Update on the safety of linezolid

Abstract

The range of adverse events of linezolid is growing; new ones, such as nephro-toxicity and Bell's palsy, have been reported. Toxicity of linezolid is mostly related with the prolonged duration of treatment and the presence of predisposing factors. Physicians must be alerted when using linezolid for indications and duration different from the approved ones, and must be aware of the possible adverse events. In case of toxicity, the main option is the discontinuation of the drug; although, not all adverse events are fully reversible. Linezolid represents an important advance in therapeutics and is still considered safe enough, but anticipated benefits must always be counterbalanced by the possible toxicity.

Randomized non-inferiority trial to compare trimethoprim/sulfamethoxazole plus rifampicin versus linezolid for the treatment of MRSA infection

“…27 In the present study, the number and nature of AEs was similar in both arms and consistent with the known safety profile of the study drugs. 7,28,29 However, five more drug reactions occurred in the combination arm, although this was statistically non-significant.…”

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

“…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.…”

“…Other linezolid models published in the literature used either parallel linear and Michaelis-Menten elimination or a kinetics that was linear initially and subsequently saturable (53)(54)(55). Lack of mitochondrial recovery is thought to be a problem largely in patients who receive prolonged courses of oxazolidinone therapy (16,(19)(20)(21)(22)(23). In these patients, the differences in mitochondrial toxicity between tedizolid and linezolid might have important implications for care.…”

“…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).…”

Lack of Neuropathological Changes in Rats Administered Tedizolid Phosphate for Nine Months

“…Many drugs, including various antibacterial agents-especially those that inhibit protein synthesis-are known to adversely influence mitochondrial function (32). Because of structural similarities between mitochondrial and prokaryotic ribosomes, oxazolidinones can also impair mammalian mitochondrial protein synthesis (MPS) (33)(34)(35), which is thought to be the underlying mechanism for peripheral and ocular neuropathies seen with prolonged use of the oxazolidinone linezolid (8,9,33,(36)(37)(38)(39)(40)(41)(42). Although tedizolid is a more potent inhibitor of MPS than linezolid on a molar basis, it has a lower potential to cause mitochondrion-related adverse events in vivo (such as myelosuppression, neuropathy, and lactic acidosis) than linezolid when each drug is assessed in the context of its respective therapeutic dosage (18).…”