1. PHL 424 Antimicrobials 9 th Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2.  Linezolid is a synthetic antimicrobial agent of a novel class of synthetic antibacterial agents called oxazolidinones  It is the first commercially available oxazolidinone antibiotic and the only marketed oxazolidinone, although others are in development Inhibitors of bacterial protein synthesis, Linezolid

3.  Mechanism of Action  Linezolid elicits its antibacterial effects by inhibiting the initiation of bacterial protein synthesis  It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70S-initiation complex Specifically, it binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit, near the interface with the 30S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process Linezolid, Mechanism of Action

4.  Resistance,  Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes  Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA, with subsequent decreased binding to the target site Linezolid, Resistance & Pharmacokinetics  Pharmacokinetics  Linezolid is 100% bioavailable after oral administration, thus dosing for oral & i.v. preparations is the same. It may be administered without regard to food  It is 30% protein-bound and has a half-life of about 4–6 hours  It is metabolized by nonenzymatic oxidative metabolism, yielding two inactive metabolites; aminoethoxyacetic acid and hydroxyethyl glycine derivatives It is neither an inducer nor an inhibitor of cytochrome P450 enzymes  Approximately 80% of the dose of linezolid appears in the urine, 30% as active compound, and 50% as the two primary oxidation products. Ten percent of the administered dose appears as oxidation products in feces No dose adjustment in renal insufficiency is recommended  Peak serum concentrations average 18  g/mL 1 to 2 hours following a 600 mg oral dose. The recommended dose for most indications is 600 mg twice daily, either orally or intraveneously

5. Linezolid, Antibacterial Activity & Uses  Antibacterial Activity  The antibacterial action of linezolid is directed primarily against gram-positive organisms, such as staphylococci, streptococci and enterococci It is primarily a bacteriostatic agent except for streptococci for which it is bactericidal  It is also moderately active against Mycobacterium tuberculosis  Its main clinical use is against the resistant gram-positive organisms, such as methicillin (MRSA ) and vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant enterococci (VRE); E. faecium and E. faecalis, and penicillin resistant streptococci  Uses  Linezolid is FDA approved for treatment of: Infections caused by VRE; Nosocomial pneumonia caused by methicillin-susceptible and-resistant strains of S. aureus; Community-acquired pneumonia caused by penicillin-susceptible strains of S. pneumoniae; Complicated or uncomplicated skin and skin-structure infections caused by streptococci & methicillin-susceptible and -resistant strains of S. aureus;  The dermatologic preparations are indicated for treatment of traumatic skin lesions and impetigo secondarily infected with S. aureus or S. pyogenes

6. Linezolid, Adverse Effects 1.Gastrointestinal upset, nausea and diarrhea, as well as headaches and rash 2.Thrombocytopenia was found to occur in about 2% of patients who were on the drug for longer than 2 weeks 3.Linezolid can inhibit monoamine oxidase activity, so patients are cautioned of concomitant therapy with an adrenergic or serotonergic agent, and not to consume large quantities of tyramine-containing foods (100 mg of tyramine/day).  Those patients may experience palpitations, headache, or hypertensive crisis  Reversible enhancement of the pressor effects of pseudoephedrine was shown to occur