With the advent of numerous resistant "superbugs", such as vancomycin-resistant Enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae, an alarm has started to resound. Growing bacterial resistance in Gram-positive pathogens means that what were once effective and inexpensive treatments for infections caused by these bacteria are now being seriously questioned, including penicillin and macrolides for use against pneumococcal infections and - in hospitals - oxacillin for use against staphylococcal infections. Physicians have been faced with an ever-growing list of resistant bacteria threatening the lives of their critically ill paediatric patients as many time-honoured drugs like vancomycin are not working against new, constantly mutating bacterial strains.

Antibiotic resistance is now acknowledged as a major public health issue, affecting virtually all major bacterial pathogens and spreading to all types of nosocomial settings as well as the community at large. In addition, multidrug-resistant bacteria have risen to prominence, and new "opportunistic" and, often, multidrug-resistant organisms are recognized increasingly as important pathogens.

As a whole, multidrug-resistant Gram-positive pathogens are rapidly becoming an urgent and sometimes unmanageable clinical problem. Given the current trend of greater severity of illness in case of hospitalized paediatric patients, it can be expected that infections due to antibiotic-resistant bacterial strains will be associated with significant morbidity and mortality, particularly when inadequate initial antimicrobial therapy is administered. In addition to greater patient mortality rates, antibiotic-resistant bacterial infections are associated with prolonged hospitalization and increased healthcare costs relative to antibiotic-sensitive bacterial infections.

The development of antibiotic-resistant pathogens has created the need for new antibiotics effective against Gram-positive organisms. LINOSPAN contains linezolid and is the first synthetically developed antibacterial drug of this new class known as the oxazolidinones, which are the first new category of antibiotics in the last 35 years. LINOSPAN was approved for paediatric use by the U.S. Food and Drug Administration (FDA) in December 2002. It offers an effective alternative for infections caused by methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococci, and other antibiotic-resistant Gram-positive bacteria.

LINOSPAN contains linezolid and is the first synthetically developed antibacterial drug of this new class known as the oxazolidinones, which are the first new category of antibiotics in the last 35 years.^1,2 Linezolid (I.V. and oral) has been approved for paediatric use by the U.S. FDA in December 2002.^3,4

LINOSPAN 100/ 300 ml I.V. Injection is supplied as a ready-to-use sterile isotonic solution for intravenous (I.V.) infusion. Each mL contains 2 mg of linezolid, 5% w/v Dextrose IP and Water for injection IP.

LINOSPAN 600 mg Tablets for oral administration contain 600 mg linezolid in the form of film-coated compressed tablets.

LINOSPAN 100 DT for oral administration Indications, Dosage and Administration contains 100 mg linezolid in the form of uncoated dispersible tablets.

The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide. The empirical formula is C₁₆H₂₀FN₃O₄. Its molecular weight is 337.35.⁵

The chemical structure¹ of linezolid (Figure 1) is unique and it does not resemble any other antimicrobial agent.⁶

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.⁵

Linezolid inhibits protein synthesis in a unique manner by binding to a site on the bacterial 23S ribosomal RNA of the 50S sub-unit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process (Figure 2). This stops the bacteria from multiplying. 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.^3,5,7

Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and inclinical infections:⁵

Enterococcus faecium ([E. faecium] vancomycin-resistant strains only)
Staphylococcus aureus ([S. aureus] including methicillin-resistant strains)
Streptococcus agalactiae [S. agalactiae]
Strepfococcus pneumoniae ([S.pneumoniae] including multidrug-resistant isolates [MDRSP]*)
Streptococcus pyogenes [S. pyogenes]

The in vitro data below 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.

Enterococcus faecaiis ([E. faecalis] including vancomycin-resistant strains)
E. faecium (vancomycin-susceptible strains)
Staphylococcus epidermidis ([S. epidermidis] including methicillin-resistant strains)
Staphylococcus haemotyticus [S. haemolyticus]
Viridans group streptococci

Pasteurella multocida

Linezolid has potent activity against other Gram-positive organisms, including Bacillus spps., Corynebacterium spps., Listeria monocytogenes, Mycobacterium tuberculosis and Rhodococcus spps.³

In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.⁵

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 that 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 1.

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 inoculums concentrations.This procedure uses paper disks impregnated with 30 μg of linezolid to test the susceptibility of microorganisms to linezolid. The disk diffusion interpretive criteria are provided in Table 1.

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 a high dosage of a 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.

When resistance to linezolid does occur, it would be found at a rate of less than one mutant per 1 billion bacteria, i.e., resistance to linezolid occurs in vintro at a frequency of 1 x10^-9 to 1 x 10^-11 .^5,9 Therefore, resistance development to linezolid is expected to occur slowly. Thus, it is useful against multidrug-resistant (MDR) Gram-positive bacteria without incurring rapid resistance development.⁹

In vitro studies have shown that linezolid resistance has been associated with bacterial mutations (point mutation) in the central loop of the Vregion domain of the 23S ribosomal RNA gene.^5,10

Resistance to linezolid has been reported among isolates of E. faecium. E. faecalis, S. aureus, and S. epidermidis. Reports have shown that in 2 children, resistant strains emerged during treatment with low-dose linezolid. In one case, with hyperimmunoglobulin E (IgE) syndrome and methicillin-resistant S. aureus (MRSA)-related skin disease, linezolid was administered orally at 7.5 mg/kg every 12 hours (q 12h) for 1.5 years and, subsequentl y, 5 mg/kg q12h for 1 year and 10 months. The second case was the sister, also affected with hyper-lgE syndrome, who received linezolid intermittently for 4 years (11 mg/kg q12h for 9 months, and subsequently 9 mg/kg q12h) because of a MRSA exacerbation of her skin disease. One isolate was documented in a boy aged 11 months who had never received linezolid.

In clinical trials, resistance to linezolid developed in 6 patients infected with E. 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 E. faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. 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 has been a report of MRSA 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. Resistance to linezolid has not been reported in Streptococcus spp., including S. pneumoniae.

When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies.⁵

Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents, i.e., linezolid acts at an early stage (initiation stage) while the other inhibitors of protein synthesis (tetracyclines, aminoglycosides, macrolides, chloramphenicol, streptogramins) act at a later stage (elongation stage); therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.

The pharmacokinetics of linezolid following a single I.V. dose were investigated in paediatric 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 paediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 2 for the paediatric populations studied and for healthy adult subjects after administration of single I.V. doses.

The C_max and the volume of distribution (V_ss) of linezolid are similar, regardless of age, in paediatric patients. However, clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than 1 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 the age of paediatric patients increases, the clearance of linezolid gradually decreases; by adolescence, mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all paediatric age groups ascompared with adults.

Similar mean daily AUC values were observed in paediatric patients from birth to 11 years of age, dosed q8h relative to adolescents or adults dosed q12h. Therefore, the dosage for paediatric patients up to 11 years of age should be 10 mg/kg q8h. Paediatric patients who are 12 years of age and older should receive 600 mg q12h.

Recommendations for the dosage regimen for pre-term neonates less than 7 days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from 9 pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants.Therefore, these pre-term neonates should be initiated with a dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of a 10 mg/kg q8h regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by 7 days of life.

Thus, several available data suggest that the pharmacokinetic parameters of linezolid may be age-related. ¹⁰

Kearns et al performed a single-dose study, which included 58 children aged 3 months to 16 years; 44 children received a single low dose (1.5 mg/kg) and 14 received a single high dose (10 mg/kg). The study was an open-label trial without a control group and was conducted in the U.S. Significant correlation between the patient age and body clearance of linezolid was observed (<em>P - 0.004). In this study, the mean standard deviation (SD) dose-normalized AUC was 3.72 (2.04) mg - h/L per mg/kg dose of linezolid; the value was -65% lower than that previously reported for adults (mean [SD], 10.51 [3.44] mg - h/L per mg/kg dose). These findings were attributed to age-related differences in non-renal clearance of the drug.

Pharmacokinetic data are limited for infants aged ≤ 1 year, and considerable interindividual variability in plasma concentrations has been observed. Hoehn et al published a pharmacokinetic case report of 2 newborns treated with linezolid, 1 of whom required dose adjustment after therapeutic drug monitoring results. In this premature infant with very low birth weight, linezolid plasma concentrations were 8.3 mg/L before infusion and 14.4 mg/L at 1 hour after the start of the infusion on day 5 of treatment. The linezolid dose was reduced from 10 mg/kg q8h to 7.5 mg/kg q8h. Therapeutic drug monitoring repeated at day 10 of treatment showed trough and peak levels of 1.9 and 7.0 mg/L, respectively. Tan suggested monitoring plasma drug concentrations in premature infants to maintain linezolid concentrations at a steady state >2 mg/L, the breakpoint for linezolid susceptibility.

Similarly, in a case report, Kosaka et al suggested the need for therapeutic drug monitoring in infants treated with linezolid. Here, 4 children (aged <30 months) received linezolid for post-surgical S. aureus-mediastinitis refractory to glycopeptides treatment When switching from I.V. to oral therapy, therapeutic concentrations were not achieved in one 3-month-old child (plasma trough levels: 1.9 mg/L) and the linezolid dose was increased from 10 to 15 mg/kg.

Another open-label, uncontrolled trial included 42 infants stratified by their gestational age (<34 weeks or ≥34 weeks) and postnatal age (<8 days or 8 days to 12 weeks). Linezolid pharmacokinetics after a single, 10 mg/kg I.V. dose was characterized over a 12-hour period. Gestational-age stratification indicated lower mean (SD) drug clearance values in infants aged <8 days (gestational age <34 weeks: 0.12 [0.06] L/h - kg; gestational age ≥34 weeks: 0.23 [0.12] L/h - kg) compared with infants aged 8 days to 12 weeks (gestational age <34 weeks: 0.31 [0.07] L/h - kg; gestationaI age ≥34 weeks: 0.31 [0.10] L/h - kg; P <0.001).

The results of a 2009 retrospective cohort study, including 10 paediatric patients with cystic fibrosis and MRSA-associated pulmonary exacerbations treated with linezolid (10 mg/kg I.V. q8h), suggest that higher doses of linezolid may be required in this particular patient population. Patients were selected by their primary physicians for treatment with linezolid based on the presence of MRSA in respiratory secretions during a pulmonary exacerbation and failure to respond to conventional antimicrobial therapy. The pharmacokinetic profile of those aged < 10 years was significantly different from patients aged ≥10 years. As age increased, total body clearance decreased (<em>P = 0.008) and AUC increased (<em>P = 0.002).The AUC/MIC ratio in children <10 years significantly differed (<em>P = 0.03) from children aged ≥10 years. Moreover, decreased total body clearance and increased AUC with a similar volume of distribution were observed in children with homozygous DF508 mutation. All children improved clinically, but the dosage regimen used in the study did not eradicate MRSA from sputum. Specific dose recommendations were not suggested by the study authors.

Pharmacokinetic information generated in paediatric patients with ventriculoperitoneal shunts showed variable linezolid concentrations in the cerebrospinal fluid (CSF) following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF.⁵

The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and I.V. doses are summarized in Table 3. Plasma concentrations of linezolid at steady state after oral doses of 600 mg q12h are shown in Figure 3.

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 in I.V. form 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 C_max is decreased by about 17% when high-fat food is given with linezolid. However, the total exposure measured as AUC_0-(infinity), values is similar under both conditions.

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 litres 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 open-ring 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 the human cytochrome P450(CYP450). However, the metabolic pathway of linezolid is not fully understood.

Non-renal 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 faeces, while approximately 6% of the dose appears in the faeces as metabolite B and 3% as metabolite A.

A small degree of non-linearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and non-renal 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 of age or older). Therefore, dose adjustment for geriatric patients is not necessary.

The pharmacokinetics of the parent drug, linezolid, is 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 (Table 4). The clinical significance of the 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 haemodialysis.

No data are available in case of paediatric patients with impaired renal function.

The pharmacokinetics of linezolid is 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 has not been evaluated.

No data are available in case of paediatric patients with impaired hepatic function.

Linezolid is not an inducer of 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 CYP 2C9. Drugs such as warfarin and phenytoin, which are CYP 2C9 substrates, may be given with linezolid without changes in the dosage regimen.

Aztreonam: The pharmacokinetics of linezolid or aztreonam is not altered when administered together.
Gentamicin: The pharmacokinetics of linezolid or gentamicin is not altered when administered together.
Rifampim: 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 C_max [15-27%] and a 32% decrease in linezolid AUC_{0- [27-37%]} The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes.

Linezolid is a reversible, non-selective 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.

A reversible enhancement of the pressor response of either pseudoephedrine HCI (PSE) or phenylpropanolamine HCI (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 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 to 52 mm Hg) and 38 mm Hg (range: 18 to 79 mm Hg) during co-administration of linezolid with pseudoephedrineor 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 versus Vancomycin in the Treatment of Known or Suspected Resistant Gram-positive Infections in Neonates¹¹

Gram-positive infections caused by susceptible and resistant strains of S. aureus, coagulase-negative staphylococci and enterococci are increasing problems in neonates. Vancomycin-containing antibacterial regimens are the most frequently prescribed by neonatologists for late-onset sepsis in newborns, but there are clearly very limited therapeutic options available for these patients, especially for infections caused by Gram-positive organisms that are of the MDR kind.

In a Phase III, randomized, open-label, comparator-controlled, multicentre study, conducted at 59 sites (U.S., Mexico and South America), 63 infants, aged 0 to 90 days, with Gram-positive, hospital-acquired infections (with known or suspected hospital-acquired pneumonia, complicated skin or skin structure infections, bacteraemia or other infections [e.g., pyelonephritis, abdominal abscess] and mixed infections) were treated with linezolid 10 mg/kg I.V. q8h or vancomycin 10 to 15 mg/kg I.V. q6-24h for a minimum of 10 days and up to 28 days.

Deville et al reported a numerically higher clinical cure rate (Figure 4) (defined as pathogen eradication, resolution in clinical signs and symptoms of infections, including body temperature, white blood cell count and lesion evaluation at chest radiography) in the linezolid group compared with the vancomycin group (84.4.% versus 76.9% [P= non significant {NS}]).

Pathogen eradication rates were similar in both the treatment groups (Figure 5). Among those with MRSA infections, the clinical success rates were 67% in the linezolid group and 50% in the vancomycin group, but, again, this difference was not statistically significant (<em>P= NS).

Fewer drug-related adverse events (Figure 6) (i.e., impaired renal function, anaphylaxis, anaemia, diarrhoea, hyperglycaemia, candidiasis, and thrombocytopenia) occurred in patients treated with linezolid ascompared to vancomycin (11.6% and 1.6%[P=NS)).

The study concluded that linezolid was not only as effective as vancomycin in neonates in the treatment of wide range of known/suspected resistant Gram-positive infections, including those caused by MRSA and MRSE, but also was safer and better tolerated than vancomycin with fewer drug-related events.

Paediatric infections caused by resistant Gram-positive infections are an increasing concern because of limited treatment options. Linezolid is active against staphylococci, streptococci and enterococci.

A randomized, multicentre study was conducted to assess clinical efficacy and the tolerability profile of linezolid (compared with vancomycin) in the treatment of suspected or proven antibiotic-resistant Gram-positive bacterial infections like nosocomial pneumonia, complicated skin and skin structure infections, catheter-related bacteraemia, bacteraemia of unknown source, or other infections (e.g., pyelonephritis, abdominal abscess) in hospitalized children (birth to 12 years of age).

Resistance was demonstrated by susceptibility tests in a central laboratory, in accordance with the National Committee for Clinical Laboratory Standards Guidelines, on bacterial isolates from suitable specimens, including blood, sputum or wound exudate.

Out of the 321 patients enrolled 219 patients received linezolid 10mg/kg via I.V., q8h for at least 3 days, and then were switched over to linezolid suspension. The other 102 received 10-15 mg/kg via I.V. q6-24h followed by appropriate oral drug. Duration of therapy was 10 to 28 days.

Clinical resolution (defined as resolution of baseline clinical signs and symptoms of infection after ≥5 days and 15 doses of treatment) did not differ significantly between the treatment groups (89.3% in the linezolid group versus 84.5% in the vancomycin group [P- NS]) (Figure 7).

Linezolid had high pathogen eradication rates and was microbiologically similar to vancomycin regardless of drug resistance (95% versus 94% [P = NS] for those with methicillin-susceptible S. aureus [MSSA]; 88% versus 90% [P = NS] for those with MRSA; and 85% versus 83% [P = NS] for those with methicillin-resistant CoNS [MRCoNS]) (Figure 8).

Drug-related adverse events were noted more often in the vancomycin group (34.3%) compared with the linezolid group (34.3% versus 18.8%; P <0.001) (Figure 9). Discontinuation of medication due to these adverse events was statistically more frequent in the vancomycin group as compared to the linezolid group. The most common adverse events were diarrhoea (3.8% in the linezolid group versus 6.1% in the vancomycin group; P = NS), rash (1.4% versus 7.1%; P <0.001), anaemia (1.4% versus 1%; P = NS), nausea/vomiting (3.3% versus 1%; P=NS), and thrombocytopenia (1.9% versus 0%; P=NS). Also, there was no evidence of "red man syndrome" on the use of linezolid as compared to vancomycin (0% versus 10.1 %; P <0.001).

The majority of patients in the linezolid group (53%) had switched over to linezolid oral compared with 31% of patients in the vancomycin group who received an oral antibiotic (Figure 10). Linezolid-treated patients required significantly fewer days of I.V. therapy compared with the vancomycin group (8% versus 10.9%; P<0.001)(Figure11).

Kaplan et al concluded that both I.V. and oral lineiolid were clinically and microbiologically (including the resistant Gram-positive organisms) as effective as vancomycin and, thus, offer advantages as an alternative to vancomycin across all infections caused by presumed or documented resistant Gram-positive pathogens across all age groups, including neonates.

The Enterococcus spps. are characterized by resistance to a large number of antibiotics like beta-lactams and, to a slight degree, to aminoglycosides and clindamycin; and acquired resistance to beta-lactams and, to a great degree, to aminoglycosides and glycopeptides.This latter type of resistance has been a growing problem during recent years due to limited therapeutic options available for treatment.

In this study performed between January 2002 and July 2004, Travaglianti et al describes the use of linezolid by analysing its clinical efficacy in vancomycin-resistant Enterococcus infections at "Juan P. Garrahan" paediatric hospital, Argentina. Altogether, 15 seriously ill paediatric patients, ranging in age from 1 month to 15 years, were enrolled in the study.

The risk factors for acquiring vancomycin-resistant Enterococcus were the presence of a central catheter, prior chemotherapy, number of concomitant antibiotics, immune status of the host earlier surgical procedures, hospitalizations within the previous 3 months, and exposure to antibiotic inducers (third generation cephalosporins, metronidazole/ornidazole and vancomycin) during the 3 months prior to the infection.

While newborns to children 11 years of age received 10 mg/kg/dose q8h, children over 12 years of age received 600 mg/dose q 12h.

The most commonly used route of administration for treatment was via I.V. followed by the exclusive oral route.

The average duration of therapy was 15 days and the averageduration of hospital stay was 74 days.

Results showed that vancomycin-resistant Enterococcus infection was documented microbiologically in 73.3% patients. All the microbiological isolations were sensitive to linezolid in disc diffusion and all microbiologically documented infections culture became negative.

The authors concluded that linezolid was efficacious and moderately well-tolerated for the treatment of vancomycin resistant Enterococcus infections in children with life threatening infections.

Gram-positive pathogens are a major cause of complicated skin and skin structure infections in children. Many pathogens are developing decreased susceptibility to currently used antibiotics, increasing the need for new therapies.

In another randomized controlled trial at 59 sites in the U.S from February December 2001, the efficacy and tolerability of LWoral linezolid and IV. vancomycin were compared in 120 hospitalized children, <12 years of age and presenting with complicated, Gram-positive, skin and skin structure infections like cellulitis, skin abscess, infected surgical incision sites, skin ulcers, erysipelas and bums. S. aureus was the most common pathogen (79.7% of isolates). In this group, 80 patients were randomly assigned linezolid lOmg/kg IV. q8 hand were switched over to linezolid oral suspension (100 ml/5 ml) 10 mg/kgq12h after 3 days. The remaining 40 were assigned vancomycin 10-15 mg/kg I.V. q6-24h, followed by an appropriate oral drug.The treatment duration was 10 to 28 days.

Rates of clinical efficacy (defined as the resolution of clinical signs or symptoms) were similar for linezolid and vancomycin (93.2% versus 90%; P = NS). Moreover, there was faster reduction in the signs and symptoms in linezolid-treated patients. Pathogen eradication rates were similar and high in both treatment groups with a higher MRSA eradication rate in the linezolid group (Figure 12).

Diarrhoea (5.1%), thrombocytopenia (3.8%) and lactic acidosis (2.5%) were the most common adverse events reported in patients treated with linezolid. As such, drug-related adverse events were significantly less common in children treated with linezolid compared with vancomycin (23% versus 48%; P <0.006> (Figure 13).

Yogev et al concluded that linezolid is not only clinically and microbiologically as effective as standard vancomycin treatment, but is much safer and better tolerated. Moreover, linezolid offers administration advantages over vancomycin as it is available in an oral formulation which is 100% bioavailable and well-tolerated in paediatric patients.

Linezolid versus Cefadroxil in the Treatment of Skin and Skin Structure Infections in Children¹⁵

Skin and skin structure infections are the common reasons for visits to paediatricians. S. aureus, S. pneumoniae and MRSAarethe most frequently isolated Gram-positive pathogens in uncomplicated skin infections.

Wible et al conducted a randomized trial at 91 sites in the U.S. from June 2000 to February 2001, which evaluated the efficacy and tolerability of linezolid (10 mg/kg dose, up to 600 mg, depending on age), compared with cefadroxil (15 mg/kg per dose, up to 500 mg, depending on age), for the treatment of uncomplicated skin and skin structure infections like abscess, cellulitis, wound infections, impetigo, erysipelas andcarbunculosis in 508children, aged 5 to 17years.

Patients with skin infections suspected of being caused by a Gram-positive bacterial pathogen were eligible for enrolment before the first dose of study medication culture specimen was obtained for gram staining, bacterial culture and antimicrobial susceptibility testing.

Both drugs had similar efficacy in terms of the clinical resolution of symptoms, defined as the resolution of clinical signs and symptoms of infection at the end of treatment and follow-up visits (91 % in the linezolid group versus 90% in thecefadroxil group; P-NS).

Both linezolid and cefadroxil had equivalent microbiological profiles. However, linezolid had the added advantage of being significantly effective against MRSA infections (92.3% in the linezolid group versus 85.7% in the cefadroxil group) (Figure 14).

Rates of adverse events were similar between the linezolid and cefadroxil groups (45.3% versus 47%; P - NS) (Table 5). Diarrhoea was the most commonly reported adverse event in both the treatment groups (7.8% in the linezolid group versus 8%in thecefadroxil group).

As such, linezolid is as safe and effective as cefadroxil in treating children with uncomplicated skin and skin structure infections and also has the added advantage of being orally available and providing antibiotic activity against MRSA.

Linezolid for the Treatment of Community-acquired Pneumonia in Hospitalized Children¹⁶

S. pneumoniae is the most common cause of bacterial pneumonia in children. Quinolones with enhanced activity against S. pneumoniae are among the preferred antimicrobials for the empiric treatment of community-acquired pneumonia in adults, but generally are not recommended in children and adolescents younger than 18 years of age.

Kaplan et al published the initial, prospective, open-label, multicentre study at 14 sites in the U.S. and Australia from July 1998 to May 1999, which examined 78 children aged 1 to 17 years who were hospitalized for community-acquired pneumonia.

They received IV. linezolid, which was then switched to oral linezolid suspension (100 mg/5 ml), both at a doseof 10 mg/kg q 12h for a median of 12 days.

S. pneumoniae, Streptococcus beta-haemolytic group A and MRSA were isolated from blood cultures or pleural fluid samples.

Clinical resolution (defined as normalization of the clinical signs and symptoms of pneumonia and improvement or lack of progression of abnormalities on the chest radiograph) was achieved in 92.4% of the patients, including all those patients with proven pneumococcal pneumonia (Figure 15).

The most common adverse effects were diarrhoea, vomiting and loose stools. These adverse gastrointestinal events were described as mild to moderate in intensity (Table6).

The trial concluded that linezolid is efficacious and well-tolerated by children whether administered by I.V. or oral route and, thus can be considered an alternative to vancomycin for treating serious infections caused by antibiotic-resistant Gram-positive cocci.

Graham et al first reported using linezolid in a preterm infant with a ventricular-peritoneal shunt and ventriculitis caused by E. faecium resistant to ampicillin, vancomycin and levofloxacin; previous antibiotic treatment with vancomycin orfosfomycin had failed.

Langgartner et al described five cases of ventriculostomy-related cerebrospinal fluid infection in pre-term infants successfully treated with linezolid 10 to 15 mg/kg I.V. or oral q8h every 14 to 16 days. Moreover, another 5 paediatric patients, 6 weeks to6 months of age, who had ventriculitis caused by Enterococcus or Staphylococcus spp infection that was responsive to linezolid 10 mg/kg I.V. q8h have been reported; all patients received a 21-day therapeutic course with no reported adverse events. Two case reports of paediatric bacterial meningitis treated with linezolid (10 mg/kg I.V. q 12h or 100 mg/kg I.V.everyday) have been published to date: one in an infant aged 6 months with coagulase negative, MDR-staphylococcal infection, and another in a child aged 17 months with Gemella hacmolysins infection. A kidney transplant recipient aged 12 years who had pneumonia and multiple brain abscesses caused by Nocardia farcinica was treated with linezolid 600 mg oral b.i.d. for 8 weeks, and 2 children (aged 4 and 15 years) were successfully treated with linezolid for subdural empyema caused by S. aureus and Srreprococcus constellaws, respectively.

Four cases of endocarditis caused by MOR-E. faecium or MRS A in children aged 4 months to 5 years, whose infections were responsive to linezolid, have been reported. The doses ranged from lO to l5 mg/kgl.V.q8h, and in one report, subsequent treatment with oral linezolid continued for 8 to 9 weeks.

Chen et al retrospectively collected data from 13 Taiwanese children aged between 3 months to 14 years who had received a linezolid-containing regimen for osteoarticular infection between 2003 and 2006. Infections were caused by S. aureus, E. faecium, or coagulase-negative staphylococci; previous therapy with conventional antibiotics had failed in all 13 children.The dosage was 10 mg/kg q8h in children aged < 11 years and 600 mg q12h in children aged >11 years. The therapy was started with I.V. treatment and subsequently switched tooral medication at the same dosages. The mean duration of therapy was 20 days. A step-down therapy with oral linezolid was undertaken in most cases. Complete recovery occurred in 84.6% of children. While 2 patients developed anaemia, none reported serious adverse events that caused suspension of therapy. In addition, there were three published case reports of paediatric osteomyelitis successfully treated with linezolid. The dosages varied from 170 mg oral q12h to 600 mg oral q12h. Treatment duration ranged from 15days to 1 year.

Overall, five paediatnc cases (including 3 pre-term infants) of abdominal enterococcal infections or necrotizing enterocolitis treated with linezolid have been reported. Clinical success was documented in several cases.The reported dosage was 10 mg/kg q8h.Treatment duration ranged from 15 to 21 days.

Combination therapy with linezolid and imipenem was effective in 2 children with severe community-acquired pneumonia, but therapeutic failure was reported in a third child with cystic fibrosis who had pneumonia caused by linezolid resistant S. aureus; the reported dosage was 300 mg/kg q12h for 18 months.

In a prospective, uncontrolled study, 65 children (mean age: 2.8 years) with acute otitis media were treated with linezolid 10 mg/kg oral q 12h for 7 lo 10 days. S. pneumoniae, Haemophilus influenzae, Haemophilus parainfluemae, and Moraxella catarrhalis were the most frequently isolated pathogens. The success rate in clinically evaluable children was 69.1%. In patients aged <2 years, the success rate was only 42.9%, whereas in children aged ^ 2 years, it was 93.3%. Adverse events occurred in 20% of the children, including diarrhoea (9.1%1, thrombocytopenia (4.7%). vomiting (4.2%), other alvus alteration (3.5%), and rash (2.8%).

In a consecutive series of 10 children, aged 8 months to 10 years, with refractory tympanostomy-tube otorrhoea and infections caused by MRSA and MDRSP, 2-week therapy with linezolid 20 mg/kg oral once daily was associated with complete resolution of symptoms and no adverse events.

Linezolid has been used in sepsis cases in 5 children, including 2 pre-term infants. The reported dosage was 10 mg/kg q8h.Treatment duration ranged from 14 days to 5 weeks.

Four cases of skin and skin structure infections treated with linezolid have been reported, including 2 children with burns. The reported dosages were 140 mg oral q12h or 600 mg oral q12h for 15 to 28 days.

Management of children with central venous catheter (CVC) infections can be difficult. CVC removal remains the treatment of choice, but catheter withdrawal may not be feasible in some circumstances, such as in children who require total parenteral nutrition lifelong.

A case report by Castagnola et al described the use of linezolid to treat a girl aged 4 years with cystic fibrosis and short-bowel syndrome who presented with recurrent CVC-related staphylococcal bacteraemia. Linezolid was administered at a concentration of 2 mg/mL in conjunction with 100 U of heparin as an 8- hour CVC lock, and was supplemented with a systemic infusion of linezolid 10 mg/kg q8h. Blood cultures were negative after the second day of treatment. Treatment was continued for a total of 20 days without.

Indications, Dosage and Administration

LINOSPAN IV. Injection and LINOSPAN Tablets/ DT are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms. Linezolid is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of LINOSPAN and other antibacterial drugs. LINOSPAN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

The recommended dosage of LINOSPAN I.V. Injection and LINOSPAN Tablets/DT for the treatment of infections is described in Table 7.

Adult patients with infection due to MRSA should be treated with linezolid 600 mg q12h.

In controlled clinical trials, the protocol-defined duration of treatment for all infections ranged from 7 to 28 days.Total treatment duration was determined by the treating physician, based on the site and severity of the infection and on the patient's clinical response.

No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteremia.

As oral bioavailability is approximately 100%, no dose adjustment is necessary. Thus, LINOSPAN I.V. Injection, Tablets or DT may be used as initial therapy. Patients whose therapy is started with LINOSPAN I.V. Injection may be switched to LINOSPAN Tablets or DT at the discretion of the physician, when clinically indicated.

LINOSPAN I.V. Injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired.

Linezolid I.V. injection should be administered by I.V. infusion over a period of 30 -120 minutes. Do not use this I.V. infusion bag in series connections. Additives should not be introduced into this solution. If linezolid I.V. injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. In particular, physical incompatibilities resulted when linezolid I.V. Injection was combined with the following drugs during simulated Y-site administration: Amphotericin B, chlorpromazine HCI, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when linezolid I.V. Injection was combined with ceftriaxone sodium.

If the same I.V. line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of linezolid I.V. injection with an infusion solution compatible with linezolid IV. injection and with any other drug(s) administered via this common line.

5% Dextrose Injection, USP

0.9% Sodium Chloride Injection, USP

Lactated Ringer's Injection, USP

Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid I.V. injection may exhibit a yellow colour that can intensify over time without adversely affecting potency.

Tablets should be swallowed whole without chewing. LINOSPAN Tablets may be taken with or without food.

Disperse the tablet in a teaspoonful (5 ml) of boiled and cooled water before administration. It may be taken with or without food.

Linezolid formulations are contraindicated for use in patients who have a known hypersensitivity to linezolid or any of the other product components.

Linezolid should not be used in patients taking any medicinal product that inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking any such medicinal product.

Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: Directly- and indirectly- acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine. norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine).

Unless patients are carefully observed for signs and/or symptoms of serotonin syndrome, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: Serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 -receptor agonists (triptans), meperidine or buspirone.

Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected haematologic parameters have risen toward pre-treatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than 2 weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.

Mortality imbalance in an investigational study in patients with catheter-related bloodstream infections, including those with catheter-site infections

An imbalance in mortality was seen in 726 patients, aged >13 years, treated with linezolid relative to vancomycin / dicloxacillin / oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections (78/363 [21.5%] versus 58/363[16%]). While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.

Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections. Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected.

Clostridium difficile (C difficile)-assoaated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C.difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C.difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require a colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use.

Detailed medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.difficile and surgical evaluation should be instituted as clinically indicated.

Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis or low bicarbonate level while receiving linezolid should receive immediate medical evaluation.

Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin re-uptake inhibitors, have been reported.

Where administration of linezolid and concomitant serotonergic agents is clinically appropriate, patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed.

Peripheral and optic neuropathy has been reported in patients treated with linezolid. primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid for less than 28 days.

If patients experience symptoms of visual impairment such as changes in visual acuity, changes in colour vision, blurred vision or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid for extended periods (≥3 months) and in all patients reporting new visual symptoms, regardless of the length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks.

Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

The use of antibiotics may promote the overgrowth of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

Linezolid has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.

The safety and efficacy of linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials.

Prescribing linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Patients should be advised on the following:

Linezolid is a reversible, non-selective 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.

Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1,2 or 3 studies. Spontaneous reports of serotonin syndrome associated with co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin re-uptake inhibitors, have been reported. Patients who are treated with linezolid and concomitant serotonergic agents should be closely observed.

In a study in healthy volunteers, co-administration of rifampin with oral linezolid resulted in a 21% decrease in linezolid C_max and a 32% decrease in linezolid AUC_0-12 The clinical significance of this interaction is unknown. Other strong inducers of hepatic enzymes (e.g., carbamazepine. phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure.

There are no reported drug-laboratory test interactions.

There are no adequate and well-controlled studies in pregnant women. Linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

It is not known whether linezolid is excreted in human milk. As many drugs are excreted in human breast milk, caution should be exercised when linezolid is administered to a nursing mother.

No dosage adjustments are required in the geriatric group in case of infections due to susceptible organisms as there are no overall differences in safety or effectiveness that were observed between these patients and younger patients.

The safety of linezolid formulations was evaluated in 215 paediatric patients ranging in age from birth through 11 years, and in 248 paediatric patients aged 5 through 17 years (146 of these 248 were in the age group of 5 through 11 years; 102 were in the age group of 12 to 17 years). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In these studies, 83% and 99%, respectively, of the adverse events reported with linezolid were described as mild to moderate in intensity. In the study of hospitalized paediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2:1 (linezolid:vancomycin), mortality was 6% (13/215) in the linezolid arm and 3% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. Table 8 shows the incidence of adverse events reported in at least 2% of paediatric patients treated with linezolid in these trials.

Table 9 shows the incidence of drug-related adverse events reported in more than 1% of paediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.

Lactic acidosis has been noted in 2.5% of children treated with linezolid. Reversible myelosuppression (including anaemia, leucopenia and thrombocytopenia) has been reported in 1.9-6.4% of paediatric cases. Vitamin B6 co-administration may help prevent or reverse cytopenias associated with linezolid therapy.

Peripheral and optic neuropathy have been reported in 0.4-9.1% of adults treated with linezolid; only three case reports of peripheral and optic neuropathy associated with linezolid in children were found in the literature. Javaheri et al reported the case of mitochondrial optic neuropathy in a child aged 6 years who was treated with linezolid for 1 year for mandibular bone osteomyelitis. This effect was thought to be the result of prolonged linezolid treatment. A progressive reduction of oedema and ocular hyperaemia, with improvement in visual acuity, was noted after the suspension of the drug. Two other cases of peripheral neuropathy in an adolescent and in a newborn (who developed auditory nerve neuropathy after linezolid treatment) have been published. The reported dosages were 10 mg/kg q8h for 14 days or 600 mg POq 12h for4 months.

Myelosuppression, peripheral and optic neuropathy, and lactic acidosis may have been caused by mitochondrial protein synthesis inhibition in patients who received linezolid. In most cases, such adverse events have been associated with a treatment duration of >28 days, which is the longest duration of linezolid therapy that the FDA has approved. Other rare linezolid-related adverse events have been reported in <1% of adult cases. Cases of myositis with elevated creatinine phosphokinase levels after 3 months of therapy, reversible posterior leucoencephalopathy, small-bowel obstruction that required intervention, severe pancreatitis, drug rash with eosinophilia. and systemic symptoms syndrome have also been reported. C.difficle-colitis may also occur with prolonged therapy.

Linezolid is a monoamine oxidase-competitive inhibitor and can, therefore, interact with other drugs and other substances that act on the serotonergic and adrenergic systems and on tyramine metabolism, such as epinephrine and norepinephrine, tyramine-containing food and beverages, selective serotonin reuptake inhibitors, tricyclic antidepressants, serotonin-receptor agonists, meperidine, or buspirone. Therefore, linezolid therapy can increase the risk of serotonin syndrome in patients taking other serotonin re-uptake inhibitors, as well as any other drugs that increase serotonin concentration in the central nervous system.

One case of serotonin syndrome apparently caused by linezolid and fluoxetine co-administration in a child aged 4 years has been described by Thomas et al.

Reversible tooth discolouration associated with linezolid use was reported in an immunocompromised 11 -year-old child with cellulitis.

The safety of linezolid formulations was evaluated in 2,046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. In these studies. 85% of the adverse events reported with linezolid were described as mild to moderate in intensity.Table 10 shows the incidence of adverse events reported in at least 2% of patients in these trials. The most common adverse events in patients treated with linezolid were diarrhoea (incidence across studies: 2.8-11%), headache (incidence across studies: 0.5-113%), and nausea (incidence across studies; 3.4-9.6%).

Other adverse events reported in Phase 2 and Phase 3 studies included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discolouration.

Table 11 shows the incidence of drug-related adverse events reported in at least 1 % of adult patients in these trials by dose of linezolid.

Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg q12h for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10%) with linezoiid and 1.5% (range among studies: 0.4 to 7%) with a comparator.

In a study of hospitalized paediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with linezoiid and 13.4% with vancomycin. In an outpatient study of paediatric patients, ranging in age from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with linezoiid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of linezoiid appears to be dependent on duration of therapy, (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for linezolid; the role of linezolid in these events cannot be determined.

Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy and were reversible. The incidence of paediatric patients and adults with at least one substantially abnormal haematologic or serum chemistry value is presented in Tables 12,13,14, and 15.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Haemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour haemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for the removal of linezolid with peritoneal dialysis or haemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in ratsand vomiting and tremors in dogs treated with 3,000 mg/kg/day and 2,000 mg/kg/day, respectively.

LINOSPAN is indicated in resistant Gram positive infections like the following:

Linezolid should be reserved as an agent of last resort for the treatment of infections caused by MDRSP. It should not be used as a first-line antibiotic and where alternative agents are likely to be to be effective. Indiscriminate use and overuse will hasten selection of resistant strains and the eventual loss of this valuable new agent⁸

Efforts must continue to focus on the prevention of the emergence and dissemination of resistance through policies of rational antibiotic use, infection control and education.²⁰

LINOSPAN 100 DT offers administration advantages as it is an oral formulation that is 100% bioavailable. which further allow rapid switch over from LINOSPAN I.V. Injection to LINOSPAN 100 DT.

Also, LINOSPAN 100 DT is an oral equivalent to antibiotics like glycopeptides, including vancomycin and teicoplanin, which are available only as I.V. without theiroral counterparts.

The possibility of switching from I.V. to oral facilitates early hospital discharge and, thus, decreases the length of hospital stay.

Switch therapy is beneficial for those patients who have infections that require prolonged therapy even after their hospital discharge.

LINOSPAN 100 DT is indicated in microbiologically confirmed uncomplicated skin and skin structure infections such as abscess, cellulitis, wound infections, impetigo, erysipelas and carbunculosis.

Linezolid Intravenous (IV) Injection,Tablets and DispersibleTablets (DT)

Each 100 ml contains:
Linezolid......................200 mg
Dextrose IP...................5%w/v
Waterfor injection IP...............qs

Each film-coated tablet contains:
Linezolid......................600 mg

Each uncoated dispersible tablet contains:
Linezolid...............................lOOmg

I.V. injection, tablet and dispersible tablet

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. 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. 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.

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

Enterococcus faecium ({E.faecium} vancomycin-resistan strains only)
Staphylococcus aureus ({S.oureus}including methicillin-resistant strains)
Streptococcus agalactiae {S. agalactiae}
Streptococcus pneumoniae ({S. pneumoniae} including multidrug-resistant isolates of 5. pneumoniae [MDRSP]*)
Streptococcus pyogenes {S. pyogenes}

*MDRSP refers to isolates resistant to two or more of the following antibiotics:

Penicillin, second-generation cephalosporins, macrotides, tetracycline and trimethoprim-sulfamethoxazole.

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.

Enterococcus faecalis ({E.faecalis} including vancomycin-resistant strains)
Enterococcus faecium({EJaecium}vancomycin-susceptible strains)
Staphylococcus haemolyticus ({S. epidermis} including methicillin-resistant strains)
Staphylococcus haemolyticus {S. haemolyticus}
Viridans group streptococci

Pasteureila multocida

The mean pharmacokinetic parameters of linezolid in adults after singleand multiple oral and intravenous (IV) doses are summarized inTable 1.

Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 12 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or in I.V. form 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 22 hours and C_max is decreased by about 17% when high-fat food is given with linezolid. However, the total exposure, measured as AUCo values, is similar under both conditions.

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 litres 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, the ratio was 0.55:1.

Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive open-ring carboxytic 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 m vitro. Linezolid is not an inducer of cytochrome P450 (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 and 3A4).

Non-renal 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 of 40 mL/min) and suggests net tubular re-absorption. Virtually no linezolid appears in the faeces; approximately 6% of the dose appears in the faeces as metabolite (B)and 3%as metabolite (A).

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

The pharmacokinetics of linezolid following a single I.V. dose was investigated in paediatric patients ranging from newborns to 17 years of age (including premature and full-term neonates). The pharmacokinetic parameters of linezolid are summarized (Table 2) for the paediatric populations studied and for healthy adult subjects after administration of single I.V. doses.

The C_max of linezolid is similar, regardless of age, in paediatric patients. With the exclusion of pre-term neonates less than 1 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 compared to adults. As the age of the paediatric patient increases, the clearance of linezolid gradually decreases.

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, is 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 (Table 4). The clinical significance of the 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 haemodialysis.

No data art available in case of paediatric patients with impaired renal function.

LINOSPAN I.V. Injection and Tablets/DT are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms:

To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid and other antibacterial drugs, linezolid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

The recommended dosage of LINOSPAN I.V. Injection and Tablets/DT for the treatment of infections is described inTable 3. Dosesoflinezolid are administered every 12hours.

No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteremia.

Adult patients with infection due to MRSA should be treated with I inezolid 600 mg q 12 hours.

As oral bioavailability is approximately 100%, no dose adjustment is necessary. Thus, LINOSPAN I.V. Injection, Tablets/DT may be used as initial therapy. Patients whose therapy is started with LINOSPAN I.V. Injection may be switched to linezolid tablets or dispersible tablets at the discretion of the physician, when clinically indicated.

Linezolid I.V. injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaksaredetecteddiscard the solution, as sterility may be impaired.

Linezolid I.V. injection should be administered by I.V. infusion over a period of 30-120 minutes. Do not use this I.V. infusion bag in series connections. Additives should not be introduced into this solution. If linezolid I.V. injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. If the same I.V. line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of linezolid I.V. injection with an infusion solution compatible with linezolid I.V. injection and with any other drug(s) administered via this common line.

5% Dextrose Injection, USP
0.9% Sodium Chloride Injection, USP
Lactated Ringer's Injection, USP
Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid I.V. injection may exhibit a yellow colour that can intensify over time without adversely affecting potency.

Tablets should be swallowed whole without chewing. LINOSPAN Tablets may be taken with or without food.

Disperse the tablet in a teaspoonful (5 ml) of boiled and cooled water before administration. It may be taken with or without food.

Unezolid formulations are contraindicated for use in patients who have a known hypersensitivity to linezolid or any of the other product components.

Linezolid should not be used in patients taking any medicinal product that inhibits monoamine o or B (e.g., phenelzine, isocarboxazid) or within 2 weeks of taking any such medicinal product

Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: Directly- and indirectly-acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine).

Unless patients are carefully observed for signs and/or symptoms of serotonin syndrome, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: Serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 -receptor agonists (triptans), meperidine or buspirone.

Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected haematologic parameters have risen toward pre-treatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid. particularly in those who receive linezolid for longer than 2 weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.

An imbalance in mortality was seen in 726 patients, aged ≥13 years, treated with linezolid relative to vancomycin / dicloxacillin / oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections.

Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections. Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected.

Clostridium difficile (C difficile)-associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C difficile.

CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Detailed medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile and surgical evaluation should be instituted as clinically indicated.

Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis or low bicarbonate level while receiving linezolid should receive immediate medical evaluation.

Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin re-uptake inhibitors, have been reported.

Where administration of linezolid and concomitant serotonergic agents is clinically appropriate, patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can beobserved.

Peripheral and optic neuropathy has been reported in patients treated with linezolid, primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid for less than 28days.

If patients experience symptoms of visual impairment such as changes in visual acuity, changes in colour vision, blurred vision or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid for extended periods ( ≥3 months) and in all patients reporting new visual symptoms, regardless of the length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks.

Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.

The safety and effectiveness of linezolid for the treatment of paediatric patients with nosocomial pneumonia, complicated skin and skin structure infections, community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years), and vancomycin-resistant E. faecium infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in paediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in paediatric patients ranging from newborns to 11 years of age.

The safety and effectiveness of linezolid for treating uncomplicated skin and skin structure infections caused by S. aureus (methicillin-susceptible strains only) or S. pyogenes have been established in a comparator-controlled study in paediatric patients ranging in age from 5 years through 17 years.The use of linezolid for the empiric treatment of paediatric patients with central nervous system infections is not recommended (Refer DOSAGE AND ADMINISTRATION).

No dosage adjustments are required in the geriatric group in case of infections due to susceptible organisms.

The most common adverse events reported with linezolid are diarrhoea, vomiting, nausea, headache and fever.

Other adverse events reported: Rash, oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discolouration. Thrombocytopenia is dependent on the duration of therapy. Other effects include mild derangements in hepatic enzymes.

In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Haemodialysis may facilitate more rapid elimination of linezolid. Data are not available for the removal of linezolid with peritoneal dialysis or haemoperfusion.

Physical incompatibilities resulted when linezolid I.V. injection was combined with the following drugs during simulated Y-site administration: Amphotericin B, chlorpromazine HCI, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when linezolid I.V. injection was combined with ceftriaxone sodium.

LINOSPAN100 ml/300 ml I.V. Injection 2 years