Linezolid

J01X - Other antibacterials ATC J01XX08 Small molecule approved 2000 Oral Parenteral

JFDA label: Zyvox

Mechanism of Action

Inhibitor of Bacterial 70S ribosome — Bacterial 70S ribosome inhibitor

Target	Action	Gene / class
Bacterial 70S ribosome efficacy	INHIBITOR

Indications

Approved

Community-acquired
Complicated
Enterococcal infections (vancomycin-resistant)
Hospital-acquired or healthcare-associated
Pneumonia
Skin and skin structure infections
Uncomplicated

Off-label

CNS infection due to methicillin-resistant S. aureus
Infective endocarditis, treatment (adults)
Intravascular catheter-associated bloodstream infection
Osteomyelitis (S. aureus [methicillin-resistant])
Osteomyelitis, native vertebral
Prosthetic joint infection
Septic arthritis (S. aureus [methicillin-resistant])
Tuberculosis, extensively drug-resistant

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: EUCAST v16 · curated · openfda-label.

Bacteria

Organism	Activity	MIC
Anaerobes	Susceptible	2.0 mg/L
Bacillus spp.	Susceptible	2.0 mg/L
Coagulase-negative staphylococci	Susceptible	4.0 mg/L
Corynebacterium spp.	Susceptible	2.0 mg/L
Enterococcus faecalis	Susceptible	4.0 mg/L
Enterococcus faecium	Susceptible	4.0 mg/L
Enterococcus spp.	Susceptible	4.0 mg/L
Pasteurella multocida	Active	—
Staphylococcus aureus	Susceptible	4.0 mg/L
Staphylococcus epidermidis	Active	—
Staphylococcus haemolyticus	Active	—
Staphylococcus spp.	Susceptible	4.0 mg/L
Streptococcus A/B/C/G	Susceptible	2.0 mg/L
Streptococcus agalactiae	Active	—
Streptococcus pneumoniae	Susceptible	2.0 mg/L
Streptococcus pneumoniae	Susceptible	2.0 mg/L
Streptococcus pyogenes	Active	—
Staphylococcus aureus	Resistant	4.0 mg/L

Class profile

gramStatus	Gram+
spectrumBreadth	Narrow
atypicalCoverage	No
isBactericidal	0
moaCategory	Protein synthesis inhibitor (50S ribosomal, 23S rRNA, unique binding site)
pdIndex	Time-dependent
postAntibioticEffect	None
mrsaCoverage	1
resistanceMechanisms	23S rRNA mutation (G2576T),cfr gene methylation,Efflux pumps (optrA,poxtA)

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Unless 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: sympathomimetic agents (eg, pseudoephedrine, phenylpropanolamine), vasopressive agents (eg, epinephrine, norepinephrine), dopaminergic agents (eg, dopamine, dobutamine). Unless carefully observed for signs and/or symptoms of serot Absolute
Hypersensitivity to linezolid or any component of the formulation Absolute
concurrent use or within 2 weeks of MAO inhibitors Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (1)

Common Headache, pruritus

Hepatobiliary disorders (2)

Common Increased serum ALT · increased serum bilirubin

Renal and urinary disorders (2)

Common Increased blood urea nitrogen · increased serum creatinine

Blood and lymphatic system disorders (6)

Very Common decreased platelet count · Decreased white blood cells

Common Anemia · decreased neutrophils · eosinophilia · thrombocytopenia

Metabolism and nutrition disorders (2)

Common Increased amylase · increased lactate dehydrogenase

Gastrointestinal disorders (4)

Very Common Diarrhea

Common increased serum lipase · nausea · Vomiting

Dosing

Source: Lexicomp

Note: Linezolid is not a preferred agent in treatment of infections requiring prolonged therapy (ie, >2 weeks) due to the risk of serious hematologic and neurologic toxicity. Use of linezolid is generally reserved for treatment of infections due to drug-resistant organisms (eg, MRSA, VRE). Enterococcal infections (vancomycin-resistant [VRE]), including concurrent bacteremia: Oral, IV: 600 mg every 12 hours Pneumonia: Community-acquired (CAP) due to multi-drug resistant S. pneumoniae: Oral, IV: 600 mg every 12 hours; duration dependent upon severity of illness and clinical response CAP due to MRSA: Oral, IV: 600 mg every 12 hours for 7 to 21 days (IDSA [Liu 2011]) Hospital-acquired (HAP) or ventilator-associated (VAP) due to MRSA, MSSA, and S. pneumoniae (generally reserved for MRSA): Oral, IV: 600 mg every 12 hours for 7 days; may consider a shorter or longer duration depending on rate of clinical improvement. When used as empiric therapy, use in combination with an antipseudomonal agent (one or two antipseudomonal agents depending on patient and institution specific risk factors) (IDSA/ATS [Kalil 2016]) Skin and skin structure infections (SSI), complicated: Oral, IV: 600 mg every 12 hours for 10 to 14 days. Note: Generally reserved as an alternative for MRSA infections. For diabetic foot infections, may extend treatment duration up to 4 weeks if slow to resolve (IDSA [Lipsky 2012]). Skin and skin structure infections (SSI), uncomplicated: Oral: 400 mg every 12 hours for 10 to 14 days. Note: Generally reserved as an alternative for MRSA infections. The dose most commonly employed clinically is 600 mg every 12 hours; a 5- to 10-day treatment course may be sufficient (IDSA [Liu 2011]; IDSA [Stevens 2014]). CNS infection due to MRSA (off-label use): Oral, IV: 600 mg every 12 hours; duration may vary depending on type and severity of infection, as well as clinical response (IDSA [Liu 2011]) Infective endocarditis (treatment), native or prosthetic valve (off-label use): IV, Oral: Enterococcus (resistant to penicillin, aminoglycosides, and vancomycin): 600 mg every 12 hours for a minimum of 6 weeks (AHA [Baddour 2015]) Intravascular catheter-associated bloodstream infection due to MRSA, methicillin-resistant coagulase negative staphylococci, or ampicillin- or vancomycin-resistant enterococcus (off-label use): Oral, IV: 600 mg every 12 hours (IDSA [Mermel 2009]) Osteomyelitis due to MRSA (off-label use): Oral, IV: 600 mg every 12 hours for a minimum of 8 weeks (for MRSA, some experts combine with rifampin, unless patient has concurrent bacteremia; in this case, clearance of bacteremia should occur first) (Birmingham 2003; IDSA [Liu 2011]; Rao 2004). Osteomyelitis, native vertebral (off-label use): Staphylococci (oxacillin-susceptible or –resistant) or Enterococcus spp (penicillin-susceptible or –resistant): Oral, IV: 600 mg every 12 hours for 6 weeks (IDSA [Berbari 2015]) Prosthetic joint infection (off-label use): Enterococcus spp (penicillin-susceptib

(For additional information see "Linezolid: Pediatric drug information") Usual dosage: Oral, IV: Children ≤11 years: 10 mg/kg (maximum: 600 mg/dose) every 8 hours Children ≥12 years and Adolescents: Refer to adult dosing. Indication-specific dosing: Enterococcal infections, vancomycin-resistant, including concurrent bacteremia: Oral, IV: Infants and Children ≤11 years: 10 mg/kg every 8 hours for 14 to 28 days Children ≥12 years and Adolescents: Refer to adult dosing. Pneumonia: Community-acquired (CAP): Manufacturer's labeling (includes concurrent bacteremia): Oral, IV: Infants and Children ≤11 years: 10 mg/kg/dose every 8 hours for 10 to 14 days Children ≥12 years and Adolescents: Refer to adult dosing. Alternate dosing: Infants >3 months and Children ≤11 years (IDSA/PIDS 2011): S. pneumoniae (MICs to penicillin ≤2.0 mcg/mL), mild infection or step-down therapy (alternative to amoxicillin): Oral: 10 mg/kg/dose every 8 hours S. pneumoniae (MICs to penicillin ≥4.0 mcg/mL): Severe infection (alternative to ceftriaxone): IV: 10 mg/kg/dose every 8 hours Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 8 hours S. aureus (methicillin-resistant/clindamycin-susceptible): Severe infection (alternative to vancomycin or clindamycin): IV: 10 mg/kg/dose every 8 hours Mild infection, step-down therapy (alternative to clindamycin): Oral: 10 mg/kg/dose every 8 hours S. aureus (methicillin- and clindamycin-resistant): Severe infection (alternative to vancomycin): IV: 10 mg/kg/dose every 8 hours Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 8 hours Children ≤11 years (Liu 2011): Oral, IV: S. aureus (methicillin-resistant): 10 mg/kg/dose every 8 hours for 7 to 21 days (maximum: 600 mg/dose) Children ≥12 years and Adolescents (IDSA/PIDS 2011): S. pneumoniae (MICs to penicillin ≤2.0 mcg/mL), mild infection or step-down therapy (alternative to amoxicillin): Oral: 10 mg/kg/dose every 12 hours S. pneumoniae (MICs to penicillin ≥4.0 mcg/mL) Severe infection (alternative to ceftriaxone): IV: 10 mg/kg/dose every 12 hours Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 12 hours S. aureus (methicillin-resistant/clindamycin-susceptible): Severe infection (alternative to vancomycin/clindamycin): IV: 10 mg/kg/dose every 12 hours Mild infection, step-down therapy (alternative to clindamycin): Oral: 10 mg/kg/dose every 12 hours S. aureus (methicillin- and clindamycin-resistant): Severe infection (alternative to vancomycin): IV: 10 mg/kg/dose every 12 hours Mild infection, step-down therapy (preferred): Oral: 10 mg/kg/dose every 12 hours Children ≥12 years and Adolescents (Liu 2011): S. aureus (methicillin-resistant): Refer to adult dosing. Hospital-acquired or healthcare-associated: Oral, IV: Manufacturer's labeling: Infants and Children ≤11 years: 10 mg/kg every 8 hours for 10 to 14 days Children ≥12 years and Adolescents: Refer to adult dosing. Alternate dosing (Liu 2011): S. aureus (methicillin-resista

Refer to adult dosing.

Mild to severe impairment: No dosage adjustment necessary. The two primary metabolites may accumulate in patients with renal impairment but the clinical significance is unknown; use with caution. End-stage renal disease (ESRD)on intermittent hemodialysis (IHD): Manufacturer's labeling: Dialyzable (~30% removed during 3-hour dialysis session): No dosage adjustment necessary; administer after hemodialysis on dialysis days. The two primary metabolites may accumulate in patients with renal impairment but the clinical significance is unknown; use with caution. Alternate dosing: If administration time is not immediately after dialysis session, may consider administration of a supplemental dose especially early in the treatment course to maintain levels above the MIC (Brier 2003). However, others have recommended no supplemental dose or dosage adjustment for patients on IHD (Heintz 2009; Trotman 2005) Peritoneal dialysis: No supplemental dose or dosage adjustment needed (Heintz 2009; Trotman 2005) Continuous renal replacement therapy (CVVH, CVVHD, CVVHDF): Some have suggested no supplemental dose or dosage adjustment needed (Heintz 2009; Trotman 2005). Others have postulated that achievement of MIC 2 mg/L may be suboptimal in ~30% of patients undergoing CVVHD or CVVHDF given 600 mg every 12 hours; however, no alternative dosing recommendations suggested (Roger 2016).

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Lactic acidosis

Has been reported with use. Patients who develop recurrent nausea and vomiting, unexplained acidosis, or low bicarbonate levels need immediate evaluation.

Myelosuppression

Has been reported and may be dependent on duration of therapy (generally >2 weeks of treatment); use with caution in patients with preexisting myelosuppression, in patients receiving other drugs which may cause bone marrow suppression, or in chronic infection (previous or concurrent antibiotic therapy). Weekly CBC monitoring is recommended; consider discontinuation in patients developing myelosuppression (or in whom myelosuppression worsens during treatment). Thrombocytopenia is the most frequently observed blood dyscrasia.

Peripheral and optic neuropathy (with vision loss)

Has been reported in adults and children and may occur primarily with extended courses of therapy >28 days; any symptoms of visual change or impairment warrant immediate ophthalmic evaluation and possible discontinuation of therapy.

Serotonin syndrome

Symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs, agents which reduce linezolid's metabolism, or in patients with carcinoid syndrome. Avoid use in such patients unless clinically appropriate and under close monitoring for signs/symptoms of serotonin syndrome or neuroleptic malignant syndrome-like reactions.

Superinfection

Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns:

Carcinoid syndrome

Use with caution and closely monitor for serotonin syndrome in patients with carcinoid syndrome; linezolid has not been studied in patients with this condition. Do not use in the absence of close monitoring.

Diabetes mellitus

Hypoglycemic episodes have been reported; use with caution and closely monitor glucose in diabetic patients. Dose reductions/discontinuation of concurrent hypoglycemic agents or discontinuation of linezolid may be required.

Hypertension

Use with caution and closely monitor blood pressure in patients with uncontrolled hypertension; linezolid has not been studied in patients with this condition. Do not use in the absence of close monitoring.

Hyperthyroidism

Use with caution and closely monitor blood pressure in patients with untreated hyperthyroidism; linezolid has not been studied in patients with this condition. Do not use in the absence of close monitoring.

Pheochromocytoma

Use with caution and closely monitor blood pressure in patients with pheochromocytoma; linezolid has not been studied in patients with this condition. Do not use in the absence of close monitoring.

Seizure disorder

Seizures have been reported; use with caution in patients with a history of seizures. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Pediatric

The manufacturer does not recommend the use of linezolid for empiric treatment of pediatric CNS infections since therapeutic linezolid concentrations are not consistently achieved or maintained in the CSF of patients with ventriculoperitoneal shunts. However, limited data in the form of case reports in pediatric and adult patients suggest that linezolid may be useful in treating gram-positive CNS infections that have failed to respond to other treatment options describing successful treatment of documented VRE and Staphylococcus aureus CNS and shunt infections in the literature (Cook 2005; da Silva 2007; Milstone 2007; Shaikh 2001; Villani 2002). Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

Phenylalanine

Some products may contain phenylalanine. Other warnings/precautions:

Appropriate use

Unnecessary use may lead to the development of resistance to linezolid; consider alternatives before initiating outpatient treatment.

Catheter-related bloodstream infections (CRBSI)

Linezolid should not be used in the empiric treatment of CRBSI, but may be appropriate for targeted therapy (Mermel 2009).

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse effects were observed in some animal reproduction studies at doses that were also maternally toxic. Information related to linezolid use during pregnancy is limited.

Lactation

Linezolid is excreted into breast milk. The manufacturer advises caution if administering linezolid to a breast-feeding woman. Nondose-related effects could include modification of bowel flora.

LactMed: monitor the infant.

Monitoring

Efficacy	Culture and susceptibility testing; clinical resolution (temperature, WBC, CRP, procalcitonin)
Toxicity	Renal function (dose adjustment in renal impairment); hepatic function for hepatically cleared agents; signs of C. difficile infection (diarrhoea)
Clinical pearl	Culture results guide de-escalation to narrower-spectrum therapy. Review antibiotic appropriateness at 48–72 h (antimicrobial stewardship).
Counseling	Complete the full course. Report persistent diarrhoea, rash, or lack of improvement after 48–72 h.

Chemistry & Properties

Formula	C16H20FN3O4
Molecular weight	337.35 g/mol
IUPAC name	N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide
CAS	165800-03-3
PubChem CID	441401
InChIKey	`TYZROVQLWOKYKF-ZDUSSCGKSA-N`
logP	1.12 (XLogP 0.7)
Polar surface area	71.11 Å²
H-bond acceptors / donors	5 / 1
Drug-likeness (QED)	0.89
Lipinski violations	0

SMILES

CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.06 h
Volume of distribution	0.596 L/kg
Protein binding	25.7%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
Monoamine oxidase B (MAOB)	Inhibitor	pIC50 5.7

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OAT1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Baricitinib	major
Bupropion	major
Certolizumab pegol	major
Cladribine	major
Cocaine (nasal)	major
Cocaine (topical)	major
Codeine	major
Deferiprone	major
Dexfenfluramine	major
Dextromethorphan	major
Diethylpropion	major
Dolasetron	major
Doxapram	major
Doxepin	major
Doxepin (topical)	major
Doxylamine	major
Ephedrine	major
Epinephrine	major
Etanercept	major
Fenfluramine	major
Fingolimod	major
Golimumab	major
Granisetron	major
Hydrocodone	major
Infliximab	major
Iobenguane (I-131)	major
Isometheptene	major
Leflunomide	major
Lorcaserin	major
Mazindol	major
Methylene blue	major
Morphine	major
Natalizumab	major
Ondansetron	major
Opium	major
Ozanimod	major
Palonosetron	major
Phentermine	major
Phenylephrine	major

Showing 40 of 100+.

Registered Products (10)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Joswe Deteria	Tablet 600 mg	30 tab pack varies	Jordan Sweden Medical & Sterilization Co.	—
Joswe Deteria	Tablet 600 mg	20 tab pack varies	Jordan Sweden Medical & Sterilization Co.	—
Lozned	Tablet 600 mg	30 tab	United Pharmaceutical	—
Lozned 600mg/300ml Solution for IV Infusion	Infusion Linezolid 2 mg/1 ml	(1 BAG)	MS Pharma Jordan	—
Zersa	Suspension 100 mg/5 ml	150 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Zersa	Tablet 600 mg	10 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Zersa	Infusion 600 mg/300 ml	1 BAG/1 BOX	Hikma Pharmaceuticals Co.Ltd/Jordan	—
ZextroÂ®	Tablet 600 mg	20 tab	Pharma International Company/ Jordan	—
Zyvox	Infusion 2 mg/ml	300 ml	Khoury Drug Store	—
Zyvox	Tablet 600 mg	20 tab	Khoury Drug Store	—