Linezolid

Pharmacological properties

linezolid is a synthetic antibacterial agent that belongs to a new class of antimicrobials - oxazolidinones. in vitro is active against aerobic gram-positive, some gram-negative bacteria and anaerobic microorganisms. linezolid selectively inhibits protein synthesis in bacterial cells through a unique mechanism of action. in particular, it binds to the site on the bacterial ribosome (23s subunit with 50s) and prevents the formation of a functional 70s-initiating complex, which is an important component of the translation process.

The following microorganisms are sensitive to linezolid: gram-positive aerobes Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus; coagulase-negative staphylococci Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, group C streptococci, group G streptococci; gram-positive anaerobes Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus sp.

Resistant microorganisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas sp.

Linezolid resistance is associated with point mutations in 23S rRNA. A decrease in sensitivity to linezolid is noted when used in patients with infections that are difficult to treat, and / or when used for a long time. Resistance to linezolid of enterococci, Staphylococcus aureus, and coagulase-negative staphylococci has been reported.

Pharmacokinetics

Absorption. Linezolid is rapidly and significantly absorbed after administration. C_max in blood plasma is reached within 2 hours after taking the drug. The oral bioavailability of linezolid is complete (almost 100%). Therefore, linezolid can be used orally or without dose adjustment. Simultaneous food intake does not significantly affect the absorption of the drug. After taking a dose of 600 mg 2 times a day, the maximum and minimum concentration in equilibrium is 21.2 and 6.15 mg / l, respectively. The equilibrium state is reached on the 2nd day of therapy.

Distribution in the body. The volume of distribution in equilibrium is an average of 40-50 l, which roughly corresponds to the total amount of fluid in the human body. It is known that linezolid is rapidly distributed in tissues with good perfusion. The degree of binding to plasma proteins is about 31% and does not depend on the concentration of the drug in blood plasma.

The ratio of linezolid concentration in saliva and perspiration to plasma concentration is 1.2: 1 and 0.55: 1, respectively. The ratio of concentration in bronchoalveolar lavage fluid and in alveolar lung cells to C_max in plasma in equilibrium - 4.5: 1 and 0.15: 1, respectively. The ratio of concentration in CSF to C_max in blood plasma after repeated administration of linezolid - 0.7: 1.

Metabolism. Linezolid is mainly metabolized by oxidation of the morpholine ring to form two inactive open-ring carboxylic acid derivatives: aminoethoxyacetic acid metabolite (PNU-142300) and hydroxyethylglycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is a predominant metabolite in humans, which is believed to be formed by a non-enzymatic process. Aminoethoxyacetic acid metabolite (PNU-142300) is detected in smaller quantities. Other "small" inactive metabolites have also been identified. It is known that linezolid is minimally metabolized with the possible participation of the cytochrome P450 system in this process. However, the metabolic pathways for linezolid are not fully understood.

In patients with normal renal function or with mild to moderate renal failure, linezolid in the equilibrium state is mainly excreted in the urine as a PNU-142586 metabolite (40%), unchanged (30%), and as a PNU-142300 metabolite (10% ) The drug in unchanged form in feces is practically not determined, while the share of each of the main metabolites, PNU-142586 and PNU-142300, is 6 and 3%, respectively. T_½ linezolid averages 5–7 hours.

Non-renal clearance is about 65% of the total clearance of linezolid. An insignificant degree of clearance nonlinearity was noted with increasing dose of linezolid. Obviously, this is a consequence of lower renal and nonrenal clearance at high concentrations of linezolid.However, this difference in clearance is negligible and does not affect the apparent T_½.

Pharmacokinetics in individual patient groups

Patients with renal failure. After a single administration at a dose of 600 mg, a 7–8-fold increase in the systemic exposure of two major plasma linezolid metabolites in patients with severe renal failure (creatinine clearance of 30 ml / min) was revealed. However, the exposure value for AUC for the parent compound remained unchanged. Although a certain amount of the main metabolites of linezolid is excreted during hemodialysis, plasma metabolites after a single dose of 600 mg were still higher after the hemodialysis procedure than in patients with normal renal function or with mild or moderate renal failure.

Patients with liver failure. Limited data indicate that the pharmacokinetics of linezolid, PNU-142300, and PNU-142586 are not impaired in patients with mild or moderate hepatic impairment (Child or Pugh class A or B). The pharmacokinetic parameters of linezolid in patients with severe hepatic insufficiency (class C on the Child-Pugh scale) have not been studied. However, since linezolid is metabolized by a non-enzymatic process, liver failure does not significantly affect its metabolism.

Children aged 12-17 years. The pharmacokinetics of linezolid was similar to that in adults when using the drug at a dose of 600 mg. The use of the drug in a dose of 600 mg every 12 hours daily provides the same exposure to the drug as in adults receiving the drug in the same dose.

Elderly patients. The pharmacokinetics of linezolid in individuals over the age of 65 does not change significantly.

Women are characterized by a lower volume of distribution of linezolid than men, and the average clearance (adjusted by body weight) is reduced by about 20%. The concentration of linezolid in blood plasma is higher in women, partly due to the difference in body weight. However, since the average T_½ in men and women it does not differ significantly, it is not expected that the concentration of the drug in the blood plasma of women will significantly exceed that which is well tolerated, therefore, dose adjustment of linezolid is not required.

Indications

Infections caused by sensitive anaerobic and aerobic gram-positive microorganisms, including infections accompanied by bacteremia, such as:

• nosocomial pneumonia:
• community-acquired pneumonia:
• complicated infections of the skin and its appendages, in particular infections against the diabetic foot without concomitant osteomyelitis caused by Staphylococcus aureus (methicillin-sensitive and methicillin-resistant isolates), Streptococcus pyogenes or Streptococcus agalactiae;
• uncomplicated infections of the skin and its structures caused by Staphylococcus aureus (methicillin-sensitive isolates only) or Streptococcus pyogenes;
• enterococcal infections, including vancomycin-resistant strains of Enterococcus faecium and faecalis.

If the causative agents of infection include gram-negative microorganisms, the appointment of combination therapy is clinically indicated.

Application

Laen is prescribed 2 times a day for regardless of food intake.

The duration of treatment depends on the pathogen, the location and severity of the infection, as well as the clinical effect. The maximum duration of treatment is 28 days. The safety and effectiveness of linezolid when used for more than 28 days have not been established.

The maximum dose for adults and children over the age of 12 years should not exceed 600 mg 2 times a day.

Recommended doses for adults and children over 12 years old

* Apply linezolid in another dosage form with the possibility of appropriate dosage.

Patients who started treatment with the parenteral form of linezolid can be transferred to the oral form, since the bioavailability of linezolid when taken orally is almost 100%.

Elderly patients. There is no need for dose adjustment.

Patients with renal failure (including creatinine clearance of 30 ml / min). The pharmacokinetics of linezolid does not change in patients with any degree of renal failure, however, the two main metabolites of linezolid are cumulated in patients with renal failure with an increase in their accumulation in patients with a greater degree of severity of renal dysfunction. Regardless of renal function, the same plasma concentrations of linezolid were achieved, therefore, dose adjustment is not recommended for patients with renal failure. However, given