Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Pfizer Laboratories (Pty) Ltd, 85 Bute Lane, Sandton, 2196, South Africa
A 20.1.1 Broad and medium spectrum antibiotic
Linezolid is a synthetic antibacterial agent of the oxazolidinone class of antibiotics. It has in vitro activity against aerobic Gram-positive bacteria and anaerobic microorganisms. It selectively inhibits bacterial protein synthesis through binding to sites on the bacterial ribosome and prevents the formation of a functional 70Sinitiation complex that is an essential component of the translation process.
The in vitro post-antibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2 hours. When measured in animal models, the in vivo PAEs were 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 that the linezolid plasma levels exceeded the minimum inhibitory concentration (MIC) of the infecting organism. Linezolid was efficacious when plasma levels exceeded the MIC of the infecting organism for a minimum of 40% of the dosing interval.
The following gives an approximate guidance on the probabilities as to whether microorganisms will be susceptible to linezolid or not. (Only microorganisms relevant to the given clinical indications are presented).
| Category |
|---|
| Susceptible organisms |
| Gram-positive aerobes: |
| Corynebacterium jeikeium |
| Enterococcus casseliflavus |
| Enterococcus faecalis (including glycopeptide resistant strains)* |
| Enterococcus faecium (including glycopeptide resistant strains)* |
| Enterococcus gallinarum |
| Listeria monocytogenes |
| Staphylococcus aureus (including methicillin resistant strains)* |
| Staphylococcus aureus (glycopeptide intermediate strains) |
| Staphylococcus epidermidis (including methicillin resistant strains)* |
| Staphylococcus haemolyticus |
| Staphylococcus lugdunensis |
| Streptococcus agalactiae* |
| Streptococcus intermedius |
| Streptococcus pneumoniae (including multidrug resistant strains [MDRSP])δ |
| Streptococcus pyogenes* |
| Group C streptococci |
| Group G streptococci |
| Viridans group streptococci |
| Gram-positive anaerobes: |
| Clostridium perfringens |
| Peptostreptococcus species |
| Peptostreptococcus anaerobius |
| Other: |
| Chlamydia pneumoniae |
| Intermediately susceptible organisms |
| Legionella species |
| Mycoplasma species |
| Moraxella catarrhalis |
| Resistant organisms |
| Haemophilus influenzae |
| Enterobacteriaceae |
| Neisseria species |
| Pseudomonas species |
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
δ MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as penicillinresistant Streptococcus pneumoniae, and are strains resistant to two or more of the following antibiotics: penicillin, second generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.
Linezolid’s mechanism of action differs from that of other antibiotics (e.g. the aminoglycosides, beta-lactams, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptogramins, tetracyclines and chloramphenicol). Therefore, there is no cross-resistance between linezolid and these classes of drugs. In vitro studies have shown that resistance to linezolid develops slowly via multiple step mutations in 23S ribosomal RNA and occurs at frequencies of less than 1 × 10-9 to 1 × 10-11.
ZYVOXID primarily contains linezolid that is biologically active and is metabolised to form inactive metabolites. The aqueous solubility of linezolid is approximately 3 mg/ml and is independent of pH between pH 3 to 9.
Maximum plasma concentrations are reached within 2 hours of dosing and absolute bioavailability is approximately 100%. It is not affected by food.
The volume of distribution at steady-state averages at about 40 to 50 litres in healthy adults and approximates to total body water. Plasma protein binding is about 31%.
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 Cmax respectively. In a small study of subjects with ventricularperitoneal shunts and essentially non-inflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma at Cmax was 0,7:1,0 after linezolid dosing.
Linezolid is metabolised by a non-enzymatic process. Metabolic oxidation of the morpholine ring results primarily in two inactive open-ring carboxylic acid derivatives. The hydroxyethyl glycine metabolite (B) is the predominant human metabolite and the amino ethoxy acetic acid metabolite (A) is less abundant. Linezolid is not detectably metabolised by cytochrome P450 (CYP) isoenzymes in vitro and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Linezolid does not significantly induce major cytochrome P450 isoenzymes in rats and does not induce human CYP2C9.
Under steady-state conditions, linezolid is primarily excreted in the urine as metabolite B (40%), parent drug (30-35%) and metabolite A (10%). The elimination half-life of the parent drug averages at about 5-7 hours. Non-renal clearance accounts for approximately 65% of the total clearance of linezolid.
The pharmacokinetics of linezolid is not significantly altered in elderly patients aged 65 and over.
No dose adjustment is necessary in patients with either mild, moderate or severe renal insufficiency, as linezolid clearance is independent of creatinine clearance. There is evidence that the primary metabolites of linezolid accumulate in patients with severe renal insufficiency (i.e. CLCR <30 ml/min). The clinical significance of this has not yet been established. As approximately 30% of a dose is removed during 3 hours of haemodialysis (beginning 3 hours after administration), ZYVOXID should be given after dialysis in patients receiving such treatment.
The pharmacokinetics of linezolid are not altered in patients with mild to moderate hepatic insufficiency. Dose adjustment in such patients is, therefore, not required. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency has not been evaluated. However, as linezolid is metabolised by a nonenzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.
The pharmacokinetics of linezolid following a single IV dose were investigated in paediatric patients ranging in age from birth through 17 years (including premature and full-term neonates).
The Cmax and the volume of distribution (Vss) are similar regardless of age in paediatric patients. However, clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of paediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence mean clearance values approach these observed for the adult population. There is wider inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all paediatric age groups as compared with adults.
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