linezolid linezolid the discovery and clinical development of effective antibiotics is most...

LINEZOLIDLINEZOLID

The discovery and clinical development of effective antibiotics

is most remarkable achievement over the past 60 years.

. Since the introduction of the sulphonamides in 1936, researchers have developed a range of antibiotic classes.

Until recently, however all new antibiotics introduced over the past 35 years have been structural modifications of existing antibiotic classes.

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The oxazolidinones represent the first truly new class of antibacterial agents. Approved in 2000 by the US FDA.

Linezolid has a unique mechanism of antibacterial action.

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Linezolid is the first of a new class of anti microbial agents, the Oxazolidinones, whose mechanism of action differs from that of existing agents.

Cross resistance to other antimicrobials is therefore less likely and has not been shown till date.

. It is approved US FDA in adults (April 2000) and children (December 2002) for the treatment of Gram Positive bacteria.

It disrupts bacterial growth by inhibiting the initiation process in protein synthesis. It binds to a site on the bacterial 23s ribosomal RNA of the 50s subunit, preventing the formation of functional 70s initiation complex which is an essential component of the bacterial translation process.

This site of inhibition process occurs earlier in the initiation process than other protein synthesis inhibitors that interfere with the elongation process.

Absorption: Well absorbed orally irrespective of timing of meal

Absorption: Well absorbed orally irrespective of timing of meal

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Bioavailability: 100%Bioavailability: 100%

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Half Life:Half Life: Preterm neonate < 1 week: 5.6 hrs. Term neonate < 1 week: 3 hrs. Term neonate > 1 week: 1.5 hrs. Infants: 1.8 hrs Children: 3 + 1.1 hrs Adolescent: 4.1 hrs

Preterm neonate < 1 week: 5.6 hrs. Term neonate < 1 week: 3 hrs. Term neonate > 1 week: 1.5 hrs. Infants: 1.8 hrs Children: 3 + 1.1 hrs Adolescent: 4.1 hrs

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Maximum Plasma concentration is reached within 1 to 2 hrs.

Distributes readily to well perfused area

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Metabolism: It is primarily metabolized by oxidation of the morphine ring which results in two inactive ring-opened carboxylic acid metabolites

A) aminoethoxyacetic acid(B) hydroxyethyl glycine

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Excretion: Non renal clearance accounts for about 65% of total clearance.

Approximately 30% of the dose appears in urine as Linezolid, 40% as metabolite B and 10% as metabolite A

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Aerobic and facultative Gram positive

microorganismsEnterococcus faecium (vancomycin resistant strains only)Staphylococcus aureus ( including

methicillin resistantstrain)Streptococcus agalactiaeStreptococcus pneumoniae

( penicillin susceptible strains only)Strptococcus pyrogenes

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Aerobic and facultative Gram positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Enterococcus faecalis (including vancomycin-resistan strains)Enterococcus faecalis (vancomycin-susceptible strains)Staphylococcus epidermidis (including methicillin- resistant strains)Staphylococcus haemolyticus.Streptococcus pneumoniae (penicillin-resistant strains)Viridans group streptococci

Pasteurella multocida

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Vancomycin-Resistant Enterococcus faecium

infections, including cases with concurrent bacteremia Nosocomial pneumonia caused by staphylococcus aureus (methicillin susceptible and resistant strains), or streptococcus pneumoniae (penicillin susceptible strains).

Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram- negative organisms.

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Complicated skin and skin structure infections caused by staphylococcus aureus (methicillin-susceptible and resistant strains), streptococcus pyogenes, or streptococcus agalactiae

Uncomplicated skin and skin structure infections caused by staphylococcus aureus (methicillin-susceptible only) or streptococcus pyogenes

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Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible strains only),including cases with concurrent bacteremia, or staphylococcus aureus (methicillin-susceptible strains).

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INFECTION DAILY DOSE DURATION OF THERAPY

complicated skin and skin structure infections

10MG/KG Q8H 10-14 DAYScommunity acquired pneumonia including concurrentbacteremia

Nosocomial pneumonia

vancomycin-resistant Enterococcus Faeciumin fections, including concurrent bacteremia

10MG/KG Q8H 14-28 DAYS

uncomplicated skin and skin structure infections.

<5 yrs 10 mg/kg q8h10 -14 days5-11 yrs 10 mg/kg q12h

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CBC, Hb & Platelet count: particularly in patients who are at increased risk for bleeding, patients with pre-existing thrombocytopenia or Myelosuppression or concomitant medications that decrease platelet count or function or produce bone marrow suppression and in patient requiring more than 2 weeks therapy.Number and type of stools /day for diarrhea

Well tolerated by most patients.Same in children & adults

The most common adverse effects are:

Myelosuppression (1 to 10%) including anemia, pancytopenia, leucopenia & thrombocytopenia

Diarrhea (4 to 8%),

Headache, Insomnia, Dizziness (2 to 6%)

Nausea, vomiting (1 to 3.7%),

Altered taste or tongue discoloration (1 to 2%)

Transient elevation in liver function test (1 to 2%).

Pseudo membranous colitis

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LINEZOLID is contraindicated for use in patients who have known hypersensitivity to Linezolid or any of the other product components.

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No dose adjustment is recommended

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No dose adjustment is recommended in case of mild & moderate hepatic insufficiency.

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Ingestion of Tyramine containing foods may cause hypertensive crisis.

Limit intake of Tyramine containing foods to less than 100 mg/meal

Linezolid is not an inducer of cytochrome p450 (CYP). Therefore no CYP 450 induced drug interactions are expected. So the drugs like Warfarin and Phenytoin can be given without dose alteration. .

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Monoamine Oxidase inhibiter: It is a reversible non selective inhibitor of monoamine oxidase. Therefore, it has potential for interaction with adrenergic and serotonergic agents such as Tricyclic antidepressants, Detromethorpan and Trazodone.

Store reconstituted preparation at room temperature and use within 21 days. Store infusion bag in over wrap until

ready to use. The yellow color of infusion solution may intensify over time without adversely affecting the potency. Store at room temperature & protect

from light. Injection is compatible with D5, RL,

NS

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Avoid excessive amount of Tyramine containing foods; Red wine, Aged cheese, Smoked or pickled fish, Beef or chicken liver, dried sausage, fava or broad bean. Notify in case of persistent or

worsening of symptoms of infection, diarrhea, nausea or vomiting. Complete course of therapy even

if symptoms improve.

-Injection: 200mg (100 ml) 400mg (200 ml) 600mg (300 ml) Infuse over 30-120 mins. Do not infuse with any other medication. Flush IV line before & after infusion with compatible solution. - Suspension: Dry powder 20mg/ml Gently invert bottle 3-5 times. Do not shake. - Tablet: 400mg, 600mg

Linospan (Cipla) Linox (Unichem) Lizolid (Integrace) Lizomed

(Aglomed)