What is the first oxazolidinone antibiotic? The Answer is Linezolid

October 8, 2025 •

2 min read

In 2000, Linezolid (brand name Zyvox) was approved by the FDA, making it the first oxazolidinone antibiotic brought to market in decades. This represented a critical development in the fight against antibiotic-resistant bacteria, particularly multi-drug resistant Gram-positive pathogens.

Quick Summary

Linezolid was the first synthetic oxazolidinone antibiotic approved for clinical use in 2000, effectively treating multi-drug resistant Gram-positive infections like MRSA and VRE.

Key Points

First Oxazolidinone: Linezolid (Zyvox) was the first synthetic oxazolidinone antibiotic approved for human use in 2000.
Unique Mechanism: Its mechanism involves inhibiting the initiation of bacterial protein synthesis, a unique target that prevents cross-resistance with many other antibiotics.
Resistant Gram-Positives: Linezolid was developed specifically to combat multi-drug resistant pathogens, including MRSA and VRE, which were becoming increasingly difficult to treat.
High Bioavailability: Featuring 100% oral bioavailability, linezolid can be administered orally or intravenously without dosage adjustment, offering a significant clinical advantage.
Risk of Toxicity: Prolonged use is associated with adverse effects like myelosuppression, peripheral/optic neuropathy, and a risk of serotonin syndrome when combined with certain drugs.
A Second Generation: Since linezolid's approval, a second-generation oxazolidinone, tedizolid, has been introduced, offering alternative treatment options.

The First of a New Class: Linezolid's Origin

The development of oxazolidinones addressed the need for new antibiotics against resistant bacteria. Although the oxazolidinone structure was known since the 1950s, its antibiotic potential was discovered later, but initial toxicity issues halted development. In the 1990s, research resumed, leading to linezolid, which received FDA approval in 2000 due to its favorable bioavailability.

A Unique Mechanism of Action

Linezolid uniquely inhibits the initiation phase of bacterial protein synthesis, a crucial first step where the 70S ribosomal complex is formed. It binds to the 23S ribosomal RNA on the 50S subunit, blocking this process. This distinct mechanism prevents cross-resistance with other antibiotic classes.

Spectrum of Activity and Clinical Use

Linezolid targets Gram-positive bacteria. It is vital for treating infections caused by multi-drug resistant organisms, including:

Methicillin-Resistant Staphylococcus aureus (MRSA).
Vancomycin-Resistant Enterococci (VRE).
Penicillin-resistant Streptococcus pneumoniae.

Clinical uses include pneumonia, complicated and uncomplicated skin infections, and VRE infections. It is generally bacteriostatic but can be bactericidal against some streptococci.

Pharmacokinetics and Administration

Linezolid has high oral bioavailability (around 100%), allowing for effective oral or intravenous administration without dosage changes. This aids in transitioning from IV to oral therapy, potentially reducing hospital stays. It is mainly eliminated through non-enzymatic oxidation.

Adverse Effects and Resistance

Adverse effects, more common with prolonged use (over 28 days), include:

Myelosuppression: Reversible reduction in blood cell counts.
Neuropathies: Peripheral and optic neuropathy, potentially irreversible with extended use.
Serotonin Syndrome: Risk when combined with serotonergic drugs due to MAOI activity.
Lactic Acidosis: Possible due to mitochondrial toxicity.

Resistance has emerged, mainly through mutations in the 23S rRNA gene, but rates are relatively low.

Comparison of Key Oxazolidinone Antibiotics


Feature	Linezolid (Zyvox)	Tedizolid (Sivextro)	Cycloserine	Vancomycin
Approval	2000	2014	1956	1958
First in Class	First synthetic oxazolidinone	Second-generation oxazolidinone	Earliest known oxazolidinone	Glycopeptide
Key Targets	MRSA, VRE, drug-resistant Strep	MRSA, Strep	M. tuberculosis	MRSA, Strep, Enterococci
Admin. Routes	Oral and IV	Oral and IV	Oral	IV only (for systemic)
Oral Bioavailability	~100%	~90%	High	Negligible
Key Side Effects	Myelosuppression, neuropathies, serotonin syndrome	Myelosuppression (lower risk), nausea, diarrhea	CNS toxicity, depression	Nephrotoxicity, ototoxicity, "red man syndrome"
Long-Term Use	Increased risk of myelosuppression and neuropathy	Lower risk of myelosuppression	High risk of side effects	Requires therapeutic drug monitoring

Conclusion: A Landmark in Antimicrobial Development

Linezolid was a significant advancement against resistant Gram-positive bacteria. Its unique action and bioavailability provided new options for serious infections like MRSA pneumonia and VRE. Subsequent oxazolidinones like tedizolid offer alternatives, sometimes with better safety profiles. However, resistance to linezolid highlights the need for careful use. As the first modern oxazolidinone, linezolid profoundly impacted infectious disease treatment.

Frequently Asked Questions

While cycloserine, an antitubercular agent discovered in 1956, contains an oxazolidinone core, it is structurally and mechanistically distinct from the modern, synthetic oxazolidinone class led by linezolid. Linezolid is recognized as the first synthetic oxazolidinone approved for clinical use against a broader range of resistant Gram-positive bacteria.

Linezolid is primarily used for severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), as well as certain strains of Streptococcus pneumoniae.

Unlike many other protein synthesis inhibitors that target the elongation phase of bacterial protein production, linezolid uniquely inhibits the initiation phase. It prevents the formation of the critical 70S ribosomal initiation complex, preventing the bacterial cell from making proteins.

Significant side effects, especially with prolonged use, include myelosuppression (reduced blood cell counts), peripheral and optic neuropathy, and the risk of serotonin syndrome when taken with certain other medications.

Linezolid's 100% oral bioavailability means it can be administered either intravenously or orally with similar efficacy. This allows for convenient and seamless transitions from IV to oral therapy, which can help reduce the length of a hospital stay.

Resistance to linezolid has emerged, but its overall rate remains relatively low compared to many other antibiotic classes. Continuous surveillance is necessary to monitor resistance patterns, particularly among enterococci and staphylococci.

No, linezolid is not effective against most Gram-negative bacteria. Its activity is largely confined to Gram-positive pathogens, and it should not be used to treat Gram-negative infections.