting tedizolid were to avoid linezolid potential toxicities or interactions (53.1%) or due to previous linezolid-related toxicities (27.2%). The most common indications were off-label, including prosthetic joint infections, osteomyelitis, and respiratory infections (77.8%). Overall, 9/81 patients (11.1%) experienced a probably associated AE. Two patients (2.5%) developed gastrointestinal disorders, 1 (1.2%) developed anemia, and 6 developed thrombocytopenia (7.4%) after a median (IQR) duration of treatment of 26.5 (17 to 58.5) days. Four (5%) patients discontinued tedizolid due to AEs. Among 23 patients with chronic renal failure (CRF), the rate of myelotoxicity was 17.4%, and only 8.7% had to stop tedizolid; 20 out of 22 with previous linezolid-associated toxicity had no AE. Long-term tedizolid treatments had good tolerance with rates of gastrointestinal AE and hematological toxicity lower than those reported with linezolid, particularly in patients with CRF and in those with a history of linezolid-associated toxicity.

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“…Of note, the reduced inhibitory effect on central nervous system (CNS) monoamine oxidase could be due to the lower CNS penetration of tedizolid compared to linezolid, as observed in rats.52 Whether or not this could also impair the efficacy of tedizolid in some possible off-label indications (eg, CNS infections) deserves further investigation. Finally, no clinically meaningful ophthalmological or neurological alterations were observed in phase I volunteers receiving tedizolid at supratherapeutic doses for 21 days 53…”

Section: Methodsmentioning

confidence: 91%

<p>Tedizolid phosphate for the treatment of acute bacterial skin and skin-structure infections: an evidence-based review of its place in therapy</p>

Bassetti¹,

Castaldo²,

Carnelutti³

et al. 2019

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Introduction Tedizolid phosphate is an oxazolidinone approved for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) and active against methicillin-resistant Staphylococcus aureus . Aims The objective of this article was to review the evidence for the efficacy and safety of tedizolid phosphate for the treatment of ABSSSI. Evidence review Approval of tedizolid phosphate for the treatment of ABSSSI was based on the results of two phase III randomized controlled trials, ESTABLISH-1 (NCT01170221) and ESTABLISH-2 (NCT01421511), comparing 6-day once-daily tedizolid vs 10-day twice-daily linezolid. In ESTABLISH-1, noninferiority was met with early clinical response rates of 79.5% and 79.4% in tedizolid and linezolid groups, respectively (difference 0.1%, 95% CI –6.1% to 6.2%, with a 10% noninferiority margin). In ESTABLISH-2, noninferiority was met with 85% and 83% rates of early clinical response in tedizolid and linezolid groups, respectively (difference 2.6%, 95% CI –3.0% to 8.2%). Pooled data from ESTABLISH-1 and ESTABLISH-2 indicated a lower frequency of thrombocytopenia in tedizolid-treated than in linezolid-treated patients. Conclusion Tedizolid offers the option of an intravenous to oral switch, allows once-daily administration, and presents lower risk of myelotoxicity when a 6-day course is used for the treatment of ABSSSI. Greater economic cost associated with this antibiotic could be offset by its shorter treatment duration and possibility of oral administration in routine clinical practice, although either sponsored or nonsponsored postmarketing observational experience remains essential for ultimately confirming the effectiveness and tolerability of tedizolid outside clinical trials.

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Characterization of Neurologic and Ophthalmologic Safety of Oral Administration of Tedizolid for Up to 21 Days in Healthy Volunteers

Cited by 16 publications

References 32 publications

Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes

Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression, Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and THP-1 Monocytes

Safety and Tolerability of More than Six Days of Tedizolid Treatment

<p>Tedizolid phosphate for the treatment of acute bacterial skin and skin-structure infections: an evidence-based review of its place in therapy</p>

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