VA Class:AM900

AHFS Class:

• Oxazolidinones 8:12.28.24

Generic Name(s):

• Linezolid

Molecular Formula:

• C₁₆H₂₀FN₃O₄

Linezolid is an oxazolidinone anti-infective agent.1,2,3,5,57

Linezolid is used for the treatment of community-acquired pneumonia,1,2,30 nosocomial pneumonia,1,2,11,51 and uncomplicated or complicated skin and skin structure infections caused by certain susceptible staphylococci or streptococci.1,2,10 Linezolid also is used for the treatment of infections caused by vancomycin-resistant Enterococcus faecium .1,2

Linezolid is not indicated for the treatment of infections caused by gram-negative bacteria.1 It is critical that an anti-infective active against gram-negative bacteria be used concomitantly if documented or presumed pathogens include gram-negative bacteria.1

Respiratory Tract Infections

Community-acquired Pneumonia

Linezolid is used for the treatment of community-acquired pneumonia (CAP), including infections associated with concurrent bacteremia, caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or Streptococcus pneumoniae ).1,2,3,30 Although not labeled by FDA for the treatment of CAP caused by methicillin-resistant S. aureus † (MRSA; also known as oxacillin-resistant S. aureus or ORSA),1 linezolid is one of several anti-infectives that have been recommended for the treatment of these infections.30

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens and local susceptibility patterns;30 treatment may then be changed (if possible) to provide a more specific regimen (pathogen-directed therapy) based on results of in vitro culture and susceptibility testing.30 The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation, whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated, and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., MRSA, penicillin-resistant S. pneumoniae , multidrug-resistant S. pneumoniae [MDRSP], enteric gram-negative bacilli, Pseudomonas aeruginosa ).30

For information regarding the treatment of CAP, current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at [Web] should be consulted.30

Clinical Experience

In 2 randomized clinical studies in patients 13 years of age or older with CAP, cure rates with linezolid (600 mg every 12 hours for 7-14 days given IV or orally initially, then orally) were approximately 90% and were similar to those achieved with oral cefpodoxime proxetil (200 mg every 12 hours for 10-14 days) or IV ceftriaxone (1 g every 12 hours) followed by oral cefpodoxime proxetil (200 mg every 12 hours) for 7-14 days.3 In a subset of hospitalized patients with CAP and associated S. pneumoniae bacteremia, linezolid was substantially more effective than a regimen of IV ceftriaxone (cure rate of 93 versus 70%, respectively).2,3

Efficacy and safety of linezolid for the treatment of CAP in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, an uncontrolled study in pediatric patients 8 months through 12 years of age, and additional data from a randomized, open-label, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age.1

Nosocomial Pneumonia

Linezolid is used for the treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or S. pneumoniae .1,2,3,11,51

For empiric treatment of hospital-acquired bacterial pneumonia, including healthcare-associated and ventilator-associated pneumonia in patients with risk factors for multidrug-resistant bacteria, the American Thoracic Society (ATS) and IDSA recommend use of anti-infectives that have a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria.51 An anti-infective active against MRSA (e.g., vancomycin, linezolid) should be included in the initial empiric regimen in hospitals where MRSA is common or if there are other factors that increase the risk for these strains.51

For information regarding the diagnosis and management of nosocomial pneumonia, current IDSA clinical practice guidelines available at [Web] should be consulted.51

Clinical Experience

In a randomized, double-blind study in adults with nosocomial bacterial pneumonia, the cure rate in clinically evaluable patients was 57% in those treated with linezolid (600 mg every 12 hours IV for 7-21 days) compared with 60% in those treated with vancomycin (1 g every 12 hours IV for 7-21 days).1,3 Both treatment groups also received concomitant therapy with aztreonam (1-2 g every 8 hours IV) for gram-negative coverage.1 In clinically evaluable patients with ventilator-associated pneumonia, the cure rate was 47% in those who received linezolid and 40% in those who received vancomycin.1 When results were stratified according to causative organism, linezolid was effective in 59% of infections caused by MRSA and 100% of infections caused by S. pneumoniae .1

Efficacy and safety of linezolid for the treatment of nosocomial bacterial pneumonia in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a randomized, open-label, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age.1 In the comparator-controlled study in pediatric patients with documented or suspected gram-positive infections, the cure rate in pediatric patients with nosocomial pneumonia (intent-to-treat analysis) was 72% in those treated with linezolid and 92% in those treated with vancomycin;1 the cure rate in clinically evaluable pediatric patients with nosocomial pneumonia was 100% in both groups.1

Skin and Skin Structure Infections

Linezolid is used for the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible strains only) or S. pyogenes (group A β-hemolytic streptococci, GAS).1,2,3 The drug also is used for the treatment of complicated skin and skin structure infections (including diabetic foot infections), without concurrent osteomyelitis, caused by susceptible S. aureus (including MRSA), S. pyogenes , or S. agalactiae (group B streptococci, GBS).1,2,3,10 The use of linezolid in the treatment of decubitus ulcers has not been studied.1,3

For information regarding the treatment of skin and skin structure infections, current IDSA clinical practice guidelines available at [Web] should be consulted.26,43

Clinical Experience

In a randomized, double-blind clinical study in adults with complicated skin and skin structure infections, the efficacy rates (clinical, microbiologic, and overall outcomes) were similar for linezolid (600 mg every 12 hours IV initially, with an option to convert to oral administration) or oxacillin (2 g every 6 hours IV) with an option to switch to oral dicloxacillin (500 mg every 6 hours) for 10-21 days.1,10 Patients in both treatment groups received concomitant aztreonam (1-2 g every 6-8 hours IV) if empiric gram-negative coverage was considered necessary.10 The cure rate in clinically evaluable patients was 90% in those treated with linezolid and 85% in those treated with oxacillin.1 When results for treatment of these complicated skin and skin structure infections were stratified according to causative organism, linezolid was effective in 88% of infections caused by S. aureus , 67% of infections caused by MRSA, 69% of infections caused by S. pyogenes , and 100% of infections caused by S. agalactiae .1

In a randomized clinical study in patients 13 years of age or older with known or suspected MRSA skin and skin structure infections, efficacy (clinical, microbiologic, and overall outcomes) was similar for therapy with linezolid (600 mg every 12 hours IV initially, with an option to convert to oral administration) or vancomycin (1 g every 12 hours IV) for 14-28 days.3 In an open-label, randomized study in hospitalized adults with documented or suspected MRSA skin and skin structure infections who received 7-28 days of treatment with linezolid (600 mg every 12 hours given IV initially, then orally) or vancomycin (1 g every 12 hours IV) given with or without concomitant aztreonam or gentamicin if clinically indicated, the cure rate in microbiologically evaluable patients was 79% in those treated with linezolid and 73% in those treated with vancomycin.1

In a randomized, multicenter open-label comparative study in adults with diabetic foot infections, efficacy rates (clinical and microbiologic outcomes) were similar in patients receiving linezolid (600 mg every 12 hours IV or orally) or an aminopenicillin (ampicillin sodium and sulbactam sodium 1.5-3 g every 6 hours IV, amoxicillin and clavulanate potassium 500-875 mg every 8-12 hours orally, or amoxicillin and clavulanate potassium 0.5-2 g every 6 hours IV [IV preparation not commercially available in the US]) for 14-28 days.1,13 Patients in both treatment groups received concomitant aztreonam (1-2 g every 8-12 hours IV) if gram-negative pathogens were isolated from the infection site and patients receiving an aminopenicillin also were treated with vancomycin (1 g every 12 hours IV) if MRSA was isolated from the foot infection.1,13 Most patients also received appropriate adjunctive treatment usually required for the treatment of diabetic foot infections (e.g., debridement).1 When results for treatment of these diabetic foot infections were stratified according to causative organism, linezolid was effective in 78% of infections caused by S. aureus , 71% of infections caused by MRSA, and 86% of infections caused by S. agalactiae .1

Efficacy and safety of linezolid for the treatment of complicated skin and skin structure infections in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a randomized, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age.1 In the comparator-controlled study in pediatric patients with documented or suspected gram-positive infections, the cure rate in pediatric patients with complicated skin and skin structure infections (intent-to-treat analysis) was 85% in those treated with linezolid and 91% in those treated with vancomycin; the cure rate in clinically evaluable pediatric patients with complicated skin and skin structure infections was 94 and 96%, respectively.1

Efficacy and safety of linezolid for the treatment of uncomplicated skin and skin structure infections in pediatric patients caused by S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pyogenes is supported by data from a comparator-controlled study in pediatric patients 5-17 years of age.1

Vancomycin-resistant Enterococcus faecium Infections

Linezolid is used for the treatment of vancomycin-resistant E. faecium infections, including infections associated with concurrent bacteremia.1,2,3

Linezolid has been used in some patients for the treatment of native valve or prosthetic valve infective endocarditis† caused by vancomycin-resistant or multidrug-resistant E. faecium .127 The American Heart Association (AHA) states that patients with infective endocarditis attributable to enterococci resistant to penicillins, aminoglycosides, and vancomycin should be managed by a team of specialists in infectious disease, cardiology, cardiovascular surgery, clinical pharmacy, and, if necessary, pediatrics.127

For information on diagnosis and management of infective endocarditis and its complications, including anti-infective treatment of enterococcal endocarditis, the current AHA guidelines available at [Web] should be consulted.127

Clinical Experience

In a randomized, double-blind study in adults comparing high-dose linezolid (600 mg every 12 hours IV or orally) with low-dose linezolid (200 mg every 12 hours IV or orally) for 7-28 days, cure rates for patients with documented vancomycin-resistant E. faecium at any infection site were 67 or 52% for those treated with high- or low-dose linezolid, respectively, based on intent-to-treat analysis.1,3 Some patients received concomitant therapy with aztreonam or aminoglycosides.1 Compared with patients in the high-dose group, there were more adverse events and more deaths among patients in the low-dose group.3

Efficacy and safety of linezolid for the treatment of vancomycin-resistant E. faecium infections in pediatric patients is supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a randomized, open-label, comparator-controlled study of documented or suspected gram-positive bacterial infections in neonates and pediatric patients through 11 years of age.1 Data from the open-label, comparator-controlled study indicate that the cure rate was 75% in the 8 microbiologically evaluable pediatric patients with vancomycin-resistant E. faecium infections who received linezolid.1

Catheter-related Bloodstream Infections

Although linezolid has been investigated for the treatment of intravascular catheter-related bloodstream infections†, linezolid is not labeled by FDA for the treatment of catheter-related bacteremia or catheter-site infections and is not indicated for the treatment of gram-negative bacterial infections.1,23

Data from an open-label, randomized study in patients with intravascular catheter-related bloodstream infections indicated that mortality was higher in patients receiving linezolid than in patients receiving comparator anti-infectives.1,23 In this study, seriously ill patients with intravascular catheter-related bloodstream infections were randomized to receive linezolid or vancomycin (patients randomized to vancomycin were switched to dicloxacillin or oxacillin if the pathogen was oxacillin-susceptible); patients could receive concomitant therapy for gram-negative infection.1,23 Although there was no difference in mortality between linezolid and the comparator regimens in patients with only gram-positive bacteria identified in the baseline culture, mortality was higher in linezolid-treated patients who had gram-negative bacterial infections, mixed gram-negative and gram-positive bacterial infections, or no pathogen identified at baseline.1,23

Mycobacterial Infections

Treatment of Active Tuberculosis

Linezolid is used in multiple-drug regimens for the treatment of multidrug-resistant (MDR) pulmonary tuberculosis† (i.e., caused by Mycobacterium tuberculosis resistant to isoniazid and rifampin).69,70,71 ATS, US Centers for Disease Control and Prevention (CDC), and IDSA state that linezolid is one of various options that can be considered for inclusion in multiple-drug regimens used for the treatment of pulmonary MDR tuberculosis.69 The World Health Organization (WHO) recommends that linezolid be included in multiple-drug regimens used for longer-term treatment (i.e., 18 months or longer) of multidrug- or rifampin-resistant (MDR/RR) tuberculosis.71

Linezolid is used in a 3-drug combination regimen that includes bedaquiline and pretomanid for the treatment of extensively drug resistant (XDR) pulmonary tuberculosis (i.e., caused by M. tuberculosis resistant to isoniazid, rifampin, any fluoroquinolone, and at least one injectable antituberculosis agent) or treatment-intolerant or non-responsive MDR pulmonary tuberculosis.67,68,69,71 WHO states that the 3-drug regimen of pretomanid, bedaquiline, and linezolid (also known as BPaL) may be used for treatment of MDR tuberculosis in patients who have not previously received either bedaquiline or linezolid (or received the drugs for no more than 2 weeks) and have documented evidence that the MDR strain also is resistant to a fluoroquinolone.71

Patients with MDR or XDR tuberculosis are at high risk for treatment failure and acquisition of further drug resistance.69,70 ATS, CDC, IDSA, and other experts recommend that such patients be referred to or that consultation be obtained from a specialized treatment center as identified by local or state health departments or the CDC.69,71

For additional information on the treatment of MDR and XDR tuberculosis, current guidelines from ATS/CDC/IDSA and WHO should be consulted.69,71

Reconstitution and Administration

Linezolid is administered orally or by IV infusion.1

Oral Administration

Orally administered linezolid may be given without regard to meals.1 However, large quantities of foods or beverages with high tyramine content should be avoided during linezolid treatment.1 (See Monoamine Oxidase Inhibition under Cautions.)

Linezolid powder for oral suspension should be reconstituted at the time of dispensing with the amount of water specified on the bottle to provide a suspension containing 100 mg/5 mL.1 After tapping the bottle gently to loosen the powder, the water should be added in 2 portions and the suspension agitated well after each addition.1

The reconstituted oral suspension should be stored at room temperature and used within 21 days.1 Prior to administration of each dose, the suspension should be gently mixed by inverting the bottle 3-5 times but should not be shaken.1

IV Administration

Linezolid premixed injection for IV administration in single-use flexible containers is administered by IV infusion without further dilution.1

Linezolid premixed solutions should be inspected visually for particulate matter prior to administration and should not be used if visible particles are evident.1,3,5 The solution may exhibit a yellow color that can intensify over time without adversely affecting potency.1 The bags should be squeezed firmly to check for minute leaks.1 If leaks are detected, the solution should be discarded since sterility may be impaired.1

Linezolid premixed injection for IV administration in single-use flexible infusion bags should not be used in series connections, and additives should not be introduced into the solution.1

Linezolid is compatible with 5% dextrose, 0.9% sodium chloride, and lactated Ringer's injection.1

During simulated Y-site administration, linezolid was physically incompatible with amphotericin B, chlorpromazine hydrochloride, co-trimoxazole, diazepam, erythromycin lactobionate, pentamidine isethionate, and phenytoin sodium.1 In addition, linezolid is chemically incompatible with ceftriaxone sodium.1

Rate of Administration

Linezolid premixed injection for IV administration in single-use flexible containers should be administered by IV infusion over 30-120 minutes.1

Dosage

When clinically appropriate, patients treated initially with IV linezolid may be switched to oral linezolid without dosage adjustment.1

The manufacturer states that safety and efficacy of more than 28 days of linezolid treatment have not been evaluated in controlled clinical trials.1 Linezolid is administered for longer durations when used in multiple-drug regimens for the treatment of multidrug-resistant (MDR) tuberculosis.67,68,69,70,71

Adult Dosage

Respiratory Tract Infections

The usual adult oral or IV dosage of linezolid for the treatment of community-acquired pneumonia (CAP) caused by susceptible Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or Streptococcus pneumoniae is 600 mg every 12 hours for 10-14 days.1

The usual adult oral or IV dosage of linezolid for the treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or S. pneumoniae is 600 mg every 12 hours for 10-14 days.1

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pyogenes (group A β-hemolytic streptococci, GAS), the usual adult oral dosage of linezolid is 400 mg every 12 hours for 10-14 days.1

The usual adult oral or IV dosage of linezolid for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by susceptible S. aureus (including MRSA), S. pyogenes (group A β-hemolytic streptococci), or S. agalactiae (group B streptococci, GBS) is 600 mg every 12 hours for 10-14 days.1

Vancomycin-resistant Enterococcus faecium Infections

The usual adult oral or IV dosage of linezolid for the treatment of vancomycin-resistant Enterococcus faecium infections, including infections with concurrent bacteremia, is 600 mg every 12 hours for 14-28 days.1

Treatment of XDR Tuberculosis or Treatment-intolerant or Non-responsive MDR Tuberculosis

When oral linezolid is used in conjunction with pretomanid and bedaquiline for the treatment of XDR pulmonary tuberculosis or treatment-intolerant or non-responsive MDR pulmonary tuberculosis in adults, the recommended dosage of the drug is 1.2 g daily for 26 weeks.67 Adjustment of linezolid dosage to 600 mg daily with further reductions to 300 mg daily or interruption of linezolid therapy may be required if myelosuppression, peripheral neuropathy, or optic neuropathy occurs.1,67

This recommended linezolid dosage must be administered in conjunction with oral pretomanid (200 mg once daily for 26 weeks) and oral bedaquiline (400 mg once daily for 2 weeks followed by 200 mg 3 times weekly [with at least 48 hours between doses] for 24 weeks).67

The 3-drug combination regimen of pretomanid, bedaquiline, and linezolid should be continued for 26 weeks, but may be extended beyond 26 weeks if necessary.67

Pediatric Dosage

General Dosage for Neonates

In premature neonates younger than 7 days of age, the manufacturer recommends an initial linezolid dosage of 10 mg/kg every 12 hours;1 a dosage of 10 mg/kg every 8 hours may be considered in those with an inadequate response to the lower dosage.1 The manufacturer recommends that all neonates 7 days of age or older receive a linezolid dosage of 10 mg/kg every 8 hours.1

When linezolid is used in neonates 7 days of age or younger, the American Academy of Pediatrics (AAP) recommends an IV dosage of 10 mg/kg every 12 hours in those with gestational age less than 34 weeks and 10 mg/kg every 8 hours in those with gestational age of 24 weeks or more.105 For neonates 8-28 days of age, AAP recommends an IV dosage of 10 mg/kg every 8 hours, regardless of gestational age.105

Respiratory Tract Infections

The usual oral or IV dosage of linezolid for the treatment of CAP caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pneumoniae is 10 mg/kg every 8 hours in pediatric patients 7 days of age through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older.1 The recommended duration of treatment is 10-14 days.1

The usual oral or IV dosage of linezolid for the treatment of nosocomial pneumonia caused by susceptible S. aureus (including MRSA) or S. pneumoniae is 10 mg/kg every 8 hours in pediatric patients 7 days through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older.1 The recommended duration of treatment is 10-14 days.1

Skin and Skin Structure Infections

For the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or S. pyogenes in pediatric patients, the usual oral dosage of linezolid is 10 mg/kg every 8 hours in those younger than 5 years of age, 10 mg/kg every 12 hours in those 5 through 11 years of age, and 600 mg every 12 hours in adolescents 12 years of age or older.1 The recommended duration of treatment is 10-14 days.1

The usual oral or IV dosage of linezolid for the treatment of complicated skin and skin structure infections caused by susceptible S. aureus (including MRSA), S. pyogenes , or S. agalactiae is 10 mg/kg every 8 hours in pediatric patients 7 days of age through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older.1 The recommended duration of treatment is 10-14 days.1

Vancomycin-resistant Enterococcus faecium Infections

The usual oral or IV dosage of linezolid for the treatment of vancomycin-resistant E. faecium infections is 10 mg/kg every 8 hours in pediatric patients 7 days of age through 11 years of age and 600 mg every 12 hours in adolescents 12 years of age or older.1 The recommended duration of treatment is 14-28 days.1

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 Data are not available regarding the pharmacokinetics of linezolid in patients with severe hepatic impairment.1

Renal Impairment

Dosage adjustments are not necessary in patients with renal impairment.1 However, the 2 principal metabolites of linezolid may accumulate in patients with renal impairment and the clinical importance of accumulation of these metabolites has not been determined.1

Because linezolid is removed by hemodialysis, patients undergoing hemodialysis should receive linezolid doses after the dialysis session.1

Geriatric Patients

Dosage adjustments are not necessary in geriatric patients.1

Contraindications

Linezolid is contraindicated in patients with known hypersensitivity to linezolid or any ingredient in the formulation.1

Linezolid should not be used in patients who are receiving (or have received within the last 2 weeks) drugs that inhibit monoamine oxidase (MAO) A or B, including MAO inhibitor antidepressants (e.g., isocarboxazid, phenelzine).1 (See Monoamine Oxidase Inhibitors under Drug Interactions.)

Warnings/Precautions

Hematologic Effects

Myelosuppression (e.g., anemia, leukopenia, pancytopenia, thrombocytopenia) has been reported in patients receiving linezolid.1

Toxicity studies in adult and juvenile dogs and rats indicate myelosuppression (bone marrow hypocellularity/decreased hematopoiesis; decreased extramedullary hematopoiesis in spleen and liver; decreased levels of circulating erythrocytes, leukocytes, and platelets) and lymphoid depletion in thymus, lymph nodes, and spleen.1

Complete blood cell counts (CBCs) should be monitored weekly during linezolid treatment, especially in patients receiving the drug for more than 2 weeks and in those who have preexisting myelosuppression, are receiving concomitant drugs that produce bone marrow suppression, or have a chronic infection that was or is being treated with concomitant anti-infective therapy.1

Discontinuance of linezolid should be considered if myelosuppression develops or worsens.1 Hematologic parameters generally have increased toward pretreatment values following discontinuance of the drug.1

Peripheral and Optic Neuropathy

Peripheral and optic neuropathies have been reported in adults and children receiving linezolid;1,24 these events have occurred principally in patients receiving the drug for longer than the maximum recommended duration of treatment (28 days).1,24 Optic neuropathy sometimes progressed to loss of vision when linezolid was used for longer than 28 days.1 Blurred vision has been reported in some patients who received the drug for less than 28 days.1

If a patient experiences symptoms of visual impairment (e.g., changes in visual acuity or color vision, blurred vision, or visual field defect), an ophthalmic evaluation should be performed promptly.1 All patients receiving linezolid for extended periods of time (i.e., 3 months or longer) should have their visual function monitored.1 In addition, all patients reporting a new visual symptom, regardless of the length of linezolid treatment, should have their visual function monitored.1

If peripheral or optic neuropathy occurs, the potential benefits of linezolid should be weighed against the potential risks of continued treatment with the drug.1

Serotonin Syndrome

Serotonin syndrome (including some fatalities) has been reported in patients receiving linezolid concomitantly with serotonergic drugs.1,5,16,17,25,27,28,29 Signs and symptoms of serotonin syndrome include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering, shaking, diarrhea, loss of coordination, and/or fever.28

Most reported cases of serotonin syndrome have occurred in patients receiving linezolid concomitantly with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).19 FDA has not concluded whether concomitant use of linezolid and other drugs with lesser degrees of serotonergic activity (e.g., tricyclic antidepressants, MAO inhibitors) is associated with a risk comparable to that reported with concomitant use of linezolid and SSRIs or SNRIs.19

Linezolid should not be used in patients with carcinoid syndrome or in patients receiving SSRIs, tricyclic antidepressants, serotonin 5-HT₁ receptor agonists (triptans), meperidine, bupropion, or buspirone unless concomitant therapy is considered clinically appropriate and patients can be carefully monitored for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions.1 (See Drug Interactions.)

Mortality

In a study in seriously ill patients with intravascular catheter-related infections†, mortality was higher in linezolid-treated patients than in those treated with a comparator anti-infective (vancomycin, dicloxacillin, oxacillin).1,23 (See Catheter-related Bloodstream Infections under Uses.)

Monoamine Oxidase Inhibition

Linezolid is a weak, nonselective, reversible inhibitor of monoamine oxidase (MAO).1,2,3 The drug potentially may interact with MAO inhibitors and adrenergic and serotonergic agents.1 (See Drug Interactions.)

A significant pressor response has been reported when tyramine doses exceeding 100 mg were used in adults receiving linezolid.1 Patients should be instructed to avoid large quantities of foods or beverages with high tyramine content during linezolid treatment.1 Foods high in tyramine include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor (e.g., aged cheeses, fermented or air-dried meat, sauerkraut, soy sauce, tap beer, red wine).1 Tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.1 For additional information on interactions in patients receiving MAO inhibitors and foods containing large amounts of tyramine, see Food under Drug Interactions, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

Risk of Hypertension

Unless patients are monitored for potential increases in blood pressure, linezolid should not be used in patients with uncontrolled hypertension, pheochromocytoma, or thyrotoxicosis or in patients receiving direct- or indirect-acting sympathomimetic agents (e.g., pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).1 (See Sympathomimetic Agents under Drug Interactions.)

Lactic Acidosis

Lactic acidosis, characterized by recurrent nausea and vomiting, has been reported in patients receiving linezolid.1,22 Patients who develop recurrent nausea and vomiting, unexplained acidosis, or a low bicarbonate concentration while receiving linezolid should undergo immediate medical evaluation.1,22

Seizures

Seizures have been reported in patients receiving linezolid.1 Some cases were reported in patients with a history of seizures or risk factors for seizures.1

Hypoglycemia

Symptomatic hypoglycemia has been reported in patients with diabetes mellitus receiving linezolid concomitantly with insulin or oral antidiabetic agents.1 (See Antidiabetic Agents under Drug Interactions.)

Although a causal relationship between linezolid and hypoglycemia has not been established, patients with diabetes mellitus should be cautioned about the potential for hypoglycemia during linezolid treatment.1

If hypoglycemia occurs, dosage reduction of insulin or oral antidiabetic agents or discontinuance of linezolid, insulin, or oral antidiabetic agents may be necessary.1

Sensitivity Reactions

Anaphylaxis, angioedema, and bullous skin disorders, including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, reported.1

Tooth Discoloration

Superficial tooth discoloration and tongue discoloration have been reported in patients receiving linezolid.1 In cases with known outcome, tooth discoloration was removable with professional dental cleaning (manual descaling).1

Phenylketonuria

Individuals who must restrict their intake of phenylalanine should be warned that linezolid for oral suspension contains aspartame, which is metabolized in the GI tract following oral administration, to provide 20 mg of phenylalanine per 5 mL of suspension.1,5

Linezolid tablets do not contain aspartame1,5 and should be used in individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine.1,5

Superinfection/Clostridioides difficile-associated Diarrhea and Colitis

Use of linezolid may result in emergence and overgrowth of nonsusceptible organisms.1 Appropriate therapy should be instituted if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridioides difficile (formerly Clostridium difficile ).1,12 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including linezolid, and may range in severity from mild diarrhea to fatal colitis.1,12 C. difficile produces toxins A and B which contribute to the development of CDAD;1,12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,12 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,12 Patients should be managed with appropriate anti-infective therapy directed against C. difficile (e.g., fidaxomicin, vancomycin, metronidazole), supportive therapy (e.g., fluid and electrolyte management, protein supplementation), and surgical evaluation as clinically indicated.1,12

Selection and Use of Anti-infectives

Linezolid is indicated only for the treatment of certain infections caused by certain gram-positive bacteria.1 The drug has no clinical activity against gram-negative bacteria and is not indicated for the treatment of infections caused by gram-negative bacteria.1

It is imperative that an anti-infective active against gram-negative bacteria be used concomitantly if documented or presumed pathogens include gram-negative bacteria.1 (See Uses.)

Safety and efficacy of linezolid given for longer than 28 days have not been evaluated in controlled clinical trials.1

To reduce development of drug-resistant bacteria and maintain effectiveness of linezolid and other antibacterials, the drug should be used only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Information on test methods and quality control standards for in vitro susceptibility testing of antibacterials and specific interpretive criteria for such testing recognized by FDA is available at [Web].1,47 For most antibacterials, including linezolid, FDA recognizes the standards published by the Clinical and Laboratory Standards Institute (CLSI).47,48

Specific Populations

Pregnancy

Available data from published and postmarketing case reports regarding use of linezolid in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1

In studies in mice, rats, and rabbits, linezolid was not teratogenic; however, embryofetal toxicities were reported.1 These nonteratogenic effects included increased post-implantational embryo death, decreased fetal body weights, and increased incidence of costal cartilage fusion in mice; decreased fetal body weights, reduced ossification of sternebrae, and decreased survival of pups in rats; and reduced fetal body weight in rabbits.1

Lactation

Linezolid is distributed into human milk.1 It is not known whether the drug affects the breast-fed infant or affects milk production.1 Available data suggest that a breast-fed infant would receive approximately 6-9% of the recommended daily therapeutic infant dose (10 mg/kg every 8 hours).1

The benefits of breast-feeding and the importance of linezolid to the woman should be considered along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1

If linezolid is used in a nursing woman, the manufacturer recommends that the breast-fed infant be monitored for diarrhea and vomiting since these are the most common adverse reactions reported in infants being treated with linezolid.1

Males of Reproductive Potential

Based on findings from animal studies, linezolid may reversibly impair fertility in males.1

In adult male rats receiving linezolid dosages of at least 50 mg/kg daily resulting in exposures approximately equal to or greater than human exposures (based on AUC), a reversible decrease in fertility and reproductive performance was reported.1 The effects on fertility were mediated through altered spermatogenesis;1 affected spermatids contained abnormally formed and oriented mitochondria and were nonviable.1 Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility.1 Similar epididymal changes were not seen in dogs.1

Pediatric Use

Safety and efficacy of linezolid for the treatment of community-acquired pneumonia (CAP), nosocomial pneumonia, complicated skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections in pediatric patients are supported by adequate and well-controlled studies in adults, pharmacokinetic studies in pediatric patients, and additional data from a comparator-controlled study of gram-positive infections in neonates and children through 11 years of age.1 Safety and efficacy of the drug for the treatment of CAP in pediatric patients also is supported by evidence from an uncontrolled study in patients 8 months through 12 years of age.1

Safety and efficacy of linezolid for the treatment of uncomplicated skin and skin structure infections in pediatric patients have been established in a comparator-controlled study in pediatric patients 5-17 years of age.1

While some pharmacokinetic parameters (i.e., peak plasma concentration, volume of distribution) are similar in children of all ages, linezolid clearance varies with age.1 Excluding neonates younger than 1 week of age, clearance is most rapid in the youngest age groups (i.e., those 7 days to 11 years of age); as children age, the clearance of linezolid decreases and clearance values in adolescents approach those observed in adults.1 Systemic exposure (mean daily area under the plasma concentration-time curve [AUC]) in pediatric patients younger than 12 years of age receiving linezolid every 8 hours generally is similar to that in adults and adolescents receiving the drug every 12 hours.1 There is wider intraindividual variability in linezolid clearance and in systemic drug exposure in all pediatric age groups relative to adults.1

The manufacturer states that linezolid is not recommended for empiric treatment of CNS infections in pediatric patients;1 therapeutic concentrations of the drug were not consistently achieved or maintained in CSF of pediatric patients with ventriculoperitoneal shunts.1

Inadequate systemic exposure, site and severity of infection, and underlying medical conditions should be considered in children with a suboptimal response to linezolid, especially those with infections caused by gram-positive bacteria that have minimum inhibitory concentrations (MICs) of 4 mcg/mL.1

Geriatric Use

No overall differences in safety, efficacy, or pharmacokinetics have been observed in geriatric adults 65 years of age or older compared with younger adults.1,2 Other clinical experience has not revealed age-related differences in response, but the possibility of greater sensitivity in some older patients cannot be ruled out.1

Renal Impairment

Linezolid pharmacokinetics are not altered in patients with renal impairment.1 However, the 2 principal metabolites of linezolid may accumulate in patients with impaired renal function and the amount of accumulation increases with the severity of renal impairment.1 Because the clinical importance of accumulation of linezolid metabolites has not been determined, the potential benefits of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of the metabolites.1 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Linezolid pharmacokinetics are not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B);1 pharmacokinetics of the drug have not been evaluated in patients with severe hepatic impairment.1

Common Adverse Effects

Adverse effects occurring in 2% or more of adults receiving linezolid include GI effects (diarrhea, nausea, vomiting), headache, anemia, rash, and dizziness.1 Adverse effects reported in 2% or more of pediatric patients receiving linezolid in clinical studies include GI effects (diarrhea, nausea, vomiting, localized or generalized abdominal pain, loose stools), headache, anemia, and thrombocytopenia.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Linezolid is minimally metabolized (possibly mediated by cytochrome P-450 [CYP] enzymes), does not induce CYP enzymes, and does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4.1

Linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by CYP isoenzymes.1

Although the mechanism of the interaction is unknown and may be related to induction of hepatic enzymes, concomitant use of rifampin and linezolid has resulted in decreased linezolid concentrations.1 It is possible that concomitant use of other potent inducers of hepatic enzymes (e.g., carbamazepine, phenytoin, phenobarbital) could result in decreased linezolid exposures.1

Antidiabetic Agents

Hypoglycemia has been reported in patients with diabetes mellitus receiving linezolid concomitantly with insulin or oral antidiabetic agents.1 Although a causal relationship has not been established, linezolid is a nonselective, reversible monoamine oxidase (MAO) inhibitor and some MAO inhibitors have been associated with hypoglycemic episodes in patients with diabetes mellitus who were also receiving insulin or oral antidiabetic agents.1 Patients should be warned of the potential for hypoglycemia.1 If hypoglycemia occurs, dosage reduction of the antidiabetic agent or discontinuance of linezolid or the antidiabetic agent may be necessary.1

Anti-infective Agents

Aminoglycosides

Concomitant use of linezolid and gentamicin does not affect the pharmacokinetics of either drug.1,2,3

In vitro studies indicate the antibacterial effects of linezolid and gentamicin or streptomycin may be additive or indifferent.1

Ampicillin

In vitro studies indicate the antibacterial effects of linezolid and ampicillin may be additive or indifferent.1

Aztreonam

Concomitant use of linezolid and aztreonam does not result in clinically important effects on the pharmacokinetics of either drug.1,3,58

In vitro studies indicate the antibacterial effects of linezolid and aztreonam may be additive or indifferent.1

Carbapenems

In vitro studies indicate the antibacterial effects of linezolid and imipenem may be additive or indifferent.1

Rifampin

Concomitant use of linezolid (600 mg twice daily for 2.5 days) and rifampin (600 mg once daily for 8 days) resulted in a 21% decrease in peak plasma concentrations of linezolid and a 32% decrease in the area under the plasma concentration-time curve (AUC) of linezolid.1 The mechanism and clinical importance of this pharmacokinetic interaction are unknown, although the interaction may be related to induction of hepatic enzymes.1

In vitro studies indicate the antibacterial effects of linezolid and rifampin may be additive or indifferent.1

Vancomycin

In vitro studies indicate the antibacterial effects of linezolid and vancomycin may be additive or indifferent.1

Monoamine Oxidase Inhibitors

Linezolid is a weak, nonselective, reversible MAO inhibitor and there is potential for pharmacologic interactions with other MAO inhibitors.1,2,3,28 Because of the potential for interaction, linezolid should not be used in patients who are receiving (or have received within the last 2 weeks) a drug that inhibits MAO-A or MAO-B (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine).1,28

Although FDA has not concluded whether the risk of serotonin syndrome associated with concomitant use of linezolid and MAO inhibitors is comparable to that reported when linezolid is used concomitantly with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs),19 linezolid generally should not be used in patients receiving serotonergic drugs, including MAO inhibitors (e.g., isocarboxazid, phenelzine, selegiline, tranylcypromine).28 (See Serotonergic Drugs under Drug Interactions.)

Phenytoin

Concomitant use of linezolid and phenytoin is not expected to affect the pharmacokinetics of phenytoin, but may possibly result in decreased linezolid exposures.1 Dosage adjustments are not required if linezolid and phenytoin are used concomitantly.1

Serotonergic Drugs

Concomitant use of linezolid and serotonergic drugs is associated with a risk of serotonin syndrome.1,3,19,28 There have been postmarketing reports of serotonin syndrome, including some fatalities, in patients who received linezolid concurrently with or shortly after discontinuance of serotonergic agents, particularly SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) or SNRIs (e.g., desvenlafaxine, duloxetine, venlafaxine).1,5,16,17,19,25,27,28,29 While FDA has not received reports of serotonin syndrome with concomitant use of linezolid and vilazodone, the risk is considered comparable to that with SSRIs.19 It is unclear whether concomitant use of linezolid and other drugs with lesser degrees of serotonergic activity, including tricyclic antidepressants (amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), MAO inhibitors (isocarboxazid, phenelzine, transdermal selegiline, tranylcypromine), amoxapine, bupropion, buspirone, maprotiline, mirtazapine, nefazodone, and trazodone, is associated with a risk of serotonin syndrome comparable to that reported when linezolid is used concomitantly with SSRIs or SNRIs.19

Because of the risk of serotonin syndrome, linezolid should not be used in patients receiving serotonergic drugs, including SSRIs, tricyclic antidepressants, serotonin 5-HT₁ receptor agonists (triptans), meperidine, bupropion, or buspirone, unless concomitant therapy is considered clinically appropriate and patients can be carefully monitored for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions.1

There may be some cases when a patient is already receiving a serotonergic antidepressant or buspirone and requires urgent treatment with linezolid (e.g., life-threatening infections caused by methicillin-resistant Staphylococcus aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA] or vancomycin-resistant Enterococcus faecium ).1,28 In these situations, if alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered.1,28 The patient should be monitored for manifestations of serotonin syndrome or NMS-like reactions (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes that include extreme agitation progressing to delirium and coma) for 2 weeks (5 weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first.1,28 The patient also should be monitored for symptoms associated with discontinuance of the antidepressant.1

Treatment with serotonergic drugs should not be initiated in a patient receiving linezolid;28 when necessary, the serotonergic drug may be started or reinitiated 24 hours after the last linezolid dose.1,28

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Sympathomimetic Agents

Concomitant use of linezolid and indirect-acting sympathomimetic agents (e.g., phenylpropanolamine, pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine) may result in a reversible enhancement of the pressor response to these agents.1

Unless patients are monitored for potential increases in blood pressure, linezolid should not be used in patients receiving direct- or indirect-acting sympathomimetic agents (e.g., pseudoephedrine), vasopressor agents (e.g., epinephrine, norepinephrine), or dopaminergic agents (e.g., dopamine, dobutamine).1

If an adrenergic agent (e.g., dopamine, epinephrine) is initiated in a patient receiving linezolid, lower initial doses of the adrenergic agent should be used and dosage titrated to achieve the desired response.1

Vitamins

Concomitant use of linezolid (600 mg orally on day 1 and day 8) and ascorbic acid (1 g daily on days 2-9) or vitamin E (800 units daily on days 2-9) increased the AUC of linezolid by 2.3 or 10.9%, respectively.1

Adjustment of linezolid dosage is not needed if the drug is used concomitantly with ascorbic acid or vitamin E.1

Warfarin

Linezolid does not have a substantial effect on the pharmacokinetics of warfarin;1 dosage adjustments are not required if linezolid and warfarin are used concomitantly.1

Pharmacokinetics

Absorption

Bioavailability

Linezolid is rapidly and extensively absorbed after oral administration;1 absolute oral bioavailability of the drug is approximately 100%.1,18

Peak plasma concentrations of linezolid are attained within 1-2 hours following oral administration.1

Food

The time to peak concentrations is delayed and peak concentrations are decreased when linezolid is administered with a high-fat meal,1 but the extent of absorption is not affected.1 This effect is not considered clinically important.1

Distribution

Extent

Linezolid is readily distributed into well-perfused tissues.1

In adults with CNS infections, IV administration of linezolid (600 mg twice daily) resulted in steady-state mean peak CSF concentrations that were 36-58% of mean peak plasma concentrations;33,34 the time to peak CSF concentrations was approximately 3-4 hours after a dose.34

In pediatric patients with ventriculoperitoneal shunts receiving single or multiple doses of linezolid, therapeutic concentrations of the drug were not consistently achieved or maintained in CSF.1

Linezolid is distributed into human milk.1

Plasma Protein Binding

Linezolid is approximately 31% bound to plasma proteins.1

Elimination

Metabolism

Linezolid is metabolized principally by oxidation of the morpholine ring to 2 inactive metabolites, an aminoethoxyacetic acid metabolite (A) and a hydroxyethyl glycine metabolite (B).1 Although metabolite A is presumed to be formed via an enzymatic pathway, in vitro studies indicate metabolite B is formed by nonenzymatic chemical oxidation.1 In vitro studies indicate linezolid is minimally metabolized and this may be mediated by the cytochrome P-450 (CYP) enzyme system.1

Elimination Route

Approximately 65% of a linezolid dose is eliminated via nonrenal clearance.1 Under steady-state conditions, approximately 30% of a linezolid dose is eliminated in urine as unchanged drug, 10% is eliminated as metabolite A, and 40% is eliminated as metabolite B.1 Mean renal clearance of linezolid is 40 mL/minute, suggesting net tubular reabsorption.1

Almost no linezolid is found in feces as unchanged drug;1 approximately 3 and 6% of a dose is eliminated in feces as metabolite A and metabolite B, respectively.1

Linezolid and its metabolites are removed by hemodialysis.1 Approximately 30% of a linezolid dose is removed by a 3-hour hemodialysis session started 3 hours after the dose.1

It is not known whether linezolid and its metabolites are removed by peritoneal dialysis.1,3,5

Half-life

The mean elimination half-life of linezolid is 4.3-6.4 hours in adults.1,18

In neonates, the mean elimination half-life of linezolid is 5.6 hours in preterm neonates younger than 1 week of age, 3 hours in full-term neonates younger than 1 week of age, and 1.5 hours in neonates 1 week to 28 days of age.1

In infants and children, the mean elimination half-life of linezolid is 1.8 hours in infants older than 28 days through 2 months of age and 2.9 hours in infants and children 3 months through 11 years of age.1

In adolescents 12 through 17 years of age, the mean elimination half-life of linezolid is 4.1 hours.1

Special Populations

Linezolid pharmacokinetics in patients 65 years of age or older are similar to the pharmacokinetics in younger adults.1,2

In pediatric patients, clearance of linezolid varies with age and there is wide intraindividual variability.1 Excluding neonates younger than 7 days of age, clearance is most rapid in the youngest age groups (i.e., those 7 days to 11 years of age);1 as children age, clearance of linezolid decreases and clearance in adolescents is similar to that observed in adults.1

Linezolid pharmacokinetics are not affected by mild to moderate hepatic impairment (Child-Pugh class A or B);1 pharmacokinetics of the drug have not been studied in patients with severe hepatic impairment.1

Pharmacokinetics of linezolid are not affected by renal impairment.1 However, the 2 principal metabolites of the drug accumulate in patients with impaired renal function and the amount of accumulation increases with the severity of renal impairment.1

Description

Linezolid is an oxazolidinone anti-infective agent.1,2,3,5,57 The mechanism of action of linezolid involves binding to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevention of formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process.1,2,3,57

In vitro, linezolid is bacteriostatic against susceptible enterococci and staphylococci and bactericidal against susceptible streptococci.1,2 Linezolid is active in vitro against most strains of Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA]),1,3,54,55,56,65 Streptococcus agalactiae (group B streptococci, GBS),1,3,65 S. pneumoniae ,1,3,54 S. pyogenes (group A β-hemolytic streptococci, GAS),1,3,65 and vancomycin-resistant Enterococcus faecium .1,3,53,54,56 Linezolid also has in vitro activity against E. faecalis (including vancomycin-resistant strains),1,3,54,56 E. faecium (vancomycin-susceptible strains),1,3 S. epidermidis (including methicillin-resistant strains [oxacillin-resistant strains]),1,3,54,56,65 S. haemolyticus ,1,3,65 viridans group streptococci,1,3 group G streptococci,65 Corynebacterium ,65 and Pasteurella multocida ;1,3,55 however, safety and efficacy of linezolid in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled clinical studies to date.1,3

Linezolid is active in vitro against Mycobacterium tuberculosis ,59,60,61,63 including some multiple-drug resistant (MDR) and extensively drug-resistant (XDR) strains.60,61 Linezolid also has activity in vitro against some strains of M. chelonaei ,62 M. fortuitum ,62 M. gilvum ,64 M. gordonae ,64 M. kansasii ,62 M. mucgenicum ,64 and M. simiae .64

Resistance to linezolid has been produced in vitro by serial passage of MRSA or enterococci (i.e., E. faecalis , E. faecium ) in the presence of increasing concentrations of the drug,8,9,57 and resistance to linezolid has emerged in patients receiving the drug for the treatment of infections caused by MRSA1,7 or enterococci.1,53 Linezolid resistance generally is associated with point mutations in the 23S rRNA gene.1,57 However, linezolid resistance in staphylococci mediated by the chloramphenicol-florfenicol ( cfr ) gene located on a plasmid has been reported and such resistance is transferable between staphylococci.1

Cross-resistance between linezolid and other oxazolidinones (e.g., tedizolid) has been reported.1,45,52 Bacteria resistant to linezolid because of mutations in chromosomal genes encoding the 23S rRNA or ribosomal proteins (L3 and L4) usually are cross-resistant to other oxazolidinones (e.g., tedizolid) and vice versa.1,44,52 However, in vitro data indicate that the presence of the cfr gene in S. aureus that results in resistance to linezolid does not necessarily result in cross-resistance to tedizolid in the absence of chromosomal mutations.44,45,46,52 Cross-resistance between linezolid and non-oxazolidinone anti-infectives is unlikely.2,3,57

Linezolid is well absorbed following oral administration (absolute bioavailability approximately 100%) and is readily distributed to well-perfused tissues.1,2,3 The drug is metabolized principally via oxidation to 2 inactive metabolites: an aminoethoxyacetic acid metabolite and a hydroxyethyl glycine metabolite.1,3 Linezolid is minimally metabolized and metabolism may be mediated by the cytochrome P-450 (CYP) enzyme system.1 Linezolid does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 and is not an enzyme inducer, suggesting that the drug is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.1

Advice to Patients

Advise patients that antibacterials (including linezolid) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

Importance of completing full course of treatment, even if feeling better after a few days.1

Advise patients that skipping doses or not completing the full course of treatment may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with linezolid or other antibacterials in the future.1

Advise patients that linezolid may be taken orally without regard to meals.1

If using the oral suspension, importance of not shaking the bottle vigorously and gently inverting the bottle 3-5 times to resuspend the drug prior to administration of each dose.1

Advise patients of the potential risk of serotonin syndrome, particularly if linezolid is used concomitantly with monoamine oxidase (MAO) inhibitors, selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, or other serotonergic drugs.28 Importance of immediately contacting clinician if signs and symptoms of serotonin syndrome develop (e.g., confusion, hyperactivity, memory problems, muscle twitching, excessive sweating, shivering, shaking, diarrhea, loss of coordination, fever).28 Importance of not discontinuing serotonergic drugs without first consulting clinician.28

Advise patients, particularly those with diabetes mellitus, that hypoglycemic reactions (diaphoresis and tremulousness) and low blood glucose concentrations may occur during linezolid treatment.1 Importance of contacting a clinician to obtain proper treatment if such reactions occur.1

Importance of avoiding large quantities of foods or beverages with high tyramine content during linezolid treatment;1 this includes foods or beverages that have been aged, fermented, pickled, or smoked to improve flavor (e.g., aged cheeses, fermented or air-dried meats, sauerkraut, soy sauce, tap beer, red wine).1 Consider that tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.1

Advise individuals with phenylketonuria that the oral suspension contains aspartame, which is metabolized in the GI tract to provide 20 mg of phenylalanine per 5 mL of suspension.1

Importance of notifying clinicians of any history of hypertension or seizures.1

Importance of notifying clinicians if recurrent nausea and vomiting occurs.1

Importance of notifying clinician if any change in vision occurs.1

Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs (e.g., antidepressants) and OTC drugs (e.g., pseudoephedrine), as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise nursing women to monitor the breast-fed infant for diarrhea and vomiting.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Pfizer. Zyvox^® (linezolid) injection, tablets, and oral suspension prescribing information. New York, NY: 2021 Sep.

2. Clemett D, Markham A. Linezolid. Drugs . 2000; 59:815-27. [PubMed 10804037]

3. Pharmacia & Upjohn. Zyvox^® (linezolid) injection, tablets, and oral suspension comprehensive review. Kalamazoo, Michigan; 2000 April.

5. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

7. Tsiodras S, Gold HS, Sakoulas G et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus . Lancet . 2001; 358:207-8. [PubMed 11476839]

8. Prystowsky J, Siddiqui F, Chosay J et al. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother . 2001; 45:2154-6. [PubMedCentral][PubMed 11408243]

9. Kaatz GW, Seo SM. In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis . Antimicrob Agents Chemother . 1996; 40:799-801. [PubMedCentral][PubMed 8851617]

10. Stevens DL, Smith LG, Bruss JB et al. Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother . 2000; 44:3408-13. [PubMedCentral][PubMed 11083648]

11. Rubinstein E, Cammarata SK, Oliphant TH et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis . 2001; 32:402-12. [PubMed 11170948]

12. McDonald LC, Gerding DN, Johnson S et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis . 2018; 66:987-994. [PubMed 29562266]

13. Lipsky BA, Itani K, Norden C et al. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis . 2004; 38:17-24. [PubMed 14679443]

16. Bernard L, Stern R, Lew D et al. Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis . 2003; 36:1197. [PubMed 12715317]

17. Hachem RY, Hicks K, Huen A et al. Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis . 2003; 37:e8-11. [PubMedCentral][PubMed 12830431]

18. Fung HB, Kirschenbaum HL, Ojofeitimi BO. Linezolid: an oxazolidinone antimicrobial agent. Clin Ther . Mar; 23:356-91.

19. Food and Drug Administration. Drug Safety Communication: Updated information about the drug interaction between linezolid (Zyvox^®) and serotonergic pyschiatric medications. 2011 Oct 20. From FDA website. [Web]

20. Anon. Choice of Antibacterial Drugs. Treat Guidel Med Lett . 2007; 5:33-50.

22. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med . 2003; 348:86-7. [PubMed 12510056]

23. Food and Drug Administration. Information for Healthcare Professionals: Linezolid (marketed as Zyvox). 2007 Mar 16. From FDA website. [Web]

24. McKinley SH, Foroosan R. Optic neuropathy associated with linezolid treatment. J Neuroophthalmol . 2005; 25:18-21. [PubMed 15756127]

25. Steinberg M, Morin AK. Mild serotonin syndrome associated with concurrent linezolid and fluoxetine. Am J Health-Syst Pharm . 2007; 64:59-62. [PubMed 17189581]

26. Lipsky BA, Berendt AR, Cornia PB et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis . 2012; 54:e132-73.

27. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis . 2002; 34:1651-2. [PubMed 12032904]

28. Food and Drug Administration. Drug Safety Communication: Serious CNS reactions possible when linezolid (Zyvox^®) is given to patients taking certain pyschiatric medications. 2011 Jul 26. From FDA website. [Web]

29. Clark DB, Andrus MR, Byrd DC. Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature. Pharmacotherapy . 2006; 26:269-76. [PubMed 16466332]

30. Metlay JP, Waterer GW, Long AC et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med . 2019; 200:e45-e67. [PubMedCentral][PubMed 31573350]

33. Myrianthefs P, Markantonis SL, Vlachos K et al. Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob Agents Chemother . 2006; 50:3971-6. [PubMedCentral][PubMed 16982782]

34. Beer R, Engelhardt KW, Pfausler B et al. Pharmacokinetics of intravenous linezolid in cerebrospinal fluid and plasma in neurointensive care patients with staphylococcal ventriculitis associated with external ventricular drains. Antimicrob Agents Chemother . 2007; 51:379-82. [PubMed 17043116]

43. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis . 2014; 59:147-59. [PubMed 24947530]

44. Sivextro. Cubist Pharmaceuticals^® (tedizolid) for injection prescribing information. Lexington, MA; 2014 June.

45. Locke JB, Zurenko GE, Shaw KJ et al. Tedizolid for the management of human infections: in vitro characteristics. Clin Infect Dis . 2014; 58 Suppl 1:S35-42. [PubMed 24343830]

46. Locke JB, Finn J, Hilgers M et al. Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. Antimicrob Agents Chemother . 2010; 54:5337-43. [PubMedCentral][PubMed 20837751]

47. US Food and Drug Administration. FDA-recognized antimicrobial susceptibility test interpretive criteria. From FDA website. Accessed 2021 Jul 8. [Web]

48. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing . 31st edition. CLSI supplement M100. Wayne, PA; Mar 2021. [Web]

51. Kalil AC, Metersky ML, Klompas M et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis . 2016; 63:e61-e111. [PubMed 27418577]

52. Chen KH, Huang YT, Liao CH et al. In Vitro Activities of Tedizolid and Linezolid against Gram-Positive Cocci Associated with Acute Bacterial Skin and Skin Structure Infections and Pneumonia. Antimicrob Agents Chemother . 2015; 59:6262-5. [PubMedCentral][PubMed 26248355]

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