Linezolid

Common adverse effects of short-term use include headache, diarrhea, and nausea. Long-term use, however, has been associated with serious adverse effects; linezolid can cause bone marrow suppression and low platelet counts, particularly when used for more than two weeks. If used for longer periods still, it may cause sometimes irreversible chemotherapy-induced peripheral neuropathy and optic nerve damage, and lactic acidosis (a buildup of lactic acid in the body), all most likely due to mitochondrial toxicity.

Therapy with linezolid has been associated with mild and transient elevations in serum aminotransferase and alkaline phosphatase levels in 1% to 10% of patients, although similar rates of elevations occur in patients with infections treated with comparable agents, and enzyme elevations were not found in normal volunteers given linezolid for short periods. On the other hand, ALT elevations during therapy have been higher with higher doses of linezolid, but in all instances the elevations occurred without symptoms and resolved with discontinuation of the drug.

The most common adverse effects experienced with linezolid use include decreased platelets, hemoglobin, white blood cell counts, headache, nausea, diarrhea, elevated pancreatic enzymes, elevated liver function tests, and neuropathy. Warnings associated with linezolid include duration-related myelosuppression (thrombocytopenia, anemia, leukopenia), serotonin syndrome, hypoglycemia; caution in patients on insulin or hypoglycemic drugs, seizures, lactic acidosis, hypertension when used with adrenergic drugs, and irreversible peripheral and optic neuropathy when used for 28 days or greater. Reports exist of blurred vision in patients receiving shorter courses of linezolid. Prolonged use may result in fungal or bacterial infection, including Clostridioides difficile-associated diarrhea (CDAD) and pseudomembranous colitis. CDAD can occur greater than 2 months after postantibiotic treatment. Lactic acidosis may also occur with use; evaluate patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate concentrations.

Toxicity is infrequent, and no antidote for linezolid is currently available. Symptomatic and supportive treatment is recommended for managing mild to severe toxicity. For severe neutropenia, administer colony-stimulating factors such as filgrastim or sargramostim. Filgrastim is dosed at 5 mcg/kg/day subcutaneous (SQ) or IV over 15 to 30 minutes, or sargramostim at 250 mcg/m2/day IV over 4 hours. Transfusion of platelets, packed red cells, or both may be necessary for patients with severe thrombocytopenia, anemia, or hemorrhage.

Linezolid targets the large 39S subunit of the mitochondrial ribosome thereby deactivation mitochondrial protein synthesis. As a result Linezolid is cytotoxic to the most metabolically active cells or tissues including the heart, liver, thymus and bone-marrow. (A7823). The likely target of Linezolid is the 16S rRNA molecule in the mitochondrial ribosome, which is analogous to the 23S rRNA in bacterial ribosomes.

/SIGNS AND SYMPTOMS/ The incidence and clinical characteristics of linezolid-induced thrombocytopenia /were evaluated/ in 19 patients who were treated with linezolid. Overall, thrombocytopenia (platelet count, <100,000 platelets/mm(3)) was observed in 32% of patients who received linezolid for >10 days; gastrointestinal bleeding was observed in 1 patient and 4 patients required platelet transfusions. These data suggest that even patients who are not considered to be at risk for development of thrombocytopenia should be monitored closely if linezolid therapy is continued for >10 days.

/CASE REPORTS/ Linezolid, a fluorinated oxazolidinone, is the first of a new class of antimicrobials designed to target resistant gram-positive cocci. Hematologic adverse effects, including reversible thrombocytopenia, were reported during phase III comparator-controlled trials. ...

/CASE REPORTS/ ... Linezolid is the first of a new class of antibiotics, the oxazolidinones. The drug is generally well tolerated. However, mild-to-moderate adverse effects have been reported, such as gastrointestinal effects (most frequent), myelosuppression, skin eruptions, elevated liver enzymes, and tongue discoloration. As with any new drug on the commercial market, not all adverse effects are elucidated during preclinical trials. An immunocompromised 11-year-old girl with cellulitis of the toe experienced tooth discoloration after receiving a 28-day course of linezolid. The discoloration was present on the enamel of her lower anterior teeth and was superficial and reversible with dental cleaning.

/CASE REPORTS/ A case of a woman who developed severe, painful peripheral neuropathy while receiving linezolid therapy for 6 months /was reported/. Nerve conduction studies indicated a sensory-motor axonal neuropathy. Extensive assessment did not show alternative explanations for her neuropathy. At the time of death 1 month after discontinuing linezolid, the neuropathy had not resolved. A review of published material shows a growing body of evidence that long-term use of linezolid may be associated with severe peripheral and optic neuropathy. 21 cases have been reported. In most cases, optic neuropathies resolved after stopping linezolid but peripheral neuropathies did not. The duration of therapy rather than indication for treatment seems to be the most important factor. The mechanism of toxicity is unknown but certain pharmacological properties of linezolid that may play a part are proposed.

For more Human Toxicity Excerpts (Complete) data for LINEZOLID (18 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Linezolid

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

The elimination half-life is estimated to be between 5 and 7 hours.

... A significant although weak correlation between age and total body clearance was observed. The mean (+ or - SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 + or - 1.1 hr, 0.34 + or - 0.15 liter/h/kg and 0.73 + or - 0.18 liter/kg, respectively. ...

The following are elimination half live values of linezolid doses in adults: 400 mg tablet (single dose) - 5.2 hours; 400 mg tablet every 12 hours - 4.69 hours; 600 mg tablet (single dose) - 4.26 hours; 600 mg tablet every 12 hours - 5.4 hours; 600 mg oral suspension (single dose) - 4.6 hours; 600 mg intravenous injection (single dose) - 4.4 hours; 600 mg intravenous injection every 12 hours - 4.8 hours;. Pediatrics ranging in age from greater than 7 days of age to 11 years of age have a shorter half-life compared with adults.

Linezolid is primarily metabolized to two inactive metabolites: an aminoethoxyacetic acid metabolite (PNU-142300) and a hydroxyethyl glycine metabolite (PNU-142586), both of which are the result of morpholine ring oxidation. The hydroxyethyl glycine metabolite - the most abundant of the two metabolites - is likely generated via non-enzymatic processes, though further detail has not been elucidated. While the specific enzymes responsible for the biotransformation of linezolid are unclear, it does not appear to be subject to metabolism via the CYP450 enzyme system, nor does it meaningfully inhibit or induce these enzymes. Linezolid is, however, a reversible and non-selective inhibitor of monoamine oxidase enzymes.

In vitro studies have not shown that linezolid is metabolized by human cytochrome p450 enzymes. Linezolid does not inhibit the cytochrome p450 enzymes.

Linezolid is primarily metabolized via oxidation of the morpholine ring. Two inactive metabolites are formed: the aminoethoxyacetic acid metabolite and the hydroxyethyl glycine metabolite. The hydroxyethyl glycine metabolite is formed via a non-enzymatic chemical oxidation mechanism in vitro.

The drug is metabolized principally via oxidation to 2 inactive metabolites; an aminoethoxyacetic acid metabolite and a hydroxyethyl glycine metabolite. Linezolid is not metabolized to any measurable extent by the cytochrome p450 (CYP) enzyme system. Linezolid does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 and is not an enzyme inducer, suggesting that the drug is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.

In vitro studies were conducted to identify the hepatic enzyme(s) responsible for the oxidative metabolism of linezolid. In human liver microsomes, linezolid was oxidized to a single metabolite, hydroxylinezolid (M1). Formation of M1 was determined to be dependent upon microsomal protein and NADPH. Over a concentration range of 2 to 700 uM, the rate of M1 formation conformed to first-order (nonsaturable) kinetics. Application of conventional in vitro techniques were unable to identify the molecular origin of M1 based on the following experiments: a) inhibitor/substrates for various cytochrome P-450 (CYP) enzymes were unable to inhibit M1 formation; b) formation of M1 did not correlate (r(2) < 0.23) with any of the measured catalytic activities across a population of human livers (n = 14); c) M1 formation was not detectable in incubations using microsomes prepared from a baculovirus insect cell line expressing CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 4A11. In addition, results obtained from an in vitro P-450 inhibition screen revealed that linezolid was devoid of any inhibitory activity toward the following CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Additional in vitro studies excluded the possibility of flavin-containing monooxygenase and monoamine oxidase as potential enzymes responsible for metabolite formation. However, metabolite formation was found to be optimal under basic (pH 9.0) conditions, which suggests the potential involvement of either an uncharacterized P-450 enzyme or an alternative microsomal mediated oxidative pathway.

Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. Linezolid is not an inducer of cytochrome P450 (CYP) in rats, and it has been demonstrated from in vitro studies that linezolid is not detectably metabolized by human cytochrome P450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).

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LINEZOLID

Established Pharmacologic Class [EPC] - Oxazolidinone Antibacterial

Chemical Structure [CS] - Oxazolidinones

Linezolid is an Oxazolidinone Antibacterial.

LINEZOLID

Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins.

Substances that inhibit the growth or reproduction of BACTERIA.

Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (Tmax) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing. The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals.

Urinary excretion is the primary means by which linezolid and its metabolic products are excreted. Following the administration of a radiolabeled dose of linezolid under steady-state conditions, approximately 84% of radioactivity was recovered in the urine, of which approximately 30% is unchanged parent drug, 40% is the hydroxyethyl glycine metabolite, and 10% is the aminoethoxyacetic acid metabolite. Fecal elimination is comparatively minor, with no parent drug observed in feces and only 6% and 3% of an administered dose found in the feces as the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite, respectively.

At steady-state, the volume of distribution of linezolid in healthy adults is approximately 40-50 liters.

Total clearance of linezolid is estimated to be 100-200 mL/min, the majority of which appears to be non-renal. Mean renal clearance is approximately 40 mL/min, which suggests net tubular reabsorption, while non-renal clearance is estimated to account for roughly 65% of total clearance, or 70-150 mL/min on average. Variability in linezolid clearance is high, particularly for non-renal clearance.

Distributed to well-perfused tissues; volume of distribution slightly lower in women than men. VolD (steady state) - 40 to 50 L.

AUC is lower for pediatric patients compared with adults and a wider variability of linezolid AUC cross all pediatric age groups as compared with adults. Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have larger AUC values than many full-term neonates and older infants.