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OXAZOLIDINONE ANTIBACTERIALS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The oxazolidinone antibacterial agents, including linezolid, tedizolid, and eperezolid, are primarily bacteriostatic against various multi-drug resistant gram-positive organisms and act by binding to the 50S ribosomal subunit and inhibiting bacterial protein synthesis.

Specific Substances

    A) EPEREZOLID (SYNONYM)
    1) Acetamide, N-((3-(3-fluoro-4(4-hydroxyacetyl)-
    2) 1-piperazynyl)phenyl-2-oxo-5-oxazolidinyl)methyl)-,(S)-
    3) PNU-100592
    4) U-100592
    5) CAS 165800-04-4
    LINEZOLID (SYNONYM)
    1) (S)-N-[(3-(3-fluoro-4(4-moroholinyl)phenyl))-2-
    2) (oxo-5-oxazolidinyl)methyl]acetamide
    3) PNU-100766
    4) U-100766
    5) CAS 165800-03-3
    TEDIZOLID (SYNONYM)
    1) Tedizolid phosphate
    2) CAS 856866-72-3

    1.2.1) MOLECULAR FORMULA
    1) LINEZOLID: C16H20FN3O4
    2) TEDIZOLID PHOSPHATE: C17H16FN6O6P

Available Forms Sources

    A) FORMS
    1) Linezolid is available in the United States as 400 mg and 600 mg tablets, 100 mg/5 mL oral suspension, and 2 mg/mL solution for intravenous infusion (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) Tedizolid phosphate is available in the United States as 200 mg tablets and 200 mg sterile, lyophilized powder in single-use vial for reconstitution for intravenous infusion (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    3) Eperezolid is not available in the United States.
    B) USES
    1) Linezolid is approved for the treatment of infections caused by various gram-positive organisms including vancomycin-resistant Enterococcus faecium, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) Tedizolid phosphate is approved for the treatment of adults with acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms of Staphylococcus aureus (including methicillin-resistant and susceptible isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (which includes S anginosus, S intermedius, and S constellatus) and Enterococcus faecalis (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Linezolid is approved for the treatment of infections caused by various gram-positive organisms including vancomycin-resistant Enterococcus faecium, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. Tedizolid phosphate is approved for the treatment of adults with acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms of Staphylococcus aureus (including methicillin-resistant and susceptible isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (which includes S anginosus, S intermedius, and S constellatus) and Enterococcus faecalis. Eperezolid is not available in the United States.
    B) PHARMACOLOGY: Linezolid is an oxazolidinones that inhibits the bacterial ribosomal translation process, of aerobic Gram-positive bacteria and certain Gram-negative and anaerobic bacteria, by selectively binding to a site on the 23S ribosomal RNA of the 50S subunit, thereby preventing initiation complex formation with the 70S ribosomal subunit. Tedizolid phosphate is the prodrug of tedizolid, an oxazolidinone antibiotic, which inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, diarrhea, and headache. OTHER EFFECTS: Rash, toxic optic neuropathy and peripheral neuropathy, tongue discoloration, elevated liver enzymes, pseudomembranous colitis, seizures, lactic acidosis, myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia.
    2) DRUG INTERACTIONS: Serotonin syndrome, characterized by fever, agitation, mental status changes, and tremors, has been reported infrequently following concomitant administration of linezolid and a selective serotonin reuptake inhibitor.
    E) WITH POISONING/EXPOSURE
    1) Human overdose information is limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Linezolid and tedizolid are classified as FDA pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Embryo and/or fetal toxicities were evident in animals at doses that caused maternal toxicity. Toxicities included increased postimplantation embryo death, increased incidence of skeletal variations, and decreased fetal body weights with administration of either linezolid or tedizolid. Linezolid, linezolid metabolites, and tedizolid were excreted in the milk of lactating rats. Reversibly decreased fertility and reproductive performance in male rats, possibly due to epithelial cell hypertrophy in the epididymis, was reported following linezolid ingestion. There were no adverse fertility or reproductive performance effects observed with tedizolid administration in either male or female rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of linezolid in humans.

Laboratory Monitoring

    A) Monitor vital signs and liver enzymes in symptomatic patients.
    B) Monitor serial CBC (with differential) and platelet count. Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported in patients receiving linezolid.
    C) Monitor serum electrolyte status in patients with significant diarrhea and/or vomiting.
    D) Monitor for clinical evidence of serotonin syndrome.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. For seizures, administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended because of potential for seizures.
    2) HOSPITAL: Consider activated charcoal in a patient with a recent, substantial overdose who is alert or in whom airway is protected.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe seizures.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes OR sargramostim 250 mcg/meter(2)/day IV over 4 hours. Transfusion of platelets, packed red cells, or both may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage.
    G) SEROTONIN SYNDROME
    1) Concomitant use of linezolid with a selective serotonin reuptake inhibitor has resulted in a serotonin syndrome; this is attributed to linezolid's action as a weak reversible monoamine oxidase inhibitor. Primary treatment is sedation with IV benzodiazepines, and cooling measures. CYPROHEPTADINE: A serotonin antagonist with high affinity for the 5-HT2 receptors; effective for milder cases of serotonin syndrome. Dose: ADULT: 12 mg orally or nasogastric tube, followed by 4 to 8 mg every 4 to 6 hours. CHILD: 0.25 mg/kg/day orally or nasogastric tube divided every 6 hours, maximum dose 12 mg/day. CHLORPROMAZINE: A phenothiazine antipsychotic with 5-HT2 antagonist activity; indicated in severe serotonin syndrome cases. Dose: 12.5 to 50 mg IV, followed by 25 to 50 mg every 6 hours. It is NOT generally recommended because it may cause severe hypotension. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with nondepolarizing agents.
    H) ENHANCED ELIMINATION PROCEDURE
    1) During a phase I clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session that began 3 hours after administration of the dose. Hemodialysis should only be considered in patients with severe toxicity not responding to supportive care.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a health care facility and monitored until symptoms resolve. Patients with unintentional ingestions who are symptomatic should be observed in a health care facility.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected linezolid overdose, the possibility of multi-drug involvement should be considered.
    K) PHARMACOKINETICS
    1) LINEZOLID: Protein binding: approximately 31%. Vd: 40 to 50 liters. Metabolism: primarily metabolized in the liver by oxidation of the morpholine ring, resulting in two inactive carboxylic acid metabolites. Excretion: Renal: approximately 30% of a linezolid dose is excreted in the urine as unchanged drug and approximately 50% of a linezolid dose is excreted in the urine as metabolites. Renal clearance: 40 mL/min. Feces: approximately 9%. Elimination half-life: 4.26 to 5.40 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression (eg, methotrexate) or elevated liver enzymes (eg, ethanol, acetaminophen).

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: LINEZOLID: ADULT: Varies by indication. Recommended dose is 400 to 600 mg IV or orally every 12 hr for 10 to 28 days depending on the indication. PEDIATRIC: PRETERM NEONATES (Less than 34 weeks), LESS THAN 7 DAYS OF AGE: Recommended initial dose is 10 mg/kg every 12 hr; some neonates may require dosing of 10 mg/kg 8 hr. NEONATES AND CHILDREN 11 YEARS AND YOUNGER: 10 mg/kg orally or IV every 8 to 12 hours depending on indication. TEDIZOLID: ADULT: 200 mg once daily orally or as an IV infusion over 1 hour once daily for 6 days. PEDIATRIC: Safety and effectiveness have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Linezolid is approved for the treatment of infections caused by various gram-positive organisms including vancomycin-resistant Enterococcus faecium, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. Tedizolid phosphate is approved for the treatment of adults with acute bacterial skin and skin structure infections caused by susceptible gram-positive microorganisms of Staphylococcus aureus (including methicillin-resistant and susceptible isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (which includes S anginosus, S intermedius, and S constellatus) and Enterococcus faecalis. Eperezolid is not available in the United States.
    B) PHARMACOLOGY: Linezolid is an oxazolidinones that inhibits the bacterial ribosomal translation process, of aerobic Gram-positive bacteria and certain Gram-negative and anaerobic bacteria, by selectively binding to a site on the 23S ribosomal RNA of the 50S subunit, thereby preventing initiation complex formation with the 70S ribosomal subunit. Tedizolid phosphate is the prodrug of tedizolid, an oxazolidinone antibiotic, which inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, diarrhea, and headache. OTHER EFFECTS: Rash, toxic optic neuropathy and peripheral neuropathy, tongue discoloration, elevated liver enzymes, pseudomembranous colitis, seizures, lactic acidosis, myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia.
    2) DRUG INTERACTIONS: Serotonin syndrome, characterized by fever, agitation, mental status changes, and tremors, has been reported infrequently following concomitant administration of linezolid and a selective serotonin reuptake inhibitor.
    E) WITH POISONING/EXPOSURE
    1) Human overdose information is limited. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) LINEZOLID
    a) TOXIC OPTIC NEUROPATHY: Toxic optic neuropathy has been reported in several patients with prolonged use (longer than the recommended duration of 28 days) of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Kulkarni & Del Priore, 2005; McKinley & Foroozan, 2005; Saijo et al, 2005; Lee et al, 2003).
    b) CASE REPORT: Two patients experienced decreased visual acuity, dyschromatopsia, and cecocentral scotomas characteristic of toxic optic neuropathy following the long-term use of linezolid for pneumonia. Visual function slowly recovered 3 to 4 months after the cessation of linezolid (McKinley & Foroozan, 2005).
    c) CASE REPORT: A 27-year-old woman developed optic and peripheral neuropathy with prolonged use of high doses of linezolid for osteomyelitis. Corticosteroid use exacerbated the visual loss. Following the discontinuation of linezolid, she recovered without further sequelae (Saijo et al, 2005).
    d) CASE REPORT: Two patients developed toxic optic neuropathy and experienced blurred vision and progressive loss of vision and color perception with prolonged use of linezolid to treat complicated methicillin-resistant Staphylococcus aureus infections. Following the discontinuation of linezolid, both patients recovered over the next few months (Lee et al, 2003).
    e) CASE REPORT: A 56-year-old man developed toxic optic neuropathy after using linezolid 600 mg twice daily for 12 months. He presented with bilateral, progressive decline in visual acuity for 6 to 8 months. Following the discontinuation of linezolid, he recovered over the next few weeks (Kulkarni & Del Priore, 2005).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) LINEZOLID: TONGUE DISCOLORATION: Brown discoloration of the tongue has been reported in up to 33% of patients following ingestion of linezolid during clinical trials. The discoloration disappeared after discontinuation of linezolid therapy (Diekema & Jones, 2000; Dresser & Rybak, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Headache may commonly occur with therapeutic administration of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Diekema & Jones, 2000).
    1) INCIDENCE: Headache has been reported in up to 11.3% of patients following linezolid administration during clinical trials (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) TEDIZOLID: In clinical trials, headache developed in 6% of patients (n=662) receiving tedizolid and 6% of patients (n=662) receiving linezolid (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    B) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) LINEZOLID
    1) POSTMARKETING EXPERIENCE: Serotonin syndrome, characterized by fever, agitation, mental status changes, and tremors, has been reported infrequently following concomitant administration of linezolid and a selective serotonin reuptake inhibitor (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010), and is attributed to linezolid's action as a weak reversible monoamine oxidase inhibitor (Miller & Lovell, 2008; Bergeron et al, 2005; Lavery et al, 2001; Wigen & Goetz, 2002).
    2) CASE REPORT: A 36-year-old woman with a history of bipolar disorder and depression receiving chronic lithium, venlafaxine, and imipramine therapy developed mydriasis, diaphoresis, tachycardia, hypertension, diarrhea, tremor, and unresponsiveness shortly after receiving linezolid (a serotonergic medication) for a MRSA empyema. Symptoms started within 36 hours. She improved within 24 hours with supportive care (Miller & Lovell, 2008).
    C) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) LINEZOLID
    1) Peripheral neuropathy has been reported in some patients with prolonged use (longer than the recommended duration of 28 days) of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) CASE REPORT: A 27-year-old woman developed optic and peripheral neuropathy with prolonged use of high doses of linezolid for osteomyelitis. Corticosteroid use exacerbated the visual loss. Following the discontinuation of linezolid, she recovered without further sequelae (Saijo et al, 2005).
    D) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Hyperlactatemia (lactate levels ranged from 26 to 59 mg/dL) and asthenia have been reported in 3 patients with prolonged use of linezolid. Following the discontinuation of linezolid, lactate levels returned to normal in all patients. The authors suggested that linezolid interferes with mitochondrial protein synthesis, probably due to similarities between bacterial and mitochondrial ribosomes (Soriano et al, 2005).
    E) SEIZURE
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Seizures have been reported in some patients treated with linezolid. A previous history of seizures or risk factors for seizures were present in some individuals (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) LINEZOLID: In rats, decreased activity and ataxia was reported following linezolid ingestions of 3000 mg/kg/day (Prod Info Zyvox(TM), linezolid, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Nausea was one of the most common adverse events following therapeutic administration of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Diekema & Jones, 2000; Chien et al, 2000). It may occur in up to 9.6% of patients treated (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) TEDIZOLID: In clinical trials, nausea developed in 8% of patients (n=662) receiving tedizolid and 12% of patients (n=662) receiving linezolid (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Vomiting has been reported in up to 3.7% of patients treated with linezolid during clinical trials (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) TEDIZOLID: In clinical trials, vomiting developed in 3% of patients (n=662) receiving tedizolid and 6% of patients (n=662) receiving linezolid (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: INCIDENCE: Diarrhea has been reported in up to 11% of all patients involved in clinical trials of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) TEDIZOLID: In clinical trials, diarrhea developed in 4% of patients (n=662) receiving tedizolid and 5% of patients (n=662) receiving linezolid (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    D) ANTIBIOTIC ENTEROCOLITIS
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Pseudomembranous colitis has been associated with therapeutic administration of linezolid and may range in severity from mild to life-threatening (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Transient elevations of liver enzyme levels have been reported with therapeutic administration of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Antony et al, 1999).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) LINEZOLID
    1) Lactic acidosis has been reported with therapeutic use of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) CASE SERIES: Hyperlactatemia (lactate levels ranged from 26 to 59 mg/dL) and asthenia have been reported in 3 patients with prolonged use of linezolid. Following the discontinuation of linezolid, lactate levels returned to normal in all patients. The authors suggested that linezolid interferes with mitochondrial protein synthesis, probably due to similarities between bacterial and mitochondrial ribosomes (Soriano et al, 2005).
    3) CASE REPORT: An 81-year-old man presented with afebrile acute respiratory failure 3 weeks after being hospitalized for an acute nephritic syndrome, that was successfully treated with high doses of corticosteroids. He was treated with cloxacillin and clindamycin after Staphylococcus aureus was observed on bronchoalveolar lavage fluid. He became febrile on day 8 and blood cultures isolated an Enterococcus faecium strain resistant to amoxicillin. He was treated with IV linezolid instead of vancomycin because of poor renal function (renal clearance 35 mL/min). He became confused, with polypnea (35 beats/min) and tachycardia (112 beats/min) 4 hours after starting linezolid (600 mg in 30 min). An arterial blood sample showed severe lactic acidosis (pH 7.03; bicarbonate 7.4 mmol/L with arterial lactate 16 mmol/L) and increased anion gap (25 mmol/L). Linezolid plasma concentration was 9 mg/L 15 hours after administration. Following the discontinuation of linezolid and supportive care, he recovered rapidly (Contou et al, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Marrow depression, including anemia, leukopenia, pancytopenia and thrombocytopenia, has been reported in patients receiving linezolid therapy (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Youssef et al, 2008; (Anon, 2001)). Linezolid-induced thrombocytopenia is thought to be immune mediated (Youssef et al, 2008).
    1) Thrombocytopenia has been reported in patients following therapeutic administration of linezolid during clinical studies (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010) and appears to be time-dependent, with the incidence of thrombocytopenia increasing when duration of linezolid therapy is longer than 2 weeks (Youssef et al, 2008).
    b) Leukopenia (nadir WBC count of 1900/mL) developed in 1 patient approximately 12 days after beginning linezolid therapy. The leukopenia resolved 3 days after completion of therapy (Chien et al, 2000).
    c) ANIMAL DATA: Myelosuppression, characterized by bone marrow hypocellularity, decreased hematopoiesis, and decreased levels of circulating erythrocytes, leukocytes, and platelets, occurred at linezolid doses of 40 and 80 mg/kg/day in dogs and rats, respectively, and appeared to be dose- and time-dependent (Prod Info Zyvox(TM), linezolid, 2000).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) LINEZOLID: Skin rash may occur following therapeutic administration of linezolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Diekema & Jones, 2000).
    1) INCIDENCE: A folliculitis-type rash was reported in 5 of 24 patients (20.5%) following ingestion of linezolid during a phase I clinical trial. The skin rash spontaneously resolved following discontinuation of linezolid therapy. The rash appeared to occur more frequently with linezolid doses of greater than 600 mg (Dresser & Rybak, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Linezolid and tedizolid are classified as FDA pregnancy category C. There are no adequate and well-controlled studies in pregnant women. Embryo and/or fetal toxicities were evident in animals at doses that caused maternal toxicity. Toxicities included increased postimplantation embryo death, increased incidence of skeletal variations, and decreased fetal body weights with administration of either linezolid or tedizolid. Linezolid, linezolid metabolites, and tedizolid were excreted in the milk of lactating rats. Reversibly decreased fertility and reproductive performance in male rats, possibly due to epithelial cell hypertrophy in the epididymis, was reported following linezolid ingestion. There were no adverse fertility or reproductive performance effects observed with tedizolid administration in either male or female rats.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of linezolid or tedizolid (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    B) ANIMAL STUDIES
    1) LINEZOLID
    a) In studies in mice, rats, or rabbits, linezolid was not teratogenic at exposure levels that were 6.5-fold, equivalent to, or 0.06-fold, respectively, that of the expected human exposure level based on AUCs (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) TEDIZOLID
    a) Animal studies in mice, rats, and rabbits, have shown that tedizolid phosphate can increase the incidence of skeletal variations, as well as reduced fetal body weight. In mice, a tedizolid phosphate dose of 25 mg/kg/day (4-fold the estimated human exposure level based on AUC) was associated with reduced fetal weights and an increased incidence of costal cartilage abnormalities. In rats, a maternally toxic tedizolid phosphate dose of 15 mg/kg/day (6-fold the estimated human exposure level based on AUC) was associated with reduce fetal weight, as well as increased skeletal variations, including reduced ossification of sternebrae, vertebrae, and skull. In rabbits, maternally toxic tedizolid phosphate doses were associated with reduced fetal weights but with no teratogenic effects (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to linezolid or tedizolid during pregnancy in humans (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified linezolid as FDA pregnancy category C (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) The manufacturer has classified tedizolid as FDA pregnancy category C (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    C) ANIMAL STUDIES
    1) LINEZOLID
    a) RATS: At linezolid doses of 15 mg/kg/day and 50 mg/kg/day (0.22 to approximately equivalent to the estimated human exposure, respectively, based on AUCs), decreased fetal body weights and reduced ossification of sternebrae were reported in rats. Maternal toxicity (reduced body weights) was also observed at the 50 mg/kg/day dose. Survival of pups was also decreased at the 50 mg/kg/day dose on postnatal days 1 to 4 when female rats were given linezolid throughout pregnancy and lactation. Preimplantation loss was demonstrated in both male and female pups when permitted to mature to reproductive age and mated (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) MICE: A linezolid dose of 450 mg/kg/day (4 times the estimated human exposure level) was associated with increased postimplantation embryo death (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    c) RABBITS: Decreased fetal body weight was reported only in the presence of maternal toxicity when rabbits were given linezolid at a dose of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs) (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) TEDIZOLID
    a) Animal studies in mice, rats, and rabbits, have shown that tedizolid phosphate can increase the incidence of skeletal variations, as well as reduced fetal body weight. In mice, a tedizolid phosphate dose of 25 mg/kg/day (4-fold the estimated human exposure level based on AUC) was associated with reduced fetal weights and an increased incidence of costal cartilage abnormalities. In rats, a maternally toxic tedizolid phosphate dose of 15 mg/kg/day (6-fold the estimated human exposure level based on AUC) was associated with reduce fetal weight, as well as increased skeletal variations, including reduced ossification of sternebrae, vertebrae, and skull. In rabbits, maternally toxic tedizolid phosphate doses were associated with reduced fetal weights but with no teratogenic effects (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    b) Studies in mice, rats, and rabbits, revealed that the no observed adverse effect levels (NOAELs) for fetal toxicity in mice (5 mg/kg/day), maternal and fetal toxicity in rats (2.5 mg/kg/day), and rabbit (1 mg/kg/day) were approximately equivalent to (mice and rats) or 0.04-fold (rabbit) the tedizolid AUC associated with the oral human therapeutic dose. A pre-postnatal study in rats found that a tedizolid dose of 3.75 mg/kg/day (approximately equivalent to the human plasma AUC exposure at the dose of 200 mg/day) caused no adverse maternal or offspring effects when animals were treated during pregnancy and lactation (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to linezolid or tedizolid during lactation in humans (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    B) ANIMAL STUDIES
    1) Linezolid and its metabolites were excreted in the milk of lactating rats at concentrations similar to those in maternal plasma (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) Tedizolid is excreted in the milk of lactating rats. A pre-postnatal study in rats found that a tedizolid dose of 3.75 mg/kg/day (approximately equivalent to the human plasma AUC exposure at the dose of 200 mg/day) caused no adverse maternal or offspring effects when animals were treated during pregnancy and lactation (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to tedizolid (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    B) ANIMAL STUDIES
    1) LINEZOLID
    a) RATS: Reversibly decreased fertility and reproductive performance in male rats, possibly due to epithelial cell hypertrophy in the epididymis, was reported following linezolid ingestion at doses of 50 mg/kg/day or greater (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) TEDIZOLID
    a) RATS: A tedizolid dose of 50 mg/kg/day in male rats (approximately 5-fold higher than the estimated human exposure level at the oral therapeutic dose) and 15 mg/kg/day in female rats (approximately 4-fold higher than the estimated human exposure level at the oral therapeutic dose) had no effect on the fertility or reproductive performance (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of linezolid in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of linezolid in animals (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).

Genotoxicity

    A) Linezolid was not mutagenic or clastogenic in the following tests: Ames bacterial reversion, CHO cell mutation, an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and liver enzymes in symptomatic patients.
    B) Monitor serial CBC (with differential) and platelet count. Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported in patients receiving linezolid.
    C) Monitor serum electrolyte status in patients with significant diarrhea and/or vomiting.
    D) Monitor for clinical evidence of serotonin syndrome.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a health care facility and monitored until symptoms resolve. Patients with unintentional ingestions who are symptomatic should be observed in a health care facility.

Monitoring

    A) Monitor vital signs and liver enzymes in symptomatic patients.
    B) Monitor serial CBC (with differential) and platelet count. Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported in patients receiving linezolid.
    C) Monitor serum electrolyte status in patients with significant diarrhea and/or vomiting.
    D) Monitor for clinical evidence of serotonin syndrome.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Not recommended because of potential for seizures.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and liver enzymes in symptomatic patients.
    2) Monitor serial CBC (with differential) and platelet count. Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported in patients receiving linezolid.
    3) Monitor serum electrolyte status in patients with significant diarrhea and/or vomiting.
    B) SEROTONIN SYNDROME
    1) Concomitant use of linezolid with a selective serotonin reuptake inhibitor has resulted in a serotonin syndrome; this is attributed to linezolid's action as a weak reversible monoamine oxidase inhibitor (Wigen & Goetz, 2002; Lavery et al, 2001).
    2) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    3) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    4) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    5) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    6) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    7) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    8) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    9) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
    C) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
    D) THROMBOCYTOPENIC DISORDER
    1) EXPERIMENTAL THERAPY - Thrombocytopenia has been reported with continued use of linezolid (greater than 2 weeks) therapy. In an open-label study of 31 patients with cancer, each received 600 mg of linezolid twice daily and 50 mg of vitamin B6 daily. All patients received vitamin B6 within 3 days of starting therapy and were matched with 62 historical control patients who received linezolid only. The mean duration of therapy was 19 days. Four patients (13%) in the B6 group required a platelet transfusion, as compared to 10 patients (16%) in the linezolid group only. The overall rates of thrombocytopenia, leukopenia, and anemia in the vitamin B6 group were 13%, 7% and 0%, respectively, as compared to 15%, 5% and 5% in the non-treatment group. B6 was not found to prevent thrombocytopenia or leukopenia; however, vitamin B6 given at 50 mg/day may limit the extent of anemia that occurs with therapy. The authors suggested further large scale studies are needed (Youssef et al, 2008).
    E) METRONIDAZOLE
    1) PSEUDOMEMBRANOUS COLITIS
    a) Metronidazole 250 mg orally four times daily for 10 days can rapidly eliminate C. difficile toxin from the stool and shorten the course of illness (Surawicz, 1998).

Enhanced Elimination

    A) HEMODIALYSIS
    1) During a phase I clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session that began 3 hours after administration of the dose (Prod Info ZYVOX(R) injection, oral tablets, oral suspension, 2007). Hemodialysis should only be considered in patients with severe toxicity not responding to supportive care.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: LINEZOLID: ADULT: Varies by indication. Recommended dose is 400 to 600 mg IV or orally every 12 hr for 10 to 28 days depending on the indication. PEDIATRIC: PRETERM NEONATES (Less than 34 weeks), LESS THAN 7 DAYS OF AGE: Recommended initial dose is 10 mg/kg every 12 hr; some neonates may require dosing of 10 mg/kg 8 hr. NEONATES AND CHILDREN 11 YEARS AND YOUNGER: 10 mg/kg orally or IV every 8 to 12 hours depending on indication. TEDIZOLID: ADULT: 200 mg once daily orally or as an IV infusion over 1 hour once daily for 6 days. PEDIATRIC: Safety and effectiveness have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) LINEZOLID
    1) COMMUNITY-ACQUIRED PNEUMONIA, COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS, and NOSOCOMIAL PNEUMONIA: Recommended dose is 600 mg IV or orally every 12 hr for 10 to 14 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    2) UNCOMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS: Recommended dose is 400 mg orally every 12 hr for 10 to 14 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    3) VANCOMYCIN-RESISTANT ENTEROCOCCUS FAECIUM INFECTIONS: Recommended dose is 600 mg IV or orally every 12 hr for 14 to 28 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    B) TEDIZOLID
    1) The recommended dose is 200 mg once daily orally or IV infusion over 1 hour once daily for 6 days (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) LINEZOLID
    1) PRETERM NEONATES (Less than 34 weeks), LESS THAN 7 DAYS OF AGE: Recommended initial dose is 10 mg/kg every 12 hr; some neonates may require dosing of 10 mg/kg 8 hr who have an inadequate clinical response (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    B) LINEZOLID: IV, ORAL
    1) COMMUNITY-ACQUIRED PNEUMONIA, COMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS, and NOSOCOMIAL PNEUMONIA:
    a) ADOLESCENTS 12 YEARS AND OLDER: Recommended dose is 600 mg IV or orally every 12 hr for 10 to 14 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Liu et al, 2011; Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) NEONATES AND CHILDREN 11 YEARS AND YOUNGER: Recommended dose is 10 mg/kg IV or orally every 8 hr for 10 to 14 days; maximum 600 mg/dose (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Liu et al, 2011; Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Kaplan et al, 2003; Jantausch et al, 2003; Yogev et al, 2003; Kaplan et al, 2003a).
    2) VANCOMYCIN-RESISTANT ENTEROCOCCUS FAECIUM INFECTIONS:
    a) ADOLESCENTS 12 YEARS AND OLDER: Recommended dose is 600 mg IV or orally every 12 hr for 14 to 28 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) NEONATES AND CHILDREN 11 YEARS AND YOUNGER: Recommended dose is 10 mg/kg IV or orally every 8 hr for 14 to 28 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Graham et al, 2002).
    3) INFECTIVE ENDOCARDITIS (E. FAECIUM STRAINS RESISTANT TO PENICILLIN, AMINOGLYCOSIDES AND VANCOMYCIN):
    a) 10 mg/kg IV or orally every 8 hr for a minimum of 8 weeks. Maximum 400 mg/dose (Baddour et al, 2005).
    C) LINEZOLID: ORAL
    1) UNCOMPLICATED SKIN AND SKIN STRUCTURE INFECTIONS:
    a) ADOLESCENTS 12 YEARS AND OLDER: Recommended dose is 600 mg orally every 12 hr for 10 to 14 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    b) CHILDREN 5 TO 11 YEARS: Recommended dose is 10 mg/kg orally every 12 hr for 10 to 14 days. Maximum 600 mg/dose (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010; Wible et al, 2003).
    c) CHILDREN YOUNGER THAN 5 YEARS: Recommended dose is 10 mg/kg orally every 8 hr for 10 to 14 days (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010).
    D) TEDIZOLID
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).

Maximum Tolerated Exposure

    A) A specific minimum toxic dose has not been established.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: An 81-year-old man with acute respiratory failure and renal dysfunction developed lactic acidosis 4 hours after starting linezolid (600 mg in 30 min). Linezolid plasma concentration was 9 mg/L 15 hours after administration. Following the discontinuation of linezolid and supportive care, he recovered rapidly (Contou et al, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Linezolid is an oxazolidinones that inhibits the bacterial ribosomal translation process, of aerobic Gram-positive bacteria and certain Gram-negative and anaerobic bacteria, by selectively binding to a site on the 23S ribosomal RNA of the 50S subunit, thereby preventing initiation complex formation with the 70S ribosomal subunit (Prod Info ZYVOX(R) intravenous injection, oral tablets, oral suspension, 2015).
    B) Tedizolid phosphate is the prodrug of tedizolid, an oxazolidinone antibiotic, which inhibits bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014).

Physicochemical

Physical Characteristics

    A) TEDIZOLID PHOSPHATE: white to yellow solid (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014)

Molecular Weight

    A) EPEREZOLID: 394.45 (RTECS , 2000)
    B) LINEZOLID: 337.35 (Prod Info ZYVOX(R) IV injection, oral tablets, suspension, 2010)
    C) TEDIZOLID PHOSPHATE: 450.32 (Prod Info SIVEXTRO(TM) lyophilized powder for intravenous injection, oral tablets, 2014)

References

General Bibliography

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