Linezolid

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

0.9

0.67

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Anti-Bacterial Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antituberculosis medicines

Danger

H372 (87.7%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

P260, P264, P270, P319, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 81 reports by companies from 16 notifications to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl linezolide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Following coadministration with linezolid, minimal but statistically significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations; a minimal but statistically significant decrease was observed in dextrorphan (the primary metabolite of dextromethorphan) plasma concentrations. Increased blood pressure (BP) was observed following the coadministration of linezolid with either pseudoephedrine or phenylpropanolamine; no significant effects were observed with dextromethorphan. None of these coadministered drugs had a significant effect on linezolid pharmacokinetics. Minimal numbers of adverse events were reported. Potentiation of sympathomimetic activity by linezolid was judged not to be clinically significant, but patients sensitive to the effects of increased BP due to predisposing factors should be treated cautiously. No restrictions are indicated for the coadministration of dextromethorphan and linezolid.

To report 2 cases of serotonin toxicity (ST) associated with concomitant use of linezolid and serotonergic drugs and review previously published case reports. Case 1. A 38-year-old white female with cystic fibrosis treated with venlafaxine 300 mg/day for one year was prescribed linezolid 600 mg intravenously every 12 hours for treatment of methicillin-resistant Staphylococcus aureus (MRSA) pulmonary infection. She displayed symptoms of ST 8 days after the introduction of linezolid. The venlafaxine dosage was decreased to 150 mg/day, and symptoms gradually abated over 36 hours. Case 2. A 37-year-old male with multiple myeloma received citalopram 40 mg/day and trazodone 150 mg/day for anxiety-related disorders. Linezolid treatment with 600 mg orally twice daily was instituted for MRSA cellulitis. The following day, the patient developed anxiety, panic attacks, tremors, tachycardia, and hypertension that persisted throughout linezolid treatment. Symptoms finally waned 5 days after linezolid treatment was stopped.

Potential pharmacologic interaction (serotonin syndrome). Although serotonin syndrome was not reported during clinical trials with linezolid, there have been a limited number of postmarketing case reports of the syndrome in patients who received linezolid concurrently with or shortly after discontinuation of certain selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, paroxetine, sertraline). Clinicians should consider the possibility if signs and symptoms of serotonin syndrome (e.g., hyperpyrexia, cognitive dysfunction) occur in patients receiving such concomitant therapy. Some clinicians suggest that linezolid be used with caution in patients receiving SSRIs, and some suggest that SSRI therapy should be discontinued before linezolid is initiated and not reinitiated until 2 weeks after linezolid therapy is completed.

Toxicity resulting from excessive intra-synaptic serotonin, historically referred to as serotonin syndrome, is now understood to be an intra-synaptic serotonin concentration-related phenomenon. Recent research more clearly delineates serotonin toxicity as a discreet toxidrome characterized by clonus, hyper-reflexia, hyperthermia and agitation. Serotonergic side-effects occur with serotonergic drugs, and overdoses of serotonin re-uptake inhibitors (SRIs) frequently produce marked serotonergic side-effects, and in 15% of cases, moderate serotonergic toxicity, but not to a severe degree, which produces hyperthermia and risk of death. It is only combinations of serotonergic drugs acting by different mechanisms that are capable of raising intra-synaptic serotonin to a level that is life threatening. The combination that most commonly does this is a monoamine oxidase inhibitor (MAOI) drug combined with any SRI. There are a number of lesser-known drugs that are MAOIs, such as linezolid and moclobemide; and some opioid analgesics have serotonergic activity. These properties when combined can precipitate life threatening serotonin toxicity. Possibly preventable deaths are still occurring. Knowledge of the properties of these drugs will therefore help to ensure that problems can be avoided in most clinical situations, and treated appropriately (with 5-HT(2A) antagonists for severe cases) if they occur.

For more Interactions (Complete) data for LINEZOLID (12 total), please visit the HSDB record page.

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 Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl linezolide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J01XX08

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

J01XX08

Linezolid is an oxazolidinone antibacterial agent effective against most strains of aerobic Gram-positive bacteria and mycobacteria. It appears to be bacteriostatic against both staphylococci and enterococci and bactericidal against most isolates of streptococci. Linezolid has shown some _in vitro_ activity against Gram-negative and anaerobic bacteria but is not considered efficacious against these organisms. Linezolid is a reversible and non-selective inhibitor of monoamine oxidase (MAO) enzymes and can therefore contribute to the development of serotonin syndrome when administered alongside serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). Linezolid should not be used for the treatment of catheter-related bloodstream infections or catheter-site infections, as the risk of therapy appears to outweigh its benefits under these circumstances.

Linezolid exerts its antibacterial effects by interfering with bacterial protein translation. It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction, thereby preventing bacteria from dividing. Point mutations in the bacterial 23S rRNA can lead to linezolid resistance, and the development of linezolid-resistant _Enterococcus faecium_ and _Staphylococcus aureus_ have been documented during its clinical use. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

Linezolid is a synthetic oxazolidinone anti-infective agent that is structurally unrelated to other anti-infectives commercially available in the US. In contrast to other anti-infectives that inhibit bacterial protein synthesis, linezolid acts early in translation by binding to a site on the bacterial 23S ribosomal RNA of the 50S subunit and preventing the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process.

Linezolid acts via inhibition of protein synthesis. It bind to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex. This step is essential for the bacterial translation process.

Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. Mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity /were studied/, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo /were evaluated/. In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences.

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).

ISQ9I6J12J

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.

THERAP CAT: Antibacterial

Use (kg; approx.) in Germany (2009): >500

For the treatment of bacterial infections caused by susceptible strains of vancomycin resistant <i>Enterococcus faecium</i>, <i>Staphylococcal aureus</i> (methicillin resistant and susceptible strains), <i>Streptococcus pneumoniae</i>, <i>Streptococcus pyogenes</i>, <i>Streptococcus agalactiae</i> (A308).

Parenteral: Injection, for IV infusion: 2 mg/mL (200 and 600 mg) in sterile isotonic solution Zyvox Injection ( in flexible containers), (Pfizer).

Oral: For suspension: 100 mg/5 mL Zyvox, (Pfizer); Tablets, film-coated: 600 mg Zyvox, (Pfizer).