Linezolid Actions

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Actions of Linezolid in details

infoThe action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Pharmacodynamics: In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single Linezolid 600-mg dose via a 1 hr IV infusion, a single Linezolid 1,200-mg dose via a 1 hr IV infusion, placebo and a single oral dose of positive control. At both the Linezolid 600 and 1,200 mg doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

Clinical Studies: Adults: Vancomycin-Resistant Enterococcal Infections: Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multicenter, double-blind trial comparing a high dose of Linezolid (600 mg) with a low dose of Linezolid (200 mg) given every 12 hrs either IV or orally for 7-28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose Linezolid and 66 patients to low-dose Linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 patients in the low-dose arm.

The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 1 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level.

Nosocomial Pneumonia: Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multicenter, double-blind trial. Patients were treated for 7-21 days. One (1) group received Linezolid IV injection 600 mg every 12 hrs and the other group received vancomycin 1 g IV every 12 hrs. Both groups received concomitant aztreonam (1-2 g IV every 8 hrs), which could be continued if clinically indicated. There were 203 Linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (122) (60%) Linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for Linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for Linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 Linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in Linezolid-treated patients and 46% in vancomycin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 2.

Pneumonia Caused by Multidrug-Resistant S. pneumoniae (MDRSP): Linezolid was studied for the treatment of community-acquired (CAP) and hospital-acquired (HAP) pneumonia due to MDRSP by pooling clinical data from 7 comparative and noncomparative phase II and phase III studies involving adult and pediatric patients. The pooled MITT population consisted of all patients with S. pneumoniae isolated at baseline; the pooled ME population consisted of patients satisfying criteria for microbiologic evaluability. The pooled MITT population with CAP included 15 patients (41%) with severe illness (risk classes IV and V) as assessed by a prediction rule. The pooled clinical cure rates for patients with CAP due to MDRSP were 35/48 (73%) in the MITT and 33/36 (92%) in the ME populations, respectively. The pooled clinical cure rates for patients with HAP due to MDRSP were 12/18 (67%) in the MITT and 10/12 (83%) in the ME populations, respectively.

Note: MDRSP refers to isolates resistant to ≥2 of the following antibiotics: Penicillin, 2nd-generation cephalosporins, macrolides, tetracycline and sulfamethoxazole/trimethoprim.

Complicated Skin and Skin Structure Infections: Adult patients with clinically documented, complicated skin and skin structure infections were enrolled in a randomized, multicenter, double-blind, double-dummy trial comparing study medications administered IV followed by medications given orally to a total of 10-21 days of treatment. One (1) group of patients received Linezolid IV injection 600 mg every 12 hrs followed by Linezolid tablets 600 mg every 12 hrs; the other group received oxacillin 2 g IV every 6 hrs followed by dicloxacillin 500 mg orally every 6 hrs. Patients could receive concomitant aztreonam if clinically indicated. There were 400 Linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (245) (61%) Linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in Linezolid-treated patients and 85% in oxacillin-treated patients. An MITT analysis of 316 Linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in Linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 4.

A separate study provided additional experience with the use of Linezolid in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. This was a randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection.

One (1) group of patients received Linezolid IV injection 600 mg every 12 hrs followed by Linezolid tablets 600 mg every 12 hrs. The other group of patients received vancomycin 1 g IV every 12 hrs. Both groups were treated for 7-28 days and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for Linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients.

Diabetic Foot Infections: Adult diabetic patients with clinically documented, complicated skin and skin structure infections (diabetic foot infections) were enrolled in a randomized (2:1 ratio), multicenter, open-label trial comparing study medications administered IV or orally for a total of 14-28 days of treatment. One (1) group of patients received Linezolid 600 mg every 12 hrs IV or orally; the other group received ampicillin/sulbactam 1.5-3 g IV or amoxicillin/clavulanate 500-875 mg every 8-12 hrs orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hrs was used for the IV regimen. Patients in the comparator group could also be treated with vancomycin 1 g IV every 12 hrs if MRSA was isolated from the foot infection. Patients in either treatment group who had gram-negative bacilli isolated from the infection site could also receive aztreonam 1-2 g IV every 8-12 hrs. All patients were eligible to receive appropriate adjunctive treatment methods eg, debridement and off-loading, as typically required in the treatment of diabetic foot infections and most patients received these treatments. There were 241 Linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (212) (86%) Linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were 68.5% (165/241) in Linezolid-treated patients and 64% (77/120) in comparator-treated patients where those with indeterminate and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the Linezolid- and comparator-treated patients, respectively. A critical post-hoc analysis focused on 121 Linezolid-treated and 60 comparator-treated patients who had a gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the Linezolid-treated patients and 63% (38/60) in the comparator-treated patients. None of the previously mentioned analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 5.

Pediatric Patients: Infections Due to Gram-Positive Organisms: A safety and efficacy study provided experience on the use of Linezolid in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, catheter-related bacteremia, bacteremia of unidentified source and other infections due to gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected gram-positive organisms were enrolled in a randomized, open-label, comparator-controlled trial. One group of patients received Linezolid IV injection 10 mg/kg every 8 hrs followed by Linezolid for oral suspension 10 mg/kg every 8 hrs. A 2nd group received vancomycin 10-15 mg/kg IV every 6-24 hrs, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a 3rd arm of the study and received Linezolid 10 mg/kg every 8 hrs IV and/or orally. All patients were treated for a total of 10-28 days and could receive concomitant gram-negative antibiotics if clinically indicated. In the ITT population, there were 206 patients randomized to Linezolid and 102 patients randomized to vancomycin. One hundred seventeen (117) (57%) Linezolid-treated patients and 55 (54%) vancomycin-treated patients were clinically evaluable. The cure rates in ITT patients were 81% in patients randomized to Linezolid and 83% in patients randomized to vancomycin (95% confidence interval of the treatment difference; -13%, 8%). The cure rates in clinically evaluable patients were 91% in Linezolid-treated patients and 91% in vancomycin-treated patients (95% CI; -11%, 11%). MITT patients included ITT patients who, at baseline, had a gram-positive pathogen isolated from the site of infection or from blood. The cure rates in MITT patients were 80% in patients randomized to Linezolid and 90% in patients randomized to vancomycin (95% CI; -23%, 3%). The cure rates for ITT, MITT and clinically evaluable patients are presented in Table 6. After the study was completed, 13 additional patients ranging from 4 days through 16 years were enrolled in an open-label extension of the VRE arm of the study. Table 7 provides clinical cure rates by pathogen for microbiologically evaluable patients including microbiologically evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of this study

Animal

Pharmacology: Target organs of Linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss and suppression of body weight gain, which may have contributed to the observed effects.

In rats administered with Linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.

These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.

Pharmacokinetics: The mean pharmacokinetic parameters of Linezolid in adults after single and multiple oral and IV doses are summarized in Table 8. Plasma concentrations of Linezolid at steady state after oral doses of 600 mg given every 12 hrs are shown in the figure.

Absorption: Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations (Cmax) are reached approximately 1-2 hrs after dosing and the absolute bioavailability is approximately 100%. Therefore, Linezolid may be given orally or IV without dose adjustment.

Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5-2.2 hrs and Cmax is decreased by about 17% when high fat food is given with Linezolid. However, the total exposure measured as AUC0-∞ values is similar under both conditions.

Distribution: Animal and human pharmacokinetic studies have demonstrated that Linezolid readily distributes to well-perfused tissues. The plasma protein-binding of Linezolid is approximately 31% and is concentration-independent. The volume of distribution of Linezolid at steady state averaged 40-50 L in healthy adult volunteers.

Linezolid concentrations have been determined in various fluids from a limited number of subjects in phase 1 volunteer studies following multiple dosing of Linezolid. The ratio of Linezolid in saliva relative to plasma was 1.2 to 1 and for sweat relative to plasma was 0.55 to 1.

Metabolism: Linezolid is primarily metabolized by oxidation of the morpholine ring which results in 2 inactive ring-opened carboxylic acid metabolites: The aminoethoxyacetic acid metabolite (A) and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway, whereas, metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that Linezolid is minimally metabolized and may be mediated by human cytochrome P-450. However, the metabolic pathway of Linezolid is not fully understood.

Excretion: Nonrenal clearance accounts for approximately 65% of the total clearance of Linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as Linezolid, 40% as metabolite B and 10% as metabolite A. The renal clearance of Linezolid is low (average 40 mL/min) and suggests net tubular reabsorption. Virtually no Linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B and 3% as metabolite A.

A small degree of nonlinearity in clearance was observed with increasing doses of Linezolid which appears to be due to lower renal and nonrenal clearance of Linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.

Special Populations: Geriatric: The pharmacokinetics of Linezolid are not significantly altered in elderly patients (≥65 years). Therefore, dose adjustment for geriatric patients is not necessary.

Pediatric: The pharmacokinetics of Linezolid following a single IV dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of Linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single IV doses.

The Cmax and the volume of distribution (Vss) of Linezolid are similar regardless of age in pediatric patients. However, clearance of Linezolid varies as a function of age. With the exclusion of pre-term neonates <1 week, clearance is most rapid in the youngest age groups ranging from >1 week to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of Linezolid gradually decreases and by adolescence, mean clearance values approach those observed for the adult population. There is wider intersubject variability in Linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.

Similar mean daily AUC values were observed in pediatric patients from birth to 11 years dosed every 8 hrs relative to adolescents or adults dosed every 12 hrs. Therefore, the dosage for pediatric patients up to 11 years should be 10 mg/kg every 8 hrs. Pediatric patients ≥12 years should receive 600 mg every 12 hrs. See Table 9.

Gender: Females have a slightly lower volume of distribution of Linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.

Renal Insufficiency: The pharmacokinetics of the parent drug, Linezolid, are not altered in patients with any degree of renal insufficiency; however, the 2 primary metabolites of Linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction. The clinical significance of accumulation of these 2 metabolites has not been determined in patients with severe renal insufficiency. Because similar plasma concentrations of Linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of Linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites. Both Linezolid and the 2 metabolites are eliminated by dialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of Linezolid. Approximately 30% of a dose was eliminated in a 3-hr dialysis session beginning 3 hrs after the dose of Linezolid was administered; therefore, Linezolid should be given after hemodialysis.

Hepatic Insufficiency: The pharmacokinetics of Linezolid are not altered in patients (n=7) with mild to moderate hepatic insufficiency (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild to moderate hepatic insufficiency. The pharmacokinetics of Linezolid in patients with severe hepatic insufficiency have not been evaluated.

Drug-Drug Interactions: Drugs Metabolized by Cytochrome P-450: Linezolid is not an inducer of cytochrome P-450 (CYP450) in rats. In addition, Linezolid does not inhibit the activities of clinically significant human CYP isoforms (eg, 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, Linezolid is not expected to affect pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of Linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin which is extensively metabolized by CYP2C9. Drugs eg, warfarin and phenytoin, which are CYP2C9 substrates, may be given with Linezolid without changes in dosage regimen.

Antibiotics: Aztreonam: The pharmacokinetics of Linezolid or aztreonam are not altered when administered together.

Gentamicin: The pharmacokinetics of Linezolid or gentamicin are not altered when administered together.

Rifampin: The effect of rifampin on the pharmacokinetics of Linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral Linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with Linezolid resulted in a 21% decrease in Linezolid Cmax (90% CI, 15-27%) and a 32% decrease in Linezolid AUC0-12 (90% CI, 27-37%). The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes.

Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, Linezolid has the potential for interaction with adrenergic and serotonergic agents.

Adrenergic Agents: A significant pressor response has been observed in normal adult subjects receiving Linezolid and tyramine doses >100 mg. Therefore, patients receiving Linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.

A reversible enhancement of the pressor response of either pseudoephedrine hydrochloride (PSE) or phenylpropanolamine hydrochloride (PPA) is observed when Linezolid is administered to healthy normotensive subjects. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, Linezolid alone and the combination of steady-state Linezolid (600 mg every 12 hrs for 3 days) with 2 doses of PPA (25 mg) or PSE (60 mg) given 4 hrs apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2-3 hrs after the 2nd dose of PPA or PSE and returned to baseline 2-3 hrs after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mmHg: Placebo=121 (103-158); Linezolid alone=120 (107-135); PPA alone=125 (106-139); PPA with Linezolid=147 (129-176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mmHg (range: 20-52 mmHg) and 38 mmHg (range: 18-79 mmHg) during co-administration of Linezolid with pseudoephedrine or phenylpropanolamine, respectively.

Serotonergic Agents: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hrs apart) with or without Linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving Linezolid and dextromethorphan.

Microbiology: Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic gram-positive bacteria. The in vitro spectrum of activity of Linezolid also includes certain gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between Linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown Linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, Linezolid was found to be bactericidal for the majority of strains.

In clinical trials, resistance to Linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg every 12 hrs, lower than the recommended dose, and 2 patients received 600 mg every 12 hrs). In a compassionate use program, resistance to Linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to Linezolid occurs in vitro at a frequency of 1 x 10-9 to 1 x 10-11. In vitro studies have shown that point mutations in the 23S rRNA are associated with Linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to Linezolid during its clinical use have been published. In 1 report, nosocomial spread of vancomycin- and Linezolid-resistant E. faecium occurred. There has been a report of Staphylococcus aureus (methicillin-resistant) developing resistance to Linezolid during its clinical use. The Linezolid resistance in these organisms was associated with a point mutation in the 23s rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies. Resistance to Linezolid has not been reported in Streptococcus spp, including Streptococcus pneumoniae.

In vitro studies have demonstrated additivity or indifference between Linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin or streptomycin.

Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, as described in the Indications section.

Aerobic and Facultative Gram-Positive Microorganisms: Enterococcus faecium (vancomycin-resistant strains only), Staphylococcus aureus (including methicillin-resistant strains), Streptococcus agalactiae, Streptococcus pneumoniae [including multi-drug-resistant isolates (MDRSP)], Streptococcus pyogenes.

The following in vitro data are available but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for Linezolid. However, the safety and effectiveness of Linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic and Facultative Gram-Positive Microorganisms: Enterococcus faecalis (including vancomycin-resistant strains), Enterococcus faecium (vancomycin-susceptible strains), Staphylococcus epidermidis (including methicillin-resistant strains), Staphylococcus haemolyticus, Viridans group streptococci.

Aerobic and Facultative Gram-Negative Microorganisms: Pasteurella multocida.

Susceptibility Testing Methods: Susceptibility testing by dilution methods requires the use of Linezolid susceptibility powder.

When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Linezolid powder. The MIC values should be interpreted according to criteria provided in Table 11.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with Linezolid 30 mcg to test the susceptibility of microorganisms to Linezolid. The disk diffusion interpretative criteria are provided in Table 11.

A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "intermediate" indicates that the result should be considered equivocal and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard Linezolid powder should provide the following range of values noted in Table 12. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within the bacteria; the specific strains used for microbiological quality control are not clinically significant.

How should I take Linezolid?

Take Linezolid only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

To use the oral suspension:

  • The liquid form of Linezolid should be gently mixed by turning the bottle upside down 3 to 5 times before each dose. Do not shake this product.
  • Measure the medicine with a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.
  • Do not use after the expiration date on the label. The medicine may not work properly after that date. If you have any questions about this, check with your pharmacist.

Keep using Linezolid for the full time of treatment, even if you or your child begin to feel better after a few days. Also, it works best when there is a constant amount in the blood. To help keep the amount constant, Linezolid must be given on a regular schedule.

Dosing

The dose of Linezolid will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Linezolid. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage forms (suspension or tablets):
    • For bacterial infections:
      • Adults and children 12 years of age and older—400 or 600 milligrams (mg) every 12 hours.
      • Children younger than 12 years of age—Dose is based on body weight and must be determined by your doctor. The dose is usually 10 milligrams (mg) per kilogram (kg) of body weight every 8 or 12 hours as determined by your doctor.

Missed Dose

If you miss a dose of Linezolid, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Keep out of the reach of children.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Store the mixed suspension at room temperature. Throw away any unused medicine 21 days after it has been prepared. If you have any questions about this, check with your pharmacist.

Linezolid administration

infoAdministration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Before taking the oral suspension (liquid), gently mix it by turning the bottle upside down 3 to 5 times. Do not shake. Measure the liquid with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Intravenous Linezolid is injected into a vein through an IV. This medicine must be given slowly, and the IV infusion can take up to 2 hours to complete. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

To be sure this medication is not causing harmful effects, your blood cells and blood pressure will need to be tested often. You may also need eye exams. Visit your doctor regularly.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Linezolid will not treat a viral infection such as the common cold or flu.

Store all forms of Linezolid at room temperature away from moisture, heat, and light. Do not freeze. Throw away any unused oral liquid that is more than 21 days old.

Linezolid pharmacology

infoPharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
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Mechanism of Action

Linezolid is an antibacterial drug.

Pharmacodynamics

In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single Linezolid 600 mg dose via a 1 hour IV infusion, a single Linezolid 1200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg Linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

Pharmacokinetics

The mean pharmacokinetic parameters of Linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of Linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.

Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following

Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)

Absorption: Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, Linezolid may be given orally or intravenously without dose adjustment.

Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with Linezolid. However, the total exposure measured as AUC0-∞ is similar under both conditions.

Distribution: Animal and human pharmacokinetic studies have demonstrated that Linezolid readily distributes to well-perfused tissues. The plasma protein binding of Linezolid is approximately 31% and is concentration-independent. The volume of distribution of Linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.

Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of Linezolid. The ratio of Linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of Linezolid in sweat relative to plasma was 0.55 to 1.

Metabolism: Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that Linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of Linezolid is not fully understood.

Excretion: Nonrenal clearance accounts for approximately 65% of the total clearance of Linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as Linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of Linezolid is 40 mL/min which suggests net tubular reabsorption. Virtually no Linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A.

A small degree of nonlinearity in clearance was observed with increasing doses of Linezolid, which appears to be due to lower renal and nonrenal clearance of Linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.

Specific Populations: Geriatric Patients: The pharmacokinetics of Linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.

Pediatric Patients: The pharmacokinetics of Linezolid following a single intravenous dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of Linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses.

The Cmax and the volume of distribution (Vss) of Linezolid are similar regardless of age in pediatric patients. However, plasma clearance of Linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, weight-based 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 a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of Linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased inter-subject variability in Linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.

Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours.

Gender: Females have a slightly lower volume of distribution of Linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.

Renal Impairment: The pharmacokinetics of the parent drug, Linezolid, are not altered in patients with any degree of renal impairment; however, the two primary metabolites of Linezolid accumulate in patients with renal impairment, with the amount of accumulation increasing with the severity of renal dysfunction. The pharmacokinetics of Linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with Linezolid 600 mg every 12 hours for 14.5 days. Because similar plasma concentrations of Linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of Linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both Linezolid and the two metabolites are eliminated by hemodialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of Linezolid. Approximately 30% of a dose was eliminated in a 3-hour hemodialysis session beginning 3 hours after the dose of Linezolid was administered; therefore, Linezolid should be given after hemodialysis.

1Metabolite B is the major metabolite of Linezolid.

1between hemodialysis sessions

2Metabolite B is the major metabolite of Linezolid.

Hepatic Impairment: The pharmacokinetics of Linezolid are not altered in patients (n=7) with mild-to-moderate hepatic impairment (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic impairment. The pharmacokinetics of Linezolid in patients with severe hepatic impairment have not been evaluated.

Drug Interactions: Drugs Metabolized by Cytochrome P450: Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, Linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, Linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of Linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with Linezolid without changes in dosage regimen.

Antibiotics: Aztreonam: The pharmacokinetics of Linezolid or aztreonam are not altered when administered together. Gentamicin: The pharmacokinetics of Linezolid or gentamicin are not altered when administered together.

Antioxidants: The potential for drug-drug interactions with Linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of Linezolid on Day 1, and another 600 mg dose of Linezolid on Day 8. On Days 2-9, subjects were given either Vitamin C (1000 mg/day) or Vitamin E (800 IU/ day). The AUC0-∞ of Linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co‑administered with Vitamin E. No Linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E.

Strong CYP 3A4 Inducers: Rifampin: The effect of rifampin on the pharmacokinetics of Linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral Linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with Linezolid resulted in a 21% decrease in Linezolid Cmax [90% CI, 15% to 27%] and a 32% decrease in Linezolid AUC0-12 [90% CI, 27% to 37%]. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in Linezolid exposure.

Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, Linezolid has the potential for interaction with adrenergic and serotonergic agents.

Adrenergic Agents: Some individuals receiving Linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response.

Tyramine: A significant pressor response has been observed in normal adult subjects receiving Linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving Linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.

Pseudoephedrine HCl or phenylpropanolamine HCl: A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when Linezolid is administered to healthy normotensive subjects. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, Linezolid alone, and the combination of steady-state Linezolid (600 mg every 12 hours for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); Linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with Linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20 to 52 mm Hg) and 38 mm Hg (range: 18 to 79 mm Hg) during co-administration of Linezolid with pseudoephedrine or phenylpropanolamine, respectively.

Serotonergic Agents: Dextromethorphan: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without Linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving Linezolid and dextromethorphan.

Microbiology

Mechanism of Action

Linezolid is a synthetic antibacterial agent of the oxazolidinone class, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of Linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction. The results of time-kill studies have shown Linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, Linezolid was found to be bactericidal for the majority of isolates.

Mechanisms of Resistance

In vitro studies have shown that point mutations in the 23S rRNA are associated with Linezolid resistance. Reports of vancomycin-resistant Enterococcus faecium becoming resistant to Linezolid during its clinical use have been published. There are reports of Staphylococcus aureus (methicillin-resistant) developing resistance to Linezolid during clinical use. The Linezolid resistance in these organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to Linezolid. Also Linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci.

Interaction with Other Antimicrobial Drugs

In vitro studies have demonstrated additivity or indifference between Linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.

Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Gram-positive bacteria: Enterococcus faecium (vancomycin-resistant isolates only)

Staphylococcus aureus (including methicillin-resistant isolates)

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Greater than 90% of the following bacteria exhibit an in vitro MIC less than or equal to the Linezolid-susceptible breakpoint for organisms of similar genus shown in Table 12. The safety and effectiveness of Linezolid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria: Enterococcus faecalis (including vancomycin-resistant isolates)

Enterococcus faecium (vancomycin-susceptible isolates)

Staphylococcus epidermidis (including methicillin-resistant isolates)

Staphylococcus haemolyticus

Viridans group streptococci

Gram-negative bacteria:

Pasteurella multocida

Susceptibility Test Methods:

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 12.

Diffusion techniques:

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg Linezolid to test the susceptibility of bacteria to Linezolid. The disk diffusion interpretive criteria are provided in Table 12.

A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection; other therapy should be selected.

Quality Control:

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard Linezolid powder should provide the following range of MIC values noted in Table 13. For the diffusion technique using the 30 mcg Linezolid disk, the criteria in Table 13 should be achieved.

aThis organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.



References

  1. DailyMed. "LINEZOLID: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. NCIt. "Linezolid: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
  3. EPA DSStox. "Linezolid: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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