Linezolid

Linezolid is an antibacterial agent belonging to the pharmacological class of Oxazolidinone Antibiotics.

Linezolid has been approved to relieve symptoms and also for the treatment and maintenance of Anthrax, systemic infection, Bloodstream infection, CNS infection, health care–associated, Cystic fibrosis, acute pulmonary exacerbation, moderate to severe, Diabetic foot infection, moderate to severe, Endocarditis, treatment, native or prosthetic valve, Intracranial abscess and spinal epidural abscess, Meningitis, bacterial, Osteomyelitis and/or discitis, Pneumonia, as a component of empiric therapy or pathogen-directed therapy for methicillin-resistant S. aureus, Prosthetic joint infection, Septic arthritis, Skin and soft tissue infection, Toxic shock syndrome, Tuberculosis, drug-resistant, Urinary tract infection, complicated.

Linezolid is highly absorbed orally, with a bioavailability of approximately 100%. Plasma concentrations peak within 1 to 2 hours after oral administration. Single doses result in concentrations of 8.1-12.9 mcg/mL, while multiple doses lead to concentrations of 11.0-21.2 mcg/mL. Food does not significantly affect linezolid absorption. The drug has a volume of distribution of about 40-50 liters in healthy adults and moderately binds to plasma proteins (31%). Linezolid is metabolized to two inactive metabolites, primarily through oxidation of the morpholine ring. The specific enzymes involved in metabolism are not well-defined, and linezolid does not significantly affect or get metabolized by the CYP450 enzyme system. However, it inhibits monoamine oxidase enzymes reversibly and non-selectively. Linezolid and its metabolites are primarily eliminated through urine, with approximately 84% of a dose recovered. Urinary excretion consists of 30% unchanged drug, 40% hydroxyethyl glycine metabolite, and 10% aminoethoxyacetic acid metabolite. Fecal elimination is minor, with only small amounts of metabolites excreted.

The common side effects involved in using Linezolid are Nausea and vomiting, Diarrhea, Headache, Dizziness, Insomnia, Rash or itching, Decreased white blood cell count (neutropenia), Anemia, Thrombocytopenia (low platelet count).

Linezolid is available in the form of Injectable solutions, Oral suspension , and Tablets.

Linezolid is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Linezolid belongs to the pharmacological class of Oxazolidinone: Antibiotics

Linezolid exerts its antimicrobial effects by disrupting bacterial protein translation. It works by binding to a specific site on the bacterial 23S ribosomal RNA within the 50S subunit, hindering the formation of a functional 70S initiation complex. This complex is crucial for bacterial reproduction, and by inhibiting its formation, Linezolid effectively prevents bacteria from dividing and multiplying.

It is important to note that point mutations occurring in the bacterial 23S ribosomal RNA can result in resistance to Linezolid. Instances of linezolid-resistant Enterococcus faecium and Staphylococcus aureus have been observed in clinical settings. To ensure adequate coverage against relevant pathogens, it is recommended to consult local antibiograms that provide information on antimicrobial susceptibility patterns specific to the geographical region. This step helps in determining the appropriateness of Linezolid's use.

Linezolid has been approved to relieve symptoms and also for the treatment and maintenance of Anthrax, systemic infection, Bloodstream infection, CNS infection, health care–associated, Cystic fibrosis, acute pulmonary exacerbation, moderate to severe, Diabetic foot infection, moderate to severe, Endocarditis, treatment, native or prosthetic valve, Intracranial abscess and spinal epidural abscess, Meningitis, bacterial, Osteomyelitis and/or discitis, Pneumonia, as a component of empiric therapy or pathogen-directed therapy for methicillin-resistant S. aureus, Prosthetic joint infection, Septic arthritis, Skin and soft tissue infection, Toxic shock syndrome, Tuberculosis, drug-resistant, Urinary tract infection, complicated.

For the recommended intravenous dose of 600 mg every 12 hours, the Cmax is approximately 10 to 15 µg/mL.After intravenous administration, the Tmax is achieved within approximately 1 to 2 hours.

The duration of action of Linezolid is generally considered to be approximately 12 hours. This means that a dose of Linezolid remains effective in the body for around 12 hours before it is eliminated or metabolized.

Linezolid is found to be available in the form of Injectable solution, Oral suspension, Tablets.

Linezolid can be used in the following treatment:

• Anthrax, systemic infection
• Bloodstream infection
• CNS infection, healthcare–associated
• Cystic fibrosis, acute pulmonary exacerbation, moderate to severe
• Diabetic foot infection, moderate to severe
• Endocarditis, treatment, native or prosthetic valve
• Intracranial abscess and spinal epidural abscess
• Meningitis, bacterial
• Osteomyelitis and/or discitis
• Pneumonia, as a component of empiric therapy or pathogen-directed therapy for methicillin-resistant S. aureus
• Prosthetic joint infection
• Septic arthritis
• Skin and soft tissue infection
• Toxic shock syndrome
• Tuberculosis, drug-resistant
• Urinary tract infection, complicated

Linezolid can help to relieve symptoms and also for the treatment and maintenance of Anthrax, systemic infection, Bloodstream infection, CNS infection, health care–associated, Cystic fibrosis, acute pulmonary exacerbation, moderate to severe, Diabetic foot infection, moderate to severe, Endocarditis, treatment, native or prosthetic valve, Intracranial abscess and spinal epidural abscess, Meningitis, bacterial, Osteomyelitis and/or discitis, Pneumonia, as a component of empiric therapy or pathogen-directed therapy for methicillin-resistant S. aureus, Prosthetic joint infection, Septic arthritis, Skin and soft tissue infection, Toxic shock syndrome, Tuberculosis, drug-resistant, Urinary tract infection, complicated.

Linezolid is approved for use in the following clinical indications:

• Anthrax, systemic infection
• Bloodstream infection
• CNS infection, healthcare–associated
• Cystic fibrosis, acute pulmonary exacerbation, moderate to severe
• Diabetic foot infection, moderate to severe
• Endocarditis, treatment, native or prosthetic valve
• Intracranial abscess and spinal epidural abscess
• Meningitis, bacterial
• Osteomyelitis and/or discitis
• Pneumonia, as a component of empiric therapy or pathogen-directed therapy for methicillin-resistant S. aureus
• Prosthetic joint infection
• Septic arthritis
• Skin and soft tissue infection
• Toxic shock syndrome
• Tuberculosis, drug-resistant
• Urinary tract infection, complicated

1. Anthrax, systemic infection: The dosing for Linezolid in the treatment of systemic anthrax is determined by the severity of the infection and should follow local guidelines or expert recommendations.
2. Bloodstream infection: The recommended adult dose for bloodstream infections is 600 mg every 12 hours.
3. CNS infection, healthcare-associated: For healthcare-associated CNS infections, the recommended adult dose is 600 mg every 12 hours.
4. Cystic fibrosis, acute pulmonary exacerbation, moderate to severe: In the treatment of acute pulmonary exacerbation in patients with cystic fibrosis, Linezolid is administered at a dose of 600 mg at every 12 hours.
5. Diabetic foot infection, moderate to severe: The adult dose for moderate to severe diabetic foot infections is 600 mg every 12 hours.
6. Endocarditis, treatment, native or prosthetic valve: In the treatment of endocarditis involving native or prosthetic valves, the recommended adult dose is 600 mg every 12 hours.
7. Intracranial abscess and spinal epidural abscess: The recommended adult dose for intracranial abscess and spinal epidural abscess is 600 mg every 12 hours.
8. Meningitis, bacterial: Linezolid dosing for bacterial meningitis should follow local guidelines or expert recommendations due to variations in causative pathogens and treatment protocols.
9. Osteomyelitis and/or discitis: In the treatment of osteomyelitis and/or discitis, the recommended adult dose is 600 mg every 12 hours.
10. Pneumonia, as a component of empiric therapy or pathogen-directed therapy for methicillin-resistant S. aureus: Linezolid is used as a component of empiric therapy or pathogen-directed therapy for pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). The recommended adult dose is 600 mg every 12 hours.
11. Prosthetic joint infection: For prosthetic joint infections, the recommended adult dose is 600 mg every 12 hours.
12. Septic arthritis: The adult dosing for septic arthritis is 600 mg every 12 hours.
13. Skin and soft tissue infection: In the treatment of skin and soft tissue infections, the recommended adult dose is 600 mg every 12 hours.
14. Toxic shock syndrome: Linezolid dosing for toxic shock syndrome should follow local guidelines or expert recommendations due to variations in treatment protocols.
15. Tuberculosis, drug-resistant: Linezolid is used in the treatment of drug-resistant tuberculosis. The dosing regimen for tuberculosis should follow local guidelines or expert recommendations.
16. Urinary tract infection, complicated: Linezolid dosing for complicated urinary tract infections should follow local guidelines or expert recommendations due to variations in causative pathogens and treatment protocols.

Injectable Solution:

Linezolid is available as an injectable solution with a concentration of 2mg/mL. It comes in infusion bags of 100mL and 300mL.

Oral Suspension:

Linezolid is available in the form of an oral suspension with a strength of 100mg/5mL.

Tablet:

Linezolid tablets are available in a strength of 600mg.

Injectable solution , Oral suspension , Tablets.

Dosage Adjustments in Kidney Patients:

Altered kidney function:

• For patients with a creatinine clearance (CrCl) of 40 to less than 130 mL/minute, no dosage adjustment is necessary for oral or intravenous administration of the medication.
• For patients with a CrCl less than 40 mL/minute, no dosage adjustment is necessary. However, some experts recommend reducing the dose to 300 mg twice daily after 72 hours with therapeutic drug monitoring for clinically stable patients with a CrCl less than 30 mL/minute and an anticipated treatment course longer than 10 days to decrease the risk of thrombocytopenia.

Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m²):

• Augmented renal clearance (ARC) is a condition observed in certain critically ill patients who do not have organ dysfunction and have normal serum creatinine levels. Patients at highest risk for ARC include those who are young (<55 years old) and admitted post trauma or major surgery, as well as those with sepsis, burns, or hematologic malignancies. Measuring urinary CrCl over an 8- to 24-hour period is necessary to identify these patients.
• For intravenous administration in patients with ARC, the recommended dose is 450 mg every 8 hours. Therapeutic drug monitoring should be utilized when available.

Hemodialysis, intermittent (thrice weekly):

• The medication is dialyzable, with approximately 30% to 57% removed via high-flux dialyzer.
• No dosage adjustment is necessary for oral or intravenous administration. When scheduled doses coincide with dialysis days, one of the twice-daily doses should be given after the dialysis session.
• Some experts suggest reducing the dose to 300 mg twice daily after 72 hours with therapeutic drug monitoring in clinically stable patients with a CrCl less than 30 mL/minute and an anticipated treatment course longer than 10 days to reduce the risk of thrombocytopenia. More frequent monitoring of complete blood count (CBC) is recommended due to an increased risk of myelosuppression.

Peritoneal dialysis:

• The medication is likely to be dialyzable due to low protein binding and a small volume of distribution.
• No dosage adjustment is necessary for oral or intravenous administration.

• Some experts suggest reducing the dose to 300 mg twice daily after 72 hours with therapeutic drug monitoring in clinically stable patients with a CrCl less than 30 mL/minute and an anticipated treatment course longer than 10 days to reduce the risk of thrombocytopenia. More frequent monitoring of CBC is recommended due to an increased risk of myelosuppression.

Dosage Adjustments in Pediatric Patients:

Bloodstream infection, resistant gram-positive infection:

• In cases of bloodstream infection caused by resistant gram-positive bacteria (e.g., vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus), the duration of therapy depends on various clinical factors including the specific pathogen, source of infection, and treatment response.
• For infants and children under 12 years old, the recommended dose of linezolid is 10 mg/kg/dose every 8 hours, with a maximum dose of 600 mg/dose.
• For children 12 years and older, the recommended dose is 600 mg every 12 hours or 10 mg/kg/dose every 12 hours, with a maximum dose of 600 mg/dose.

Endocarditis caused by vancomycin-resistant Enterococcus faecium:

• In cases of endocarditis caused by vancomycin-resistant Enterococcus faecium, treatment should be guided by pathogen-directed therapy.
• The duration of therapy is prolonged (typically more than 4 to 6 weeks), and consultation with an Infectious Diseases specialist is recommended.
• In pediatric patients, the dosing recommendations are the same as those mentioned for bloodstream infections caused by resistant gram-positive bacteria.

Enterococcus faecium (vancomycin-resistant) infection:

• In cases of Enterococcus faecium infection that is resistant to vancomycin, the recommended duration of therapy is 14 to 28 days, although individualization based on the specific infection, response, and other factors is necessary.
• For infants and children under 12 years old, the recommended dose of linezolid is 10 mg/kg/dose every 8 hours, with a maximum dose of 600 mg/dose.
• For children 12 years and older, the recommended dose is 600 mg every 12 hours.

Exit-site or tunnel infection in peritoneal dialysis catheter:

• For exit-site infection in peritoneal dialysis catheters, treatment should be continued for at least 2 weeks (or 3 weeks for Staphylococcus aureus) and for an additional 7 days after complete resolution.
• For tunnel infections, treatment should be continued for 2 to 4 weeks.
• The dosing recommendations for linezolid in infants, children, and adolescents are provided based on their age and weight.
  

There are no specific dietary restrictions related to the use of Linezolid mentioned in the available information. However, it is always advisable to follow a healthy and balanced diet while undergoing any medical treatment.

Linezolid may be contraindicated under the following conditions:

1. Monoamine Oxidase Inhibitors:
• Linezolid should not be used in combination with medications that inhibit monoamine oxidases A or B, such as phenelzine or isocarboxazid.
• Additionally, linezolid should not be taken within two weeks of using any such medication.
2. Potential Interactions Leading to Increased Blood Pressure:
• Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, or those taking certain medications without proper monitoring for potential increases in blood pressure.
• Medications to be cautious with include sympathomimetic agents (directly and indirectly acting), vasopressive agents, and dopaminergic agents.
3. Potential Serotonergic Interactions:
• Linezolid should not be given to patients with carcinoid syndrome or those taking specific medications without careful observation of signs and symptoms of serotonin syndrome.
• Medications of concern include serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, and buspirone.

• Myelosuppression:
• Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, has been observed in patients receiving linezolid.
• Discontinuation of linezolid should be considered in patients who develop or experience worsening myelosuppression.
• Regular monitoring of complete blood counts is advised, particularly in patients receiving linezolid for more than two weeks, those with pre-existing myelosuppression, those taking concomitant drugs that suppress bone marrow function, or those with chronic infections who have received previous or concurrent antibiotic therapy.
• Mortality Imbalance in Catheter-Related Bloodstream Infections:
• An imbalance in mortality was observed in seriously ill patients with intravascular catheter-related infections who were treated with linezolid compared to those treated with vancomycin/dicloxacillin/oxacillin.
• This imbalance primarily occurred in linezolid-treated patients with Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen identified at baseline.
• Linezolid is not approved or recommended for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.
• Limited Efficacy Against Gram-Negative Pathogens:
• Linezolid does not exhibit clinical activity against Gram-negative pathogens.
• It should not be used for the treatment of Gram-negative infections.
• Immediate initiation of specific Gram-negative therapy is crucial if a concomitant Gram-negative pathogen is documented or suspected.
• Clostridium difficile Associated Diarrhea (CDAD):
• CDAD, ranging from mild diarrhea to fatal colitis, has been reported with the use of antibacterial agents, including Linezolid (linezolid).
• C. difficile produces toxins A and B that contribute to the development of CDAD.
• Infections caused by hypertext-producing strains of C. difficile can be severe and may require colectomy.
• CDAD should be considered in patients presenting with diarrhea following antibiotic use, and appropriate management and evaluation should be implemented.
• Lactic Acidosis:
• Lactic acidosis has been reported in patients using Linezolid.
• Patients experiencing repeated episodes of nausea, vomiting, unexplained acidosis, or low bicarbonate levels while receiving Linezolid should seek immediate medical evaluation.
• Serotonin Syndrome:
• Cases of serotonin syndrome have been reported when Linezolid is co-administered with serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs).
• Close monitoring for signs and symptoms of serotonin syndrome is recommended in patients receiving Linezolid and serotonergic agents.
• Discontinuation of either one or both agents should be considered if signs or symptoms occur.
• Peripheral and Optic Neuropathy:
• Peripheral and optic neuropathy have been observed in patients treated with Linezolid, especially those treated beyond the recommended duration of 28 days.
• Prompt ophthalmic evaluation is recommended if patients experience symptoms such as visual impairment or changes in visual acuity.
• Visual function should be monitored in patients receiving Linezolid for extended periods or reporting new visual symptoms.
• Convulsions:
• Convulsions have been reported in patients receiving linezolid, particularly those with a history of seizures or risk factors for seizures.
• Overgrowth of Nonsusceptible Organisms:
• Antibiotic use may promote the overgrowth of nonsusceptible organisms.
• Appropriate measures should be taken if superinfection occurs during therapy.

While there is no specific food interaction between Linezolid and alcohol, it's generally recommended to avoid alcohol when taking any antibiotic medication. Alcohol can interfere with the effectiveness of the medication and may also exacerbate certain side effects.

Linezolid, along with its metabolites, is eliminated in the milk of lactating rats, with concentrations in the milk comparable to those in the mother's bloodstream. The excretion of linezolid in human milk is not yet understood. Considering that numerous medications are excreted in human milk, caution should be exercised when administering Linezolid to a nursing woman.

Pregnancy Category C

Linezolid did not demonstrate teratogenic effects in mice, rats, or rabbits at exposure levels corresponding to 6.5-fold (in mice), equivalent (in rats), or 0.06-fold (in rabbits) the expected human exposure based on AUCs. However, certain toxicities were observed in embryos and fetuses (see Non-teratogenic Effects). There are no sufficient and well-controlled studies conducted on pregnant women. The use of Linezolid during pregnancy should only be considered if the potential benefits outweigh the potential risks to the fetus.

Non-teratogenic Effects

In mice, embryo and fetal toxicities were observed only at doses that caused maternal toxicity, indicated by clinical signs and reduced body weight gain. An administration of 450 mg/kg/day (equivalent to 6.5-fold the estimated human exposure based on AUCs) resulted in increased postimplantational embryo death, including total loss of the litter, decreased fetal body weights, and an increased incidence of costal cartilage fusion.

In rats, mild fetal toxicity was noted at doses of 15 and 50 mg/kg/day (exposure levels ranging from 0.22-fold to approximately equivalent to the estimated human exposure based on AUCs). These effects included decreased fetal body weights and reduced ossification of sternebrae, which is often associated with decreased fetal body weights. Slight maternal toxicity, characterized by reduced body weight gain, was observed at a dose of 50 mg/kg/day.

In rabbits, reduced fetal body weight was observed only when maternal toxicity was present, indicated by clinical signs, reduced body weight gain, and decreased food consumption. This effect occurred at a dose of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).

When female rats were treated with 50 mg/kg/day of linezolid (approximately equivalent to the estimated human exposure based on AUCs) during pregnancy and lactation, the survival of pups was reduced during postnatal days 1 to 4. Male and female pups allowed to reach reproductive age showed an increase in preimplantation loss when mated.

Linezolid does not have significant interactions with food, and its absorption is not significantly affected by co-administration with meals. Therefore, Linezolid can generally be taken with or without food.

The adverse reactions related to Linezolid can be categorized as follows:

Common:

• Nausea
• Diarrhea
• Headache
• Vomiting
• Taste alteration (metallic or bitter taste)
• Insomnia

Less common:

• Dizziness
• Fatigue
• Constipation
• Abdominal pain
• Dry mouth
• Skin rash or itching
• Increased sweating
• Muscle or joint pain

Rare:

• Decreased white blood cell count (neutropenia)
• Low platelet count (thrombocytopenia)
• Anemia
• Allergic reactions (e.g., hives, itching, swelling)
• Serotonin syndrome (when used with certain medications)
• Peripheral neuropathy (nerve damage in the extremities)
• Vision changes or optic neuropathy (rare cases).

Monoamine Oxidase Inhibition:

Linezolid, as a reversible and nonselective inhibitor of monoamine oxidase, can interact with adrenergic and serotonergic agents, potentially leading to adverse effects.

Adrenergic Agents:

When individuals receive Linezolid, there is a possibility of experiencing an enhanced pressure response to indirect-acting sympathomimetic agents, vasopressors, or dopaminergic agents. Specifically, commonly used drugs like phenylpropanolamine and pseudoephedrine have been studied in this regard. To mitigate risks, it is recommended to reduce initial doses of adrenergic agents such as dopamine or epinephrine and titrate them carefully to achieve the desired response.

Serotonergic Agents:

Clinical studies in Phase 1, 2, and 3 did not indicate any association between the co-administration of linezolid and serotonergic agents and the occurrence of serotonin syndrome. However, there have been spontaneous reports of serotonin syndrome when Linezolid was used alongside serotonergic agents, including antidepressants like selective serotonin reuptake inhibitors (SSRIs). Patients who are prescribed Linezolid along with serotonergic agents should be closely monitored, as described in the PRECAUTIONS section under the General considerations.

The following are the side effects involving Linezolid:

• Nausea and vomiting
• Diarrhea
• Headache
• Dizziness
• Insomnia
• Rash or itching
• Decreased white blood cell count (neutropenia)
• Anemia
• Thrombocytopenia (low platelet count)
• Elevated liver enzymes
• Serotonin syndrome (when taken with certain medications)
• Peripheral and optic neuropathy (rare)

Pregnancy:

Pregnancy Category C

Linezolid did not demonstrate teratogenic effects in mice, rats, or rabbits at exposure levels corresponding to 6.5-fold (in mice), equivalent (in rats), or 0.06-fold (in rabbits) the expected human exposure based on AUCs. However, certain toxicities were observed in embryos and fetuses (see Non-teratogenic Effects). There are no sufficient and well-controlled studies conducted on pregnant women. The use of Linezolid during pregnancy should only be considered if the potential benefits outweigh the potential risks to the fetus.

Non-teratogenic Effects

In mice, embryo and fetal toxicities were observed only at doses that caused maternal toxicity, indicated by clinical signs and reduced body weight gain. An administration of 450 mg/kg/day (equivalent to 6.5-fold the estimated human exposure based on AUCs) resulted in increased postimplantational embryo death, including total loss of the litter, decreased fetal body weights, and an increased incidence of costal cartilage fusion.

In rats, mild fetal toxicity was noted at doses of 15 and 50 mg/kg/day (exposure levels ranging from 0.22-fold to approximately equivalent to the estimated human exposure based on AUCs). These effects included decreased fetal body weights and reduced ossification of sternebrae, which is often associated with decreased fetal body weights. Slight maternal toxicity, characterized by reduced body weight gain, was observed at a dose of 50 mg/kg/day.

In rabbits, reduced fetal body weight was observed only when maternal toxicity was present, indicated by clinical signs, reduced body weight gain, and decreased food consumption. This effect occurred at a dose of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).

When female rats were treated with 50 mg/kg/day of linezolid (approximately equivalent to the estimated human exposure based on AUCs) during pregnancy and lactation, the survival of pups was reduced during postnatal days 1 to 4. Male and female pups allowed to reach reproductive age showed an increase in preimplantation loss when mated.

Lactation:

Linezolid, along with its metabolites, is eliminated in the milk of lactating rats, with concentrations in the milk comparable to those in the mother's bloodstream. The excretion of linezolid in human milk is not yet understood. Considering that numerous medications are excreted in human milk, caution should be exercised when administering Linezolid to a nursing woman.

Pediatric:

The safety and efficacy of Linezolid in pediatric patients with various infections are supported by evidence from well-controlled studies conducted in adults, as well as pharmacokinetic data obtained from pediatric patients. Additionally, data from a comparator-controlled study involving pediatric patients aged from birth to 11 years further support its use in the treatment of Gram-positive infections. These infections include nosocomial pneumonia, complicated skin and skin structure infections, community-acquired pneumonia (also supported by an uncontrolled study in patients aged 8 months to 12 years), and vancomycin-resistant Enterococcus faecium infections.

A separate comparator-controlled study in pediatric patients ranging in age from 5 to 17 years has established the safety and efficacy of Linezolid in treating uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

Pharmacokinetic information obtained from pediatric patients with ventriculoperitoneal shunts has shown variable concentrations of linezolid in the cerebrospinal fluid (CSF) following single and multiple doses. Therapeutic concentrations in the CSF were not consistently achieved or maintained. Therefore, the use of linezolid for empirical treatment of pediatric patients with central nervous system infections is not recommended.

The maximum concentration (Cmax) and volume of distribution (Vss) of linezolid in pediatric patients are similar regardless of age. However, linezolid clearance varies with age. Clearance is highest in the youngest age groups (>1 week old to 11 years), resulting in lower systemic exposure (AUC) and shorter half-life compared to adults. Clearance gradually decreases as pediatric patients grow older, with mean clearance values approaching those observed in adults during adolescence. There is also greater inter-subject variability in linezolid clearance and systemic exposure (AUC) across all pediatric age groups compared to adults.

In pediatric patients up to 11 years of age, the recommended dosage regimen is 10 mg/kg every 8 hours. For pediatric patients aged 12 years and older, the recommended dosage is 600 mg every 12 hours.

Dosage recommendations for pre-term neonates (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 pre-term neonates. These neonates may have lower systemic clearance and larger AUC values compared to full-term neonates and older infants. Therefore, a dosing regimen of 10 mg/kg every 12 hours is recommended for pre-term neonates, although consideration may be given to using a 10 mg/kg every 8 hours regimen in neonates with sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life.

Limited clinical experience has shown clinical cures in 5 out of 6 (83%) pediatric patients with infections caused by Gram-positive pathogens with MICs of 4 μg/mL when treated with Linezolid. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared to adults. When assessing the clinical response in pediatric patients, especially those with a sub-optimal response and pathogens with MIC of 4 μg/mL, factors such as lower systemic exposure, site and severity of infection, and underlying medical condition should be taken into consideration.

Geriatric Use:

Among the patients enrolled in Phase 3 comparator-controlled clinical trials and treated with Linezolid, comprising a total of 2046 individuals, 589 (29%) were aged 65 years or older, and 253 (12%) were aged 75 years or older. Notably, no significant disparities were observed in terms of safety or efficacy between these older patients and the younger patient population as a whole.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Linezolid.

Management of Overdosage

• In cases of linezolid overdosage, supportive care is recommended, with emphasis on maintaining glomerular filtration.
• Hemodialysis may be considered to facilitate more rapid elimination of linezolid in cases of severe overdosage.

Hemodialysis and Linezolid Elimination

• A Phase 1 clinical trial reported that approximately 30% of a linezolid dose was removed during a 3-hour hemodialysis session initiated 3 hours after administration of the dose.
• There is currently no available data regarding the removal of linezolid through peritoneal dialysis or hemoperfusion.

Acute Toxicity in Animals

• Animal studies have shown signs of acute toxicity in response to high doses of linezolid.
• Rats treated with a dose of 3000 mg/kg/day exhibited decreased activity and ataxia.
• Dogs treated with a dose of 2000 mg/kg/day showed vomiting and tremors.

Pharmacodynamics

Linezolid's Antibacterial Activity

• Linezolid belongs to the oxazolidinone class of antibacterial agents and is effective against aerobic Gram-positive bacteria and mycobacteria.
• It exhibits bacteriostatic activity against staphylococci and enterococci while demonstrating bactericidal activity against most streptococci isolates.
• Although linezolid has demonstrated some in vitro activity against Gram-negative and anaerobic bacteria, it is not considered effective against these types of organisms.

Linezolid and Monoamine Oxidase (MAO) Inhibition

• Linezolid acts as a reversible and non-selective inhibitor of monoamine oxidase (MAO) enzymes.
• Co-administration of linezolid with serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs), can potentially lead to the development of serotonin syndrome.

Limitations in Catheter-Related Infections

• Linezolid is not recommended for the treatment of catheter-related bloodstream infections or catheter-site infections.
• In these particular cases, the potential risks associated with linezolid therapy are considered to outweigh its therapeutic benefits.

Pharmacokinetics

Absorption

● Linezolid is highly absorbed after oral administration, with an absolute bioavailability of approximately 100%.

● Peak plasma concentrations (Tmax) are achieved within 1 to 2 hours after dosing.

● After single doses, plasma concentrations range from 8.1-12.9 mcg/mL, and after multiple dosing, concentrations range from 11.0-21.2 mcg/mL.

● Co-administration with food does not significantly affect the absorption of orally administered linezolid, allowing it to be taken with or without meals.

Volume of Distribution

● In healthy adults at steady-state, the volume of distribution of linezolid is approximately 40-50 liters.

Protein Binding

● Linezolid exhibits approximately 31% plasma protein binding, primarily to serum albumin.

● Protein binding is concentration-dependent.

Metabolism

● Linezolid undergoes metabolism to two inactive metabolites: PNU-142300 and PNU-142586.

● Both metabolites result from oxidation of the morpholine ring in linezolid.

● The hydroxyethyl glycine metabolite (PNU-142586) is the most abundant metabolite.

● The specific enzymes responsible for linezolid's metabolism are unclear, and it does not appear to be metabolized via the CYP450 enzyme system.

● Linezolid acts as a reversible and non-selective inhibitor of monoamine oxidase enzymes.

Route of Elimination

● Urinary excretion is the primary route of elimination for linezolid and its metabolites.

● Under steady-state conditions, approximately 84% of radioactivity from a radiolabeled dose of linezolid is recovered in the urine.

● Unchanged parent drug accounts for approximately 30% of the urinary excretion, while the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite account for approximately 40% and 10%, respectively.

● Fecal elimination is minor, with no detectable parent drug in feces and only small amounts of metabolites (6% for hydroxyethyl glycine metabolite and 3% for aminoethoxyacetic acid metabolite) excreted in feces.

1. https://medlineplus.gov/druginfo/meds/a602004.html
2. https://reference.medscape.com/drug/Linezolid-linezolid-342574
3. https://www.mayoclinic.org/drugs-supplements/linezolid-oral-route/side-effects/drg-20067254?p=1
4. https://www.webmd.com/drugs/2/drug-18168-6154/linezolid-oral/linezolid-oral/details
5. https://www.pfizer.ca/en/our-products/Linezolidam-linezolid-tablets
6. https://go.drugbank.com/drugs/DB00601
7. https://www.rxlist.com/linezolid/generic-drug.htm
8. https://www.drugs.com/mtm/linezolid-oral-injection.html
9. https://pdf.hres.ca/dpd_pm/00045786.PDF
10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021130s016,021131s013,021132s014lbl.pdf