Linezolid

337.35

337.35

2017-001-1

ISQ9I6J12J

DTXSID5046489

C29158

White crystals from ethyl acetate and hexanes

J01XX08|J - Antiinfectives for systemic use

29419000

71.1

0.7

white to off-white

1.302±0.06 g/cm3(Predicted)

73-76 °C

585.5±50.0 °C(Predicted)

DMSO: >20mg/mL

Store at RT

6.9X10-11 mm Hg at 25 deg C (est)

D20 -9° (c = 0.919 in chloroform)

Henry's Law constant = 1.8X10-14 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 1.3X10-10 cu cm/molecule-sec at 25 °C (est)

3

20/21/22

36-24/25

AC2720000

Xn

P260, P264, P270, P314, P501

H372

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.

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.

Stevens DL et al; A Review of Linezolid: The First Oxazolidinone Antibiotic; Expert Rev Anti Infect Ther 2 (1): 51-9 (2004)

|Danger|H372 (92.81%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]|P260, P264, P270, P314, and P501|Aggregated GHS information provided by 139 companies from 10 notifications to the ECHA C&L Inventory.

Clinical signs of acute toxicity lead to decreased activity, ataxia, vomiting and tremors.

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.|Therapy with tedizolid has been associated with mild and transient elevations in serum aminotransferase and alkaline phosphatase levels in 1% to 4% of patients, although similar rates of elevations occur in patients with infections treated with comparable agents including linezolid. In all instances, the elevations occurred without symptoms or jaundice and resolved with discontinuation of the drug.

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.

This retrospective case-control study compared the tolerability and efficacy of linezolid therapy for patients with end-stage renal disease and patients with non-end-stage renal disease, all of whom had gram-positive bacterial infections. There were 58 men and 33 women enrolled in the study, with a mean age of 61.5 years (range, 45.4-81.2 years). Among these patients, 28 (30.8%) were receiving hemodialysis at the start of linezolid treatment. The end-stage renal disease group had a higher percentage of patients with diabetes mellitus (57.1% vs. 33.3%; P = .029) and an older mean age (+ or - SD) (72.1 + or - 10.8 years vs. 56.8 + or - 20.4 years; P < .001), compared with the non-end-stage renal disease group. Severe thrombocytopenia (platelet count, < 100 x 10+9 platelets/L) and anemia were significantly more frequent in the end-stage renal disease group, compared with the non-end-stage renal disease group (78.6% vs. 42.9% (P = .003) and 71.4% vs. 36.5% (P = .003), respectively). The independent risk factors for thrombocytopenia identified by logistic regression analysis were pretreatment disease severity score (odds ratio OR, 1.34; 95%, confidence interval (CI), 1.13-1.60; P = 0.001), central catheter-related infection (OR, 4.96; 95% CI, 1.08-22.73; P = 0.046), and end-stage renal disease (OR, 6.14; 95% CI, 1.63-23.26; P = .007). End-stage renal disease was the only independent risk factor for anemia (OR, 4; 95% CI, 1.50-10.64; P = 0.006). Survival analysis for the development of thrombocytopenia or death showed significant differences between patients with end-stage renal disease and patients with non-end-stage renal disease (P < 0.001). The lower tolerability of linezolid in patients with end-stage renal disease, compared with those with non-end-stage renal disease, is evidenced by the higher rates of thrombocytopenia and anemia in the former group. The severity of these conditions necessitates treatment discontinuation for patients with end-stage renal disease more often than for patients with non-end-stage renal disease.

31%

Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk.

For the treatment of bacterial infections caused by susceptible strains of vancomycin resistant Enterococcus faecium, Staphylococcal aureus (methicillin resistant and susceptible strains), Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae.|FDA Label

Linezolid is an oxazolidinone class antibiotic that is used for serious or problematic infections caused by resistant enterococcal or staphylococcal organisms. Prolonged therapy with linezolid has been linked to rare instances of lactic acidosis and liver injury probably as a result of hepatic mitochondrial toxicity.|Tedizolid is an oxazolidinone antibiotic, similar to linezolid, which has a broad spectrum of activity against gram positive bacteria including methicillin resistant Staphyloccocal aureus (MRSA). Tedizolid has been associated with a low rate of transient serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.

Antiinfective Agents

Antibacterial|Intravenous and oral linezolid is indicated in the treatment of nosocomial pneumonia caused by methicillin-susceptible and methicillin resistant Staphylococcus aureus or penicillin-susceptible strains of Streptococcus pneumonia. /Included in US product labeling/|Intravenous and oral linezolid is indicated in the treatment of vancomycin-resistant Enterococcus faecium infections. /Included in US product labeling/|Oral linezolid is indicated in the treatment of uncomplicated skin and soft tissue infections caused by methicillin-susceptible strains of Staphylococcus aureus or Streptococcus pyogenes. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for LINEZOLID (16 total), please visit the HSDB record page.

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.|Lactic acidosis has been reported with the use of Zyvox. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving zyvox should receive immediate medical evaluation.|Spontaneous reports of serotonin syndrome associated with the co-administration of Zyvox and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Where administration of Zyvox and concomitant serotonergic agents is clinically appropriate, patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuation of either one or both agents.|Peripheral and optic neuropathy have been reported in patients treated with Zyvox, primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with Zyvox for less than 28 days. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Zyvox for extended periods (> or = 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Zyvox. If peripheral or optic neuropathy occurs, the continued use of Zyvox in these patients should be weighed against the potential risks.|For more Drug Warnings (Complete) data for LINEZOLID (18 total), please visit the HSDB record page.

Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Linezolid is active in vitro and in clinical infections against most strains of Enterococcus faecium (established in vancomycin-resistant strains only), Staphylococcus aureus (including oxacillin-resistant strains), Streptococcus agalactia (group B streptococci), S. pneumoniae (established in penicillin-susceptible strains only), and S. pyogenes (group a beta-hemolytic streptococci). Linezolid also has demonstrated in vitro activity against Enterococcus faecalis (including vancomycin-resistant strains), E. faecium (vancomycin-susceptible strains), S. epidermidis (including oxacillin-resistant strains [previously known as methicillin-resistant strains]), S. haemolyticus, S. pneumoniae (penicillin-resistant strains), viridans group streptococci, and Pasteurella multocida; however, safety and efficacy of linezolid in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled clinical studies to date.|In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg every 12 hr, lower than the recommended dose, and 2 patients received 600 mg every 12 hr). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10 -9 to 1 x 10 -11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published. In one report nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred. There has been a report of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use. The linezolid resistance in these organisms was associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies. Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.

Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Susceptible organisms include methicillin- and vancomycin-resistant staphylococci, vancomycin-resistant enterococci, penicillin-resistant pneumococci and anaerobes. Oxazolidinones inhibit protein synthesis by binding at the P site at the ribosomal 50S subunit. Resistance to other protein synthesis inhibitors does not affect oxazolidinone activity, however rare development of oxazolidinone resistance cases, associated with 23S rRNA alterations during treatment have been reported. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.

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. (See all compounds classified as Protein Synthesis Inhibitors.)|Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%.|40 to 50 L [healthy adult volunteers]|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.|Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200 mg kg(-1) day(-1)) and dog (10-80 mg kg(-1) day(-1)) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V(ss)) approximately equal to total body water. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. Radioactivity recovery was essentially complete within 24-48 hr. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.|In two randomized, double-blind, placebo-controlled, dose-escalating trials, subjects were exposed either to oral (375, 500 or 625 mg) or intravenous (500 or 625 mg) linezolid or placebo twice daily. Serial blood and urine samples were obtained after the first- and multiple-dose administrations for up to 18 days. Non-compartmental pharmacokinetic analyses were used to describe the disposition of linezolid. Plasma linezolid concentrations and area under the concentration-time curves (AUC) increased proportionally with dose irrespective of the route of administration. Plasma linezolid concentrations remained above the MIC90 for susceptible target pathogens (4.0 mg/L) for the majority of the 12 hr dosing interval. Mean clearance, half-life and volume of distribution were similar irrespective of dose for both the oral and intravenous routes. Linezolid was well tolerated and the frequency of drug-related adverse events was similar between the linezolid and placebo groups. Oral and intravenous linezolid exhibit linear pharmacokinetics, with concentrations remaining above the target MIC90 /minimal inhibitory concentration/ for most of the dosing interval. These results support a twice-daily schedule for linezolid and demonstrate the feasibility of converting from intravenous to oral dosing without a dose adjustment.|For more Absorption, Distribution and Excretion (Complete) data for LINEZOLID (16 total), please visit the HSDB record page.

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|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).

4.5-5.5 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 a synthetic antibacterial agent of the oxazolidinone class of antibiotics. It has in vitro activity against aerobic Gram positive bacteria, certain Gram negative bacteria and anaerobic microorganisms. It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex. Specifically, linezolid 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 an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains. Linezolid is also a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.|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.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/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.

100766, U

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).

Analyte: linezolid; matrix: blood (plasma), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 251 nm; limit of quantitation: 10 ng/mL

A method for determining linezolid concentration in human serum using micellar electrokinetic capillary chromatography by direct injection of serum is described. A borate buffer (pH 8.0) containing sodium dodecyl sulfate was used as a run buffer and detection of linezolid was performed at 250 nm (its absorption maximum). The migration time of linezolid was 5.5 min and the detection limit was 0.5 mg/l (S/N=3). The precision and accuracy of this method was good with no interference with the detection from bilirubin, hemoglobin and chyle of high concentrations. This provides a simple and easy method where samples of micro-quantity are used.

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