Pharmacology: Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of the other bacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotic is unlikely to happen. 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.
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 Zyvox (600 mg) with a low dose of Zyvox (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. (See Table 1.)
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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 Zyvox IV injection 600 mg every 12 hrs, and the other group received vancomycin 1 g every 12 hrs IV. Both groups received concomitant aztreonam (1-2 g every 8 hrs IV), 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. (See Table 2.)
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Pneumonia Caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP*): Zyvox was studied for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) due to MDRSP by pooling clinical data from 7 comparative and non-comparative Phase 2 and Phase 3 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. (See Table 3.)
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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 for a total of 10-21 days of treatment. One group of patients received Zyvox IV injection 600 mg every 12 hrs followed by Zyvox tablets 600 mg every 12 hrs; the other group received oxacillin 2 g IV every 6 hrs followed by dicloxacillin 500 mg every 6 hrs orally. 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. A 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.
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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 group of patients received Zyvox IV injection 600 mg every 12 hrs followed by Zyvox 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), multi-center, 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 Zyvox 600 mg IV or orally every 12 hrs; 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 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 the comparator-treated patients, where those with indeterminated 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 clinical
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. (See Table 5.)
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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 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
E. 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
E. 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 one report, nosocomial spread of vancomycin- and linezolid-resistant
E. faecium occurred. There have been reports 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
S. 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 under Indications.
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.
*MDRSP refers to isolates resistant to ≥2 of the following antibiotics: Penicillin, 2nd-generation cephalosporins, macrolides, tetracycline and trimethoprim/sulfamethoxazole.
Susceptibility Testing: Note: 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 minimum inhibitory concentrations (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 6.
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 interpretive criteria are provided in Table 6. (See Table 6.)
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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 7. (See Table 7.)
Note: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.
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Pharmacokinetics: The mean pharmacokinetic parameters of linezolid after single and multiple oral and IV doses are summarized in Table 8. (See Table 8.)
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Absorption: Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations 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 C
max is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC
0-∞ 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 1.2:1 and for sweat relative to plasma was 0.55:1.
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 B is mediated by a non-enzymatic chemical oxidation mechanism
in vitro. Linezolid is not an inducer of cytochrome P-450 (CYP450) in rats, and it has been demonstrated from
in vitro studies that linezolid is not detectably metabolized by human CYP450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).
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: Elderly: The pharmacokinetics of linezolid are not significantly altered in elderly patients (≥65 years). Therefore, dose adjustment for geriatric patients is not necessary.
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 (see Table 9). However, there was no increase in AUC of parent drug. 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. Although there is some removal of the major metabolites of linezolide by hemodialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency. 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. The clinical significance of these observations has not been established as limited safety data are currently available.
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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. However, as linezolid is metabolized by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.
Drug-Drug Interactions: Drugs Metabolized by CYP450: Linezolid is not an inducer of CYP450 in rats. It is not detectably metabolized by human cytochrome P-450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected with linezolid. 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.
Rifampicin: The effect of rifampin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered linezolid 600 mg twice daily for 2.5 days with and without rifampin 600 mg once daily for 8 days. Rifampin decreased the linezolid Cmax and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.
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 of >100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content (see Information for Patients under Precautions).
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 (see Interactions). 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. The effects of other serotonin re-uptake inhibitors have not been studied.
Toxicology: 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. 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.
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