Linezolid is a synthetic oxazolidinone antimicrobial drug. It is indicated for gram-positive infections and approved for the treatment of bacterial pneumonia, skin and skin structure infections, and vancomycin-resistant enterococcal (VRE) infections, including infections complicated by bacteremia. Linezolid does not have approval for the treatment of gram-negative infections, catheter-related bloodstream infections, or catheter site infections.
Linezolid’s primary place in therapy is an alternative to vancomycin in inpatient settings. Vancomycin remains a standard treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. However, vancomycin-resistant isolates of S. aureus have emerged, and there are increasing reports of vancomycin-resistant isolates worldwide. Alternative treatment agents merit consideration prior to using linezolid in outpatient settings, as inappropriate use has led to an increase in linezolid-resistant VRE (vancomycin-resistant enterococci).
Linezolid has activity against a broad range of antimicrobial susceptible and resistant gram-positive bacteria, including activity against MRSA with intermediate resistance to glycopeptides like vancomycin.
Linezolid is a recommended empirical therapy option for MRSA in hospitalized adult patients with complicated skin and soft tissue infection, for community-associated MRSA skin and soft tissue infection, and MRSA associated purulent and non-purulent cellulitis; linezolid is an alternative option for MRSA in hospitalized pediatric patients.
Non-FDA uses include anthrax, bone and joint infections, brain abscess, febrile neutropenia, infectious arthritis, meningitis, orthopedic device-related infection, osteomyelitis, sepsis, subdural empyema, and ventriculitis.
Linezolid has demonstrated activity against most strains of the following microorganisms: Enterococcus faecalis, Enterococcus faecium, Pasteurella multocida, Staphylococcus aureus (MRSA and MSSA, i.e., methicillin-sensitive), Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus agalactiae (group B streptococci), Streptococcus pneumonia, Streptococcus pyogenes (group A beta-hemolytic streptococci), and viridians group streptococci (S. mutans, S. salivarius, S. anginosus, S. mitis, S. sanguinis, and S. bovis).
Linezolid is the first available oxazolidinone to inhibit bacterial protein synthesis by interfering with translation. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit, which prevents the formation of a functional 70S initiation complex. This activity essentially inhibits protein production and prevents bacteria from multiplying.
Linezolid is bacteriocidal against the majority of streptococcal strains and bacteriostatic against staphylococci and enterococci; this makes linezolid a poor option for immunosuppressed patients.
Linezolid is also a reversible, non-selective monoamine oxidase (MAO) inhibitor. Monoamine oxidase inhibition leads to an increased concentration of the neurotransmitters epinephrine, norepinephrine, dopamine, and serotonin in the central nervous system and sympathetic nervous system. Inhibition may also lead to desensitization of alpha- and beta-adrenergic and serotonin receptors. In the GI tract and liver, inhibition of MAO can result in systemic absorption of large amounts of tyramine from the diet and potentially cause life-threatening hypertension.
Linezolid is available in tablets, suspension, and injection. The dosage of IV and tablet formulations are interchangeable; there is no need to make dose adjustments. Renal dosing is not required. Invert gently to mix before administration; do not vigorously shake oral suspension. Administer without regard to meals; food delays the rate, but not the extent of oral absorption.
Administer linezolid intravenous infusion over 30 to 120 minutes. Do not mix or infuse with other medications. When using the same IV line for sequential infusion, flush the line with D5W, NS, or LR before and after infusing linezolid. The yellow color of the injection may intensify with time without affecting potency.
Therapeutic doses vary by indication. The recommended dose is between 400 and 600 mg IV or orally every 12 hours for 10 to 28 days, depending on the indication.
Absorption is rapid and extensive. Linezolid has excellent tissue penetration into the lungs and CNS and exhibits 100 percent oral bioavailability.
Linezolid use may result in a suboptimal clinical response when treating organisms with a MIC (minimum inhibitory concentration) of 4 mcg/ml or greater and warrants a complete ID re-assessment and change in drug therapy.
The most common side effects experienced while taking linezolid include decreased platelets, hemoglobin, and white blood cell counts, headache, nausea, diarrhea, elevated pancreatic enzymes, elevated LFTs, and neuropathy.
Warnings associated with linezolid include duration-related myelosuppression (thrombocytopenia, anemia, leukopenia), serotonin syndrome, hypoglycemia; caution in patients on insulin or hypoglycemic drugs, seizures, lactic acidosis, hypertension when used with adrenergic drugs, and irreversible peripheral and optic neuropathy when used for 28 days or greater; however, reports exist of these events (i.e., blurred vision) in patients receiving shorter courses of linezolid. Prolonged use may result in fungal or bacterial infection, including Clostridioides difficile-associated diarrhea (CDAD) and pseudomembranous colitis; observations of C. difficile-associated diarrhea also may occur greater than two months of postantibiotic treatment.
Lactic acidosis may also occur with use; evaluate patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate concentrations.
Monitoring parameters include heart rate, blood pressure, blood glucose, weekly CBC, and visual function. Blood pressure requires close monitoring in patients with untreated hyperthyroidism. Patients with disease-related concerns such as diabetes mellitus, hypertension, hyperthyroidism, pheochromocytoma, and carcinoid syndrome also require close monitoring.
Toxicity is rare, and there is no antidote for linezolid. Symptomatic and supportive treatment is the recommendation for the management of mild to severe toxicity.
For severe neutropenia, administer colony-stimulating factors such as filgrastim or sargramostim. Filgrastim 5 mcg/kg/day SQ or IV over 15 to 30 minutes, or sargramostim 250 mcg/m2/day IV over 4 hours. Transfusion of platelets, packed red cells, or both may be necessary for patients with severe thrombocytopenia, anemia, or hemorrhage.
Transfusions are given as needed for severe thrombocytopenia, bleeding. For seizures, administer IV benzodiazepines; barbiturates or propofol may be an option if seizures persist or recur. Airway management may be necessary for patients with severe seizures. The primary treatment for serotonin syndrome is sedation with IV benzodiazepines, and cooling measures; cyproheptadine is an option for milder cases. Activated charcoal is a consideration in patients who are alert and airway protected with a recent overdose of linezolid tablets and co-ingested potentially dangerous medications, e.g., tricyclic antidepressants.
Monitoring is necessary for vital signs and liver enzymes in symptomatic patients; additionally, monitor serial CBC (with differential) and platelet count. Reports exist of myelosuppression, including anemia, pancytopenia, leukopenia, and thrombocytopenia in patients receiving linezolid. Monitoring of serum electrolyte status is indicated for patients with significant diarrhea and/or vomiting — monitor for clinical evidence of serotonin syndrome.
The healthcare team, e.g., physicians, nurses, and pharmacists, need to work together to ensure that the patient correctly takes linezolid and that the patient monitors for adverse drug reactions. Educate the patient about signs of significant adverse drug reactions, e.g., wheezing, chest tightness, seizures, swelling of the face, lips, tongue, or throat and severe diarrhea, etc. Encourage the patient to consult the healthcare team for questions about linezolid treatment. To prevent the inappropriate clinical use of linezolid, most hospitals have a committee that includes a pharmacist and an infectious disease expert who must first permit the use of the drug.
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