"Dec. 26, 2012 -- Johnnie McKee thought she was out of the woods.
McKee, a 72-year-old grandmother of four from Bethpage, Tenn., was one of nearly 14,000 people who found out this fall that they'd been exposed to tainted medications made by "...
PharmacodynamicsIn a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single ZYVOX 600 mg dose via a 1 hour IV infusion, a single ZYVOX 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 ZYVOX doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous (IV) doses are summarized in Table 1. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.
Table 1: Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults
|Dose of Linezolid||Cmax μg/mL||Cmin μg/mL||Tmax hrs||AUC * μg•h/mL||t½ hrs||CL mL/min|
|400 mg tablet|
|single dose †||8.1||---||1.52||55.1||5.2||146|
|every 12 hours||11||3.08||1.12||73.4||4.69||110|
|600 mg tablet|
|every 12 hours||21.2||6.15||1.03||138||5.4||80|
|600 mg IV injection ‡|
|every 12 hours||15.1||3.68||0.51||89.7||4.8||123|
|600 mg oral suspension|
|single dose||11.00 (2.76)||---||0.97 (0.88)||80.80 (35.10)||4.60 (1.71)||141 (45)|
|* AUC for single dose = AUC0-∞; for multiple-dose =
†Data dose-normalized from 375 mg
‡Data dose-normalized from 625 mg, IV dose was given as 0.5-hour infusion.
Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; Tmax = Time to Cmax; AUC =Area under concentration-time curve; t½ = Elimination half-life; CL = Systemic clearance
Figure 1: Plasma Concentrations of Linezolid in Adults at
Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation,
Linezolid is rapidly and 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-∞ values is similar under both conditions.
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 for sweat relative to plasma was 0.55 to 1.
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.
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.
The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.
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 2 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 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 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 of age dosed every 8 hours (q8h) relative to adolescents or adults dosed every 12 hours (q12h). Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h (see DOSAGE AND ADMINISTRATION).
Table 2: Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or
600 mg Linezolid (Mean: (%CV); [Min, Max Values])
|Age Group||Cmax μg/mL||Vss L/kg||AUC* μg•h/mL||t ½ hrs||CL mL/min/kg|
|Pre-term** < 1 week (N=9)†||12.7 (30%) [9.6, 22.2]||0.81 (24%) [0.43, 1.05]||108 (47%) [41, 191]||5.6 (46%) [2.4, 9.8]||2.0 (52%) [0.9, 4.0]|
|Full-term*** < 1 week (N=10)†||11.5 (24%) [8.0, 18.3]||0.78 (20%) [0.45, 0.96]||55 (47%) [19, 103]||3.0 (55%) [1.3, 6.1]||3.8 (55%) [1.5, 8.8]|
|≥ 1 week to ≤ 28 days (N=10)†||12.9 (28%) [7.7, 21.6]||0.66 (29%) [0.35, 1.06]||34 (21%) [23, 50]||1.5 (17%) [1.2, 1.9]||5.1 (22%) [3.3, 7.2]|
|> 28 days to < 3 Months (N=12 )†||11.0 (27%) [7.2, 18.0]||0.79 (26%) [0.42, 1.08]||33 (26%) [17, 48]||1.8 (28%) [1.2, 2.8]||5.4 (32%) [3.5, 9.9]|
|3 months through 11 years† (N=59)||15.1 (30%) [6.8, 36.7]||0.69 (28%) [0.31, 1.50]||58 (54%) [19, 153]||2.9 (53%) [0.9, 8.0]||3.8 (53%) [1.0, 8.5]|
|Adolescent Subjects and Patients|
|12 through 17 years‡ (N=36)||16.7 (24%) [9.9, 28.9]||0.61 (15%) [0.44, 0.79]||95 (44%) [32, 178]||4.1 (46%) [1.3, 8.1]||2.1 (53%) [0.9, 5.2]|
|Adult Subjects§ (N= 29)||12.5 (21%)||0.65 (16%)||91 (33%)||4.9 (35%)||1.7 (34%)|
|[8.2, 19.3]||[0.45, 0.84]||[53, 155]||[1.8, 8.3]||[0.9, 3.3]|
|*AUC = Single dose AUC0-∞
** In this data set, “pre-term” is defined as < 34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days)
*** In this data set, “full-term” is defined as > 34 weeks gestational age
†Dose of 10 mg/kg
†Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg
§ Dose normalized to 600 mg
Cmax = Maximum plasma concentration; Vss= Volume of distribution. AUC = Area under concentration-time curve;
t½ = Apparent elimination half-life; CL = Systemic clearance normalized for body weight
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.
The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the two 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 3). The clinical significance of accumulation of these two 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 two 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-hour dialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.
Table 3: Mean (Standard Deviation) AUCs and Elimination
Half-lives of Linezolid and Metabolites A and B in Patients with Varying
Degrees of Renal Insufficiency After a Single 600-mg Oral Dose of Linezolid
|Parameter||Healthy Subjects CLCR > 80 mL/min||Moderate Renal Impairment 30 < CLCR < 80 mL/min||Severe Renal Impairment 10 < CLCR < 30 mL/min||Hemodialysis-Dependent|
|Off Dialysis*||On Dialysis|
|AUC0-∞, μg h/mL||110 (22)||128 (53)||127 (66)||141 (45)||83 (23)|
|t½, hours||6.4 (2.2)||6.1 (1.7)||7.1 (3.7)||8.4 (2.7)||7.0 (1.8)|
|AUC0-48, μg h/mL||7.6 (1.9)||11.7 (4.3)||56.5 (30.6)||185 (124)||68.8 (23.9)|
|t½, hours||6.3 (2.1)||6.6 (2.3)||9.0 (4.6)||NA||NA|
|AUC0-48 , μg h/mL||30.5 (6.2)||51.1 (38.5)||203 (92)||467 (102)||239 (44)|
|t½, hours||6.6 (2.7)||9.9 (7.4)||11.0 (3.9)||NA||NA|
|* between hemodialysis sessions
NA = Not applicable
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.
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.
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. Coadministration 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 (see PRECAUTIONS: DRUG INTERACTIONS).
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 more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content (see PATIENT INFORMATION).
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 PRECAUTIONS: DRUG 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 q12h 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: 20-52 mm Hg) and 38 mm Hg (range: 18-79 mm Hg) 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 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.
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, crossresistance 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 q12h, lower than the recommended dose, and 2 patients received 600 mg q12h). 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.1 In one report nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred2. There has been a report of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use.3 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.4,5 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 AND USAGE section.
Aerobic and facultative Gram-positive microorganisms
Enterococcus faecium (vancomycin-resistant strains
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]*)
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
Enterococcus faecium (vancomycin-susceptible strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Viridans group streptococci
Aerobic and facultative Gram-negative microorganisms
Susceptibility Testing Methods
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 method6,7 (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 4.
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 procedure7,8 requires the use of standardized inoculums concentrations. This procedure uses paper disks impregnated with 30 p,g of linezolid to test the susceptibility of microorganisms to linezolid. The disk diffusion interpretive criteria are provided in Table 4.
Table 4: Susceptibility Interpretive Criteria for
|Pathogen||Susceptibility Interpretive Criteria|
|Minimal Inhibitory Concentrations (MIC in μg/mL)||Disk Diffusion (Zone Diameters in mm)|
|Enterococcus spp||≤ 2||4||≥ 8||≥ 23||21-22||≤ 20|
|Staphylococcus sppa||≤ 4||---||---||≥ 21||---||--|
|Streptococcus pneumoniaea||≤ 2b||---||---||≥ 21c||---||--|
|Streptococcus spp other than S pneumoniaea||≤ 2b||---||---||≥ 21c||---||---|
|a The current absence of data on resistant
strains precludes defining any categories other than “Susceptible.” Strains
yielding test results suggestive of a “nonsusceptible” category should be
retested, and if the result is confirmed, the isolate should be submitted to a
reference laboratory for further testing.
b These interpretive standards for S. pneumoniae and Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20 to 24 hours.
c These zone diameter interpretive standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35°C for 20 to 24 hours.
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.
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 5. 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.
Table 5: Acceptable Quality Control Ranges for Linezolid
to be Used in Validation of Susceptibility Test Results
|QC Strain||Acceptable Quality Control Ranges|
|Minimum Inhibitory Concentration (MIC in μg/mL)||Disk Diffusion (Zone Diameters in mm)|
|Enterococcus faecalis ATCC 29212||1 - 4||Not applicable|
|Staphylococcus aureus ATCC 29213||1 - 4||Not applicable|
|Staphylococcus aureus ATCC 25923||Not applicable||25 - 32|
|Streptococcus pneumoniae ATCC 49619d||0.50 - 2e||25 - 34f|
|d This organism may be used for validation of
susceptibility test results when testing Streptococcus spp. other than S.
e This quality control range for S. pneumoniae is applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35 °C for 20 to 24 hours.
f This quality control zone diameter range is applicable only to tests performed using Mueller- Hinton agar supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35°C for 20 to 24 hours.
Vancomycin-Resistant Enterococcal Infections
Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of ZYVOX (600 mg) with a low dose of ZYVOX (200 mg) given every 12 hours (q12h) either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 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 in the low-dose arm.
The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 15 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.
Table 15: Cure Rates at the Test-of-Cure Visit for ITT
Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at Baseline
|Source of Infection||Cured|
|ZYVOX 600 mg q12h
|ZYVOX 200 mg q12h
|Any site||39/58 (67)||24/46 (52)|
|Any site with associated bacteremia||10/17 (59)||4/14 (29)|
|Bacteremia of unknown origin||5/10 (50)||2/7 (29)|
|Skin and skin structure||9/13 (69)||5/5 (100)|
|Urinary tract||12/19 (63)||12/20 (60)|
|Pneumonia||2/3 (67)||0/1 (0)|
|Other*||11/13 (85)||5/13 (39)|
|*Includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection.|
Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients were treated for 7 to 21 days. One group received ZYVOX I.V. Injection 600 mg q12h, and the other group received vancomycin 1 g q12h IV. Both groups received concomitant aztreonam (1 to 2 g every 8 hours 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 (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 16.
Table 16: Cure Rates at the Test-of-Cure Visit for
Microbiologically Evaluable Adult Patients with Nosocomial Pneumonia
|Staphylococcus aureus||23/38 (61)||14/23 (61)|
|Methicillin-resistant S. aureus||13/22 (59)||7/10 (70)|
|Streptococcus pneumoniae||9/9 (100)||9/10 (90)|
Pneumonia caused by multi-drug resistant S.pneumoniae (MDRSP*)
ZYVOX was studied for the treatment of community-acquired (CAP) and hospital-acquired (HAP) pneumonia due to MDRSP by pooling clinical data from seven 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 rule11. 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.
Table 17: Clinical cure rates for 36
microbiologically-evaluable patients with CAP due to MDRSP* who were treated
with ZYVOX (stratified by antibiotic susceptibility)
|Susceptibility Screening||Clinical Cure|
|2nd generation cephalosporin-resistantb||19/22||86|
|a n= pooled number of patients treated
successfully; N= pooled number of patients having MDRSP isolates that exhibited
resistance to the listed antibiotic
b 2nd-generation cephalosporin tested was cefuroxime
c macrolide tested was erythromycin
Complicated Skin and Skin Structure Infections
Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered IV followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received ZYVOX I.V. Injection 600 mg q12h followed by ZYVOX Tablets 600 mg q12h; the other group received oxacillin 2 g every 6 hours (q6h) IV followed by dicloxacillin 500 mg q6h 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 (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 modified intent-to-treat (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 18.
Table 18: Cure Rates at the Test-of-Cure Visit for
Microbiologically Evaluable Adult Patients with Complicated Skin and Skin
|Staphylococcus aureus||73/83 (88)||72/84 (86)|
|Methicillin-resistant S. aureus||2/3 (67)||0/0 (-)|
|Streptococcus agalactiae||6/6 (100)||3/6 (50)|
|Streptococcus pyogenes||18/26 (69)||21/28 (75)|
A separate study provided additional experience with the use of ZYVOX 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 I.V. Injection 600 mg q12h followed by ZYVOX Tablets 600 mg q12h. The other group of patients received vancomycin 1 g q12h IV. Both groups were treated for 7 to 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 to 28 days of treatment. One group of patients received ZYVOX 600 mg q12h IV or orally; the other group received ampicillin/sulbactam 1.5 to 3 g IV or amoxicillin/clavulanate 500 to 875 mg every 8 to 12 hours (q8-12h) orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours (q6h) was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin 1 g q12h IV 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 to 2 g q8-12h IV. All patients were eligible to receive appropriate adjunctive treatment methods, such as 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 (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 above analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 19.
Table 19: Cure Rates at the Test-of-Cure Visit for Microbiologically
Evaluable Adult Patients with Diabetic Foot Infections
|Staphylococcus aureus||49/63 (78)||20/29 (69)|
|Methicillin-resistant S. aureus||12/17 (71)||2/3 (67)|
|Streptococcus agalactiae||25/29 (86)||9/16 (56)|
Infections Due to Gram-positive Organisms
A safety and efficacy study provided experience on the use of ZYVOX 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 ZYVOX I.V. Injection 10 mg/kg every 8 hours (q8h) followed by ZYVOX for Oral Suspension 10 mg/kg q8h. A second group received vancomycin 10 to 15 mg/kg IV every 6 to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a third arm of the study and received ZYVOX 10 mg/kg q8h IV and/or orally. All patients were treated for a total of 10 to 28 days and could receive concomitant Gram-negative antibiotics if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients randomized to linezolid and 102 patients randomized to vancomycin. One hundred seventeen (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%). Modified intent-to-treat (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 20. After the study was completed, 13 additional patients ranging from 4 days through 16 years of age were enrolled in an open- label extension of the VRE arm of the study. Table 21 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.
Table 20: Cure Rates at the Test-of-Cure Visit for Intent
to Treat, Modified Intent to Treat, and Clinically Evaluable Pediatric Patients
by Baseline Diagnosis
|Any diagnosis||150/186 (81)||69/83 (83)||86/108 (80)||44/49 (90)||106/117 (91)||49/54 (91)|
|Bacteremia of unidentified source||22/29 (76)||11/16 (69)||8/12 (67)||7/8 (88)||14/17 (82)||7/9 (78)|
|Catheter-related bacteremia||30/41 (73)||8/12 (67)||25/35 (71)||7/10 (70)||21/25(84)||7/9 (78)|
|Complicated skin and skin structure infections||61/72 (85)||31/34 (91)||37/43 (86)||22/23 (96)||46/49 (94)||26/27 (96)|
|Nosocomial pneumonia||13/18 (72)||11/12 (92)||5/6 (83)||4/4 (100)||7/7 (100)||5/5 (100)|
|Other infections||24/26 (92)||8/9 (89)||11/12 (92)||4/4 (100)||18/19 (95)||4/4 (100)|
|* MITT = ITT patients with an isolated Gram-positive pathogen at baseline|
Table 21: Cure Rates at the Test-of-Cure Visit for
Microbiologically Evaluable Pediatric Patients with
|Vancomycin-resistant Enterococcus faecium||6/8 (75)*||0/0 (-)|
|Staphylococcus aureus||36/38 (95)||23/24 (96)|
|Methicillin-resistant S. aureus||16/17 (94)||9/9 (100)|
|Streptococcus pyogenes||2/2 (100)||1/2 (50)|
|* Includes data from 7 patients enrolled in the open-label extension of this study.|
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 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.
1. Gonzales RD, PC Schreckenberger, MB Graham, et al. Infections due to vancomycin- resistant Enterococcus faecium resistant to linezolid. The Lancet 2001;357:1179.
2. Herrero IA, NC Issa, R Patel. Nosocomial spread of linezolid-resistant, vancomycin- resistant Enterococcus faecium. The New England Journal of Medicine 2002;346:867- 869.
3. Tsiodras S, HS Gold, G Sakoulas, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. The Lancet 2001;358:207-208.
4. Goldman DA, RA Weinstein, RP Wenzel, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant microorganisms in hospitals. A challenge to hospital leadership. The Journal of the American Medical Association 1996;275:234-240.
5. Centers for Disease Control and Prevention. Guideline for hand hygiene in health-care settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Morbidity and Mortality Weekly Report 2002;51 (RR-16).
6. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.
7. National Committee for Clinical Laboratory Standards. Twelfth Informational Supplement. Approved NCCLS Document M100-S12, Vol. 21, No. 1, NCCLS, Wayne, PA, January 2002.
8. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.
11. Fine MJ, Auble TE, Yealy DM, et al. A Prediction Rule to Identify Low-Risk Patients with Community-Acquired Pneumonia. The New England Journal of Medicine. 1997;336 (4):243-250.
* MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.
Last reviewed on RxList: 2/24/2012
This monograph has been modified to include the generic and brand name in many instances.
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