Linezolid

Absorption

Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (Tmax) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing.
The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals.

Toxicity

Clinical signs of overdosage observed in rats were decreased activity and ataxia (2000 mg/kg/day) and in dogs were vomiting and tremors (3000 mg/kg/day). Treatment of overdose should involve symptomatic and supportive measures and may include hemodialysis if clinically necessary.

Description

Linezolid reached the US market for the treatment of patients with infections caused by serious Gram-positive pathogens, particularly skin and soft tissue infections, communityacquired pneumonia and vancomycin-resistant enterococcal infections. Linezolid is the (S)-enantiomer of an oxazolidin-2-one synthesized in a multistep process from 3,4- difluoronitrobenzene, the key step being the cyclization of a carbamate, using a chiral epoxyester, into an enantiomerically pure oxazolidin-2-one. Linezolid can be considered as the first of a new class of antibacterial agents known as oxazolidinones, its mechanism of action being related to the inhibition of early ribosomal protein synthesis without directly inhibiting DNA or RNA synthesis. In vitro studies demonstrated that linezolid was effective, at potency levels similar to vancomycin, against staphylococcal, streptococcal and pneumococcal infections (MIC values in the range of 0.5 to 2 μg/ml), enterococcal species including VRE and VSE (MIC values about 4 μg/ml), but also other vancomycin-resistant bacteria. Linezolid is rapidly absorbed orally, its bioavailability is nearly complete at 250 mg dose giving a Cmax to MIC ratio sufficient to have pathogenic strain eradication in the clinical setting. It is considered that this new promising agent may offer new options for therapy of multi-drug infections.

Description

Linezolid (trade name Zyvox) is a synthetic antibiotic that was developed by the Upjohn Co. in the late 1990s. It was approved by the US Food and Drug Administration in 2000 and is now one of the top-selling antibiotics in the world. Linezolid is used to treat methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and other Gram-positive pathogenic bacteria.
Linezolid is relatively safe, but it can cause diarrhea, headache, nausea, and vomiting. Like other antibiotics, its ability to suppress a wide range of bacteria may lead to fungal infections.

The Uses of Linezolid

Linezolid has been used in checkerboard-type drug combination MIC (minimum inhibitory concentrations) assay to determine whether ivacaftor shows positive interaction with linezolid. It has been used for the determination of minimum biofilm inhibitory concentration and for the treatment of Mycobacterium abscessus-infected Drosophila melanogaster w1118 flies.

Indications

Linezolid is indicated in adults and children for the treatment of infections caused by susceptible Gram-positive bacteria, including nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections. Examples of susceptible bacteria include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae.
Linezolid is not indicated for the treatment of Gram-negative infections, nor has it been evaluated for use longer than 28 days.

Background

Linezolid is a synthetic antibiotic which is used for the treatment of infections caused by aerobic Gram-positive bacteria. Its effects are bacteriostatic against both enterococci and staphylococci and bactericidal against most isolates of streptococci. Linezolid exerts its antibacterial activity by inhibiting the initiation of bacterial protein synthesis - more specifically, it binds to the 23S ribosomal RNA of the 50S subunit and, in doing so, prevents the formation of the 70S initiation complex which is essential for bacterial reproduction.
Linezolid was initially approved in 2000 and was the first member of the oxazolidinone antibiotic class. A second member of this class, tedizolid, was approved by the FDA in 2014 and is considered generally more effective and tolerable than its predecessor.

Pharmacokinetics

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

Metabolism

Linezolid is primarily metabolized to two inactive metabolites: an aminoethoxyacetic acid metabolite (PNU-142300) and a hydroxyethyl glycine metabolite (PNU-142586), both of which are the result of morpholine ring oxidation. The hydroxyethyl glycine metabolite - the most abundant of the two metabolites - is likely generated via non-enzymatic processes, though further detail has not been elucidated.
While the specific enzymes responsible for the biotransformation of linezolid are unclear, it does not appear to be subject to metabolism via the CYP450 enzyme system, nor does it meaningfully inhibit or induce these enzymes. Linezolid is, however, a reversible and non-selective inhibitor of monoamine oxidase enzymes.