Linolid Mechanism of Action

Pharmacotherapeutic Group: Antibacterial for systemic use, other antibacterials. ATC code: J01XX08.
Pharmacology: Pharmacodynamics: Linolid contains Linezolid, which is a synthetic, antibacterial agent that belongs to a new class of antimicrobials, the oxazolidinones. It has in vitro activity against aerobic Gram positive bacteria and anaerobic micro-organisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 50S subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process.
The in vitro postantibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2 hours. When measured in animal models, the in vivo PAE was 3.6 and 3.9 hours for Staphylococcus aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic parameter for efficacy was the time for which the linezolid plasma level exceeded the minimum inhibitory concentration (MIC) for the infecting organism.
Breakpoints: Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for staphylococci and enterococci are Susceptible ≤ 4mg/L and Resistant >4 mg/L. For streptococci (including S. pneumoniae) the breakpoints are Susceptible ≤ 2 mg/L and Resistant >4 mg/L.
Non-species related MIC breakpoints are Susceptible ≤ 2 mg/L and Resistant > 4 mg/L. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that have not been given a specific breakpoint and not for those species where susceptibility testing is not recommended.
Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Category: Susceptible organisms: 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 species.
Resistant organisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas species.
*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
Whereas linezolid shows some in vitro activity against Legionella, Chlamydia pneumoniae and Mycoplasma pneumoniae, there are insufficient data to demonstrate clinical efficacy.
Resistance: Cross resistance: Linezolid's mechanism of action differs from those of other antibiotic classes. In vitro studies with clinical isolates (including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin- and erythromycin-resistant streptococci) indicate that linezolid is usually active against organisms which are resistant to one or more other classes of antimicrobial agents.
Resistance to linezolid is associated with point mutations in the 23S rRNA.
As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed with linezolid. Resistance to linezolid has been reported in enterococci, Staphylococcus aureus and coagulase negative staphylococci. This generally has been associated with prolonged courses of therapy and the presence of prosthetic materials or undrained abscesses. When antibiotic-resistant organisms are encountered in the hospital it is important to emphasize infection control policies.
Information from clinical trials: Studies in the paediatric population: In an open study, the efficacy of linezolid (10 mg/kg q8h) was compared to vancomycin (10- 15mg/kg q6-24h) in treating infections due to suspected or proven resistant gram-positive pathogens(including nosocomial pneumonia, complicated skin and skin structure infections, catheter related bacteraemia, bacteraemia of unknown source, and other infections), in children from birth to 11 years. Clinical cure rates in the clinically evaluable population were 89.3% (134/150) and 84.5% (60/71) for linezolid and vancomycin, respectively (95%CI: -4.9, 14.6).
Pharmacokinetics: Linolid primarily contains (s)-linezolid which is biologically active and is metabolised to form inactive derivatives.
Absorption: Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of linezolid (oral and intravenous dosing in a crossover study) is complete (approximately 100%). Absorption is not significantly affected by food and absorption from the oral suspension is similar to that achieved with the film-coated tablets.
Plasma linezolid C_max and C_min (mean and [SD]) at steady-state following twice daily intravenous dosing of 600 mg have been determined to be 15.1 [2.5] mg/l and 3.68 [2.68] mg/l, respectively.
In another study following oral dosing of 600 mg twice daily to steady-state, C_max and C_min were determined to be 21.2 [5.8] mg/l and 6.15 [2.94] mg/l, respectively. Steady-state conditions are achieved by the second day of dosing.
Distribution: Volume of distribution at steady-state averages at about 40-50 litres in healthy adults and approximates to total body water. Plasma protein binding is about 31% and is not concentration dependent.
Linezolid concentrations have been determined in various fluids from a limited number of subjects in volunteer studies following multiple dosing. The ratio of linezolid in saliva and sweat relative to plasma was 1.2:1.0 and 0.55:1.0, respectively. The ratio for epithelial lining fluid and alveolar cells of the lung was 4.5:1.0 and 0.15:1.0, when measured at steady-state C_max, respectively. In a small study of subjects with ventricular-peritoneal shunts and essentially non-inflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma at C_max was 0.7:1.0 after multiple linezolid dosing.
Metabolism: Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is the predominant human metabolite and is believed to be formed by a non-enzymatic process. The aminoethoxyacetic acid metabolite (PNU-142300) is less abundant. Other minor, inactive metabolites have been characterised.
Elimination: In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily excreted under steady-state conditions in the urine as PNU-142586 (40%), parent drug (30%) and PNU-142300 (10%). Virtually no parent drug is found in the faeces whilst approximately 6% and 3% of each dose appears as PNU-142586 and PNU-142300, respectively. The elimination half-life of linezolid averages at about 5-7 hours.
Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of non-linearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and non-renal clearance at higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.
Special populations: Renal impairment: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of linezolid in the plasma of patients with severe renal insufficiency (i.e. creatinine clearance < 30 ml/min). However, there was no increase in AUC of parent drug. Although there is some removal of the major metabolites of linezolid by haemodialysis, metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.
In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak plasma levels of linezolid were not affected.
The clinical significance of these observations has not been established as limited safety data are currently available (see Dosage & Administration and Precautions).
Hepatic impairment: Limited data indicate that the pharmacokinetics of linezolid, PNU-142300 and PNU-142586 are not altered in patients with mild to moderate hepatic insufficiency (i.e. Child-Pugh class A or B). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (i.e. Child-Pugh class C) have not been evaluated. However, as linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism (see Dosage & Administration and Precautions).
Paediatric population (< 18 years old): There are insufficient data on the safety and efficacy of linezolid in children and adolescents (< 18 years old) and therefore, use of linezolid in this age group is not recommended (see Dosage & Administration). Further studies are needed to establish safe and effective dosage recommendations. Pharmacokinetic studies indicate that after single and multiple doses in children (1 week to 12 years), linezolid clearance (based on kg body weight) was greater in paediatric patients than in adults, but decreased with increasing age.
In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours daily gave exposure approximating to that achieved with 600 mg twice daily in adults.
In neonates up to 1 week of age, the systemic clearance of linezolid (based on kg body weight) increases rapidly in the first week of life. Therefore, neonates given 10 mg/kg every 8 hours daily will have the greatest systemic exposure on the first day after delivery. However, excessive accumulation is not expected with this dosage regimen during the first week of life as clearance increases rapidly over that period.
In adolescents (12 to 17 years old), linezolid pharmacokinetics were similar to that in adults following a 600mg dose. Therefore, adolescents administered 600 mg every 12 hours daily will have similar exposure to that observed in adults receiving the same dosage.
In paediatric patients with ventriculoperitoneal shunts who were administered linezolid 10mg/kg either 12 hourly or 8 hourly, variable cerebrospinal fluid (CSF) linezolid concentrations were observed following either single or multiple dosing of linezolid. Therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empirical treatment of paediatric patients with central nervous system infections is not recommended.
Elderly: The pharmacokinetics of linezolid is not significantly altered in elderly patients aged 65 and over.
Female patients: Females have a slightly lower volume of distribution than males and the mean clearance is reduced by approximately 20% when corrected for body weight. Plasma concentrations are higher in females and this can partly be attributed to body weight differences. However, because the mean half-life of linezolid is not significantly different in males and females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and, therefore, dose adjustments are not required.