Mechanism of Action of Linezolid (Oxazolidinone Antibiotics)

Introduction

Linezolid is a synthetic bacteriostatic antibiotic belonging to the oxazolidinone class. It is primarily active against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae. Unlike other protein synthesis inhibitors, Linezolid binds to the 50S ribosomal subunit and blocks the initiation step of protein synthesis, making its mechanism unique and high-yield for medical exams like USMLE, NCLEX, GPAT, and NEET-PG.

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Stepwise Mechanism of Action of Linezolid

1. Entry into bacterial cell
   Linezolid diffuses into the bacterial cell and targets the ribosome.
2. Binding to 23S rRNA on 50S ribosomal subunit
   It specifically binds to the 23S portion of the 50S subunit of the bacterial ribosome.
3. Prevention of initiation complex formation
   This binding inhibits the formation of the initiation complex required for protein synthesis — the step where the 30S and 50S subunits join with mRNA and initiator tRNA.
4. Halting of bacterial protein synthesis
   As the initiation step is blocked, the translation process cannot begin, leading to bacteriostatic action.
5. Selective inhibition
   Linezolid does not affect human ribosomes, making it selectively toxic to bacteria.

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Pharmacokinetic Parameters of Linezolid

Parameter	Value
Bioavailability	~100% (excellent oral absorption)
Half-life	~5–7 hours
Protein binding	~31%
Metabolism	Hepatic (non-CYP enzymes)
Excretion	Renal and non-renal routes
CNS penetration	Good

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Clinical Uses of Linezolid

• MRSA infections (skin, soft tissue, pneumonia)
• Vancomycin-resistant Enterococci (VRE)
• Penicillin-resistant Streptococcus pneumoniae
• Nosocomial pneumonia
• Complicated skin and soft tissue infections
• Drug-resistant tuberculosis (off-label)
• *Alternative to vancomycin in Gram-positive sepsis

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Adverse Effects of Linezolid

• Myelosuppression (esp. thrombocytopenia with prolonged use)
• Peripheral and optic neuropathy (with long-term use)
• Lactic acidosis (rare but serious)
• Serotonin syndrome (when combined with SSRIs or MAO inhibitors)
• GI upset – nausea, vomiting, diarrhea
• Headache and dizziness

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Comparative Analysis: Linezolid vs Vancomycin

Feature	Linezolid	Vancomycin
Ribosomal target	23S rRNA of 50S	Peptidoglycan precursors
Protein synthesis step	Initiation ✅	Not targeted
Spectrum	Gram-positive only	Gram-positive only
Oral bioavailability	High (~100%) ✅	Poor (systemic use is IV only)
CNS penetration	Good ✅	Poor
TDM required	No	Yes (for IV)

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Practice MCQs

Q1. Linezolid inhibits which step of protein synthesis?
a. Elongation
b. Termination
c. Initiation ✅
d. Translocation

Q2. Linezolid binds to which part of the bacterial ribosome?
a. 16S rRNA
b. 23S rRNA of 50S ✅
c. 30S A-site
d. Peptidoglycan

Q3. A major side effect with prolonged use of Linezolid is:
a. Hepatotoxicity
b. Myelosuppression ✅
c. Ototoxicity
d. QT prolongation

Q4. Linezolid is primarily used to treat:
a. Gram-negative infections
b. Fungal infections
c. Gram-positive resistant infections ✅
d. Viral pneumonia

Q5. Risk of serotonin syndrome increases with:
a. NSAIDs
b. MAO inhibitors or SSRIs ✅
c. Antacids
d. Beta-blockers

Q6. Which of the following infections is not treated with Linezolid?
a. VRE
b. MRSA pneumonia
c. Gonorrhea ✅
d. Drug-resistant TB

Q7. Linezolid should be avoided with which drug class?
a. Antipsychotics
b. SSRIs ✅
c. Diuretics
d. Antacids

Q8. What makes Linezolid unique among protein synthesis inhibitors?
a. Targets DNA
b. Inhibits initiation ✅
c. Inhibits elongation
d. Inhibits RNA polymerase

Q9. How is Linezolid administered?
a. Only IV
b. Only oral
c. Both IV and oral ✅
d. Intrathecal only

Q10. Linezolid has good penetration into which site?
a. Joints
b. CSF ✅
c. Bone marrow
d. Alveoli only

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FAQs

Q1: Is Linezolid bactericidal or bacteriostatic?
It is bacteriostatic, except for Streptococcus pneumoniae, where it may be bactericidal.

Q2: Can Linezolid be given orally?
Yes, it has excellent oral bioavailability (~100%), equivalent to IV dosing.

Q3: Is Linezolid used in Gram-negative infections?
No, it lacks Gram-negative activity due to limited penetration and efflux.

Q4: What labs should be monitored with prolonged therapy?
Complete blood count (CBC) due to risk of myelosuppression.

Q5: What is the mechanism behind serotonin syndrome with Linezolid?
It is a weak MAO inhibitor, so when combined with SSRIs or SNRIs, it can cause serotonin excess.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK534844/