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PHL 424
Antimicrobials
9th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Inhibitors of bacterial protein synthesis,
Linezolid
 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
Linezolid, Mechanism of Action
 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, Resistance & Pharmacokinetics
 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
 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 mg/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
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
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