Linezolid-induced optic neuropathy: a mitochondrial disorder?

Javaheri, Michael; Khurana, Rahul N.; OʼHearn, Thomas M; Lai, Michael M.; Sadun, Alfredo A.

doi:10.1136/bjo.2006.102541

Cited by 85 publications

(62 citation statements)

References 31 publications

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“…Because impairment of MPS seems to be the primary trigger of certain clinical adverse effects that can occur with longterm linezolid treatment, such as myelosuppression, neuropathy, and lactic acidosis (8,(11)(12)(13)(14)(15)(16)(17)(18)(19), we initially conducted an in vitro study to compare the abilities of linezolid and tedizolid to inhibit MPS. The results clearly demonstrated dose-and time-dependent inhibition of MPS, which was more pronounced with tedizolid than with linezolid.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, oxazolidinones, a class of antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit, can impair mitochondrial protein synthesis (MPS) (4-7) due to structural similarities between mitochondrial and prokaryotic ribosomes (8)(9)(10). Inadvertent inhibition of MPS is thought to be the underlying mechanism for several well-known side effects of prolonged use of the oxazolidinone linezolid, such as myelosuppression, lactic acidosis, and peripheral and ocular neuropathies (8,(11)(12)(13)(14)(15)(16)(17)(18)(19). Although being generally, but not always, reversible, these toxicities can significantly limit the use of linezolid during long-term therapy (16,(19)(20)(21)(22)(23)(24); cautions are included in the official prescribing information for this drug (25).…”

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confidence: 99%

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Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Flanagan

McKee

Das

et al. 2015

Antimicrob Agents Chemother

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e Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [؎ standard error of the mean] 50% inhibitory concentration [IC 50 ] for MPS of 0.31 ؎ 0.02 M versus 6.4 ؎ 1.2 M). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC 50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Flanagan

McKee

Das

et al. 2015

Antimicrob Agents Chemother

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“…The ribosomal similarity between the mitochondria in mammalian nerve cell and that of bacteria is the basis of neurological adverse effects in human [3].…”

Section: Discussionmentioning

confidence: 99%

“…[3] It has a spectrum of activity against a variety of multidrug-resistant organisms including MRSA, VRE and MDR Mycobacterium tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

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Linezolid induced optic neuropathy, a serious yet reversible adverse effect: a case report

Shah¹,

Lamichhane²

2017

EJMCR

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Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Wang,

Li,

Gordeev

et al. 2024

J of Applied Toxicology

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Contezolid acefosamil (CZA) is an intravenous prodrug of oxazolidinone antibiotic contezolid (CZD). It is being developed to treat infections due to Gram‐positive bacteria including multidrug‐resistant pathogens, while addressing myelosuppression and neurotoxicity limitations associated with long‐term use of this class of antibiotics. In vivo, CZA is rapidly deacylated into its first metabolite MRX‐1352, which is then dephosphorylated to release active drug CZD. Four‐week repeat‐dose toxicity studies of intravenous CZA were conducted in Sprague–Dawley rats (40, 80, and 160/120 mg/kg/dose twice a day [BID]) and beagle dogs (25, 50, and 100/75 mg/kg/dose BID). The high doses administered to both rats and dogs were adjusted due to adverse effects including decreased body weight and food consumption. Additionally, a dose‐dependent transient reduction in erythrocyte levels was recorded at the end of dosing phase. Importantly, no myelosuppressive reduction in platelet counts was observed, in contrast to the myelosuppression documented for standard‐of‐care oxazolidinone linezolid. The no‐observed‐adverse‐effect level (NOAEL) of CZA was 80 and 25 mg/kg/dose BID in rats and dogs, respectively. Separately, 3‐month neuropathological evaluation in Long–Evans rats (25, 37.5, and 50 mg/kg/dose, oral CZA, BID) demonstrated no neurotoxicity in the central, peripheral, and optical neurological systems. Toxicokinetic data from these studies revealed that CZD exposures at NOAELs were higher than or comparable with that for the intended clinical dose. These results confirm the favorable safety profile for CZA and support its clinical evaluation for long‐term therapy of persistent Gram‐positive infections, beyond the application for earlier oxazolidinones.

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Linezolid-induced optic neuropathy: a mitochondrial disorder?

Cited by 85 publications

References 31 publications

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Linezolid induced optic neuropathy, a serious yet reversible adverse effect: a case report

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

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